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FDA Storytelling—FDA Inspectional Observations & Warning Letter Citations Relating to Qualification & Validation | IVT

The following FDA Form 483 Inspectional Observations and FDA Warning Letter citations are examples of significant violations of current good manufacturing practice (cGMP) regulations for Finished Pharmaceuticals, Code of Federal Regulations Title 21 Parts 210 and 211, identified by FDA investigators at various companies.

The purpose of this supplement is to review the compiled inspectional observations and warning letter citations and learn from the GMP violations made publicly available on the FDA’s website. By studying these GMP gaps noted during an FDA inspection, one can address ways to avoid similar non-GMP compliant practices in one’s company. The intent of this supplement is not to find fault in any company.

FDA inspectional observations listed on a Form FDA 483 are posted on the ORA FOIA Electronic Reading Room. Some records have been redacted by FDA to remove non-public information. As noted on the Form FDA 483, observations made by the FDA representative(s) during the inspection of a facility do not represent a final FDA determination regarding a firm’s compliance.

FDA warning letters are posted on the FDA website. As noted on the website, matters described in FDA warning letters may have been subject to subsequent interaction between FDA and the letter recipient that may have changed the regulatory status of issues discussed in the letter. Some records have been redacted by FDA to remove non-public information.

Selected examples of warning letters are presented in Part I of this supplement while selected examples of inspectional observations are presented in Part II of this supplement.

For guidance on how to avoid the following warning letters and inspectional observations, dowload "Conduct a Gap Analysis of a Validation Program," from IVT's 2nd Annual Validation Week Canada.


Part I: FDA Warning Letters

Part 211 Subpart B – Organization and Personnel, Sec 211.22 Responsibilities of quality control unit

Failure to establish and follow written procedures applicable to the responsibilities of the quality control unit [21 CFR 211.22(d)]. Your SOP A138 entitled "Procedure for Process and Product Validations" addresses review and approval of validation protocols/reports and states that Team Quality is responsible for assuring the SOP is followed. However, during the inspection the investigators documented numerous and significant discrepancies in your Process Validation Report PCR-099-Striztn, Rev.A., which was approved by Team Quality on December 12, 2006. For example: 

a. Section 5.4.5 of the report documents results that conflict with sterilization cycle descriptions outlined in Section 5.2 of the report. 

i. Section 5.2 of the report describes Validation Cycle A with a heat exposure "... not to exceed [redacted] minutes and [redacted] seconds ..." The results reported in Section 5.4.5 of the report state".exposure of [redacted] minutes." 

ii. Section 5.2 of the report describes Validation Cycle C with a heat exposure "... not to exceed [redacted] minutes and [redacted] seconds ..." The results reported in Section 5.4.5 of the report state "... minimum exposure of [redacted] minutes." 

iii. Section 5.2 of the report describes Validation Cycle D with a heat exposure "... not to exceed [redacted] minutes and [redacted] seconds..." The results reported in Section 5.4.5 of the report state "...." minimum exposure of [redacted] minutes." 

iv. Section 5.2 of the report describes Validation Cycle A as a"... [redacted] mL Type [redacted] Glass Bottle, [redacted] mL fill," and [redacted] type." The results reported in Section 5.4.5 of the report state "50 mL S. C. bottle, 40 mL fill: a closed crimp ..."

b. Table 2 entitled "Executed Sterilization Cycle Parameters" reports heat exposure time as [redacted] Heat exposure time for Validation Cycle C on November 9, 2006, is recorded as "16:24:10." Section 5.2 of the report describes Validation Cycle C with a heat exposure"... not to exceed [redacted] minutes and [redacted] seconds ..." Similar discrepancies were noted in Table 2 for Validation Cycles D, E, and F.

[Cytosol Laboratories, Inc., Date Issued: October 30, 2007]


Failure to establish and follow written responsibilities and procedures applicable to the quality control unit [21 CFR 211.22(d)]. For example: ...

Written procedure 1-013, "Validation Policy," dated 12/29/05, was not followed when a change was made to the manufacturing process used for Pyrantel Pamoate Suspension Canine-2X (4.54 mg / mL), Lot [redacted] in April 2006. A planned deviation changed the compounding tank, mixer speeds and mixing times used to make this [redacted] batch of suspension product. The Validation Department did not determine if the modification was major or minor as defined in Section 7.2 of SOP 1-013. In addition the Validation Department did not address the need to do additional testing to assure the product was equivalent to that made by the validated process. 

... The response to the second example does not address the issue of the failure to follow the validation policy SOP when a change was made in the compounding tank, mixer speeds and mixer times for the production of a lot of suspension product (Pyrantel Pamoate Canine (4.54 mg / mL). The response says, in the future, your firm will only make this suspension product in kettles with dual motion sweep agitation. However, your firm made one lot in Tank #8 for the purpose of process validation. We do not understand why, if First Priority determined a new mixing tank should be used for suspension products, was a lot manufactured in Tank #8? The validation consisted of collecting 3 samples, one from the top, one from the middle and one from the bottle of the tank. The three values ranged from [redacted] mg / mL [redacted] %) to [redacted] %). There is no discussion or explanation of the relatively low results provided with the response. If this lot was formulated for 100% as required by cGMPs, we question what happened to almost 5% of the active ingredient in the middle sample and we wonder why this lot was made using Tank #8 when your firm identified the need to change the mixing process using a kettle which has dual motion sweep agitation

[First Priority, Inc., Date Issued: July 9, 2007]


The responsibilities and procedures applicable to the quality control unit are not fully followed. [21CFR 211.22(d)]

During upgrading your (b)(4) system in July 2007, your distribution loop and (b)(4) pump were accordingly modified for purportedly eliminating dead legs and allowing continuous recirculation for both distribution line (b)(4) and (b)(4). However, your Quality Control Unit failed to follow your change control procedure (SOP-3141, dated on December 15, 1998) to document and also assess the impact of these changes on the new (b)(4) system prior to commissioning of this new equipment.

Your firm's response indicated that your firm modified the distribution loop after updating the system in July 2007 and again after inspection. Please provide details, including a scientific rationale, of the two modifications implemented, especially for the post-inspection modifications.

Meanwhile, your response provided only one training record to showing that one person from the production department has received training. Your response did not demonstrate that other people who have been involved with the change control procedure have been trained, as well. Please clarify and provide any supportive documentation if applicable.

[Laboratoire Atlas, Inc., Date Issued: June 25, 2009]


Failure to have an adequate quality control unit and adequate laboratory facilities available for the quality control unit for the testing and approval (or rejection) of components, in-process materials, drug products, and all procedures or specifications impacting on the identity, strength, quality, and purity of the drug products as required by 21 CFR § 211.22(a), 211.22(b), and 211.22(c). 

Your quality control unit (QCU) has allowed failing product to remain in distribution, released product to the market without adequate stability data to support the expiration dates, failed to conduct adequate investigations of discrepancies, failed to adequately review all analytical data prior to release, and failed to assure adequate analytical method validations were conducted for numerous finished product test procedures. 

During the meeting conducted on June 12, 2007, at the Atlanta District's office your consultant stated that the result of the cultural assessment review conducted at the Fort Mill site revealed that upper management responsible for overseeing the QCU was "out of touch" with the events occurring, had "minimal presence", and was "largely unaware of the quality concerns in the laboratory" at the site. 

In addition, an investigation of the test procedure LC-111-05, the impurity test method for [redacted] caplets, conducted by the Quality Control Director in October 2006 revealed that the procedure was unreliable and concluded that the method should be revalidated. Despite this finding, the Quality Control Director did not implement any corrective actions to remedy this deficiency and your company continued to use the inadequate test method. Your QCU was aware of these issues and took no corrective and preventive action with respect to the product on the market and other lots of this product which continued to be manufactured and distributed after testing the products with the unreliable finished product test method. The Senior Vice President and Chief Science Officer decided to recall all lots of this product only after this matter was brought to the firm's attention by our investigators. 

Furthermore, our investigators found that numerous products were tested using analytical methods, provided by outside sources, which had not been validated/verified according to SOP CO-S850-001-03, "Laboratory Technology transfer of Analytical Methods" and SOP CO-S880-002-02, "Method Validation Requirements" to determine these methods suitability for their intended use. 

In addition, our investigators documented many instances with extensive manipulation of data with no explanation regarding why the manipulation was conducted. This manipulation would include changing integration parameters or re-labeling peaks such that previously resolved peaks would not be integrated and included in the calculation for impurities

[Leiner Health Products, LLC, Date Issued: August 28, 2007]


Failure of your quality unit to provide confidence that API manufacturing processes will consistently yield a product meeting its intended specifications.  Your firm manufactures USP products at your facility without applying the appropriate controls and GMPs.  For example,

a) Our inspection of your facility revealed that your firm failed to perform process validation for three USP products:  (b)(4).  This is a repeat observation.  The June 2001 FDA inspection reported that your firm failed to conduct process validation studies for (b)(4) , a USP product manufactured at your facility. 

b) Your firm failed to perform stability studies for (b)(4) to support the (b)(4) year expiration date currently assigned.  This is a repeat observation.  The June 2001 FDA inspection documented your failure to perform stability studies on (b)(4), a USP product manufactured at your facility. 

c) Your firm failed to perform cleaning validation studies to support the use of "city water" to clean all your equipment.  Your firm lacks data to support the use of city water for the cleaning operation.  Also, the inspection documented that (b)(4) #2 and (b)(4) #4 are non-dedicated pieces of equipment, and that they can be used for various USP products.  The potential for product carry-over between batches or manufacturing campaigns underscores the importance of a robust cleaning procedure.   

Your response lacks the appropriate documentation corrections to these deviations regarding process validation, stability studies, and cleaning validation for all drug products manufactured at your facility, intended for the U.S. market.

[Macco Organiques, Inc., Date Issued: December 10, 2010]


The quality control unit does not adequately exercise its responsibilities to approve procedures or specifications that may impact the identity, strength, quality, and purity of the drug product [21 C.F.R. § 211.22(c)]. For example,

There was inadequate oversight of the media fill process conducted for batch #(b)(4).  Furthermore, the "responsibility" section of procedure JZ-V/JK-053, Validation of Aseptic Manufacturing and Filling Process Using the PST (media fill), makes no mention of the quality control unit having an active role in the oversight of media fill studies.

Your response indicates that procedural corrections will be implemented.   Please provide more information in your response regarding how the quality control unit’s role has evolved including describing its function relating to observation and approval of media fills (e.g., recent March 2011 media fills). 

We remind you that it is your responsibility to implement sustainable corrective actions to ensure that you firm’s drug manufacturing operations are in compliance with the applicable requirements, including the CGMP regulations. FDA expects Pharmaceutical Company Jelfa SA to undertake a comprehensive assessment of the manufacturing operations to ensure that drug products conform to FDA requirements.

We are particularly concerned with your firm’s failure to implement a robust Quality System. Repeat citations from prior inspections indicate that your quality control unit is not exercising its responsibilities, and may not have the appropriate authority to carry out its responsibilities. Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant having appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that your drug products consistently meet standards for identity, strength, quality, and purity.

In addition to the items listed above, this inspection identified other worrisome deficiencies. These deficiencies include, but are not limited, to:  inadequate vendor qualification of your API suppliers and inadequate smoke study results for aseptic filling line (b)(4).

[Pharmaceutical Company Jelfa SA, Date Issued: July 14, 2011]


Failure of your quality control unit to ensure cleaning procedures are validated.

For example, your firm has no cleaning validation (cleaning and drying for reuse) for the large flexible bags you use to hold the (b)(4) of the (b)(4) after the (b)(4) step, and before the (b)(4) step. Although you use these bags to hold material from the different (b)(4)  manufacturing processes executed at your site, you have not performed a validation of the current cleaning procedure. These bags are also not dedicated to a specific process or (b)(4). In addition, you do not follow the current cleaning procedure as written. Examples of inconsistencies between the procedure itself, HES-III-SEI-514, “SOP for Cleaning of the Flexible Large Bags and what your employees actually perform include, the (b)(4) of the bags in (b)(4) for (b)(4) minutes and “Hand washing” is not define as using (b)(4) on the (b)(4) of the bag.

Your response indicates that you will revise HES-III-SEI-514, “SOP for Cleaning of the Flexible Large Bags,” and you will validate the cleaning procedure. Include in your response to this letter an English translation copy of the revised procedure, the training documentation for this procedure, and an English translation copy of the validation protocol for this cleaning procedure. Also, if you plan to validate the cleaning of these bags using a matrix approach based on the worst case (e.g. hardest to clean) (b)(4) include a justification for the choice of the selected worst case (b)(4).

[Yamaguchi Production Center, Date Issued: September 29, 2010]


Part 211 Subpart J – Records and Reports, Sec 211.192 Production record review

Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

For example, your firm’s microbiology laboratory does not perform species identification on a routine basis of the yeast and molds detected in your production area. There was no identification raw data available for the media fill that failed in November 2009. Additionally, your firm does not perform challenge testing to the sterility media with environmental isolates from the environmental monitoring program.

[CP Pharmaceuticals, Ltd., Date Issued: October 29, 2010]


Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, as per 21 CFR 211.192.  For example,

a. You failed to investigate environmental monitoring data recorded in your aseptic processing suite, which failed to meet your established limits.

Your response states that you have revised your environmental monitoring form to allow space for explanation when needed; however, your response is not adequate.  You have not investigated the cause of the environmental monitoring results that exceeded the limits on your “Performance Qualification Data HVAC Validation” and “Routine Environmental Monitoring” worksheets, nor have you justified your assessment of the product impact caused by those excursions.

[Dakota Laboratories, LLC, Date Issued: March 17, 2011]


1) Failure to thoroughly investigate unexplained discrepancies (including a percentage of theoretical yield exceeding the maximum or minimum percentage established in the master production and control records) or the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. [21 C.F.R. § 211.192]. For example,

a) Aloxi (Palonosetron HCl) injection batches (b)(4) failed to meet the yield limits; no root cause was identified.

In particular, batches (b)(4) failed to meet yield limits of (b)(4)%– (b)(4)%. Validation batches (b)(4) reported yield out-of-limit (OOL) values of (b)(4)%, (b)(4)%, and (b)(4)%, respectively. You indicated that the result obtained for batch (b)(4) was due to a high particle per volume content documented during manufacturing and product visual inspection of the vials. However, the root cause for the increased number of particles in the product remains unclear. There is also no information regarding the overall impact of the problem in the quality of the product, or the corrective actions implemented to prevent recurrence of the problem. You identified the defect but were unable to determine the root cause. In addition, you failed to assess the product yield OOL values documented for batches (b)(4).

Because your firm was unable to determine the root cause of the yield OOL values in the first validation batch ((b)(4)), you could not implement corrective and preventive actions for the subsequent batches. Consequently, the second and third validation batches ((b)(4)) and ((b)(4)) also reported yield OOL values.

b) Out-of-limit results obtained during the in-process fill weight examination for validation batches (b)(4) were not investigated.

Specifically, you reported 31 in-process fill weight OOL results for validation batch (b)(4), while reporting 11 and 3 OOL results for batches (b)(4), respectively. In addition, the batch record does not contain any evidence that you evaluated the in-process results to determine the impact of the out-of-limit fill weight results in product quality.

During our review of data pertaining to the validation of batch (b)(4), we noted the use of two different in-process fill weight specifications. On December 17, 2008, the fill weight record reflects that the specification for fill weight was (b)(4)g – (b)(4)g, but on December 18, 2008, the specification used was (b)(4)g – (b)(4)g. The investigator noticed that for batch (b)(4), you reported a total of 31 OOL results in the fill weight, but failed to conduct an investigation. In your response to this letter, please clarify which limits are correct, the scientific rationale for using two different limits, and the resulting impact on the product filled using the incorrect limit.

c) During the filling of validation batches (b)(4), you obtained OOL results for the non-viable particle (NVP) count of 0.5 μm and 5.0 μm particles,
but did not adequately investigate these results.

In batch (b)(4), the monitoring data for non-viable particles reported a maximum value of 10,319 particles. This result was obtained in a critical area—class 100 (ISO 5)—where the recommended limit for 0.5 μm particles is 3250/m3 particles.You failed to investigate these NVP excursions and determine the impact on product quality or its possible relation to the higher particulate content observed in batch (b)(4). During the inspection, your firm provided the investigator a copy of procedure 15.89.01/1 “NVP Monitoring.” This procedure was made effective on June 18, 2009, approximately seven months after you manufactured the validation batches.

d) A self-check test of validation batches (b)(4) reported 19 and 6 trays, respectively, with critical defects (particles) during your routine visual inspection evaluation. No investigation was conducted.

The intent of the self-check test is to challenge the operator effectiveness in the visual inspection process. You conducted a 100% visual inspection after inspecting the batches twice in the Brevetti automatic visual machine. Your investigation report number 6237 indicates that batches (b)(4) were 100% re-inspected, however, you failed to document such re-inspection. You also failed to evaluate the impact of the particle content on the quality of batches (b)(4).

Your procedure for the visual inspections of filled vials is inadequate in that it fails to demonstrate adequate control (detection) of critical defects (particles) in vials. We are concerned that you found vials with critical defects (particles) after two Brevetti automatic inspections and a 100% visual inspection conducted by your manufacturing operators. We are also concerned with your OOL yield, the number of particles per volume in your product, and the effectiveness of your visual inspections. Your QCU failed to ensure that manufacturing deviations documented in the validation studies were investigated in a timely manner. Your response states that you implemented corrective actions and that you will manufacture a mock batch to demonstrate validation of the Aloxin manufacturing process. We disagree that performing validation studies of an additional batch is sufficient to show that the process is validated. Provide us the root cause analysis of this deviation and any implemented corrective
actions, and address our aforementioned concerns.

[Pierre Fabre Medicament Production – Aquitaine Pharm International 2, Date Issued: March 26, 2010]


Part 211 Subpart I – Laboratory Controls, Sec 211.165 Testing and release for distribution

2. Your firm has failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211.165(e)]. For example:

a. Your firm has not conducted validation studies for analytical methods routinely used for assay determination of the drug products. Some examples of the methods without validation studies include: (1) PCMX Assay by HPLC, and; (2) Capsaicin Assay for gel sample by HPLC.

b. Your firm's method validation studies for multiple methods used in the testing of drug products are incomplete and are not validated. Some examples of these methods include: (1) Hydroquinone raw material Assay by HPLC; (2) Hydroquinone USP Assay by HPLC as applied to finished drug products; (3) Lidocaine Hydrochloride USP Assay by HPLC; (4) Triclosan USP Assay by HPLC as applied to finished drug products; (5) Hydrous Benzoyl Peroxide by titration; (6) Sulfur by Titration, and; (7) Tartartic Acid by Titration.

In your response, your firm states that the expected completion date for the validation of all analytical methods is June 2012. Your response, however, is not adequate since you have not provided interim actions to ensure the reliability of data until the analytical methods are validated.

In addition, your response states that the standardization of the volumetric solutions used in the above referenced titration methods will be addressed as part of this overall revalidation plan. All volumetric solutions should be standardized prior to use in order to obtain accurate assay results. This is a corrective action that can, and should be, implemented immediately.

[Deibel Laboratories of Illinois, Inc., Date Issued: September 1, 2011]


Your firm has failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211. 165(e)].

For example, your firm performed analytical method transfers for 236 protocols without determining whether those methods had been properly validated by your clients.

In your response, your firm states that you will develop a new procedure to ascertain the validation status of your client's methods and to assure that all methods used for product release testing are properly validated. You also state that your firm will conduct and document employee training. However, your response does not include a plan for conducting a retrospective review of your client's methods to ensure that they are adequately validated and that the method transfer was sufficient to ensure accurate results.

[Advanced Testing Laboratory, Inc., Date Issued: October 12, 2010]


Failure to verify and document the suitability of testing methods under actual conditions of use.

Specifically, your firm failed to conduct and document a verification under actual conditions of use of the following laboratory testing methods: related substances method (HPLC) used for release and stability testing of (b)(4) API, identification (IR) method for release testing of (b)(4) API, microbial and endotoxin testing methods used to monitor the quality of the purified water, and assay (titration) method for release and stability testing of (b)(4) API. In addition, during the inspection your firm could not provide forced degradation data to support suitability of the HPLC test method for stability testing of (b)(4) API. Review of the chromatograms from the release testing of related substances for (b)(4) API lots (b)(4) and (b)(4) show peaks that do not separate, suggesting the method is not capable of detecting all related substances present.

In your response, you propose to perform a verification of the methods according to your firm’s requirements. Your response fails to provide the procedures and acceptance criteria for the verification studies and failed to determine the impact of the inadequately validated/verified methods on previously released materials. 

In your response to this letter, please address these issues and provide a risk assessment for possible impurities present in (b)(4) lots (b)(4) and (b)(4). You are responsible for ensuring that all analytical methods are verified prior to continuing manufacture and release of API lots to US. You are also responsible to ensure that the methods used for releasing product to U.S. comply with CGMP requirements for U.S. (i.e., use of USP methods).

[Ercros S.A., Date Issued: June 20, 2012]


Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211.165(e)].

For example,

a. Your firm failed to validate methods used for the assay analysis of six Poly-Vitamin Drop products, four Tri-Vitamin Drop products, and Sodium Fluoride Drops.

b. Your firm failed to include the following characteristics: accuracy, robustness, ruggedness and specificity in your validation of the HPLC assay method (b)(4) used for the analysis of Pyridoxine Hydrochloride (Vitamin B6), Riboflavin 5' Phosphate Sodium (Vitamin B2) and Thiamine Hydrochloride (Vitamin B1) in Poly-Vitamin Drop products.

c. Your firm failed to generate and document chromatographic data to support the validation of the analytical method (b)(4) used for determination of Urea in Urea Cream 40%. In addition, your firm failed to generate and document chromatographic data to support stress studies for Paregoric Liquid USP to demonstrate that the method is suitable for determining stability.

[Hi-Tech Pharmacal Co., Inc., Date Issued: June 28, 2010]


The test methods used for sterility testing are inadequate. [21 CFR 211.165] There is a lack of data to demonstrate that the methods are capable of recovering low levels of organisms that would be found in a typical non-sterile drug product. The study summaries and raw data lacked any counts for the inoculated controls and samples, and there is insufficient data to interpret whether the product inhibits growth of organisms. The reproducibility of the method was not demonstrated. For example, only one result following a negative recovery was used to validate the [redacted] Method.

It was also noted that you have not completed [redacted]

Validation for 7 of 15 products with [redacted]

In the August 22, 2002 response, it states that the methodology complies with the requirements of USP Sterility Test [redacted] Validation for [redacted]. It clarified that the counts used to initially inoculate the test and control samples are quantified, but you don’t explain how the procedure is done. It also states that an update to the validation requirement such that three validation tests will be performed in order to comply with the requirements of Validation of [redacted] from Pharmacopeial Articles [redacted].

Further, the response included a commitment to repeating the Validation for [redacted] testing three times for any new formulations/presentations. The validation will be performed twice on existing products the next time the batches are manufactured. As to the products requiring [redacted] inclusion in the validations, this will be scheduled for the next production batches being produced. 

Until this validation is completed, the sterility test methods used are inadequate in that there is no documentation, which demonstrates the accuracy and repeatability for [redacted] from Pharmacopeial Articles. Also there is no assurances that the sterility positive ... identified as errors were accurate assessments because of the inadequacy of the test methods.

[Mayne Pharma Pty., Ltd., Date Issued: November 21, 2002]


Part 211 Subpart I – Laboratory Controls, Sec 211.160 General requirements

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. [21 CFR 211.160(b)]

Validation of the sterility test method failed to specify or document the amount of (b)(4) used to reconstitute the following parenteral antibiotic powders: (b)(4), Cefoxitin (1g, 2g, and 109), Cefazolin (500 mg, 1g, and 109), Cefepime (1g and 2g), and (b)(4).

The reconstitution liquid ((b)(4)) assists with the inactivation of the antibacterial properties of the drug products; therefore, the quantity of the reconstitution fluid is important and should be documented to show that a validated amount is being used during routine testing of the finished products, in order to avoid false negative results.

Your response of December 30, 2008, is incomplete in that it fails to address the lack of a documented reconstitution fluid for the following parenteral antibiotic powders: Cefazolin (10g) (b)(4) and Cefoxitin (1g, 2g, and 10g). Your response only included the material specification sheets for these products. Although you indicate that the reconstitution volume is described, and that the total contents of the reconstituted product are (b)(4) during routine analysis, your response does not demonstrate that the correct amount of fluid was used during the sterility validation studies for Cefazolin (0g), (b)(4), and (b)(4)

Please include in your response to this letter, a copy of the validation protocol specifying the amount of fluid to be used [as you did for Cefepime (1g & 2g); Ceftazidime (1g, 2g, & 6g), and Cefazolin (500mg & 1g)], or demonstrate that the protocol refers to the laboratory procedure that was effective at the time of the validation, indicating the amount of fluid to use for reconstitution. Further, the material specifications revised in 2008, and submitted in your initial response, lack the original effective dates. Thus, if you cannot provide evidence that the reconstituted fluid was described in the protocol, or in a document directly referenced in the protocol, you should consider repeating the sterility validation for Cefazolin (10g), (b)(4) and Cefoxitin (1g, 2g, & 10g).

[Antibioticos do Brasil Uda, Date Issued: July 24, 2009]


Your quality control laboratory has not followed written procedures for testing and laboratory controls designed to assure that the drug products you tested have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.160(a)(b)(3)(4)].

For example,

d. Your firm’s procedure, SOP-GEN-0029 Rev.1, "Master Validation Plan," requires that all instruments, whether newly purchased or already in use, be qualified prior to being release for general use.

The inspection found that your Fluorometer and Atomic Absorption have not been qualified. Your firm’s response lacks the specific corrective actions you plan to implement to ensure that Master Validation Plan is followed. In your response please provide the evaluation conducted to assure the validity of all results generated by the non-qualified Fluorometer and Atomic Absorption equipment.

We are concerned that the failure to follow established procedures is a repeat violation, also cited during the 2007 inspection.

Please note that as a contract testing laboratory, it is your responsibility to ensure the integrity of the data generated and that all test results be properly documented, maintained and reported.

[Alpha Laboratories, Inc., Date Issued: May 5, 2011]


Your firm has not established scientifically sound and appropriate specifications designed to assure that components and drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

For example, your firm uses a rapid diagnostic test method (i.e., (b)(4) to test water samples from your Purified Water system and your drug products. This culture media system has not been shown to be equivalent to current compendial microbiological test methods. Your firm lacked any studies to show fitness for use of these methods for your firm’s drug products.  Furthermore, your firm does not perform growth promotion testing on the media systems utilized for purified water and finished drug product testing.

In your response, your firm proposes to develop new protocols at your contract laboratory with appropriate method validation. Your response, however, fails to provide the completion and/or implementation dates of the proposed protocols and method validation. In addition, your firm has yet to provide an update on the use and qualification of the current rapid diagnostic media test kit. 

[Dental Technologies, Inc., Date Issued: September 15, 2011]


Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)]. For example,

a) The specificity test, included in the method validation reports for KWAN LOONG OIL® PAIN RELIEVING AROMATIC OIL (Kwan Loong) (active ingredients: methyl salicylate, and menthol) and Tiger Balm (active ingredients: camphor, menthol, and capsicum extract), is inadequate. It has not been shown to be capable of detecting potential impurities. In addition, no forced degradation studies were conducted for the validation of these two methods. The analytical methods used for release and stability (for batches (b)(4) and (b)(4) of Kwan Loong and (b)(4) and (b)(4) of Tiger Balm) have not been determined as appropriate for determining and monitoring the impurity profile. We are concerned that several unknown peaks were observed at the time of release and during the stability studies for Tiger Balm, but no attempt was made to identify these peaks. The inspection also reported that the instruments and method parameters used are not documented.

In your response to this letter, provide the updated validation reports of both assay methods, including the specificity studies performed to demonstrate that both assay methods are stability indicating and appropriate for determining and monitoring impurity profiles.

b) Your firm failed to assess the (b)(4) in your finished products for both Kwan Loong and Tiger Balm, which are marketed in the United States. In addition, the certificate of analysis for methyl salicylate API (Active Pharmaceutical Ingredient) provided by your supplier lacks a residual solvents test result.

Your firm has a memo from the API manufacturer assuring you that the API (methyl salicylate) does not contain any solvents included in the USP residual solvent tables, except (b)(4), of which the concentration is very low. Subsequently, there is no assurance that your manufacturer tested or confirmed that the level that may be present is within the (b)(4) USP limit.

Please provide corrective actions to this issue with supportive documents, including testing criteria for (b)(4) in your Certificate of Analysis, for both of your finished products and methyl salicylate API.

c) Your assay method validation of methyl salicylate API by gas chromatography (GC) analysis is inadequate in that it lacks a specificity determination. During the inspection, your laboratory supervisor indicated that a (b)(4) standard was injected. However, no evidence or documentation confirming that this standard was injected during the chromatographic run was available. As explained by your laboratory supervisor, (b)(4) was identified as a possible impurity present in the API.

Please provide a completed validation report for the GC assay method as part of your response to this letter. It should include the specificity studies performed to demonstrate that the assay method is capable of analyzing methyl salicylate without interference from other impurities, including (b)(4).

The inspection also reported that the syringe used during your GC analysis is a 10.0 μL syringe. However, the current method injection volume is 0.2 μL. Please provide supportive data to justify whether the 10.0 μL syringe used in the method for GC injection can precisely and accurately measure 0.2 μL of the methyl salicylate API sample solution.

d) Your GC and high performance liquid chromatography (HPLC) analyses for both finished products and raw materials lack appropriate system suitability determinations. Your SOP TMA-KLOF2/02, “Method of Analysis of Kwan Loong” and SOP MA/TBPW/10, “Tiger Balm Plaster - RD/Tiger Balm Medicated Plaster - RD/Tiger Balm Patch,” each specify three standard solution injections. Both methods are used for testing of drug products at batch release and during stability study. In addition, your assay test of methyl salicylate API (lot (b)(4)) by GC analysis was conducted with a single injection of pure standard, and a single injection of sample.

Your laboratory supervisor indicated that you do not perform system suitability because the analysis consists of an injection of pure methyl salicylate standard without dilution. He also indicated that the potency is determined using the total percent peak area results. Please note that the system suitability test is an integral part of a chromatographic method, regardless of the drug product or API being tested. It is your responsibility to have appropriate specifications and acceptance limits as part of your system suitability determination. You are required to ensure that the chromatographic system is adequate for its intended analysis prior to use. Otherwise, the accuracy and precision of HPLC data collected are potentially compromised. Please provide corrective actions with supportive documentation to address this issue.

[Haw Par Healthcare Limited, Date Issued: July 20, 2010]


Your firm failed to establish scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. §211.160(b)].

The following are examples of this violation:

a.Your firm failed to prove that the methods used to perform the bacteriostasis and fungistasis tests on Povidone-Iodine Gel Swab Sticks are equivalent to or better than the USP methods. The test methods used to evaluate the inhibitory effects of the Povidone-Iodine on the ability of the (b)(4) and (b)(4) to support microbial growth lacked the requirement to use (b)(4) as part of the validation test as well as adequate incubation times and temperatures.

In your response to the FDA 483, you stated that you will perform a method validation on the bacteriostasis and fungistasis testing according to USP; however you failed to provide the protocol you will use to perform the validation.  

b.Your “Protocol of sterility test” states (b)(4) and (b)(4) will be incubated for (b)(4) days at (b)(4)°C and (b)(4)°C, respectively. However, according to your “Report of sterility test,” the sterility testing was conducted using only (b)(4) incubated at (b)(4)°C for (b)(4) days. Your protocol entitled “Protocol of sterility test” for the Povidone-Iodine Gel Swab Sticks is not supported by the “Report of sterility test.”

You did not address this in your FDA483 response.

In your response, include the test method validation and studies that you have conducted to ensure reliable testing for sterility. Identify the method used to neutralize the antimicrobial effects of the Povidone-Iodine. Identify the microbial cultures, incubation times, temperatures, and media used during sterility testing. Also provide sample size justification if it is different from the USP-recommended sample size. In addition, provide your risk assessment of the impact of this deficiency on products distributed to the US that are still within expiry, and any actions planned for these lots.

The items listed above, as well as other deficiencies found at your site, lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility. It is apparent that you have not implemented a robust quality system at your firm. Examples are the presence of objectionable microorganisms in non-sterile products and inadequate validations to ensure sterility of products purporting to be sterile.  Be advised that corporate management has the responsibility to ensure the quality, safety, and integrity of its drug products. FDA expects that your executive management will immediately undertake a comprehensive and global assessment of your manufacturing operations, including facility design, procedures, personnel, processes, and systems, including your aseptic processing and sterilization capabilities, to ensure that drug products conform to FDA requirements.

Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant with appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that the drugs you manufacture have their appropriate identity, strength, quality, and purity.

[Jiangsu Province Jianerkang Medical Dressing Co., Ltd., Date Issued: July 30, 2012]


Part 211 Subpart D – Equipment, Sec 211.68 Automatic, mechanical, and electronic equipment

Failure to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, or electronic equipment, including computers, used in the manufacture, processing, packing and holding of a drug product. [21 CFR 211.68]

A. The Enterprise Resource Planning System known as the firm's Systems Applications and Products (SAP) computer database allows rejected batches of drug product to be in Unrestricted Status (to be released for distribution). Refer to Form FDA 483, Observation #3.

Please provide additional information to support that your current Enterprise Resource Planning SAP system provides limited access to only "approved QA personnel" versus warehouse or production personnel. Your December response states any correction or change in Usage Decision (UD) will require next-level QA authorization in SAP. Explain how you are able to ensure that only QA authorized personnel are changing the status of the lots in the SAP system, and how it is documented and/or tracked.

In addition, your December response in Attachment #4, "Performance Qualification Report for SAP R/3 Enhancement", shows lots that can be "Partially Approved" without selecting a Usage Decision. Provide an explanation as to what "Partially Approved" is defined as, who has the authority to make this decision, how it is documented, and why this status is "not applicable" in the Usage Decision status.

B. Failure to retain original calibration data for [(b)(4)] used in the re-qualification of the [(b)(4)]. Refer to Form FDA 483, Observation #4b.

During the inspection, you provided our FDA investigators a spreadsheet that you stated contained data for calibration of [(b)(4)], however, you were not able to provide the raw calibration data. In addition, the calibration data for the [(b)(4)] that you provided in your December response in Attachment #9 do not correspond to the [(b)(4)] observed by our FDA investigators. The [(b)(4)] observed during our inspection had a different manufacturer, tag number, and temperature range than the [(b)(4)] for which you provided data in your response. Please explain this discrepancy.

C. Written records of calibration were not adequately verified. Refer to Form FDA 483, Observation #9.

The inspection team was shown internal calibration certificates for [(b)(4)] that were performed at readings of [(b)(4)], yet the raw data does not document these readings. This data was verified and signed by a second individual and calibration certificates were generated. In addition, the calibration of a [(b)(4)] shows incorrect entries on the Instrument Calibration record. Yet this record was also verified and signed by a second individual. Your response do not show that investigations were conducted. Please provide the investigation reports.

Your December response states all data is now concurrently verified by immediate supervisors, however this is not stated in your attached, revised procedure, "[(b)(4)], Calibration of Instruments." In addition, you stated in your response that calibration records will be routinely reviewed by QA. Provide the relevant written procedure(s) to reflect this review is conducted.

[Lupin Limited, Date Issued: May 7, 2009]


Appropriate controls are not exercised over computers or related systems to assure that changes in analytical methods or other control records are instituted only by authorized personnel [21 CFR 211.68(b)]. Specifically,

a) There was a failure to validate the [redacted] software to assure that all data generated by the system was secure. This software runs the laboratory HPLC equipment, generates and stores data, and performs calculations during testing of raw materials, in-process materials, finished products, and stability samples. 

b) User access levels for the [redacted] software were not established and documented. Currently, laboratory personnel use a common password to gain access to the system and there are no user access level restrictions for deleting or modifying data. Furthermore, your system does not have an audit trail to document changes. 

[Medico Labs, Inc., Date Issued: April 16, 2007]


Your firm failed to ensure that the automatic, mechanical, or electronic equipment, or other types of equipment including computers or related systems, will perform a function satisfactorily [21 C.F.R. § 211.68(a)]. For example:

a. The initial qualification for the (b)(4) Cutting and Packing Machine, Model (b)(4) was completed on June 7, 2007. Approximately 25 major and minor changes were implemented between June 14, 2007, and July 15, 2010, before your approval of the re-qualification report for equipment (b)(4). 

In your response, your firm states that (b)(4) Cutting and Packing Machine is a custom-made unit. The unit consists of subunits that perform functions independently of one another and that modification to one subunit does not necessarily adversely impact other subunits or the equipment as a whole. You added that the requalification requirement was documented in each approved Change Control. Your response, however, is inadequate because you have neither provided documentation to demonstrate your claims of independently functioning subunits, nor have you provided your rationale why each equipment change did not necessitate a re-qualification and/or a re-validation of the (b)(4) Cutting and Packing machine.

In addition, your firm states that further system enhancement will be made to validation procedures. However, it is not clear as to your estimated completion date because the content of your proposal entitled, “(b)(4),” is so broad. Furthermore, we are not able to evaluate the adequacy of your corrective actions without sufficient details of your proposed enhancement.

b. You failed to adequately qualify the (b)(4), to detect missing patches.  

For each product size of 25/50/75/100 mcg/hr dosage strengths, only forty ((b)(4)) samples were tested through the checkweigher to qualifying the equipment as a subsystem. There is no statistical basis for the selected sampling size. Furthermore, checkweigher (b)(4) was not validated in conjunction with the (b)(4) equipment using appropriate samples that represented the approximate batch sizes of (b)(4) units (25 mcg/hr), (b)(4) units (50 mcg/hr), (b)(4) units (75 mcg/hr), and (b)(4) units (100mcg/hr).

In your response, your firm states that the function to reject under-weight and over-weight sample is tested every month per SOP (b)(4) and that this procedure will be revised to include a functionality test at the beginning, after each break (if applicable), and end of the commercial production run to verify further control over the system. Your response, however, is inadequate because although you may have enhanced the Quality Control verification aspect of the checkweighing equipment, you did not address how you will correct the qualification deficiency as addressed above.

In addition, you firm states that “[a]s is industry standard with checkweigher qualification studies, the purpose is to seed the run with a known number of rejects and recover 100% of said rejects at the end of the study.” We disagree with your assessment because you did not provide a sound scientific rationale for selecting a sample size of (b)(4).  Your manufacturing process has variability that affects your outputs.  The number of samples chosen for the Performance Qualification needs to reflect the variability in your manufacturing process. Also, your multiple customer complaints of missing patches serve as evidence that your checkweigher may not be adequately qualified to ensure your missing patches can be identified consistently and reliably.

[Anonymous Pharmaceutical Company, Date Issued: August 25, 2011]


Your firm failed to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance [21 C.F.R. § 211.68(a)].

For example, your firm has not conducted performance qualification for the (b)(4) unit-dose packaging machine (b)(4)™ to ensure its proper performance. Your firm has also failed to provide documentation to establish that the (b)(4)™ or (b)(4)“ Bingo Card” repackaging
equipment (for liquid and solid oral doses, respectively) has been qualified before use.

In your response of January 18, 2010, you stated that your firm has completed “machine validation” on several pieces of repackaging equipment used in production and will complete the process by the end of February 2010. This response is inadequate in that it fails to adequately describe how and on which pieces of equipment qualification will be performed. Your response provides an intended future date of completion, but fails to address whether manufacturing operations will continue before the machine qualifications are finalized, and, if so, what additional controls will be implemented during this interim period.

[Shamrock Medical Solutions Group, Date Issued: April 8, 2010]


Your firm has failed to exercise appropriate controls over computer or related systems to assure that changes in master production and control records, or other records, are instituted only by authorized personnel [21 C.F.R § 211.68(b)].

For example, your firm lacks control of the (b)(4) computer system which monitors equipment, room differential pressure, room humidity, and stability chambers. Although the system is password protected for temperature and humidity set points, all employees have access to the room where the (b)(4) computer system is located and the external hard drive is not password protected. During the inspection we observed that an employee was able to alter or delete data without a password and save the changed file.

In your response, your firm states that additional controls were implemented including validating the remote access to the (b)(4) computer, password protecting the room where the computer is stored, and limiting the (b)(4) control room to authorized personnel only. Although your corrective actions may adequately address the protection of the (b)(4) computer from non-traceable changes, your firm has not taken a global approach to this deficiency. It is our expectation that your other manufacturing and laboratory computerized systems will be reviewed to ensure similar deficiencies do not exist.

[Cephazone Pharma, LLC, Date Issued: April 25, 2011] 


Your firm has not exercised appropriate controls over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel [21 CFR 211.68(b)].

For example, your firm lacks systems to ensure that all electronic data generated in your Quality Control laboratory is secure and remains unaltered. All analysts have system administrator privileges that allow them to modify, overwrite, and delete original raw data files on the (b)(4) used (b)(4) in the High Performance Liquid Chromatography (HPLC) units. There are no procedures that address the security measures in place for generation and modification of electronic data files for these instruments used for raw material, in-process, finished product and stability testing. In addition, your firm's review of laboratory data does not include a review of an audit trail or revision history to determine if unapproved changes have been made.

Your September 17, 2009 response states that you replaced the (b)(4) HPLC systems operating on (b)(4) software with (b)(4) new qualified HPLC units from (b)(4) software. This validation information will be reviewed at the next inspection. In addition, your response is inadequate because it lacks a retrospective evaluation of the data from the former HPLC units. This will prevent an alteration of data prior to implementation of your corrective actions. Further, your response does not address security procedures to ensure that the data generated using the new HPLC units is secure and remains unaltered.

[Sunrise Pharmaceutical, Inc., Date Issued: January 14, 2010]


Part 211 Subpart D – Equipment, Sec 211.63 Equipment design, size, and location

Your firm failed to use equipment in the manufacture, processing, packing, or holding of a drug product of appropriate design to facilitate operations for its intended use and for its cleaning and maintenance [21 CFR 211.63].

For example, your firm failed to ensure your water system was of adequate design. We note your firm also has not performed a formal validation of the purified water system, although you collected data that indicates your firm is now apparently producing purified water of adequate quality for your products. We acknowledge your firm's commitment to upgrade the design of their USP Purified Water System, replace all existing stainless steel piping and filter housing, and conduct a performance qualification of the purified water system.

[Balchem Corporation, Date Issued: December 22, 2009]


Your firm failed to assure that equipment used in the manufacture, processing, packing, or holding of a drug product is of appropriate design for its intended use [21 C.F.R. § 211.63]. For example:

The calibration of thermocouples (TCs) used during the validation of your terminal steam sterilizers is not performed before or after the autoclave cycles. Your response failed to provide data to support that the TCs used during the validation runs are within acceptable calibration range. The calibration of these TCs provides assurance of an accurate reading of the temperature in the sterilizer. Please provide your sterilization cycle summary for all the terminal sterilizers and cycles used by your facility, with the appropriate parameters and conclusion of the data generated.

[Claris Lifesciences Limited, Date Issued: November 1, 2010]


Your firm has failed to use equipment in the manufacture, processing, packing, or holding of drug products that are of appropriate design, of adequate size, and suitably located to facilitate operations for its intended use [21 C.F.R. § 211.63]. 

For example, your firm has failed to validate the deionized water system that supplies the process water used in all drug products manufactured at your facility.  Further, your firm has not established a maintenance program for your water system or validated the biweekly sanitization process to ensure that it extends to all areas of the recirculation loop and that the deionized water meets specifications. 

In your response, your firm plans to include additional sampling points for your water system to qualify the water quality of the holding tank.  Your response is inadequate because you fail to specify where these sampling sites are located.  In addition, your response does not include any details describing the following:  (1) the 12-month study to determine whether an increase in sanitization frequency is required; (2) the monitoring of conductivity and Total Organic Carbon (TOC), or; (3) documentation for revising the Piping & Instrumentation Diagram (P&ID).   Also, the minimum acceptable quality standard for water used in drug product manufacture is found in the United States Pharmacopeia.  Please see the Purified Water, USP, monograph.  Also, see FDA’s Guide to Inspections of High Purity Water Systems (1993) for discussion of appropriate microbial action levels and water system validation approaches.

[GAR Laboratories, Inc., Date Issued: December 6, 2010] 


Failure to demonstrate equipment used in the manufacture, processing, packing, or holding of drug products is of appropriate design to facilitate operations for its intended use [21 CFR 211.63]. For example:

A) The validation of Cycles #2 and # 3 for the (b)(4) Washers #1 and #2 did not include an evaluation or validation with (b)(4). Such an evaluation or validation is necessary to demonstrate that the acceptance criterion of "(b)(4)" in bacterial endotoxin is met. In addition, there was no other evidence provided, such as results from any ongoing sampling and testing of the stoppers for endotoxin.

The validation report referenced in your response of August 10 and September 4, 2009, appears to address the observation. We will verify the data associated with the report during a future inspection.

B) The study to support the chemical and microbiological stability of Propofol bulk emulsion was not based on sampling from the (b)(4) mixing vessel, but on samples drawn from a (b)(4) "pressure can."

Your response, dated August 10, 2009, included a protocol (b)(4) for hold time validation and also discussed your plans to perform additional bulk hold testing during the week of August 10, 2009. The report of this validation was included in your September 4, 2009 response and appears to be adequate. However, your response lacks raw data to support the chemical and microbiological test result. We will evaluate this data during a future inspection.

C) (b)(4) were used to monitor the interior temperature of the autoclave when revalidating temperature uniformity in the (b)(4) Sterilizer empty chamber. Your revalidation procedure does not describe how the (b)(4) temperature probe is secured to avoid its contact with metallic surfaces.

Your response, dated August 10, 2009, appears to be adequate. Your response refers to an updated procedure #(b)(4) that include instructions for positioning the (b)(4) to prevent contact with metallic surfaces. We will review this procedure during a future inspection.

[Teva Parenteral Medicines, Inc., Date Issued: April 28, 2004]


Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use. [21 C.F.R. § 211.63) For example,

a. Our review of the equipment qualifications for multiple automated Tablet Testing System (TTS) machines, used to conduct in-process tablet testing (weight, hardness and thickness) revealed that performance qualification was not conducted to ensure the accuracy of the machine at the various available speed settings. A February 2010 investigation of OOS tablet weights for Digoxin tablets revealed that the TTSs were giving incorrect tablet weights for lighter weight ( < 200 mg) tablets when run at the default speed of (b)(4) and concluded it would give accurate results only when run at a speed of (b)(4) However, your firm failed to make a further assessment of the overall reliability of the TTS machines, including evaluating their accuracy with other products and other tablet weights at other speeds.

b. Your firm has not adequately qualified the in-line Pressure Control Device (PCD)-2 Automatic Tablet Weight Control System on the (b)(4) and (b)(4) tablet press machines. Your firm did not Qualifications (PQ) that are representative of all of the products run on the tablet presses to assure proper functioning, including evaluating the reject station timing in relation to tablet press rpm. There is no assurance that the PCD-2 system is accurately rejecting the "marked" OOS tablets throughout the compression run.

In your response, you fail to address interim measures to assure proper weight control of your tablet presses during batch manufacturing while you are qualifying the TTS and PTS systems.

[West-Ward Pharmaceuticals Corp., Date Issued: February 3, 2012] 


Equipment used in the manufacture of Benztropine Mesylate Tablets and other drug products was not adequately qualified. [21 CFR 211.63] For example:

a) The re-qualification of the [redacted], which was used in the production of Benztropine Mesylate Tablets, batch RBR-2137, did not have clearly defined acceptance criteria. In addition, there. was no discrepancy report to explain why equipment drawings, equipment schematics, equipment manuals, and purchase orders were not available, what steps had been taken in an attempt to obtain these materials, and why the re-qualification was acceptable without this information.

b) The specified utility requirements were not met in the equipment re-qualification for [redacted] which was used in the production of Benztropine Mesylate Tablets batch RBR-2137. There is no discrepancy report to explain why this failure to meet the specification is or is not acceptable.

c) There were no equipment qualifications for the Lydon Brothers, Inc., [redacted].These ovens are used in the production of Benztropine Mesylate Tablets as well as more than fifteen other drug products.

[Actavis Totowa, LLC, Date Issued: February 1, 2007]


Part 211 Subpart D – Equipment, Sec 211.67 Equipment cleaning and maintenance

Failure to establish and follow written procedures for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product[21 CFR211 .67(b)] in that:

a) The cleaning of the ultrafiltration/diafiltration (UF/DF) unit used in the manufacture of [redacted] has not been adequately validated. 

b) The UF/DF filter cartridges have no established maximum number of uses.

[Bayer Corporation, Date Issued: July 24, 2001]


Your firm has not established written procedures for cleaning and maintenance of equipment [21 C.F.R. § 211.67(b)].

Your cleaning validation was limited to the cleaning process of a plastic 55-gallon drum used in the manufacture of Hydroquinone Skin Lightening Formula. You have not established an adequate rationale, including determining whether this product is the most difficult product to clean. The validation also does not include other equipment used in the manufacture and packing of this product.

We acknowledge your December 31, 2009 response that describes your cleaning validation protocols and that cleaning validation will be performed on all equipment used to manufacture OTC products. However, during the follow-up inspection dated January 2 - 4, 2010, your cleaning validation protocols were not available. Further, your February 8, 2010 response provided an incomplete cleaning validation protocol for one piece of equipment. In addition, it was not clear whether cleaning validation will still be performed on other equipment.

[BENEV Company, Inc., Date Issued: May 18, 2010]


4. Your firm has failed to establish appropriate written procedures for cleaning the equipment used in the manufacture or processing of a drug product [21 C.F.R. § 211.67(b)]. For example,

a) Using your available method validation data, there is no assurance that the current method for testing (b)(4) residue can adequately evaluate equipment cleanliness.

b) Your cleaning validation studies for non-dedicated equipment do not show that product residues are decreased to an acceptable level. Specifically, the percent of recovery at (b)(4)% was arbitrarily established without supporting data.

In addition, the recovery swab studies to validate the swab methods did not provide sufficient data to demonstrate manual recovery variability. For example, your "(b)(4)" was validated based on swab recovery study that was conducted at a (b)(4) concentration and used a (b)(4) swab.

We have reviewed your response and cannot determine its adequacy since your swab recovery studies were not complete at the time of your response. The effectiveness of your corrective action will be evaluated during the next inspection of your facility. In addition, it is our expectation that a thorough and comprehensive review of all cleaning protocols and reports will be performed to ensure that all studies have been adequately conducted.

[Capricorn Pharma, Inc., Date Issued: April 20, 2010]


Written procedures for cleaning and maintaining equipment used in the manufacture, processing, packing, or holding of a drug product, are inadequate. [21 CFR § 211.67(b)]

For example, The Validation Master Plan for Morphine Sulfate Concentrate Oral Solution does not address the use of [redacted] as a cleaning solution, and the Process Validation/Equipment Performance report does not address removal of [redacted] from the equipment.

This issue is not addressed in your May 26 response. Your October 4 response on this issue is inadequate. For example, [redacted] Used Equipment Cleaning Form, does not address what agents are used to clean the equipment. This SOP must address, among other things, what will be manufactured in the equipment, the reactivity of the equipment with the cleaning solutions, and the residues that may exist after cleaning. Obviously, previous product residues may be transferred to current product being manufactured, and depending on the product being manufactured, cleaning compound residue may transfer to the drug product. Also, there is no indication if the final rinse verification by QC is still visual, or if there is a rinse analysis to ensure that the equipment is clean.

[Cody Laboratories, Inc., Date Issued: April 7, 2006]


Failure to adequately clean, maintain, and sanitize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product and failure to follow written procedures for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product as required by 21 CFR 211.67(a) & (b). 

For example, your firm failed to have cleaning validation studies for all the products you manufacture with the shared manufacturing equipment used to manufacture drug products and household cleaning agents and other industrial products. Also, the Cleaning Validation Master Protocol does not include a scientific rationale for the products selected, sampling sites, equipment used, and acceptance criteria established. In addition, your firm's cleaning and sanitization records do not document whether the required contact times (times detergents and solvents are in contact with the equipment surface) described in the procedure are met or document the preparation of either the cleaning agent [redacted] or the sanitizing agent, Sodium Hypochlorite, 12.5%, used during cleaning. 

Your firm's response indicated that two cleaning validation studies had been completed and your commitment to complete cleaning validation for all other drug products. The response also stated that a high performance liquid chromatography (HPLC) instrument was purchased. You also stated that you intend to perform some of the analytical testing currently performed by a contract laboratory and that you are in the process of hiring an analytical chemist to perform testing and participate in the cleaning validation studies. The response, however, did not include documentation of the cleaning validation studies already completed for our evaluation. It also failed to specify for which two drug products the studies were completed. In addition, the response did not include a timeline for completion of the remaining cleaning validation studies. 

Your firm's response also mentioned you are planning to buy additional manufacturing equipment and states your commitment to dedicate this equipment to the manufacture of household and cleaning products. However, interim corrective actions were not proposed for those drug products manufactured after the manufacture of household cleaning and industrial products, particularly in light of your failure to complete cleaning validation studies. 

Please note that deficiencies with cleaning validation were documented in the inspections conducted on September 29, 2004, and September 30, 2005. In a letter dated December 12, 2005, you indicated that cleaning validation studies would be completed by approximately December 2006.

Part 211 Subpart C – Buildings and Facilities, Sec 211.42 Design and construction features

Your firm has not established separate or defined areas or such other control systems to prevent contamination during aseptic processing [21 C.F.R. § 211.42(c)]. For example,

a. There is no documentary evidence of in-situ air pattern analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Your firm failed to demonstrate that the appropriate design and controls are in place to prevent turbulence and stagnant air in the critical area. It is essential that you evaluate airflow patterns for turbulence that can act as a channel for air contamination. The studies should be well documented with written conclusions, and should include an evaluation of the impact of aseptic manipulations (e.g., interventions) and the equipment design.

b. Your aseptic processing control systems and operations do not provide assurance that the production rooms and equipment maintain aseptic conditions. Additionally, your environmental monitoring practices do not include adequate routine examination of the facilities and equipment to ensure that possible contaminants can be detected.

The inspection documented mold contamination in the class 100 production room and poor conditions of a wall in the freeze dryer room, even though maintenance is conducted on the freeze dryer every (b)(4) months. An incident report, initiated in November 2009, identifies holes in the ceiling and visible light coming from the roof near the ventilation system, bubbling of the vinyl and disintegration of the wall under vinyl in the freeze dryer room, visible black mold on the wall, a poor drain system for the freeze dryer steam venting system, and a soft (spongy) wall.

c. Operators involved in the filling operations for the sterile drug products manufactured at your facility do not practice adequate aseptic techniques to prevent product contamination. The environmental monitoring performed at the end of the production run consist of sampling the chest and the hand most frequently used (right or left) of the employee's gown. Also, this procedure is performed by the gowned operator and is not monitored by a second qualified person (e.g., supervisor; quality unit personnel) to ensure the proper techniques are being applied. This practice is unacceptable. We expect that all operators who conduct operations within aseptic processing areas be properly trained and monitored to ensure that proper techniques are utilized during all operations, including aseptic filling operations and personnel sampling.

[CP Pharmaceuticals, Ltd., Date Issued: October 29, 2010] 


The controls to prevent contamination in defined (critical) areas are deficient regarding operations related to aseptic processing of products. [21 CFR 211.42(c)(10)]

A. Smoke studies of Class [(b)(4)] in critical areas were inadequate in that they were not performed under dynamic conditions and the results were not recorded for subsequent review. Refer to FDA Form 483, Observation #5.

You included a CD ROM of the smoke study summary report with your December response. However, this CD ROM was unable to be opened for review, thus we could not read the attached documents. Re-submit the supporting documentation including the video showing the smoke study your firm conducted on November 19, 2008.

[Lupin Limited, Date Issued: May 7, 2009]


The controls to prevent contamination or mix-ups in defined (critical and supporting clean) areas are deficient regarding operations related to aseptic processing of drug products [21 CFR 211.42(c)(10)]. 

A. For parenteral operations, smoke studies were not conducted to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions during numerous aseptic operations in classified areas of the vial filling facility. For example: 

1. Various manual operations performed with the [redacted] such as dispensing sterile API and connecting equipment to this [redacted] were not included in smoke studies. 

2. Other significant manual aseptic activities that can affect airflow, including opening and closing the fill equipment access panels during routine aseptic filling operations, were not evaluated in smoke studies. 

3. There was no evaluation performed to demonstrate that personnel activities (e.g., manual transfer of material into or out of the ISO [redacted] and ISO [redacted] areas) do not compromise the unidirectional airflow pattern. 

4. There was no evaluation performed to demonstrate that the horizontal airflow from the [redacted] does not negatively impact upon the vertical airflow within the aseptic Willing areas. 

Your response indicates that you have prepared a comprehensive protocol for performing airflow pattern testing to include all aseptic operations in both the dispensing and filling areas and hope to video record these tests. Your response also indicates that the Quality Review of these smoke studies will be completed and approved prior to initiation of media fill studies, which were targeted to be completed by April 30, 2008. However, your firm has not provided an update on all airflow pattern findings and your evaluation of these study results. 

B. For sterile API operations, smoke studies were not representative of actual operations to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions during numerous aseptic operations in classified areas processing sterile APIs. For example: 

1. There are no smoke study evaluations to demonstrate that the personnel activities during the [redacted] of sterile API from the [redacted] do not disturb the unidirectional airflow in front of the to prevent compromising the sterile API. 

2. The smoke study performed for the set up of the [redacted] equipment did not actually reflect the manner with which the equipment and manual aseptic connections are made. 

3. There are no controls (e.g. physical barrier, curtains) in place to ensure that the [redacted] room's ISO [redacted] unidirectional airflow conditions were not compromised during routine operations performed within the ISO [redacted] area. 

4. The smoke study performed for the [redacted] steps did not accurately reflect the manner in which routine aseptic connections are made. 

Your response indicates that you have prepared comprehensive protocols for performing airflow pattern testing to include all aseptic operations in line with sterile API production and hope to video record these tests. According to your protocol, smoke studies were to be completed prior to the next media fills which were targeted to be completed by May 15, 2008. However, your firm has not provided an update on all airflow pattern findings and your evaluation of these study results. 

C. Failure to conduct aseptic connections of sterile API materials in critical areas (ISO [redacted]) and demonstrate providing [redacted] unidirectional air flow over the connections. For example, the manual aseptic connections for sterile APIs performed prior to [redacted] were done in an ISO [redacted] (supporting clean) area. 

Your response indicates that your new [redacted] unidirectional air flow (UAF) unit would be qualified by April 7, 2008 and the smoke study would be completed prior to media fills that were targeted to be completed by May 15, 2008. However, your firm has not provided an update on the airflow pattern findings for the [redacted] UAF unit and your evaluation of these studies. 

D. Viewing locations are inadequate to assess processing operations in ISO [redacted] sterile API and drug product operations. The aseptic processing facility lacks appropriate viewing facilities for aseptic operations in order to assess the control systems necessary to prevent contamination or mix-ups during the course of aseptic processing. For example, the door windows and their locations, used to observe routine operations, precludes the In-Process Quality Assurance (IPQA) and Management from observing all phases of either the [redacted] aseptic API processes or the aseptic finished drug product processes. 

Your response indicates that new procedures are being prepared with respect to activities to be reviewed, identification of all critical operations, and locations from where each operation has to be viewed (whether from view panel or inside critical areas). However, your response fails to indicate the adequacy of the facility to provide appropriate viewing of sterile processing operations in critical areas for both sterile APIs and finished dosage forms. Placing additional personnel such as IPQA personnel in critical areas can increase the risk of contamination and require additional operational qualifications. Please indicate if you intend to improve your viewing facilities. 

In summary, we are concerned that your aseptic operations are conducted under extensive steps, manual handling, and inadequate equipment usage as reported above under S.C., D. and E., and 6.C. For example, manual operations under aseptic conditions should be conducted with minimum operator intervention and no exposed critical surfaces and product. Therefore, it is not appropriate to try to overcome major flaws in clean room design and equipment by attempting to validate difficult to perform, intensive manual procedures. These manual practices have the potential to increase the risk of contamination on critical surfaces and are considered inadequate manufacturing practices which can not be justified nor validated. Furthermore, design concepts and use of contemporary equipment and automation technologies should be explored and assessed for suitability to prevent unnecessary activities that could increase the potential for introducing contaminants into the aseptic environment. We recommend that you conduct an extensive evaluation of your facilities for opportunities to minimize steps and manual handling. Additionally, appropriate equipment and usage in all related aseptic operations for APIs and finished dosage forms should be evaluated. Please provide this evaluation in your response showing improvements to current operations. 

[Ranbaxy Laboratories Limited, Date Issued: September 16, 2008] 


2. Controls to prevent contamination in defined (critical and support clean) areas are deficient regarding operations related to aseptic processing of product [21 C.F.R. § 211.42(c)(10)].

For example, there are no dynamic smoke study evaluations to demonstrate that the personnel activities during aseptic filling do not compromise the sterile API. The activities conducted during your documented smoke studies are not representative of actual operations.

According to your response, smoke studies were to be completed within the first two weeks of January 2010. Your response is inadequate because it does not provide an update on all airflow pattern findings and your evaluation of these study results. An in situ air pattern analysis should be conducted at all critical areas, under dynamic conditions, to demonstrate unidirectional airflow and sweeping action at critical work areas. These studies should evaluate the impact of aseptic manipulations (e.g. interventions) and equipment design, and include documentation for the activities performed with written conclusions. Provide a copy of the smoke study recordings that can be read using Windows Media Player (as an mpeg file, for example) along with supporting documentation. Please also identify the different videos by file name to indicate what is being presented in each file.

[Ribbon Pharmaceutical and Chemical Products, Date Issued: May 27, 2010]


You failed to assure an adequate system for cleaning and disinfecting aseptic processing areas and equipment [21 CFR 211.42(c)(10)(v)].  For example:

a. Report C017795 entitled “Year 2010 Re-Evaluation of the Approved Disinfectants/Sporicidal Agents” (effective date October 8, 2011) used bacterial and  mold spores to test the effectiveness of disinfectants and sporicidal agents used at your facility, including the BCG aseptic manufacturing areas in  Building (b)(4). The effectiveness study is inadequate in that it did not evaluate use of the disinfectants and sporicidal agents on surfaces other than (b)(4)

b. Your SOP entitled “Disinfection Program for Equipment and Manufacturing Areas in Building (b)(4); BCG Department” is inadequate.  Sporicidal disinfection of aseptic manufacturing areas using (b)(4) is only required to be performed (b)(4). There have been no less than 58 documented non-conformances relating to the isolation of mold within the BCG aseptic processing areas (Grade (b)(4) areas) of Building (b)(4) since August 2010. 

c. There is no documented evidence that corrective action in followup to non-conformances relating to the isolation of mold within the BCG aseptic manufacturing areas includes cleaning with a sporicidal agent. 

[Sanofi, Date Issued: July 12, 2012]


Part 211 Subpart C – Buildings and Facilities, Sec 211.46 Ventilation, air filtration, air heating and cooling

There is a failure to assure that the air filtration system, including prefilters, is working correctly when used on air supplies to the production areas for both finished dosage forms and APIs. [21 CFR § 211.46]

For example, API products sold as dry powders are manufactured in a suite[redacted] solution drug product is manufactured. There have been no studies showing whether contamination of the solution drug product by the dry powders cannot occur when doors to the manufacturing suites are opened at the same time. The air handling system, including the air filters and filter combinations, have not been qualified to demonstrate that the drug product does not become contaminated with the dry powders. There are no diagrams showing the flow of air through the rooftop vents, fans, and air return units.

This issue is not addressed in your May 26 response. Your October 4 response on this issue is inadequate. For example, the air flow diagrams provided in this response indicate that the API production rooms have [redacted] airflow and the oral solution rooms have [redacted] airflow. However, [redacted] issued and approved on [redacted] requires that these conditions are measured and certified at least [redacted] a year, but makes no provision for installation of a manometer to provide an indication of the proper air pressure differential when the manufacturing rooms are in use. In addition, no mention is made of a schedule to change or replace the filters for air entry points into the manufacturing rooms.

[Cody Laboratories, Inc, Date Issued: April 7, 2006]


Part 211 Subpart F – Production and Process Controls, Sec 211.100 Written procedures; deviations 

Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR § 211.100(a)].

For example, process validation for several drug products (e.g.,(b)(4) mg; (b)(4) mg; (b)(4) mg; and (b)(4) mg) was not adequate. During the inspection, our investigator identified at least four products for which process validation was performed using a (b)(4) ; however, these four tablet products were also being manufactured using the (b)(4). Using a (b)(4) when products were validated on a (b)(4) was not in your approved validation procedure, and you had no data to demonstrate equivalence of the different (b)(4).

In your response, you state that there are controls in place to control variability in the process and in the final product. These controls and variability should have been prospectively assessed through completion of successful process validation studies. In addition, you reference the Cpk values for processes using a (b)(4) versus the processes using the (b)(4). Your response is inadequate because a Cpk value alone is not an appropriate metric to demonstrate statistical equivalence. Cpk analysis requires a normal underlying distribution and a demonstrated state of statistical process control (ASTM E2281). Statistical equivalence between the (b)(4) and (b)(4) could be demonstrated using either parametric or non-parametric (based on distribution analysis) approaches (comparing means and variances). Your response to Observation #1 does not utilize either of these approaches, and lacks the proper analysis to support your conclusion that no significant differences existed between the two (b)(4) processes.

Further, your response attempts to demonstrate equivalence of the (b)(4) and (b)(4) processes through uniformity and dissolution data, although you did not provide any data regarding (b)(4) or (b)(4) parameters. Also, in Attachment VI of your response, you attempt to demonstrate the equivalence of the (b)(4) processes by providing data obtained through your “SAS” system that contains projected expiry information. However, the data you present for the “projected expiry” of (b)(4) mg does not confirm that the two processes are equivalent; instead, this data demonstrates the variability in your process and the expected failure of lot (b)(4), asset #(b)(4), produced using the (b)(4). Therefore, we find your response inadequate to address our concerns regarding your failure to validate the above-noted products on the (b)(4) equipment.

This is a repeat violation from the August 2008 Warning Letter issued to the Wilson, North Carolina facility.

[Novartis International AG, Date Issued: November 18, 2011]


Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].

Three examples of violations of § 211.100(a) are as follows: 

b. The investigator also observed for Batch #36659 that one out of every six bottles did not receive the dose of active homeopathic drug solution due to the wobbling and vibration of the bottle assembly during filling of the active ingredient. The active ingredient was instead seen dripping down the outside of the vial assembly. Your firm lacked controls to ensure that the active ingredient is delivered to every bottle.

Your response indicates that the line speed was “unusually” high, and you state that you have corrected the problem to prevent recurrence. However, your response is inadequate because it does not provide a risk assessment for the U.S.-distributed products previously manufactured on the faulty line.

Please provide a risk assessment for all products within expiry, distributed to the U.S., manufactured on the line at high speed. Additionally, provide evidence that the line has been successfully validated to ensure each bottle contains the appropriate dose of active homeopathic drug solution.

c. The dosing process has not been validated appropriately. Specifically, your surrogate validation study, “Medication of un-medicated pillules with (b)(4),” visually demonstrates the variability of the amount of (b)(4) for the pillules in one vial. Your firm lacks control of the variation for the amount of the active ingredient in the pillules.

The validation study demonstrated that pillules at the top of the bottle contain more active ingredient than pillules at the bottom. There are no controls in place to ensure that the dosing procedure is homogenous and reproducible.

Please provide evidence that the dosing process is uniform, as well as a risk assessment for all Clikpak products, distributed to the U.S., dosed with an inconsistent or excessive amount of active ingredient, regarding their safety for consumers.

[A Nelson & Co., Ltd, Date Issued: July 26, 2012]


Failure to have adequate written procedures for procedures and process control to assure that drug products have the identity, strength, quality and purity they purport or are represented to possess [21 CFR 211.100(a)]. For example:

[redacted] tablet lot #79298AF00 was one of the batches included in the process validation study for this product. This lot was not produced using the manufacturing process discussed in the validation study protocol. Lot #79298AF00 was subjected to several reconditioning steps, due to particulate contamination, that were not listed in the master batch record. Some of the actions taken with respect to this lot, such as the hand pouring of the granules from a drum and [redacted] were steps that were performed for the production of the two additional [redacted] lots used in the validation study.

The master batch manufacturing instructions for the production of [redacted] differ from the procedures used in manufacturing the batches produced in the validation study. The drying process for the tablet granulation component used in the validation batches used a different type of dryer and different time and temperature parameters from the procedures directed in the master batch manufacturing.

[Abbott Laboratories, Inc., Date Issued: September 24, 2002]


Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].

For example, three initial process validation batches (#HP0793, #HP0706, #HP0794) for Oxcarbazepine 300 mg tablets failed the dissolution test specification (Q=NLT (b)(4)% at 30 minutes) and the batches failed to meet the 30 minutes dissolution specification. Dissolution out of trend (OOT) results were also obtained for Oxcarbazepine 150 mg and 600 mg tablets. The same (b)(4) was used for the process validation of Oxcarbazepine 300 mg, 150 mg, and 600 mg tablets.

During your second attempt to perform the process validation, three batches of Oxcarbazepine tablets 300 mg (lot #HT8606, #HT8607, and #HT8608) were made from one (b)(4) that failed to meet the 30 minutes dissolution specification. You released Oxcarbazepine 150 mg and 600 mg tablets that were manufactured from the same (b)(4) that was used to manufacture the 300 mg strength. Your investigation Q-note 200071071 concluded that the dissolution results were affected by the order in which the excipient (b)(4), USP was added during the (b)(4) process. Appropriate process design studies were not conducted to scientifically establish the correct order of adding excipients, e.g., (b)(4), during the (b)(4) operation to ensure proper dissolution of the drug product.

In addition, please explain your rationale for releasing different lots of product (Oxcarbazepine 150 mg, 300 mg, and 600 mg) manufactured from the same defective (b)(4).

[Apotex Inc., Date Issued: March 29, 2010]


Failure of the appropriate organizational unit and the QCU to review and approve any changes to established written procedures [21 CFR § 211.100(a)]. 

a. Your manufacturing process, has not been validated for repeated changes to the drying time parameter of the oven dryers in the [(b)(4)] granulation. The changes were implemented in an attempt to ensure granulation is not too dry without establishing a minimum specification and without an assessment of product quality. 

Your July 10, 2008 response regarding the failure to establish acceptable range for the LOD (loss on drying) states in part that "The LOD specification for [(b)(4)] has always been NMT [(b)(4)]" However, your response does not address statements made by the Vice President of Manufacturing and Director of Quality regarding concerns of granulation becoming too dry which prompted the change in drying times to obtain acceptable product. Please clarify the conditions and specifications which may produce a granulation too dry for compression with supporting documentation and your firm's plan to prevent this from recurring.

b. For [(b)(4)] tablets, lot [(b)(4)] nine process change requests were implemented without evaluating the impact of the changes to product quality. 

[Caraco Pharmaceutical Laboratories, Ltd, Date Issued: October 31, 2008] 


Failure to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess as required by 21 CFR 211.100(a). 

For example, process validation studies have not been conducted for any of the human drug products manufactured by your firm. 

Your firm's response included copies of a draft Master Validation Plan and draft Process Validation Forms that will be used in the execution of a process validation study and a draft of the Process Validation Protocol for Capsaicin Gels as an example. The response does not provide a timeline, plan, or estimated completion date for the process validation studies. 

[Concept Laboratories, Inc., Date Issued: August 27, 2008]


Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100(a)]. 

For example, your contract manufacturer, [b4],performed a process re-validation study for a change in the [b4] supplier and for using a new tablet press for your [b4] drug product manufacturing process. These process re-validation batches were sent to Gilead in [b4] and Gilead in San Dimas, California [b4] and [b4]  for packaging. Lots manufactured during the process validation study ([b4]) exhibited excessive amounts of defective tablets ([b4], and [b4]) above the pre-determined acceptance criteria.

You stated in your response that the investigation into the re-validation study concluded that neither the new tablet press nor the [b4] from the secondary supplier had an adverse effect on the [b4] manufacturing process. We disagree with your assessment and we do not consider your process validated. Your investigation report conclusion was based on finished product test results alone, and did not consider in-process testing and analyses.

[Gilead Sciences, Inc., Date Issued: September 21, 2010]


Your firm fails to follow written production and control procedures in the execution of the various production and process control functions [21 CFR § 211.100(b)].

For example, ...

b) Operators fail to follow the diagram of the validated (b)(4) load configuration provided in SOP QAS-296 entitled Validation/Re-validation of Sterilization Cycles in the (b)(4) and SOP PGSI-087:  Injectables Machine Parts Preparation Before Sterilization and Batch Processing. 

SOP QAS-296 entitled Validation/Re-validation of Sterilization Cycles in the  (b)(4) and SOP PGSI-087:  Injectables Machine Parts Preparation Before Sterilization and Batch Processing provide a diagram of the load configurations; however, our inspection found that the operator performing this function for the parts to be used in the production of  (b)(4) Injection lot  (b)(4), can not follow this load pattern due to insufficient space on the  (b)(4) trolley.  The current  (b)(4) load configuration used by production operators to  (b)(4) sterilize filling machine parts has not been validated.

Your response states, “The subject employee inadvertently did not follow the validated load pattern for  (b)(4) sterilization of filling machine parts.”  It should be noted that your firm’s personnel explained that the failure to follow the validated load pattern was not inadvertent, but was the prevailing practice.  Your response indicates an incident report was raised, all operators were retrained, and a sign-off sheet for load configuration was added to the batch record.  However, your response is inadequate because it fails to address the disposition of  (b)(4) Injection lot  (b)(4) as well as any other batches that may have been impacted by this failure to follow validated sterilization load configurations.   

c)  Your firm fails to perform gowning qualification for operators prior to working in aseptic processing areas, and all operators are not requalified for gowning on an annual basis as required according to Report QR-103: Report for Aseptic Gowning Qualification Program for Cleanroom Personnel.

Your response states that you issued and implemented SOP QAS-406: Procedure for Gowning Qualification/Requalification of Clean Room Personnel and you revised re-qualification protocols to include all staff entering Class 100 areas.  Your response is inadequate in that it does not address how you will prevent individuals who have not undergone the appropriate gowning qualifications from accessing cleanroom areas.  Your response also refers to the personnel monitoring conducted during media fill operations and states, “we were under the impression that including the operator for media fill & intensively monitoring the gown is enough to re-qualify a personnel…”.  With this statement, you disregard your firm’s failure to follow your existing SOPs which state that all personnel entering the cleanrooms will be re-evaluated for gowning qualification annually as per a written protocol.  It is your quality unit’s responsibility to ensure that the established program to regularly assess conformance of personnel to aseptic manufacturing requirements is followed.

[Gulf Pharmaceutical Industries, Date Issued: February 23, 2012] 


Part 211 Subpart F – Production and Process Controls, Sec 211.110 Sampling and testing of in-process materials and drug products

There was a failure to establish written control procedures to monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. [21 C.F.R. § 211.110(a)]. In addition, there was a failure of the quality control unit to reject in-process materials during the production process that were tested for identity, strength, quality and purity. [21 C.F.R. § 211.110(c)]. For example: 

Despite the fact that some lots passed finished product testing, your firm does not have valid scientific data to demonstrate that endotoxin present at the in-process stage is reduced to an acceptable level in the finished product. In March 2006, three lots of Propofol exceeded the finished product specification for endotoxins ([redacted]/ml). As a result of an investigation into these failures, a [redacted] test for endotoxin was added to the master production record (MPR). The limit in the MPR is consistent with final product specifications. Your firm indicated that the results of this in-process test would provide an early indicator of objectionable endotoxin levels and provide pertinent investigational information. Our inspection found that lots included endotoxin at levels above the in-process limit. Although these lots had endotoxin levels above the in-process limit, your firm released these same lots, on the basis of passing finished product testing . Your quality control unit should have, during the production process, rejected the in-process materials that had the elevated endotoxin levels.

In response to current inspection findings, your firm conducted studies that were intended to demonstrate the ability of the sterilization process to achieve significant endotoxin reduction in the final product. However, as explained further below, your studies lacked adequate information to support this assertion. 

In addition, your firm does not have data to support that endotoxin (when present) is uniformly distributed in Propofol vials . Due to the nature of the product (a non-aqueous emulsion) and non-uniform endotoxin content from unit to unit upon retest (e.g., lot 919086), we are led to the conclusion that end-product testing alone is insufficient to assure that your firm's finished product meets its endotoxin specifications. For example, the original finished product endotoxin testing result (from [redacted] vials) for lot 919086 was [redacted] EU/ml (below the ([redacted] EU/ml limit). However, since lot 919086 was manufactured during the same time period as two (919087/88) rejected lots (for high endotoxin results) your firm properly performed additional testing on lot 919086. Upon retest, all [redacted] additional vials from lot 919086 were above the [redacted] EU/ml limit. Consequently, the lot was rejected. 

We are also concerned with your quality control unit's (QCU) decision to eliminate the practice of taking in-process samples of the bulk Propofol emulsion for endotoxin testing during the inspection. Your QCU explained to FDA investigators that since this in-process testing for endotoxin was not a commitment in a drug application, it would be eliminated (despite previous failing of in-process limits of some lots). Please note that in-process controls beyond those described in submissions to FDA are a routine aspect of a firm's quality program to assure compliance with the cGMP regulations. Because we think that it would be appropriate to test your in-process materials for identity, strength, quality, and purity, we believe that eliminating this in-process endotoxin test would be in violation of 21 C.F.R. § 211.110(c). 

[Ben Venue Laboratories, Inc., Date Issued: November 16, 2007]


Your firm has failed to have adequate sampling and testing to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product as required by 21 CFR 211.110. Specifically, review of the process validation for Oxytetracycline HCl revealed: 

  • At least three validation runs were performed over a three year period of time using Validation Protocols PQPS-035, approved 4/14/2000; PQPS-035-01, approved 9/19/2000; and PQPS-035-01 SUPPLEMENT, approved 5/28/02. As documented, none provide assurance that a comprehensive study was performed. 
  • Your firm failed to adequately record process details, including sample size and method of collection, to demonstrate Oxytetracycline HCI was tested in accordance with the validation protocol and approved methods. 
  • Your documentation does not substantiate rigorous in-process testing was conducted to demonstrate the effectiveness and reproducibility of the process. The sample size used for testing is not always statistically significant. 
  • The in-process granulation and hopper depletion sample test results fell outside the NADA and validation protocol predefined specification of Blend uniformity has not been adequately demonstrated. 

[Boehringer Ingelheim Vetmedica, Inc., Date Issued: October 20, 2004] 


Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product [21 CFR 211.110(a)]. For example: 

There is no process validation data available for Levoxine (Levothyroxine Sodium) Powder (a prescription drug product) that demonstrates the current ingredients, formula and manufacturing process consistently produce a powder that meets density requirements to assure that each level teaspoon contains 12 mg of T4, as stated on the label. 

The only process validation data available is for one lot (H1R) made in 1999 that was re-worked because it did not meet the density requirement. According to statements made on the "Re-Work Procedure" form, the initial batch was screened through a [redacted] Different grades of Sodium Chloride and Calcium Carbonate and additional amounts of Levothyroxine Sodium were added to the batch and blended as Parts I and II. 

The density requirements are not defined in the process validation protocol. Density testing and results are not documented in the process validation data. There is no data to show that the reworked Lot met density requirements. Currently, there are no density specifications for Levoxine Powder. 

Levoxine Powder, Lot [redacted], was manufactured in September and approved for release on 9/15/06. The only tests done on the finished product are assay and loss on drying. The assay result is reported as a percentage ([redacted]%). The assay method determines the quantity in mg of Levothyroxine sodium per gram of the sample. 

The process validation data for Pyrantel Pamoate Suspension Canine (2.27 mg / mL) manufactured in tank #12 does not demonstrate that the mixing process consistently produces a uniform batch. A process validation batch uniformity study (Protocol [redacted]) was done in 2005 to "verify that the blending procedure as described in the master formula is adequate to provide uniform suspension for [redacted] lots of [redacted] batches." The final report, which is dated 5/27/05, concludes, that based on the evaluation of test data, the validation was successfully completed. However, the raw data for one of the batches [redacted] does not demonstrate batch uniformity. The assay results of the three samples of Lot [redacted] range from [redacted] mg / mL [redacted] % of label claim) to [redacted] mg / mL [redacted] % of label claim). The variability of the results are not discussed in the final report of Protocol [redacted] Tank 12 is currently used to manufacture [redacted] batches of Pyrantel Pamoate Suspension Canine (2.27 mg / mL). For example, Lot [redacted] is a [redacted] batch made in Tank 12 on 5/31/06. This lot was approved for release on 6/7/06 based on the finished product testing of one sample of the bulk suspension collected from the mixing tank. 

This observation is discussed in your written response to FDA-483 item #9. Our comment on the response to this observation is as follows: 

The response to this observation addresses the three specific products listed on the FDA-483. We note however, that First Priority does not make a commitment to assure that adequate process validation studies are performed for all veterinary drug products. In addition, process validation studies for the products listed on the FDA-483 have not been completed. According to the response, process validation testing was done on one lot of Levoxine Powder and one lot of Chlorhexidine Antiseptic Ointment. Two additional lots of each product will be tested when the batches are manufactured. No estimated completion date for these studies is discussed. The response says the Pyrantel Pamoate Suspension products will no longer be made in compounding tanks, but in kettles with dual motion sweep agitation. A validation study using the kettle for the 2.27 mg / mL product reportedly was completed in 2005. That data is not included with the response. 

Our review of the response to this FDA-483 item is, in summary, 1) the validation studies of the three products listed on the FDA-483 are not complete; 2) there is no assurance that acceptable process validation studies have been or will be conducted for all drug products; and 3) the Levoxine Powder study is questionable because samples were mixed before testing. 

[First Priority, Inc., Date Issued: July 9, 2007] 


Your firm has not established written procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and drug product [21 C.F.R. § 211.110(a)]. For example:

a. Your firm failed to demonstrate that the manufacturing process for the Fenofibrate 200mg capsules is capable of controlling weight variations.

Between February and June 2010, your firm rejected validation lot T003011 and significant portions of validation lots T001006 and T002002 due to weight variability (low and high weight capsules). In June 2010, your firm also found weight variations in lot T006003. Lots T006002, T006003, and T006004 were manufactured under the same conditions as the rejected validation lot T003011. Portions of the identified lots were distributed although the process was not validated. Even though your firm has noted that micronized Fenofibrate powder sticking to the dosator pins during encapsulation may be a contributing factor, your firm has failed to identify a cause for these weight variations or to propose and implement corrective actions to address the discrepancies.

We acknowledge your voluntary recall of Fenofibrate capsules 200 mg, lots T0010061, T0020021, T0060021, T0060031 and T0060041, your commitment to revalidate the manufacturing process, and to continue your investigation into the capsule weight variations. However, your response is inadequate because it does not include details on what specific steps you are taking to conduct the investigation (e.g., whether your firm will perform a retrospective lot evaluation, the number of lots to be evaluated and the criteria for selection, or whether your firm will evaluate distributed lots).

b. Your firm does not have data to support the temperature range of (b)(4)°C used during the granulation process of Colestipol Hydrochloride 1g tablets (lots 601066, 601067, and 601068). During the validation studies for the granulation process, your firm established a temperature range of (b)(4)°C. Your process validation study does not provide any data to support the process range allowed in the Master Batch Records. 

In your response, your firm states that you plan to evaluate all critical process parameters and that those results will be reviewed to determine final operating ranges. Your response, however, is inadequate in that it does not address: 1) specific details about your re-validation plans and in particular, whether you will determine the root cause to clearly demonstrate a full understanding of your products and processes before initiating the re-validations, and; 2) the controls involved with issuing, reviewing, and revising manufacturing batch records to ensure validation criteria are captured and accurate. In addition, your firm has not committed to review batch records of distributed lots of Colestipol HCl 1g tablets to ensure it was manufactured within the temperature range specified in the validation studies.

[Impax Laboratories, Inc., Date Issued: May 31, 2011]


Failure to establish control procedures which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product as required by 21 CFR § 211.110 (a). Specifically,

a. Sinex Long Acting Nasal Spray had appearance failures in stability samples in February 2007(50591720K1 and 50541720K2 at 24 and 36 months), May 2008 (71241720K1 at 12 months) and May 2008 (61791720K1 at 24 months). The precipitate detected was identified as a salt formation of one of the preservatives. Appearance failures occurred previously from 2000 to 2002. At that time, you identified the precipitate as chlorhexidine dyhydrochloride. Your firm concluded that the exposure to the amount of chlorhexidine in this salt was acceptable as compared with exposure to chlorhexidine via mouth rinses. In February 2001, changes to the manufacturing process were implemented to eliminate the precipitate formation. However, these changes were not effective to prevent the precipitate formation as evidenced by the latest stability failures.

Technical justification (b)(4), approved in (b)(4), proposed a reduction of the upper limit of the preservative in the formulation to eliminate the precipitate. You determined that the change in the formula did not require a new validation because the issue is only seen over time. In addition, as of no information about stability studies with the new formulation had been provided. You have not demonstrated that this proposed action will prevent the recurrence of the stability failures. Based on your firm's past history with this product, it not clear that your firm has a thorough understanding of the physical stability of the product throughout its shelf life.

Moreover, technical justification (b)(4) states that a potential effect of this failure could be seen in complaints reporting "clogged nozzle," "residue at nozzle," "product never dispensed," etc. A review of complaints received from July 2006 to August 2008 found approximately 35 complaints reporting similar issues. However, your firm identified these complaints as "Action Level 2", meaning that no investigation was required.

We reviewed your October 31, 2008 response letter which addressed this observation and found it inadequate. You indicated that a formulation change is being pursued for your Sinex Long Acting Nasal Spray, but you do not mention whether you are planning to validate the new manufacturing process, and we note, as discussed above, that you have made other changes to the formulation of this product without validating their effectiveness. You have observed the formation of this precipitate since 2000. You have stability data at ambient conditions showing the formation of this precipitate since the 18-month stability testing station. In 2001 you made changes to the manufacturing process without conducting a revalidation of the process. Specifically, you reduced the speed from (b)(4) to (b)(4) efficiency and to ensure that particles that produced the turbidity were removed. You also modified the (b)(4) and established a new (b)(4). These changes were not effective in eliminating the formation of the salt precipitate as evidenced by the stability appearance failures observed in stability samples analyzed in February 2007 and May 2008 (for example, lot 71241720K1 at 12 months). We find it highly objectionable that corrective actions identified in the technical justification (b)(4) report, which documents the investigation of stability failures from February 2007, have not been validated or implemented as of September 18, 2008, and that you continued manufacturing and distributing this product. When our investigator asked your Quality Manager the reason for the delay she explained that this was a lower priority based on the firm's assessment of the safety/health risk and your firm was focused on other priorities.

[Procter and Gamble, Date Issued: April 24, 2009]


Part 211 Subpart F – Production and Process Controls, Sec 211.111 Time limitations on production

Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product [21 C.F.R. § 211.111].

For example, your firm has not validated your bulk or process hold times assigned for most products (studies have been done for only 5 products out of approximately (b)(4). The assigned (b)(4)-day hold time limits for solutions and (b)(4) day limits for suspensions are largely unsupported. Your firm also lacks data to support the adequacy of your process hold times even though some of your products contain (b)(4) that are known to be absorbed by your hoses.

In your response, your firm states that you will review the historical data of (b)(4) lots for all products to establish hold times. Your response, however, fails to provide a justification for how these lots will be selected. Moreover, maximum hold times should be supported by stability data to ensure that the marketed product will remain within specification throughout their shelf-life. Your firm has provided a completion date of May 1, 2012, to review specific problems relating to hold times (i.e., (b)(4) evaporation prior to and during filling and the hose absorption of (b)(4)). This timeline is not acceptable to address these known problems.

[Beach Products, Inc., Date Issued: August 29, 2011]


Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product per 21 CFR 211.111.  For example,

a. Your firm has failed to provide a justification for the hold times (i.e., (b)(4)) used in current batch records for sterile ophthalmic eye drop products. 

In your response, your firm provided a report entitled “ (b)(4) Study Report” to justify your use of a (b)(4) day hold time. This report, however, is inadequate because your study tested lots on Day (b)(4) that did not correspond to or match the lots tested on Day (b)(4)  Your study should compare the same lot for microbial recovery on Day (b)(4) to Day (b)(4) to determine whether the bulk products originally tested still had levels of bioburden within your validated sterilization ranges.

b. In addition, your response failed to address the inadequate investigations for those batches where the hold times of the bulk product exceeded your hold time limits.

[Dakota Laboratories, LLC, Date Issued: March 17, 2011] 


Part 211 Subpart F – Production and Process Controls, Sec 211.113 Control of microbiological contamination

Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. Such procedures include validation of the sterilization process [21 CFR § 211.113(b)]. For example:

a) Your media fill studies were insufficient to establish that the aseptic process is in control. During media fill studies, you failed to establish appropriate criteria for reconciliation of filled vials (total units evaluated/incubated as compared to the total number of units filled) resulting in inconsistent and inaccurate media fill results. For six media fill lots manufactured from 2009 to 2011, the number of units filled did not match the number being evaluated/incubated. The number of units evaluated/incubated in some media fill runs was smaller than what had been filled, and in other media fill runs, the number of units evaluated/incubated was greater than what had been filled. Your firm lacked a justification for these discrepancies. For example:

i. Your media fill Lot# (b)(4) (filling end date August 20, 2009) shows that (b)(4) ampoules were received for incubation and  (b)(4)  ampoules were evaluated.

ii. Your media fill Lot# (b)(4) (filling end date October 30, 2009) shows that (b)(4) vials were received for incubation and (b)(4) vials were evaluated.

iii. Your media fill Lot# (b)(4) (filling end date July 1, 2010) shows that (b)(4) vials were filled and only (b)(4) vials were incubated. The number of media fill vials sent for manual visual inspection was also inconsistent with the number of units sent to the microbiology laboratory.

iv. Your media fill Lot# (b)(4) (filling end date November 18, 2010) shows that (b)(4) vials were received for incubation and only (b)(4) vials were evaluated.

v. Your media fill Lot# (b)(4) (filling end date December 14, 2010) shows that (b)(4) vials were received for incubation and only (b)(4) vials were evaluated.

b) You failed to follow your procedures for validation of aseptic processing. Your procedure, SOP P.200.136 (Media Fills), indicates that investigations will be initiated when there is a discrepancy between the units received by the laboratory and the units received for incubation. Your response indicated that an investigation was conducted for media fill lot# (b)(4) on July 23, 2010. As a result of this investigation, you proposed the following corrective actions: modify the sensor, improve documentation, and re-train personnel. However, two additional incidents (November 18, 2010 and December 14, 2010) occurred after the implementation of these corrective actions.

In your response to the FDA form 483 (Observation # 4a), you committed to update SOP P200.136 (Media Fills) to correct the reconciliation discrepancy at each step of the media fill: filling, visual inspection, receipt at the microbiology laboratory, mid-incubation, and final evaluation.

Please provide any data/documentation available from your investigations that establishes reconcilability of all media fill units. Total accountability of media fill units includes: units filled, rejected, received by microbiology department for incubation, removed for positive controls, and final inspection. Without this data, the acceptability of the above media fill runs and the capability of the process used to manufacture sterile drugs during this period is questionable. Please provide your firm’s evaluation of the impact on products produced during this period.

This is a repeat observation from the July 2009 inspection at the Boucherville, Quebec facility.

[Novartis International AG, Date Issued: November 18, 2011] 


Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)]. For example:

a. The qualification of your disinfectant (b)(4) failed to demonstrate that it is suitable and effective to remove microorganisms from different surfaces. Specifically, this disinfectant failed to meet qualification criteria when challenged with multiple organisms.

Your disinfectant qualification for (b)(4) and (b)(4) bi-spore disinfectants documented that the log reduction criteria (Bacteria ≥ 4, Fungi ≥ 3) was not met when challenged with multiple organisms in a variety of surfaces. After disinfection, you recovered Micrococcus luteus on vinyl, (b)(4), stainless steel, glass, and wall laminate and Enterobacter cloacae, Rhodococcus sp, Burkholderia cepacia, Pseudomonas aeruginosa, Methylobacterium mesophilicum and, Acinetobacter lwoffi on glass. However, your procedures for routine cleaning of the aseptic manufacturing area continue to require the use of unqualified disinfectants during days (b)(4) through (b)(4) of your disinfectant program.

Your firm’s response indicates that the failure to meet the log reduction criteria was due to the test conditions and not the efficacy of the disinfectant. However, you did not include documentation to support this conclusion. Moreover, your firm submitted an updated Technical Report (LT8R1310) “Interim Report for the Disinfectant Validation Study of the (b)(4) and (b)(4) Performed by (b)(4)”, signed by your Quality Assurance (QA) on July 27, 2011, indicating that the disinfectant (b)(4) has been unable to comply with the three-log reduction for Micrococcus luteus microorganism on some surfaces.

b. Procedure SOP PMC6169 “Aseptic & Support Area Sanitization Following Maintenance Shutdown” is inadequate.

A media fill conducted during January 2011 resulted in two contaminated units. Your firm attributed the failures to stopper bags left inside the class 100 area for a long period of time (throughout a shutdown that took place prior to the media fill in January 2011 shutdown). There is inadequate information available to support your conclusion, including information regarding the microorganisms recovered from the stopper bags and the sterility test conducted, along with an evaluation of your sampling procedure and environmental monitoring program.

Significantly, your firm had intended to use the media fill data to extend the sterility holding times for product contact components, without the approval of your Quality Unit. We also are concerned that your SOP PMC6169 did not require manufacturing materials to be removed to an appropriate area for storage during shut-down of operations and prior to bringing the area back into classified status.

c. Personnel gown monitoring conducted during routine aseptic filling of (b)(4)g ((b)(4)cc and (b)(4)cc) and (b)(4)g ((b)(4) cc) is inadequate.

The inspection documented that your firm conducts personnel monitoring on a (b)(4) basis and upon (b)(4) the classified manufacturing rooms by only sampling the hood, goggles, and sleeves. We are concerned about your current gowning monitoring approach as operators may perform substantial interventions into the Restricted Access Barriers (RABs), where sterile product is exposed, several times per week. In addition, the investigators noticed during the inspection one of the operators sanitizing his hands with (b)(4) immediately prior to conducting his own personnel monitoring sampling. Your personnel monitoring program should include appropriate sampling and practices to reflect whether personnel maintain asepsis during sterile drug manufacture.

In your response to this letter, please provide a detailed description of the controls implemented to ensure operators that enter the class 100 (ISO 5) area are sampled adequately in the "QA Grade B Room” (ISO 6). Also provide this same information for operators who enter the aseptic processing room for non-aseptic filling activities. Please include your rationale for these monitoring schedules.

In addition, the (b)(4)“Dynamic Airflow Visualization” video provided in your firm’s response shows an operator spraying his hands with (b)(4)(b)(4)(b)(4)% directly over the air viable microbial plate. This practice is unacceptable because the environmental monitoring results from plates sprayed with (b)(4)% may be inaccurate and may not reflect the actual microbiological environment of the Class 100 (ISO 5) room.

[SmithKline Beecham Limited, Date Issued: October 7, 2011]


Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of all aseptic and sterilization processes [21 C.F.R. § 211.113(b)].  For example:

a. Your firm has failed to conduct a media fill representative of the different packaging configurations of your drug products for the past two years. Your firm has been using a volume of (b)(4) for media fills; however, commercial products are available in (b)(4) and (b)(4). In addition, you have not established maximum aseptic fill duration.

In your response, your firm states that you have amended your Standard Operating Procedure (SOP) (b)(4) to “bracket” the container sizes by utilizing both the (b)(4) and (b)(4) volumes. Your response, however, is inadequate because you have not provided a risk assessment that examines the effects of differences between product fill sizes (i.e., fill speed, operating methods, container opening size, mass) to determine if bracketing is appropriate.  

b. Your firm’s qualifications of the Getinge Model 4300 autoclave and the Grieve CLE-500 oven are inadequate in that you have not qualified this equipment with representative loads. Your firm’s practice is to qualify the equipment using minimum loads as opposed to actual loads during routine operation (e.g., Grieve CLE-500 oven was qualified to depyrogenate glass vials using (b)(4) tray when the actual load is a maximum of 60 trays). 

In addition, your use of biological indicators and penetration thermocouples in the qualification studies are inadequate. Your firm has not used any penetration thermocouples during the qualification of Getinge Model 4300 since February (b)(4), nor have you incorporated the use of biological indicators. During the maximum load configuration study, your firm only used a (b)(4) penetration thermocouple and failed to use any biological indicators.  

In your response, your firm commits to evaluate the adequacy of your current procedure, to qualify your minimum and maximum load on each of your manufacturing operations, and to include penetration thermocouples and biological indicators in appropriate areas and in appropriate quantities. However, your response is inadequate because you did not explain how you will determine the appropriate locations and quantities for the thermocouples and the biological indicators. Since your firm is currently manufacturing sterile drug products using unqualified equipment, your response fails to include any additional controls to assure the quality of your drug products while you are evaluating your current procedures.

 

[McGuff Pharmaceuticals Inc., Date Issued: December 28, 2010]


 

Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of human drug products purporting to be sterile, including the validation of any sterilization process [21 CFR 211.113(b)]. For example:

a. The validation/revalidations of your steam sterilization cycles are inadequate.

i. Your validation/revalidations do not calculate accumulated heat exposure contributed during heat-up/cool-down of the steam sterilization cycles to demonstrate it is equivalent to exposure at [redacted]; therefore, there is no assurance that required temperatures ire achieved during routine steam sterilization cycles. 

ii. Your validation/re-validations do not include the thermocouple locations monitored during routine use when a minimum load is placed into the steam sterilizers. 

iii. Your validation/revalidations do not document an evaluation of the average total accumulated heat exposure to product at the coldest location for a maximum load in your steam sterilizer. Further, there is no evidence that the total accumulated heat exposure to product at the coldest location for a maximum load was compared to the total accumulated heat exposure to product at the coldest location for a minimum load. 

iv. Your validation/revalidations do not determine the distribution of steam within your empty sterilizers ; heat distribution studies were conducted by placing thermocouples into water-filled bottles and the temperature of the water within the bottles was determined. Heat distribution studies did not evaluate minimum/maximum load configurations.

b. Biological indicators (BIs) are used in biological challenges during validation/revalidations. They are prepared by [redacted]. There is no documentation supporting the use of the spore strips in this manner or confirming the D-value of BIs prepared in this manner. 

c. Your validation supplement PCR- 101 -Misc-Supp# 1, Rev. A, dated December 18, 2006, is inadequate. The purpose of the validation supplement was to determine the maximum amount of time a vacuum could be pulled after sample filtration without adversely affecting sample bioburden levels, thereby potentially altering the outcome of further testing. Initial bioburden levels of control samples used in the validation were not determined; therefore, bioburden recovery in the test samples could not be accurately demonstrated. Furthermore, results from [redacted] of [redacted] validation test runs were excluded from evaluation since recovery after initial filtration was less than [redacted]/100mL. This supplement was intended to validate the "hold time" of the filtration method used in your SOP E100 entitled "Sterility Testing;" SOP E103 entitled "Microbiological Testing of Water," and SOP E111 entitled "Microbiological Testing of Final Product Before Autoclaving." 

[Cytosol Laboratories, Inc., Date Issued: October 30, 2007] 


 

Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. Such procedures include validation of the sterilization process [21 C.F.R. § 211.113(b)].

For example,

a) You failed to perform unidirectional airflow pattern studies (i.e. smoke studies) for the ampoule filling line used for the production of (b)(4) Lot (b)(4), distributed to the U.S. on July 13, 2010.

This is a repeat observation from the December 2004 inspection at this facility. Our current inspection found that your firm failed to perform smoke studies for the ampoule filling line. Your firm was previously cited in 2004 for a failure to conduct smoke studies for your vial filling line.

Your response of October 28, 2011, is inadequate because you failed to describe the specific steps that you are taking to ensure adequate oversight by the quality unit over critical aseptic operations such as unidirectional airflow pattern studies. 

b) The unidirectional airflow studies performed for the vial filling line are inadequate in that the studies do not show unidirectional airflow. 

These unidirectional airflow studies showed turbulent airflow in the following areas: above the (b)(4) just prior to entry into the filling (b)(4), over the stopper (b)(4) adjacent to the filling (b)(4), and over the (b)(4) tray filled with partially-stoppered vials during the automatic loading of vials into the (b)(4).  We are concerned that your quality unit failed to identify these instances of turbulent airflow. 

Although you state in your response that (b)(4) will perform complete smoke pattern studies for the ampoule filling line and the vial filling line, you have not proposed the implementation of additional actions or controls needed while you complete smoke studies and demonstrate that these areas are suitable for aseptic manufacturing of sterile drug products.  In addition, you failed to provide your risk assessment for all sterile products within expiry that were manufactured under these unacceptable conditions.

c) HEPA air velocity is not evaluated proximal to the working level. 

SOP ECPI-021: Calibration Procedure for unidirectional Airflow Unit and Bench is deficient in that it only requires HEPA air velocity checks to be performed (b)(4) inches below the filter face, but does not require that the air velocity be evaluated proximal to the working level. 

Your response is inadequate because your corrective action for your failure to evaluate air velocity proximal to the working level consisted of providing a revised procedure and training, but you have not yet evaluated the current air velocity at the working level.

d) Your firm demonstrated poor aseptic technique in gowning and production during the manufacture of (b)(4) Injection Lot (b)(4) on Sept 28, 2011.

During gowning and production operations, investigators observed poor aseptic practices, including, but not limited to, excessive touching of the outside of hood and gown during gowning, exposing aseptic processing equipment and equipment parts in the Class 1000 area prior to introduction into the Class 100 area, disrupting airflow with hands and forearms over the stopper bowl while transferring (b)(4) stoppers, and excessive and repeated touching of parts of the filling machine and (b)(4) barriers. 

Your response references corrective actions through training employees, equipment purchase, and procedural improvements.  However, your response fails to specifically address the observed deficiencies in aseptic operations and the impact to the sterility of (b)(4) Injection Lot (b)(4) and other products.

e) The revalidation of the (b)(4) sterilization cycles for machine parts is deficient in that the exact placements of the biological indicators (BIs) and (b)(4) are not documented and consequently can not be confirmed as the worst case locations. 

Your response indicates that BI locations are now identified in SOP QAS 296 and that retraining has occurred.  However, SOP QAS 296, provided in your response, indicates that BIs are not attached with the (b)(4) in several locations including, but not limited to, (b)(4) of the (b)(4), within the (b)(4) attached to the (b)(4), and (b)(4) through the (b)(4) with (b)(4) and (b)(4).  Your response is inadequate because it fails to include your rationale for not routinely placing BIs next to the (b)(4) in the areas you have designated as most difficult to sterilize. 

[Gulf Pharmaceutical Industries, Date Issued: February 23, 2012]


Part II: FDA Inspectional Observations

Part 211 Subpart B – Organization and Personnel, Sec 211.22 Responsibilities of quality control unit

The Quality control unit lacks authority to review production records to assure that no errors have occurred and fully investigate errors that have occurred

Specifically,

The Quality Control Unit failed to adequately review Ketoprofen Validation Protocol and Report No.002PV005 and, as a result, it released and distributed between March and July 2005 six batches of Ketoprofen ER capsules (lot#’s: 520E017, 520F0368,520E018,F520F0840,F520F1030, and F520F1031) that were manufactured with a process that showed significant variability and was not adequately validated.

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006]


The Responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Specifically:

a. Recognizing that an Out-of-Specification Test Result was obtained in [REDACTION] specification of [REDACTION] as per requirement of your Quality Control/Quality Assurance Standard Operating Procedure for OOS Investigation, SOP Number 2802, Reporting, Investigation and Disposition of Out of Specification (OOS) Laboratory Results, effective 02/05/09 and previous revisions, it appears that you avoided to perform an Investigation for the assay test result of [REDACTION]. In addition, you failed to perform a complete assessment for the failure of the microbiology laboratory autoclave qualification that took place in February 2009. These incidents were never informed to the respective head of departments (QA/QC) which are not stationed here at your Gloversville, NY facility.

b. Procedures are not established which are designed to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of, are notified in writing of investigations conducted or any unexplained discrepancy.

The QC Director and QA Associate Director which are stationed in a different State, as well as your Plant Manager and QA Supervisor were not notified of the failure of the Microbiology Autoclave Validation as well as the [REDACTION] OOS test result that was treated as an out-of-trend results (OOT), among others. According to your statements, they were not informed of the events, therefore, no assessment was ever performed to determine the magnitude, impact and significance of such failures.

On 08/06/09, the Vice-President QA and QC [REDACTION] stated that the information of the delay stability samples with the difference (in days) from pull out to testing were not informed by the local employees to upper management.

[Ohm Laboratories, Inc., Date Issued: 08/12/2009]


The quality control unit lacks responsibility to approve and reject all procedures or specifications impacting on the identity, strength, quality, and purity of drug products.

Specifically, 

a. The ANDA submits for the “Validation of Aseptic Operations (Sterile Media Fills) are performed “To minimize the bioburden levels during the manufacturing process, strict aseptic manufacturing procedures are followed.” “Aseptic media fill runs are performed in order to confirm the established aseptic manufacturing procedures used by the company.” “Process simulation runs (media fill runs) are performed[REDACTION] at a minimum) to requalify the total aseptic manufacturing operations for the filling process” to support of the Sterility Assurance Validation” for the “Validation of Aseptic Fill and Terminal Sterilization Processes for Small Volume Parenteral Products”. However, the company has not performed media fills since the original 1998 ANDA submission. 

b. The company has not submitted, for example a Post Approval Change or a Change Being[REDACTION] for the ANDA that addresses the cessation of aseptic media fills and/or provides the scientific rationale with respect to the cessation and impact on the “Sterility Assurance Validation” for the finished product. 

c. The company has not submitted, for example, a Post Approval Change or a Change Being [REDACTION] for the ANDA regarding the use of a BI challenge for the[REDACTION] steam sterilization process with less than a [REDACTION] spore population.

[Teva Parenteral Medicines Inc., Date Issued: 07/24/2009]


Quality assurance reviewed and approved a final validation report for the use of Bagged Serum Stoppers in Liquid Fill Finish Processes in the Fill/Finish Area at Allston Landing, study [REDACTION] which did not meet the protocol requirements.

[Genzyme Corporation, Date Issued: 10/10/2008] 


The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. 

Specifically, 

1. The written procedure, AA204 Media Fill Process Simulation, does not adequately describe the instructions for the aborting and invalidating of media fill batches. For example,

a. Media Fill Batch [REDACTION] Code 7002, 100mL vials, performed in filling area AH and lyophilisation in room AJ on 7-28-08 when it was invalidated after growth promotion acceptance criteria were not met. The instructions in the written procedure do not describe when a media fill batch is invalidated.

b. Media Fill Batch [REDACTION] Code 7002, 100mL vials, performed in filling Area AH and lyophilisation in room AJ on 9/30/08 when it was aborted because of a malfunction of the surge vessel. The instructions in the written procedure do not describe when a media fill batch is aborted.

2. There is no written procedure that describes the storage conditions and storage location of integral rejects (intervention rejects) after the media fill is completed at one facility before they are transferred to another facility for incubation. For example,

a. Media Fill Batch [REDACTION] for Code 7002, 100mL vials, performed in filling Area AH and lyphilization in room AJ on 1/23-24/08 had 75 integral rejects (intervention integral rejects).The integral rejects were accidently disposed of by a production employee along with non-integral rejects while awaiting transfer to the incubator at another facility.

3. There is no written procedure that describes for the requirement for Quality Assurance to approve handwritten changes (pen amendment changes) to the batch records by production personnel before they are done. For example a production employee was allowed to cross out the non-braided tubing, part number [REDACTION] listed in the media fill batch record and to make handwritten changes using a pen for the purpose of using a similar tubing, part number ASTP-16F, without Quality Assurance approval at the time it was actually used in the media fills Pen amendment changes were made to the the Media Fill Batches 61268, 61278, 61188, 61178, 61378, and 61058.

4. The written procedure, “Batch Record Review: Product Release/Closeout & Media Review/Closeout”, No. QA101, does not adequately describe the instructions for the aborting manufacturing batches. For example, 

a. Lot 21039, Product Code 5010, 100mg/mL, 5mL vials, performed in filling area K on 04/27/2009 was aborted. The batch record does not include any information for aborting the lot. NO investigation was included with the bath record.

b. Lot 91208, Product Code 5010, 100mg/mL 5mL, vials, performed in filling area K on 09/09/2008. The batch record does not include a thorough investigation detailing abortion of the lot.

[Akorn, Inc., Date Issued: 06/30/2009] 


The responsibilities and procedures applicable to the quality control unit are not fully followed.

Your Quality system is deficient and lacks an overall oversight of drug products manufactured at your site to ensure they have validated processes before release for commercial distribution. Specifically, your Quality approved and released products that were compressed on [REDACTION] tablet press but only validated on [REDACTION] tablet press during process validation. A few examples of products compressed on [REDACTION] but only validated on [REDACTION] tablet presses are:  Benazapril 5mg  Benazapril 10mg, Labetalol 200mg, Labetalol 300mg, Lovastatin 20mg, and Methimazole 10mg.

[Sandoz Inc., Date Issued: 06/22/2011]


The “Quality Manual”, document #030-SOP-OP-01340, dated 28 Feb 2011, “describes the pharmaceutical quality system (PQS) as implemented at BVL. The Quality Manual identifies the elements of the PQS and the sequences, linkages, and interdependencies of related processes, and the responsibilities of Management to ensure effective implementation.”The “Quality Manual includes the principles and responsibilities for implementation of BVL’s PQS and pertains to all BVL departments involved in performing and/or supporting the development, manufacturing, testing, holding, distribution, and marketing of pharmaceutical products.” However, the following observations document a lack of adequate oversight by the Quality Unit to approve or reject the products manufactured and processed, as well as, approve or reject the established procedures and/or specifications impacting the quality of the drug product.

a. The Quality Unit is not following the established procedures in that senior management is not notified within [REDACTION] hours of [REDACTION] initiated with an initial assessment of critical per procedure. For example, [REDACTION] 115576 (failing vial washer re-qualification),discovered on 3/17/11, was opened on 4/14/11 with an initial critical designation and senior management was not notified. On 4/18/11, this [REDACTION] was downgraded from critical to major with no evidence to show management was notified. Furthermore, there is no documented justification to show why this[REDACTION] was downgraded. 

b. The Quality Unit is not initiating investigations and documentation of those investigations in a timely manner. For example [REDACTION] 115576 was discovered on 3/17/11 (failing vial washer re-qualification) and the [REDACTION] was not opened until 4/14/11.

c. Routine preventative maintenance activities are not performed at their scheduled intervals. As of 11/11/11, there were approximately 107 required preventative maintenance activities for GMP equipment past their scheduled due date. To be considered past due, the event must be greater than [REDACTION] days past due date. There is no evidence to show the Quality Unit took action on these overdue preventative maintenance issues concerning equipment qualifications and validations of the respective processes.

[Ben Venue Laboratories, Inc., Date Issued: 12/02/2011]


The Validation group lacks appropriate oversight and technical expertise to perform their duties. Specifically:

a. The validation group failed to perform periodic reviews and] [REDACTION] qualifications as required by their Validation Controlled Lists. Regulatory Deviation report [REDACTION] 11827, details 10 pieces of GMP equipment that were not qualified within the required time frames.

b. The report for the [REDACTION] qualified of vial washer VIAL [REDACTION] located in the Phase IV facility that was performed on 5/23/10, was not reviewed by the validation staff or other quality unit personnel. The report was misplaced and the firm did not discover the error until3/17/2011 during the preparation of the next [REDACTION] qualification. The incident is detailed in [REDACTION] 114632. Furthermore, the [REDACTION] qualification of vial washer VIAL [REDACTION] conducted on 5/23/10 did not meet acceptance criteria for the particulate challenge test for the [REDACTION] Vail size and continued to be used in manufacturing operations.

c. The investigation [REDACTION] (115576) into the misplaced report [REDACTION] (114632) concluded that human error was the root cause, however, the investigation failed to examine other possible causes such as the lack of an oversight system to alert the validation group that equipment qualifications were past due.

d. There is no scientific rationale for event driven re-qualifications to various pieces of equipment such as, Portable Laminar Flow (HEPA) carts, clean steam system, distillation system, vial filler, and headspace analyzers. This equipment is only re-qualified on this event driven basis, whereby the system must undergo a change or atypical even before the need to re-qualify assessed. Furthermore, the required periodic review to assess the need for re-qualification for the Phase IV clean steam system, Phase IV and South vial filler, various distillation systems, and the portable headspace analyzer units is either past due by approximately 1 year or has not been performed.

e. Although the quality unit discovered the missing [REDACTION] qualification report for VIAL ([REDACTION] on 3/17/2011 the investigation [REDACTION] 115576) into the incident was not opened until 4/14/2011.

f. The quality unit failed to follow procedure 030-SOP-Q-10 which requires immediately reporting “Critical” findings to the Vice President of Quality Operations and the Vice President of Operations. [REDACTION] 115576 was opened as a critical deviation on 4/14/11 and downgraded to “Major” on 4/18/11/without the approval or knowledge of senior management. During this current FDA inspection, the Vice President of Quality Operations and the Vice President of Operations when asked of this event, replied they did not know about this and were just informed of this issue. Furthermore, the firm did not provide any justification for the downgrade.

g. Personnel did not follow company procedures (030-SOP-P-11) requiring employees to “tag out” equipment during [REDACTION] qualification. Vial washer VIAL [REDACTION] was not tagged out during [REDACTION] qualification. The tag out procedure is a visual notification to production employees that a piece of equipment is out-of-service until returned to service by the quality unit.

h. There is no oversight ensuring validation group employees complete required training. For example, one validation manager is overdue for process validation safety training by more than 168 days.

i. There is no scientific rationale for the location for the placement of the thermocouples used to monitor incubator rooms WH[REDACTION] WH[REDACTION] and WIP[REDACTION] Room [REDACTION] used to incubate media fills in that the thermocouples are not placed in the appropriate locations to detect the maximum and minimum temperatures as determined by the respective qualifications. The locations were determined by taking the lowest and highest temperature registered during qualification and not the locations registering the overall lowest and highest temperatures. Rooms WH [REDACTION] (ft3), WH[REDACTION] (ft3), and WIP [REDACTION] (ft3) were used to incubate the media fill vials for qualifications performed in 2010 and 2011.

Furthermore, for WI [REDACTION] the monitoring thermocouple TC B601 could not be located during this inspection. Upon investigation by the firm, this monitoring thermocouple, that is actively monitoring the room, was determined to be located behind a wall and not within the incubator room, This was not discovered until brought to the firm’s attention during this inspection. This monitoring location corresponds to a location that registered approximately 15 minimum temperature data points during the most recent qualification dated 11/2008.

[Ben Venue Laboratories, Inc., Dated Issued: 12/02/2011] 

The responsibilities and procedures applicable to the quality control unit are not fully followed.

QA and Compliance Department overall responsibilities per the firm’s [REDACTION] is deficient as follows: it does not maintain adequate laboratory facilities for the testing and approval (or rejection) of components and drug products; in neglects review and approval of validation protocols regarding changes in product processes and equipment to determine when revalidation is or should be warranted; it is default in investigations, tracking, trending and maintenance of consumer complaint follow-up; and it lacks trending of products, components (i.e., water), and complaints to demonstrate a broad perspective to assure plant conformance with CGMPs.

[McNeil Consumer Healthcare, Div of McNeil-PPC, Inc., Date Issued: 04/30/2010] 


Part 211 Subpart J – Records and Reports, Sec 211.192 Production record review 

There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been thoroughly distributed. 

Specifically, your firm failed to perform adequate investigations with scientifically justifiable conclusions to incidents of out-of-specification results or production deviations and/or failed to implement appropriate corrective actions for the root cause determination. The deficiencies are evidenced in the following:

Phase II Investigations related to Equipment Cleaning:

a. SOP QC-0135, “Evaluation of Extraneous Peaks During the Analysis of Cleaning Validation Swab Samples”, establishes the criteria to determine when an unknown peak in a cleaning swab should be investigated. According to the SOP, if any individual unknown peak is not more than [REDACTION] of the target analyte peak or if the sum of the unknown peaks per swab location is not more than [REDACTION] of the maximum allowable residue limit of the target analyte, no further action is required. A Technical Services Supervisor said that their rationale for the limits stated in their SOP is based on a consultant’s article. The article indicates that “it might be appropriate to allow an unknown peak provided it is no more than 5-10% of the height or area of the target residue (the active, for example) at it residue limit” and that “Some companies will then have an additional stipulation that the sum of all peak heights or areas of unknown peaks be no more than 20-40% of the height or area of the target residue at its limit.” However, the article also states that “In this case, it is expected that an investigation has been done to identify the unknown peak, and that it still remains unknown.” The article also indicates that the amount of the unknown peak cannot be accurately determined unless a detector such a [REDACTION] is used because the relative absorbance is not known.  

SOP QC-0135 allows unknown peaks at percentages even higher than the ones recommended by the Consultant on a routine basis without first making a reasonable attempt at identifying the extraneous peaks. The firm manufactures a wide variety of products with different toxicities and allowable residue levels, and even uses the same equipment used for commercial manufacture to manufacture products that are still under development. Applying the limits stated in SOP QC-0135 without first investigating the source of the unknown could result in allowing higher levels of residue than would normally be allowed had the identity of the extraneous peak been known. In addition, since the absorptivity of the unknown peak is not known and the actual amount of residue cannot be determined with the detectors used by the firm, the actual amount of residue could be even higher than the amount estimated by using the target analyte peak.

b. At least 24 cleaning swab samples containing extraneous peaks above the limits specified in SOP QC-0135 were reported for ten different pieces of equipment from May of 2005 through February of 2006. The inspection disclosed the following deficiencies regarding the investigations conducted for these unknown peaks:

1. TWRs 1374, 1580, 1591, 1594, 1744, 1868, 1895, 1896, and 1964 are all related to unknown peaks in swab samples and were investigated under TWR 1555. The 2006; however, the QCU failed to adequately monitor the implementation of this corrective action and, as a result, the valves were not installed and the use of these dissolution baths with potentially malfunctioning valves continued for dissolution testing of all Cartia, Diltia, Taztia, Metformin, Naproxen Sodium, and Ketoprofen drug products.

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006]  


Written records of investigations into unexplained discrepancies do not include the conclusions and follow-up.

Specifically,

The cleaning swab failure investigations reported under TWRs 1545, 1555, 2194, 2259 disclosed that the root cause was the failure to thoroughly rinse or clean equipment or that the cleaning procedures were not specific enough. The QC Unit failed to follow up on these findings and none of the SOPs involved in these investigations have been revised to make the rinsing and/or cleaning instructions more specific.

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006]


Records are not kept for maintenance and inspection of equipment.

Specifically, the firm failed to document the placement of metal spacers in the [REDACTION] CIP assembly unit and the replacement of the diaphragm in the [REDACTION] line for the [REDACTION] machine during the production run of the stability batch prior to the production of batch [REDACTION] for the Acetaminophen Injection, 10mg/ml solution. Per equipment manufacturer’s recommendations, metal spacers were inserted into the [REDACTION] CIP assembly unit to increase the service life of the diaphragm. Subsequently, during the production of batch [REDACTION] the operator noted water in the [REDACTION] line post final filler prior to the [REDACTION] machine. This batch was disposed of and the metal spacers were then removed from the [REDACTION] CIP assembly unit. All batches prior to [REDACTION] were processed without spacers. [REDACTION] was processed with spacers, and [REDACTION] was processed without spacers. The firm failed to requalify this equipment for these modifications.

During the production of batch # [REDACTION] a CIP water leak was noted which had seeped into the electrical control panel via the electrical conduit from the [REDACTION] CIP assembly unit. The firm has no documentation of the effect upon equipment operation of this water leak into the electrical control panel or how long this water seepage had occurred.

[Baxter Healthcare Corporation, Date Issued: 02/05/2010]


According to the “Qualification of PTS Cartridges/Analysts and Validation of Samples using the [REDACTION] Test System”, validation document #QC-051-40, effective 04/25/08,establishes the [REDACTION] acceptance criteria for running this assay is between [REDACTION] The December 4th and 8th,2008 [REDACTION] samples fell outside of the [REDACTION] and [REDACTION] respectively. Despite [REDACTION] acceptance criteria established in the validation document, the tests were still approved. 

[Genzyme Corporation, Date Issued: 11/13/2009]


Corrective action has not been implemented for the previous FDA 483 observation regarding the failed Systems cleaning validation study CVR/0016/00 dated August 16 2000. For example,  

a. The firm’s response to the previous FDA 483 stated the evaluation of the study concluded there was no impact on Fluvirin. From March 2001 through 2002 at least 30 [REDACTION] Monovalent Blend Pool lots failed biobuden testing.

b. Validation protocol for the executed study CVP/001/03 dated April 7, 2003, changing the sanitizing agent to [REDACTION] did not include bioburden reduction by assessing microbial load prior to use or storage between uses.

c. Design and operation of the [REDACTION] filtration unit located in the Formulation area allows operator error to potentially reverse the flow of product under filtration. The [REDACTION] has a piece of masking tape over flow direction dial on which is written “Do Not Use”. Use of the flow director would reverse the flow of product. The dial is located next another dial that requires regular use of pressure regulation.

[Evans Vaccines, Date Issued: 6/10/03] 


Not all deviations from normal production are documented and explained in the MI or other documents. For example, 

It was noted that pancreatin batch 1206-1495, load #2, was loaded into dryer [REDACTION] as observed on 1 DEC 2009, with [REDACTION] trays partially filled and extending off of the shelves by 5” – 6”. It was stated by management that this has reportedly occurred on several occasions in the past. The amount loaded was [REDACTION] kg per MI. The most recent validation for this dryer shows the maximum load (by weight) is [REDACTION] kg. Current version of SOP 17-0005 still shows the former amount, [REDACTION] kg, is allowed, yet as shown in this instance, [REDACTION] kg would not fit normally into the dryer. No deviation or discrepancy was written into the MI.

[Scientific Protein Laboratories, LLC., Date Issued: 15 December 2009]


Deviations from written production and process control procedures are not justified

Fryma cleaning procedure as documented in the protocol SAN [REDACTION] ,for validation of the [REDACTION]  cleaning agent, included hand written changes to the directions for batch [REDACTION] dated 11/8-9/06 and Batch [REDACTION] dated 11/20/06 without justification for these changes or documented evidence that these changes were included in the ongoing validation of the cleaning procedure.

[L. Perrigo Company., Date Issued: 12/15/2006] 

Deviations from written production and process control procedures are not justified. 

Your Process Simulation Policy, Document Number: 10-01-03-0108 requires that all integral rejects vials must be documented, segregated and incubated. Media fills simulation for parenteral (sterile drug products) filling operations were inadequately performed to qualify aseptic processes. On 06/20/11, it was observed during the second media fill batch (lot 7025353) of a campaign of [REDACTION] integral vials been removed after the capping operation and placed them in a 5 gallon white pail labeled in part: “TO BE DESTROYED” and no documentation was performed as to the specific reasons (assignable cause) why integral filled vials were removed. The removal and destruction of filled vials (integral units) may present a bias to the final media fill results. These media fill runs were executed after the discovery of numerous vials with particulate matter on previous Media Fill Batch 7025073 

[APP Pharmaceuticals, LLC., Date Issued: 07/08/2011]


Following a number of failing “Clean hold validation Studies” for multiple equipments based on bioburden/endotoxin results which did not meet acceptance criteria and which were concluded to be related to the WFI supply to those specific equipments:

  • The firm failed to conduct a comprehensive investigation of the WFI system in building [REDACTION] to determine the root cause/source.
  • The firm enlisted the services of contract firm to conduct a sanitization and passivation of the system, however, there was no comprehensive investigation to examine system design, work order histories and other system related information which may have identified contributing factors(s)/underlying cause of the WFI related failures.

[Regeneron Pharmaceuticals, Inc., Date Issued: 31 March 2010]


There is a failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. 

Specifically,

The firm failed to investigate out of specification (OOS) laboratory results as per SOP QCP 05.002, “Laboratory Investigations Procedure”. Additionally, laboratory investigations have lacked scientific justification to support the dismissal of OOS/OOT results and conclusions of the investigations.

1. The firm failed to adequately investigate in process OOS pH results for Quelicin Injection, USP, Lot 02-284-EV during the mixing revalidation (VCR 10091).An unapproved laboratory investigation form (WCQLIR) was used to investigate the results. This form was an attachment to SOP B6120 0200, “Procedures for In-Product Testing” effective 12/8/08.The procedure was revised on 10/12/09 to remove the WCQLIR form and stated that all in process OOS results are to be investigated per SOP QCP 05.002, “Laboratory Investigations Procedure”. 

However, form WCQLIR continued to be utilized for not only in-process testing but also finished product testing in the Quality Control laboratory to invalidate data without a formal laboratory investigation. Also, on 3/31/11, a new corporate SOP was implemented (SOP QCO.01.006, “Laboratory Data Handling Practices Procedure”) which allows invalidation of data if objective evidence shows that the test method was not followed, system suitability requirements were not met, instrument failure occurred after starting the analysis, a dilution/mixing/ pipetting error occurred, error occurred, or other errors as described in the “Example Data Invalidation Form “attached to this procedure. The SOP also states” Scientific due diligence to support that data are invalid must be documented on a data invalidation form (an example is provided in Attachment A). There must be a clear scientific justification of why a Laboratory Investigation Report (LIR) is not required and the rationale must be approved by the lab management, prior to invalidating the data set.” This procedure is in direct conflict with the requirements of Corporate SOP QCP.05.002, “Laboratory investigations Procedure” which states that only pre-run/post-run system suitability failures or miscalculations do not initially require a laboratory investigation. There were approximately 250 invalidation events (not related to system suitability failures) in the Analytical Services Laboratory from January 2009 to present. There have been over a thousand invalidation events (not related to system suitability failures) in the QC Laboratory from January 2009 to present. These have been categorized as analyst error. Instrument failure, poor chromatography, method related, and other. Examples include the following: standard preparation error, sample, preparation error, instrument stopped during analysis, inadequate cleaning of equipment, extraneous peaks in chromatograms, retention time shifts during HPLC analysis, interfering peaks, possible mobile phase contamination, poor peak separation, poor integration, titration stopped before end point reached, and unknown peaks in IR spectra.

[Hospira, Inc., Date Issued: 08/04/2011] 


Part 211 Subpart I – Laboratory Controls, Sec 211.165 Testing and release for distribution

The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented. Specifically, your firm failed to perform an adequate method validation for Taztia XT Capsules. The current approved analytical procedure for the analysis of [REDACTION] for drug release (STM 696, 697, 698, 699,700) requires the use of [REDACTION] as the dissolution media. The method validation for this product was performed using [REDACTION] as the dissolution media.

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006]


The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented.

Specifically,

a. The microbiological testing of drug products is deficient:

1. The method for microbiological testing of drug products including the antiseptic Techni-care (#CCQC38.1) has not been adequately validated in that:

The preparatory test for absence of inhibitory (antimicrobial) properties in the drug products has not been performed.

There has been no comparison of the in-house method with the Microbial Limits Test specified in the USP. The USP method requires a preparatory test, the use of a pour plate and specifies a sample size of 10ml. The in-house method requires the [REDACTION] 

2. [REDACTION] Neutralizing agar plates and [REDACTION] plates which are purchased from an outside source and used to test drug products for microbiological quality, are not growth promoted to ensure they will support growth. 

3. Positive and negative controls are not used during microbial testing of drug products.

4. The microbiological agar plates are not incubated at the appropriate temperature and time for yeast and fungi [REDACTION] . Additionally, there is no evidence to show the current method will detect yeast and fungi if samples are only incubated for [REDACTION]. The manufactures certificate of performance for the [REDACATION].

Neutralizer Agar instructs. [REDACATION] 

b. The assay method CCQC35.1 “QC Method for HPLC Analysis of liquid, Gel, and Crème Care-Tech Products Containing Chloroxylenol, USP (PCMX) (Cont’d) is deficient in the method does not describe the necessity (according to management) to heat, mix and cool the sample prior to analysis.

c. The firm has not evaluated the equivalency of the HPLC to the GC which is required for analysis in the monograph for the Techni-care surgical scrub active ingredient Chloroxylenol (PCMX)

[Care-Tech Labs Inc., Date Issued: 05/22/2008]


The suitability of all testing methods is not verified under actual conditions of use.

Specifically, your analytical method for Related Substances of Metformin HCI Solution that was initiated at your NY Gloversville site, but was completed in New Jersey and submitted to the agency

a. The Validation Protocol MVP002/03 and/or method did not specify the spike level of the known impurities needed to perform the impurity test and impurity mix standard.
 
b. The gradient system used in this HPLC system is neither documented in the notebook nor in the chromatograms.
 
c. The System Suitability solution chromatogram show signs of a shoulder in the [REDACTION]. The firm failed to investigative such to determine if it was a degradation of the solution or a co-eluting peak.
 
d. The laboratory notebook does not reference where the test took place.
 
e. The HPLC configuration tubing, at the time of method validation may not be similar to actual ones used possibly affecting the resolution,. In addition, the Chromatographic Parameters of Validation Protocol No:MPV001/003 states that the column oven temperature was ambient. This analytical method was never transferred to your Gloversville, NY site.

[Ohm Laboratories, Inc., Date Issued: 08/12/2009]


Verification of the suitability of the testing methods is deficient in that they are not performed under actual conditions of use. 

Specifically:

a. The competence of the receiving laboratory to use validated methods was not demonstrated through the test. For example; running samples in parallel between the transferring and receiving laboratories, the rational of the test, knowledge of critical parameters, the accuracy and precision of system suitability, and samples and standard preparation. Additionally, the SOP #10-08-00-0001 Transfer of ‘Analytical Methods’ was not followed during method verification. The precision of the method was not performed by the Transfer Site Analyst, instead was done by the originating site analyst. Process knowledge depends on accurate and precise measuring techniques uses to test and examine the quality of drug components, in-process materials, and finished products. For instance:

  • Test Method TM 10-08—3-6398 Determination of Impurities in Gemcitabine HCL in Gemcitabine HCL, USP and Gemcitabine for Injection, USP
  • Test Method TM 10-08-6389 Determination and Identification of Gemcitabine HCL in Gemcitabine HCL, USP and Gemcitabine in Gemcitabine for injection, USP
  • Test Method TM 10-08-03-6463 Determination of Assay and Impourities in Levetiracetam Injection by HPLC
  • Test Method TM 10-08-01-6400 Determination of Residual [REDACTION] in Levetiracetam raw Material by[REDACTION] 
  • Test Method TM 10—8—01-6391Assay [REDACTION] Purity and Identification of Levetiracetam in Leveriracetam Raw Material.

b. During method transfer or verification performed at APP Pharmaceuticals, LLC Grand Island, NY between November 2009 and January 2011, API samples have been tested concurrently with the technology transfer samples. Additionally. SOP 10-08-00—0001 ‘Transfer of Analytical Methods’ V.4 and V.3 effective during the aforementioned time period does not address the requirements of completing the appropriate transfer or verification and approval of the methods prior to testing of API samples. 

[APP Pharmaceuticals, LLC., Date Issued: 07/08/2011] 


The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented.

a. As the method “HPLC Analysis- Phenylephrine HCI Content for Gel, Suppositories, Ointment #WI-LAB-0117 effective 5/28/08 is currently being run, it has not been validated.

b. The medthod HPLC Analysis-Phenylepphrine HCI and Pramoxine HCI Content #WI-LAB-0120 effective 6/15/07 has not been validated.

[H & P Industries, Inc., Date Issued: 07/17/2009]


The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented.

Specifically,

Method validation and performance qualification for the [REDACTION] to test the sterility of sterile injectable drug products manufactured is inadequate for the following reasons:

  1. Your firm did not adequately execute a side by side comparison of this method with compendia sterility method as required in your validation. There is no justification for comparing the [REDACTION] results with a [REDACTION] when the current USP method requires a 14 day incubation.
  2. The population for the challenge microorganisms used in validation w as never evaluated.
  3. The method was validated by [REDACTION] of the challenge microorganisms. Furthermore, there is no data to support that the lowest level of detection was challenged during validation.
  4. There is no adequate data to support the reproducibility of the [REDACTION] method. Specifically, on numerous occasions the firm performed multiple [REDACTION] of the same sample 

[Ameridose, LLC., Date Issued: 11/09/2012]


Part 211 Subpart I – Laboratory Controls, Sec 211.160 General requirements

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release.

Specifically, 

a. The [REDACTION] is the [REDACTION] used to perform sterility test on aseptically filled finished products. Review of the last performance qualification entitled “2011 Periodic Performance Qualification (PPQ)< Biological Quality Laboratory [REDACTION] revealed the following deficiencies:

1. The study does not include a documented rationale for the placement of [REDACTION] within the [REDACTION] Additionally, there were no air distribution studies performed to demonstrate adequate distribution of [REDACTION] throughout the [REDACTION] and visualize the hardest to reach areas within the [REDACTION]

2. Performance qualifications for the unit are performed every [REDACTION] years. The rationale for this timeframe is not documented. Aside from normal preventative maintenance performed by the BQ technicians, no periodic review is performed between qualifications. Validation stated that as a part of the periodic review which is currently on schedule for approximately every [REDACTION] year, they look back at the environmental trending data in a report provided by the BQ laboratory. However, the report that is provided by the BQ laboratory is not negative trends may not be revealed during the periodic review. 

b. SOP6131_0013 “Procedures for Testing Positive Isolates Found in Sterile Products, Effective: 11/21/2005” describes procedures that may result in a false negative being reported during a sterility test positive investigation by instructing the following:

1. The subculture incubation period is only [REDACTION] This could preclude the proliferation of slower growing organisms. 

2. The subculture procedure for [REDACTION] only requires anaerobic incubation. [REDACTION] also supports the growth of organisms with reduced oxygen requirements that may be excluded if aerobic incubation is not performed as well.

[Hospira, Inc., Date Issued: 03/01/2013]


Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans designed to assure that components conform to appropriate standards of identity, strength, quality and purity. 

Specifically [REDACTION] water samples are not representative of the manufacturing process in that they are collected using [REDACTION]

[H&P Industries, Inc., Date Issued: 03/28/2011]


Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that components and drug products conform to appropriate standards of identity, Strength, quality and purity. 

a. The method validation titled “Validation of Microbiological Testing” #VAL-R-0011 dated 12/23/09 for the microbiological testing of all products and Deionized, Water, used in production and cleaning, was not completed adequately in that the following were not determined: Precision, Specificity, and Linearity/Accuracy. In addition, the failure of the system suitability was not investigated and only a few of the many products tested were used in the method validation.

b. Method transfers were not completed on the following test methods prior to using them to release oral adult and children’s drug products. In addition, there is no documentation to support that these methods, which are used for stability testing, are stability indicating.

Document# Title Effective Date

WI-LAB-0188 REDACTION 05/19/10

WI-LAB-0189 REDACTION 08/06/10

WI-LAB-0190 REDACTION 06/11/10

WI-LAB-0192 REDACTION 08/07/10

WI-LAB-0194 REDACTION 07/29/10

WI-LAB-0195 REDACTION 08/07/10

WI-LAB-0197 REDACTION 05/22/10

WI-LAB-0204 REDACTION 09/03/10

WI-LAB-0205 REDACTION 10/11/10

[H & P Industries, Inc., Date Issued: 01/07/2011]


Laboratory records do not include complete data derived from all test, examinations and assay necessary to assure compliance with established specifications and standards.

Specifically, no raw data could be provided to support the cleaning Validation Report for the Glycerin Suppository Press dated 12/29/09

[H & P Industries, Inc., Date Issued: 05/18/2010]


Laboratory controls do not include the establishment of scientifically sound and appropriate standards and test procedures designed to assure that in-process materials and drug products conform to appropriate standards of identity, strength, quality and purity.

Akorn Inc. failed to validate each individual media lot of Tryptic Soy Agar (TSA) rodac plates used to challenge the performance growth promotion of positive control standards used identify Clostridium (C.) sporogenes, a pathogenic anaerobic organism reportedly associated in gangrenous infections. It has been identified since approximately 11/2003 to approximately 06/2008 the microbiology department did not utilize the appropriate media for environmental monitoring. TSA with lecithin and polysorbate 80 rodac plates vendor [REDACTION] did not support C. Sporogenes growth. It was noted that vendor’s Certificate of Analysis of rodac plates did not include C. Sporogenes. The rodac plates are used to monitor anaerobes in Level I  environments of areas C,K,P,AH,&AJ. As a result, of the media used which did not support the growth of C. Sporogenes, Akorn cannot assure that monitoring of areas utilized for manufacturing of sterile drug products do not include contamination of Clostridium sporogenes. 

a. For Year 2008 Akorn purchased and used for environmental monitoring approximately [REDACTION] lots of TSA, which did not support growth of C. Sporogenes; Year 2007 Akorn approximately [REDACTION] lots of TSA; Year 2006 approximately [REDACTION] lots of TSA; Year 2005 approximately[REDACTION] lots of TSA; Year 2004 approximately [REDACTION] lots of TSA; Year 2003 approximately [REDACTION] lots of TSA. In total Akorn purchased and used approximately [REDACTION] lots which did not support growth of C. Sporogenes.

[Akorn, Inc., Date Issued: 06/30/2009]


Laboratory records do not include complete data derived from all test, examinations and assay necessary to assure compliance with established specifications and standards. 

Specifically,

a. Your firm submitted to the FDA theoretical weight values for Metformin spike recovery instead of actual values. Specifically, the Metformin method validation, on section 5.6 of “Analytical method validation Report # MVR00093v2, Table 13 titled” Assay Accuracy/Recovery solution preparations” the theoretical weight values for the [REDACTION] level were reported as [REDACTION] However, the actual weight values are 56.9, 56.4, 56.7, 116.0, 116.2, 119.1, 231.1, 229.8, 230.1mg according to Book 4681 page 053. These actual weight values were not reported as part of the method validation for this product. Also method validations do not include carryover analysis to preclude unknown impurities co-elution interferences.

[Sandoz Inc., Date Issued: 06/22/2011] 


Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. 

Specifically,

a. The firm has failed to conduct method transfers for the following:

  • Fentanyl Citrate Injection, USP-Assay and Impurities by HPLC (Method 90.C-2209 in use since 8/20/08).
  • Quelicin (Succinylcholine Chloride) Injection, USP–Assay and Identification by HPLC (Method 90.C-0915 in use since 8/20/81)
  • Ketorolac Tromethamine Injection, USP-Assay and Identificaftion by HPLC (Method 90.C-1603 in use since 2/22/95)
  • Dopamine HCI Injection, USP- In process Assay by UV (Method 90.C-0739 in use since 01/11/78) 

b. Corporate SOP QVO.19.012, “Chemical Tedst methods Validation Procedure” does not require that method verifications are done at the laboratory site where the method will be utilized The firm has failed to conduct method verifications at this site for the following:

  • Atropine Sulfate Injection, USP-Assay by HPLC (Method 90.C-0850 in use since 3/30/80)
  • Dopamine HCI Injection, USP-Assay and Identification by HPLC (Method 90.C-895 in use since 12/2/80)

c. The current corporate SOP QVO.19.014, “Test Method Transfer Procedure” effective on 06/05/09 states that formal method transfer studies are not required in the following instances:

  • When test procedures employing the techniques are already in use by the receiving laboratory and therefore, the method is not new.
  • When the receiving lab analysts are trained by the R&D or originating lab scientist.

d. Corporate SOP QVO.19.014, “Test Method Transfer Procedure” (Versions effective 04/17/07 through 10/31/08) stated that formal method transfer studies were not required in the following instances:

  • When test procedures employing the techniques are already in use by the receiving laboratory and therefore, the method is not new.
  • When the test procedure has built-in controls to verify the performance with each use. 
  • When based on professional judgement a formal transfer study in not required but the rationale must be documented
  • When the receiving lab analysts are trained by the R&D or originating lab scientist.

[Hospira, Inc., Date Issued: 08/04/2011]


Part 211 Subpart D – Equipment, Sec 211.68 Automatic, mechanical, and electronic equipment

Input to and output from the computer, related systems of formulas, and records or data are not checked for accuracy.

Specifically, 

Input and output verification from the computer, related systems of formulas, and records or data are not checked for accuracy.

Specifically, the program used to electronically calculate the assay of Techni-care by HPLC has not been validated and calculations performed computer are not checked for accuracy.

[Care-Tech Labs Inc., Date Issued: 05/22/2008]


Procedures describing the calibration of instruments and apparatus are deficiently written or followed. 

Specifically:

a. The calibration program for your stability chamber is deficient in that is does not include specific directions and schedules. You do not perform re-qualification of the stability chambers. The original qualification of all chambers only included mapping studies with empty chambers. The chambers were never challenged by filling the storage space and proceeding with mapping studies. These chambers were observed to be fully loaded.

b. Vault [REDACTION] used for the storage of stability samples for [REDACTION] This room was never qualified, including initiation of mapping study, by the firm. Also, this room is only monitored for temperature with only one probe. The firm does not have the capability to monitor humidity within the room. The vault is approximately [REDACATION] long by [REDACATION] wide [REDACATION] high 

[Ohm Laboratories, Inc., Date Issued: 08/12/2009]


You failed to always maintain a backup file of data entered in the computer or related system as well as failed to have a procedure in place for backup operation to assure that the data is exact, complete, and secure from alteration, erasure or loss through keeping hard copy or alternate systems.

a. There is no procedure to backup data from the personal computer (PC) connected to the HPLC [REDACATION] and the UV/VIS Spectrophotometer [REDACATION] 

b. There is no backup data for the UV/VIS Spectrophotometer, instrument use for testing the clarity of all finished drug products such as and not limited to Loratadine Oral Solution, Sertraline  Hydrocholride  Liquid Concentrate, [REDACATION] Ranitidine Hydrocholride Syrup, Metformin HCI Liquid Solution. 

c. You maintain back-up data for the HPLC Systems since 04/2002 until May 26, 2009. No back-up of the systems has been performed since then. The instruments were used for testing raw material, in-process bulk, stability samples and finished product release. Examples are...

d. Original data for Nortriptyline HCL Oral Solution exhibit batch [REDACATION] HPLC chromatographic data for the stability studies of Long Term Study 3-month test point [REDACATION] and Accelerate [REDACATION] At 3- month test point was not available for review when requeted.

[Ohm Laboratories, Inc., Date Issued: 08/12/2009]


Appropriate controls are not exercised over computers or related systems to assure the changes in master production and control records or other records are instituted only by authorized personnel.

Specifically:

a. The dedicated PC attached to HPLC Systems [REDACATION] was not secure in the access to the [REDACATION] software was not granted by a unique username and password to avoid any omissions or changes to data. For example on 07/20/09, it was observed that both Chemists used a common username and password during an [REDACATION] software demonstration.
 
b. This password can allow access to all levels of the software, including administrative capabilities such as editing methods sites and projects.
 
c. Security measures have not been instituted prevent the computer screen from remaining active and not protected from unauthorized access.
 
d. No written procedure for this computer system that outlines the responsibilities and privileges of the laboratory personnel who utilize the software.

[Ohm Laboratories, Inc., Date Issued: 08/12/2009] 


Temperature mapping study has not been conducted for the [REDACTION] degrees centigrade freezer, Serial  [REDACTION] used in the storage of frozen master and working seeds used in the manufacture of Fluvirin. (Protocol #10QP/0040/03 dated 5/19/03 for the qualification of the freezer is currently in place).

[Evans Vaccines, Date Issued: 6/10/03]


Lack of validation and periodic re-qualification of the [REDACTION] titrator used for measuring leaning foamer [REDACTION] which is used to clean the Grinder/Chipper [REDACTION] equipment assembly used for grinding pancreas glands. The concentration of [REDACTION] measured and mixed with water was never tested or documented to assure appropriate concentrations are measured in a reproducible fashion.

[Scientific Protein Laboratories, LLC., Date Issued: 05/08/09] 


No IQ/OQ/PQ performed for Freezer [REDACTION] installed in 1992. No temperature mapping of the [REDACTION] has been completed to date. Firm has [REDACTION] temperature probes, [REDACTION] (i.e. the one closest to the door of the walk-in freezer) was last calibrated on 01/10/07 and was not placed out of service until on or about 04/30/09. The currently used temperature probe, [REDACTION] was not calibrated to a national standard for its intended use at freezer storage temperatures between -10 to -25C (set point -14.4C)

[Scientific Protein Laboratories, LLC., Date Issued: 05/08/09]


Process water used for the production of Pancrealipase has not been validated in that:

a. On and before 04/28/09, the sample port in room [REDACTION] is hot process water for cleaning; production uses domestic cold water for processing.

b. There is no scientific basis for the [REDACTION] sampling frequency and the location of the sample ports

c. Sample locations are not identified on the CAD diagram

d. Sample locations are not physically identified at the sampling ports

e. The effect of the chlorine in city water on the product has not been evaluated 

[Scientific Protein Laboratories, LLC., Date Issued: 05/08/09]


[REDACTION] studies executed August 2007 during the operational qualification of the HVAC system for fill suite FF2-16, did not demonstrate the following:

  • Critical aseptic connections
  • Routine functions of aseptic core operators, for example:

a. Manually placing stoppers or reorienting stoppers using forceps for filled vials
 
b. Withdrawing unfilled vials from the filling line for weight checks 
 
c. Redirecting filled vials typically with stoppers on the exit feed wheel

  • Unidirectional air flow surrounding the rotary in-feed table
  • Opening the lyophilizer door or the automated double doors, as typically operated, into the aseptic preparation area and the effects on unidirectional airflow
  • Active viable air sampling and the effects on unidirectional airflow

[Genzyme Corporation, Date Issued: 10/10/2008]


The aseptic filling of all drug products into vials at higher speeds on the  [REDACTION] filling line has not been adequately qualified for its current use. The [REDACTION] filling line is currently run at [REDACTION] per minute for the 20ml vials. The data reported in validation studies documents that above [REDACTION] per minute, the stoppers clog in the stoppering machine and performance of the machine is affected. 

[Genzyme Corporation, Date Issued: 10/10/2008] 


For the Cryoshippers which are used to transport master cell banks and working cell banks between manufacturing facilities:

  • The use of these cryoshippers has not been validated
  • The manual for these shippers lists preventative maintenance steps for maintenance and annual maintenance. The Firm has not conducted any maintenance on any of [REDACTION] shippers currently in use.
  • The manual for these shippers states that the life expectancy of the shippers is 5 years. [REDACTION] of these shippers have been in use since 2002/2003 

[Genzyme Corporation, Date Issued: 10/10/2008] 


Initial qualification and routine calibration, maintenance and cleaning of automatic, mechanical, and electronic equipment is not performed according to a written grogram designed to assure proper performance. Specifically,

a. The [REDACTION] Oven used to depyrogenate glass vials and to sterilize filled 20-cc glass vials of HPC has not been qualified, maintained or cleaned according to a written program.

b. The [REDACTION] The Fully Automatic Autoclave used for the sterilization of all aqueous injectable solutions and rubber stoppers has not been qualified, maintained or cleaned according to a written program. In addition, the programmed sterilization cycles have not been validated and thermometer has not been calibrated against an NIST standard.

c. The [REDACTION] bench-top incubator used for the incubation of media fills and environmental monitoring samples has not been qualified, maintained or cleaned according to a written program. Visual inspection of the incubator showed a-1/4 gap between the door and chamber when closed and the temperature dial only showed a single handwritten setting of 30C.

[Infupharma, LLC., Date Issued: 09/27/2011] 


Input to and output from computer and related systems of formulas are not checked for accuracy. 

Specifically, the [REDACTION] software program version [REDACTION] used in the Quality Control Laboratory, has not been validated to generate results from the electronic data generated during testing. Additionally, the analytical formula used in the [REDACTION] to calculate the result of moisture in raw material and finished product has not been verified or validated. The following are examples of finished product and raw materials tested. This was used on Gemcitabine HCL raw material lots [REDACTION] and [REDACTION] Gemcitabine for Injection, USP lots [REDACTION] and[REDACTION] and Levetiracetam Injection lot [REDACTION] and [REDACTION]

[APP Pharmaceuticals, LLC., Date Issued: 07/08/2011]


Records of the inspections of automatic, mechanical or electronic equipment, including computers or related systems are not maintained. 

Specifically, the Infant and Adult Glycerin Suppository Molding Press Machine and the [REDACTION] Scale Automatic Weighing Machine (used for packaging the Glycerin Suppositories ) have no records of qualification. 

[H & P Industries, Inc., Date Issued: 07/17/2009] 


The use of instruments not meeting established specifications was observed 

Specifically, the [REDACTION] HPLC was used for assay of several OTC finished products prior to the PM/OQ/PV being completed

[H & P Industries, Inc., Date Issued: 07/17/2009] 


Routine checking of automatic equipment is not performed according to a written program designed to assure proper performance. 

Specifically, Akorn Inc., Quality Control Unit failed to review, approve, and perform corrective actions to the following: 

  1. The Quality Control Unit failed accurately validate the [REDACTION] Inspection Machine for Fluorescein Injection, USP, (AK-Fluor) 100mg/mL 5mL vial, jProduct Code 5010, to detect new type of foreign mater rejects due to a change in [REDACTION] stoppers. Akorn did not re-validate [REDACTIOION] Stoppers after the vendor change to a higher [REDACTION] level within the stoppers. It was only identified after Akorn experienced numerous Non-Laboratory OOS investigations during AQL inspections for foreign matter rejects. Approximately 16. Foreign Matter rejects for Year 2007 and for Year 2008 approximately 5 Foreign Matter rejects for AK-Fluor, with specification rejection rate over [REDACTION] % to include but not limited to the following....
  2. The written procedure SOP ML 157, Identification of Microbial Isolates, does not include instructions for the user to evaluate the power spikes (surges) when a card is in the reader on the [REDACTION] Identification System. The power spikes (surges) could affect the reading of the card inside the [REDACTION] which identifies the microorganism. Cards that are not read (meaning there are no identification results) could be related to the power spikes (surges).The performance of the [REDACTION] is evaluated by the results from the readings on the cards.
    • For example, on 2/5/08 at 1743, the message recorded on the [REDACTION] Error Log said that “the reader experienced a power failure”. There is a note that one card was in [REDACTION] at time of power failure. No ID, identification, will be repeated. The results from this reading were not within the acceptable range of the database for microorganisms within the [REDACTION] and the test was repeated. But Management said the ability of the card to be read or not be read by the equipment could be related to the power spike (surge). There is no documentation of an evaluation of the performance of the [REDACTION] when the card is not read due to a power spike (surge).

[Akorn, Inc., Date Issued: 06/30/2009]


Qualifications for the [REDACTION] System are incomplete in that the Qualification Final Report was not prepared [REDACTION] as required by the protocol. The installation and Operational Qualifications was conducted by an outside vendor and signed off on 4/10/98 but was not approved by QA until 2/7/2000. This system has been in place since 1987. In addition there is no justification for the [REDACTION] cleaning of the [REDACTION] System.

[McNeil Consumer Healthcare, Date Issued: 3/9/2000] 


There is no audit trail or documentation for when and who changed the Fluid Bed Dryers preventive maintenance procedures in the [REDACTION] System. This system monitors, schedules, and maintains all maintenance [REDACTION] records for manufacturing equipment.

[McNeil Consumer Healthcare, Date Issued: 3/9/2000]


The firm’s installation and Operational Qualification report of the Waters Millennium 32 HPLC Computer System does not verify the calculation for the analytical results (manual vs automatic calculation) as part of the validation.

[McNeil Consumer Healthcare Inc., Date Issued: 02/13/01]


Software validation activities and results for computers or automated data processing systems used as part of production have not been adequately documented.

Specifically,

Not all activities reported on the [REDACTION] #60025082, Rev A., including test requirements/ design/ procedures and acceptance criteria for the verification of the [REDACTION] used to control the [REDACTION] cycle, were fully documented to comply with the requirements described on the plan. For example, section 8.4 of the [REDACTION] (approved on June 2009) includes the CFR 21 part 11 Compliance and System Security requirements, describing procedures and levels of access to be granted for uses accessing the controller. However, no formal procedure was established on site for the implementation of the system security requirements prior or during the execution of the protocol to control users with access to the system. Furthermore, no documented evidence was included with the execution of the plan to confirm that compliance with the system security was in fact executed.

[St. Jude Medical Puerto Rico LLC., Date Issued: 10/02/2012]


Part 211 Subpart D – Equipment, Sec 211.63 Equipment design, size, and location

Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use. Specifically, 

a. Your firm upgraded the refrigeration skid which is used to run the lyophilizer January 2003. This included the replacement of equipment and computer upgrades. There are [REDACTION] LYOPHILIZER. The operational Qualification performed on the system did not include functional tests for all critical steps. There was an error in one of the bits for compressor [REDACATION] This bit was entered as [REDACTION] start compressor #1 condenser cooling [REDACTION] and the bit should have been entered as [REDACTION] Due to this error, there was an issue on 5/15/07 during the lyophilizer cycle for Cerezyme lot A7034 which did not allow the compressor to cycle off the required manual intervention.

b. The [REDACTION] filling line has been in place and in use since 1994. The [REDACTION] filling line has not been calibrated for line speed, stopper bowl or volumetric control.

[Genzyme Corporation, Date Issued: 11/13/2009]


Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use.

Specifically.

a. The June 2008 revalidations of the[REDACTION] stopper washer document number RV08-035 establishes “The objective of this revalidation was to demonstrate the ability of the [REDACTION] Stopper Washer [REDACTION] to reduce endotoxin and detergent residue and to monitor bioburden and particulate matter (PM) levels on the stoppers per SOP QOV -1118/revision 4.” The revalidation for Cycle [REDACTION] and Cycle [REDACTION] consists of “detergent with no siliconization” and non-detergent with no siliconization”, respectively. The cycles did not include an evaluation with silicon to demonstrate a bacterial endotoxin reduction to achieve “a minimum log reduction meeting the acceptance criterion”. In addition,

  1. The November 2008 revalidation for [REDACTION] Stopper Washer referenced in document number RV08-056, establish that Cycle [REDACTION] and [REDACTION] condisted of a “detergent cycle with siliconization and “non-detergent with no siliconization”, respectively. However for Cycle [REDACTION] the [REDACTION] The cycles did not include an evaluation with silicon to demonstrate a bacterial endotoxin reduction to achieve “a minimum [REDACTION] reduction meeting the acceptance criterion”.
  2. Despite the review and final approval by the Directors of Validation, Microbilogy, Component Preparation and Quality Systems of the aforementioned 2008 Huber Stopper revalidations, Cycle [REDACTION] is not a validated cycle

b. The Final Report No. SC99005: Concurrent Validation of Propofol Injectable Emulsion 10mg/ml, (Preserved with Microfluidization Process, sign off date May 25, 2000 submits[REDACTION] 

c. The [REDACTION] is used to sterilize the Propofol Injectable Emulsion finished products. The ANDA submits that the steam sterilization validation will include the use of Bacillus coagulans biological indicators (BI) with “a minimum of a [REDACTION] pores” . However, in August 2004 [REDACTION] (runs), 2005 [REDACTION] (runs), 2007 [REDACTION] (runs) and in 2008 [REDACTION] (runs) the BI used for room vials consists of a [REDACTION] spore population. (Please note that steam sterilization cycle is not designed or intended to reduce the levels of bacterial endotoxin). In addition,

  1. During the [REDACTION] will generate an alarm message that signals any aberrant events that may occur during routine steam sterilization process. Examples of some alarms include “chamber pressure lack”, external steam lack, phase time excess, sterilization temperature lack, circulation [[REDACTION] lump alarm, and sterilization time suspended. (Please note that these are examples of alarms and they are not intended to be an all inclusive list of [REDACTION] alarms).As described by the Production Supervisor for Sterilization and Lyophilization the alarms are assessed, for example, before a deviation report is generated, request for maintenance, or decisions are made that no corrective measures are needed in response to the alarm events. However, there is no established written procedure to describe the manner with which the assessment and triage of the steam sterilization processing alarms are performed.
  2. The [REDACTION] revalidation of the empty chamber temperature uniformity uses [REDACTION] to monitor the temperature of the autoclave interior. The establish procedures Revalidation of [REDACTION] Autoclave- Terminal Sterilization #QOV-1041 describe how the [REDACTION] are positioned and secured to the equipments interior. However, the procedure does not address the manner with which the [REDACTION] temperature probe is secured to assure that the temperature monitoring probe does not contact any metallic surfaces

d. Utility [REDACTION] micron filters used for nitrogen flush was not replaced with approved nitrogen filtration unit in accordance with SOP PGP-1007 titled “Utility Filters for Production Equipment, dated 3/10/09.” The [REDACTION] failed bubble point as less than [REDACTION] final integrity testing on 6/20/2008 at drop [REDACTION] and was replaced with unapproved [REDACTION] on 6/16/2008 which also failed final integrity testing on 8/22/2008. This nitrogen filter supplies nitrogen to the microfluidizer during the processing of Propofol Injectable Emulsion. From 06/16/08 to 08/22/08, the firm produced the following numbers of propofol 10mg/ml lots [REDACTION]

[Teva Parenteral Medicines Inc., Date Issued: 07/24/2009


There is no data to provide assurance that the conveyance and capping of product filled Avastin vials is performed in “Controlled Primary HEPA filtered Area”, as described in section 3.2.P3.3 of your firm’s Bevacizumab BLA (#125085).

The current design of the capping area as observed during our tour of Area [REDACTION] on 09/21/11, appears to allow a gap between the end of the HEPA filter coverage and the semi-permanent plastic barriers. This gap appears to permit the influx of air from the class [REDACTION] work environment, which would then be passed over the vials during the conveyance and capping process.

Additionally, your firm uses displaced stopper detector (DSD) equipment located upstream of the vial capping equipment in Room [REDACTION], to verify the displace between the stopper and vial. The parameter settings for the DSD equipment were derived from Document No.TR 10-050 vol 1, titled “Defining the Reject Limit for the Displaced Stopper Detectors for [REDACTION] 3” and microbial challenge studies performed by a contract laboratory. Your firm lacks adequate documented evidence to support the integrity of the microbial challenge studies performed by your contract laboratory. For example, during microbial challenge studies, [REDACTION] were used to implement a pre-defined displacement between stopper and vial of study vials. There is no assurance that the thickness of the [REDACTION] as reported were verified and accurate.

[Genentech Inc., Date Issued: 09/27/2011]


Equipment used in the manufacture, processing, packing or holding of drug products is not suitably located to facilitate operations for its intended use. 

Specifically, the stopper hopper of your fill room line [REDACTION] was noted to be at waist height and not protected by barrier. On the evening of 06/15/11, during the manufacturing operation of Gemcitabine for Injection lot 7025152, was observed the operators inside the class 100 area reaching over the stopper bowl as well as over some empty vials prior to been filled during the unloading empty vials process. In addition, according to your investigation 13762, dated 10/08/10 related to a positive unit found during media fill lot 7021321, even though is subject to a different filling line, filling operators had revealed some concerns on the lack of space in the filling room when needed to perform  necessary adjustment to move jammed vials. 

[APP Pharmaceuticals, LLC., Date Issued: 07/08/2011] 


Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use and cleaning and maintenance.

Specifically, an apparent dead leg was noted in the high purity water supply loop. This -3’ x 1.5” vertical pipe is just downstream from a [REDACTION] inlet valve. The system has no stand or surge tank so any water used must be immediately replenished or damage to the system could occur. As described to me by the firm, when new D1 water is needed [REDACTION] also opens this inlet valve. Understandably this valve remains closed much of the time, including during operational down time. If the valve is closed, the described pipe section about three feet or so, likely will not drain because there appears to be no way to let air or vacuum break into the top of the pipe, allowing flow. 

In addition, it appears that this could cause an issue during heat sanitation of the supply loop for the same reason. It appears that there would be no substantive circulation into and thru that portion of the tube to sanitize it without re-directed plumbing. This was not described to me as taking place. 

[H&P Industries,Inc., Date Issued: 03/28/2011]


Part 211 Subpart D – Equipment, Sec 211.67 Equipment cleaning and maintenance

Written procedures are not followed for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.

Specifically,

a. The firm’s Equipment cleaning Validation Policy, TSP-0001, indicates that [REDACTION] or other [REDACTION] used for final rinse shall be the same quality, or better, as that used for manufacturing or by regulation”. According to this policy, [REDACTION] should be used for the final rinse of the equipment because it is the quality of [REDACTION] used for manufacturing. In addition, SOP PD-0018 indicates that [REDACTION] should be used for the rinse of equipment. A tour of the manufacturing area disclosed the presence of [REDACTION] points of use; however, an interview with the Manufacturing Director [REDACTION] and an operator [REDACTION] disclosed that [REDACTION] is never used to rinse equipment. The incoming city water is not treated and, although it is sampled once a week, the test performed (microbial) is for information only. 

b. Operator [REDACTION] said that he executes the cleaning procedures by memory based on his experience; he said that he only reads the SOP when there are changes.

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006] 


Equipment and utensils are not cleaned at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically,

a. Filters used in [REDACTION] and [REDACTION] are cleaned using [REDACTION] but are not included in the cleaning validation studies to confirm that the rinsing procedures are effective in removing [REDACTION] residues.

b. Report number QCR-05-051-MTH, “Analytical Test Method Report for the Determination of [REDACTION] on [REDACTION] Surfaces”, shows that the recoveries obtained by lower than the recoveries of the other two analysts. Since the test would not meet acceptance criteria using the recovery data obtained by Analyst [REDACATION] in these two surfaces, the firm changed the analyst and calculated the correction factor for residues using the data from the fourth analyst. No investigation of Analyst [REDACTION] swabbing technique was conducted to determine the reason of her low recoveries and no corrective actions were implemented to make sure her swabbing technique effectively recovers residues from equipment. However, Analyst [REDACTION] is still swabbing equipment for cleaning validation and verification purposes. The firm does not have any procedure to make sure that the analysts’ swabbing techniques are adequate before the analysts are allowed to perform swabbing for validation and verification studies.

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006]


Equipment and utensils are not cleaned and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically,

a. There are a number of microbiology investigative reports (MIR) that report bacterial endotoxin recovery in various Water For Injection and Reverse Osmosis water ports. For example;

MIR 08-042, 5/28/08, WFI port [REDACTION]

MIR 08-061, 7/10/08, WFI port [REDACTION]

MIR 08-075, 10/14/08, WFI port [REDACTION]

MIR 08-083, 12/4/08, WFI port [REDACTION]

MIR 08-044, 5/19/08, RO port [REDACTION]

MIR 08-081, 12/1/08, RO port [REDACTION]

MIR 09-001, 01/20/09, RO port [REDACTION]

MIR 09-010, 5/26/09, RO port [REDACTION]

b. The firm has not performed fogging validation study to support SOP # BMS-1001 titled “Sterile Area Fogging Procedure” 

c. The firm’s cleaning validation study VAL285-1, Compounding Vessels and Associated Equipment in the Propofol Compounding Area using the [REDACTION] CIP (Clean-in-Place) system, approved 10/20/00 was inadequate in that the firm failed to show that the process demonstrates that after cleaning, the equipment microbial bioburden and endotoxin levels meet predetermined acceptable limits. The firm utilized tailings of previously produced Propofol batches to “soil” the equipment. There was no known initial bioburden or bacterial endotoxin levels present in these tailings or solutions used in the soiling of the equipment. There was no other activity to show that the cleaning detergent, CP-3155, utilized by the CIP system is effective in the reduction of microbial bioburden and bacterial endotoxin to predetermined acceptable limits.

[Teva Parenteral Medicines Inc., Date Issued: 07/24/2009


Regarding equipment supporting manufacturing operations in the Egg virus Unit (EVU):

a. There is no sprayball coverage cleaning studies for the harvest tank, bulk holding tank inactivation vessel [REDACTION] and inactivation vessel [REDACTION] 

b. There are no studies to determine the swab sampling sites for the harvest tank, bulk holding tank, inactivation vessel [REDACTION] and inactivation vessel [REDACTION]

[Evans Vaccines, Date Issued: 15 October 2004]


Records are not kept for the maintenance and inspection of equipment.

Specifically,

On 04/20/10, hoses on the [REDACTION] were said to not be dedicated to products processed on these two fluid bed dryers by an operator and team leader Cleaning validation of the equipment did not evaluate cleaning of the 2.5 foot hose on [REDACTION] because the cleaning validation followed [REDACTION] Cleaning of equipment lacks documentation that [REDACTION] was followed and / or a statement that the 2.5 foot hose was removed and replaced after the campaign was completed for each drug product processed in the [REDACTION] For example, cleaning on 04/17/10 by operator [REDACTION] and verified by operator TE. In addition, the person verifying that cleaning was performed [REDACTION] on 04/17/10 was a temporary person from a different McNeil site and lacked training on [REDACTION] 

[McNeil Consumer Healthcare, Div of McNeil-PPC, Inc., Dated Issued 04/30/2010]

Part 211 Subpart C – Buildings and Facilities, Sec 211.46 Ventilation, air filtration, air heating and cooling

Equipment for adequate control over air pressure, humidity, and temperature is not provided when appropriate for the manufacture, processing, packing or holding of a drug product.

Specifically,

a. The [REDACTION] is a computer based automated system that is used to provide control and monitoring of both CGMP and non-CGMP systems throughout the [REDACTION] and [REDACTION] facilities. Examples of CGMP functionality at this plant include Differential Air Pressures (AP) monitoring and alarming in the Aseptic/TS cores and HVAC systems. Regarding the[REDACTION] measure points, the Senior Maintenance Supervisor confirmed that [REDACTION] measurement points monitor CGMP “important” parameters. The following provide a brief summary of observations;

  1. The [REDACTION] is accessed remotely by designated and approved Level 1 (administrative privileges) individuals that include a [REDACTION] contractor. The Level -1 privileges include for example, configure items, adjustments, resets and override capability, analysis, and trending report. However, there is no record to document computer system have taken the requisite CGMP training modules;
  2. Regarding the aforementioned access by the [REDACTION] contractor with Level 1 access privileges, there is no standard procedure that establishes a periodic review(e.g., Quality Assurance oversight) of the remotely accessed computer data related events e.g., configure items, adjustments, resets and override capability, an alysis, and trending reports;
  3. The Senior Maintenance Supervisor confirmed that in the last nine months there have been approximately 4,000and 3,800 alarmed events that have occurred in the [REDACTION] and [REDACTION] buildings. However there is no record to document that the [REDACTION] alarms are reviewed on a periodic base to assure that the alarmed events do not document a negative trend for the[REDACTION] measurement points;
  4. The [REDACTION] will provide an audio and visual alarm to alert the production and engineering staff of the air pressure alarm when the differential air pressure exceeds the established upper and lower levels between the aseptic fill rooms and the surrounding manufacturing areas. An alarm text message is printed out in a production office. However, the computer print out does not include the actual air pressure measurement that generated the alarm event. The Senior Maintenance Supervisor confirmed that the actual air pressure measurements can be printed out and the information can be provided, that is, if the Manufacturing Quality (MQ) personnel specifically request a print out;
  5. In the absence of an air pressure alarm print out, the Senior Maintenance Supervisor and the MQ personnel do not periodically review the air pressure measurements to assure that the differential air pressures do not present a negative or outward drift from the established upper or lower air pressure levels.

b. The Senior Maintenance Supervisor confirmed that there are no As Built engineering diagrams for the Air Condition (AC) [REDACTION] The [REDACTION] units provide high quality HEPA filtered air for the fill rooms [REDACTION] (ISO-5 and ISO-7) aseptic filling rooms and for the ISO-7 and ISO-8 manufacturing support areas leading to the aseptic fill rooms, respectively. And, the simplified block Air Flow Diagrams K-RM-5-M101c and K-RM-5-M101a for AC-1 and AC-2, respectively, that illustrate the air systems are not current or up-dated.

[Hospira, Inc., Date Issued: 03/01/2013]


Part 211 Subpart F – Production and Process Controls, Sec 211.100 Written procedures; deviations

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

Specifically,

a. Retrospective “Techni-Care Process Validation Update” for Techni-care surgical scrub performed 3/21/2008 is deficient. The validation did not include an evaluation of all out-of-specification (OOS) batches over the selected time frame 2003-2007 (5 years0. The validation was based on data from released batches after reprocessing. The validation id not address batches that may have required reprocessing due to OOS results for % chloroxylenol, pH, and viscosity.

b. The “Techni-Care Process Validation Update” report did not include manufacturing directions for reprocessing batches to bring them into compliance for pH and the active ingredient Choloroxylenel.

The “Techni-Care Process Validation Update “ validation states in [REDACTION] micro tests, Techni-care has performed as expected and passed each and every micro test, for example:

The micro validation results did not include the out-of-specification dated 6/13/07 for batch [REDACTION] manufactured on 6/4/07 which failed the initial [REDACTION]. Neutral Agar micro streak case [REDACTION] of incubation.. The retest passed at [REDACTION] 

The micro validation results did not include the out-of-specification dated 8/14/06 for batch manufactured on 8/9/06 which failed the initial Neutral Agar micro streak for the last case after [REDACTION] of incubation. Lab notebook NB029-060 entry at [REDACTION]. The retest passed at [REDACTION]

Micro validation results did not include the OOS sated 10/30/06 for Batch [REDACTION] manufactured on 10/24/06 which failed initial case [REDACTION]. Lab notebook NB029-085 entry at [REDACTION]. The retest passed at [REDACTION]

The micro validation results did not include the out-of-specification dated 9/19/05 for batch [REDACTION] manufactured on 9/13/05 which failed the initial [REDACTION]. Lab notebook NB021-051 entry at [REDACTION]. The retest passed at [REDACTION].

Additionally, “Techni-Care Process Validation Update” allows for [REDACTION]. However, these conditions are not defined and the firm lacks written environmental control procedures such as temperature and humidity. Finally, the validation did not include an evaluation of critical operating parameters such as time and temperature.

c. The “Microbiologic Plate Streaking Validation” dated 7/26/04 is deficient. The validation did not include the sample size in which to inoculate each plate with finished product. In addition, the validation did not include an evaluation of all out-of-specifications due to growth.

d. Process validation has not been conducted for Formula Magic (Benzethonium Chloirde).  

e. Process validation has not been conducted for Tech 2000 Dental Rinse since the 2005 installation and 6/26/06 validation of the water purification system.

f. There is no written procedure for the cleaning validation of the ribbon blender including the responsibility for development, performance and approval of the validation study.

[Care-Tech LabsInc., Date Issued: 05/22/2008]


Written production and process control procedures are not followed in the execution of production and process control functions and documented at the time performance.

Specifically,

The firm does not have quality assurance system in place which requires the timely revalidation of processes whenever there are changes in formulation and processes which could have impact on the effectiveness or product characteristics, and whenever there are changes in product characteristics. For example.

a. The monograph for % Cetylpyruidium Choloride active ingredient used in the manufacturing of Tech 2000 dental rinse product was changed. However, the firm failed to perform revalidation to assure analytical method is suitable for the Tech 2000 dental rinse process. In addition updates to the validation plan and procedure according to the changes has not been implemented 

b. There was failure to document a significant change in the preparation of the standard stock for Techni-care surgical scrub. For example, method CCQC35: “QC Method for HPLC Analysis of Liquid, Gel, and Crème Care-Tech Products Containing Chloroxylenol, USP (PCMX)” in the initial validation for the detection of PCMX in Tech-Care products instruct to weigh approximately [REDACTION] of Chloroxylenol, USP to make the standard stock. The firm amended this amount to [REDACTION] without the proper change control. In addition there was no justification or written documentation regarding a significant unit change from [REDACTION] when calculating the Percent PCMX in the product.

[Care-Tech Labs Inc., Date Issued: 05/22/2008]


Written production and process control procedures are not followed in the execution of production and process control functions. 

Written procedures did not coincide with established in process control documents in the following:

a. Coating solution hold study, SAN [REDACTION] supporting coating solution hold times specified a flush of “at least 200ml of solution” through the bottom valve prior to sampling for microbiological analysis. SOP [REDACTION] also requires a flush prior to starting the coating process, but does not specify an amount. Additionally, batch card coating instructions reviewed for product [REDACTION] were observed specifying only a 100g sample (for appearance testing) required to be collected prior to coating. 

b. The Process Qualification Report for this same hold study (SAN [REDACTION] ) did not encompass a worst case scenario as permitted per incoming raw material specifications regarding microbial limits, particularly for [REDACTION] limits 

Specifically, as stated in the study, [REDACTION]

[L. Perrigo Company., Date Issued: 12/15/2006]


There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to posses. Specifically,

a. The aseptic repackaging processes of the Avastin and Human Chorionic Gonadotropin (HCG) injectables and the high-risk compounding process of Hydroxyprogesterone caproate (HPC) injectable were not validated through adequate [REDACTION] media fills performed by all compounding personnel in accordance with a written program. For example, between 7/18/11, you stated on multiple occasions that you did not conduct media fills. However, upon resuming the inspection on 9/19/11, you provided two (2) [REDACTION] Logs which you identified as media fill records. These records documented that media fills were conducted for low and medium-risk level compounding (not for high-risk) by three pharmacy technicians on separate dates as follow: 11/19/08 [REDACTION] 7/8/09 [REDACTION] 1/29/10 [REDACTION] and 8/15/10[REDACTION] As per your statement on 9/19/11, you are the only one currently authorized perform aseptic operations but there is no documentation that you have conducted any media fills. Also the media fill records documented that you have conducted any number of days; however, your firm’s unqualified incubator only has a handwritten setting on the temperature dial of 30C .There was no documentation that the correct temperature was maintained and monitored during the incubation periods. 

b. Your firm’s sterilization processes by filtration with a [REDACTION] filter, autoclaving [REDACTION] or by [REDACTION] have not been validated according to a written program. For example, the effectiveness of [REDACTION] or [REDACTION] sterilization was verified by using appropriate biological indicators and other confirmation methods such as temperature-sensing devices. In addition, the suitability of the [REDACTION] filter (Product code: [REDACTION] ) used for the filtration of different aqueous and oily preparations was not established and documented. 

Moreover you had two formulation instructions for the high-risk compounding of HPC injectable which differed in the temperature and length of the sterilization process by [REDACTION] of the compound filled in vials. One formulation required a temperature of [REDACTION] for [REDACTION] hours and the other required a temperature of [REDACTION] for [REDACTION] hour. You lacked data to demonstrate that both methods were equally effective in sterilizing without affecting the stability and quality of compound. Furthermore, you lacked documentation showing which method was used by your firm.

c. The effectiveness of the [REDACTION] depyrogenation cycle for glassware, e.g, vials, was not conducted according to a written program incorporating the use of endotoxin. In addition, there was no documentation of the depyrogenation of vials used in your aseptic process for HPC.

[Infupharma, LLC., Date Issued: 09/27/2011]


Written procedures are not drafted, reviewed and approved by the appropriate organizational units and reviewed and approved by the quality control unit. 

a. Product Code 5132, Lot No [REDACTION] initially started with [REDACTION] mixer attached to Tank [REDACTION] however, during the addition of Ofloxacin, USP at [REDACTION] it was noted that the [REDACTION] mixer did not disperse the Ofloxacin, USP powder into the solution. A [REDACTION] mixer [REDACTION] was installed and used for formulation. Akorn did not initiate an investigation detailing the change to include new equipment. A very brief summary was noted in the comment section, however, the comments did not identify a root cause for new equipment. 

b. Product Code 5132, Lot No [REDACTION] 

  • During manufacture of validation batch, the Quality Control Unit failed to implement an investigation or detailed information or detailed information related to the change from [REDACTION] mixer to [REDACTION] mixer that was identified in manufacture of 1st batch Lot No. [REDACTION] at step [REDACTION] Akorn did not initiate an investigation detailing the change to include new equipment. A very brief summary was also noted in the comment section.
  • The production staff utilized the [REDACTION] mixer at Step [REDACTION] During manufacture of 1st batch Lot No. [REDACTION] it was instructed to discontinue use of the [REDACTION] mixer for future manufacture; however, the staff continued use of the mixer. The Master Batch Record and Process Validation ProtocolOfloxacin Opthalmic Solution, USP, 0.3%, Protocol No. P215-08-00, did not include instructions for an additional remix at Step [REDACTION] An investigation wa not initiated to identify the need for utilizing the discontinued [REDACTION] mixer and also an additional re-mixing procedure.

c. Product Code 5133,Lot No [REDACTION]

  • During manufacture of validation batch, the Quality Control Unit failed to implement an investigation or detailed information or detailed information related to the change from [REDACTION] mixer to [REDACTION] mixer that was identified in manufacture of 1st batch Lot No. [REDACTION] at step [REDACTION] Akorn did not initiate an investigation detailing the change to include new equipment. A very brief summary was also noted in the comment section.
  • The production staff utilized the [REDACTION] mixer at Step [REDACTION] During manufacture of 1st batch Lot No. [REDACTION] it was instructed to discontinue use of the [REDACTION] mixer for future manufacture; however, the staff continued use of the mixer. The Master Batch Record and Process Validation ProtocolOfloxacin Opthalmic Solution, USP, 0.3%, Protocol No. P215-08-00, did not include instructions for an additional remix at Step [REDACTION] An investigation wa not initiated to identify the need for utilizing the discontinued [REDACTION] mixer and also an additional re-mixing procedure.

[Akorn, Inc., Date Issued: 06/30/2009]


Part 211 Subpart F – Production and Process Controls, Sec 211.110 Sampling and testing of in-process materials and drug products

Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

Specifically,

On 2/25/05, the QCU approved Doc.No.0002PV05 titled “Process Validation Protocol-Manufacture of Ketoprofen [REDACTION] using [REDACTION] readings documented from the [REDACTION] to evaluate the accuracy of scale reading versus[REDACTION] reading for the sustained release coating process as the difference in the [REDACTION] readings was identified as the cause for the shift in dissolution performance at the 8th hr. Five(5) commercial batches of [REDACTION] (520E017, 520E018, 52050, 55797 and 57043)were manufactured under this validation protocol, which resulted in three batches (52050,55797and 520E018,sublot #4) that failed dissolution specifications at the 8th hr. And a batch (57043) that deviated from the target capsule fill weight specified in the manufacturing batch record in order to meet dissolution specification at the 8th hr. The remaining six (6) finished product batches (520E017, 520F0368, 520E018, F520F0840, F520F1030, and F520F1031) of Ketoprofen ER Capsules that had acceptable dissolution results were released by the Quality Control Unit and distributed between March and July 2005 despite the demonstrated variability and significant inconsistencies of the manufacturing process documented in interim reports 002PV05-01i, 002PV05-02i, 0002PV05-03i, and the final validation report 0002PV05 approved on 7/28/05

[Andrx Pharmaceutical, Inc., Date Issued: 04/18/2006]


Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

Specifically, at least two (2) lots of drug products have been rejected and one (1) manipulated during the validation phase. First validation batch for [REDACATION] was rejected due to solubility problems. A second batch manufactured was noted to have multiples cross-outs on the approved validation batch specifications, all related to the suggested stirring speed and no change control issued. It is not clear if this manually changed parameter was prior or after the product been manufacture. In addition, you failed to document the actual stirring speed [REDACATION] and no deviation was ever lifted. This is the same step of Exhibit batch [REDACTION]submitted to the agency in support of ANDA [REDACTION] that according to the batch record as well as dispensing sheets you documented the charge of [REDACTION] to the vessel prior to dispensing such.

First validation batch of Oxcarbazepine Suspension, lot [REDACTION] was rejected due to not meeting viscosity specification, although excipients utilized for the manufacture of the lot are all meeting pre-determined specification

[Ohm Laboratories, Inc., Date Issued: 08/12/2009.]


Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. 

a. Products to be transferred from the New Jersey facility include oral liquids, powders, nasal sprays, and tablets. There was no strategic plan documenting the transfer of the manufacture of these products to this location. Originally the company anticipated the transfer of all production of these new products to be complete by [REDACTION] The [REDACTION] validation studies for that the batching/ compounding processes are capable of consistently delivering quality products. The following observations were made during review of the validation studies:

  1. The oral products are made in bulk mixing tanks [REDACTION] In addition, a number of portable tanks can be used for premixes which will then be transferred to one of the bulk mixing tanks. Each of the bulk mixing tanks and each of the portable tanks are different in their dimensions, capacities, type of mixer and mixing speeds. No documentation is available at the firm to demonstrate that the tanks are operationally equivalent or that the specified mixing parameters listed in the validation batch records for each tank are equivalent. Some of the products involve the use of multiple tanks which, in the absence of a comparability study, introduces the potential for batch-to-batch variability as multiple combinations of tanks can be used.
  2. For each of the validation studies, the initial validation batch record contains several handwritten annotations for process improvements which are then transcribed on the batch records for the subsequent validation batches. These process improvements are also listed in the validation reports. The amount of annotations on the initial validation batch records and their nature, such as [REDACTION] renders the initial run a research and development batch and demonstrates that the batching process is not well established at the outset of the validation study. In addition, many of the Validation studies involve [REDACTION] batch size from the batch size previously validated at the New Jersey facility. Examples of products in which the validation studies involved [REDACTION] batch size to [REDACTION] batch size at the Hartland facility include, Sore Throat Liquid Spray-Cherry, Sore Throat Liquid Spray-Menthol, [REDACTION] Children’s Mixed Berry, and [REDACTION] Children’s Grape.
  3. The oral products may be transferred from one of the main mixing tanks to a holding tank following batch release testing and prior to finished product packaging. No studies have been conducted to determine the duration that the oral products can remain in holding tanks. [REDACTION] prior to finished product packaging time, can range from [REDACTION] hours. In addition, the holding tanks do not have agitators in them. The firm’s “Tote or Tank Activity Record” (Form No: WI-PM-0090) identifies the batches held in the holding tanks, but it does not demonstrate the duration for which the batches were held.
  4. Amendment o1, associated with VAL-0120-MBF-002, for [REDACTION] Children’s Multi-Symptom-Very Berry, was written to include tank [REDACTION] in the manufacture of this product without re-validation of the batching process. The original validation of this product was conducted in tanks [REDACTION] The justification to not re-validate was based on thank [REDACTION] being used in the validations for [REDACTION] Children’s Cherry and [REDACTION] Mixed Berry, which were both deemed successful. However, each Multi-Symptom Very Berry product contains the active ingredients Guaifenesin Dextromethorphan Hydrobromide, and Phenylephine HCI whereas the Children’s Cherry product contains Guaifenesin and Dextromethorphan Hydrobromide and the Children’s Mixed Berry product contains Guaifenesin and Phenylephrine HCI.
  5. Multiple finished product lots manufactured from the validation batches were released to inventory prior to formal documented approval of the validation reports. The products and associated finished product lot numbers for products released prior to approval of the validation report include:
    • Night Time Cold & Multi-Symptom Liquid- Warming Honey Lemon, lot OF227
    • Sore Throat Liquid Spray –Menthol, lot OJ117
    • [REDACTION] Children’s- Mixed Berry, lots OJ118,OJ150,OJ138
    • Acetaminophen Oral Suspension Infant’s Drops – Grape, lot OJ289
    • Children’s Night Time Cough  & Cold –Grape, lots OH177,OH175
    • [REDACTION] Children’s Multi-Symptom-Very Berry, lots OH153,OH159,OH156
    • [REDACTION] Children’s Cherry, lots OH260,OH261,OH262

6. Finished product lots made from the validation batches were not always put on Stability. The product and associated lot numbers representing validation batches that were not put on stability include:

    • [REDACTION] Children’s Mixed Berry, lot OJ150
    • Night Time Cold Liquid – Cherry, lots OE229, OE223
    • Night Time Cold Liquid & Multi-Symptom Liquid- Warming Honey Lemon, lot OG150
    • Sore Throat Liquid Spray – Cherry, lots OJ143,OJ144

7. The three process validation batches for Night Time Cold & Multi-Symptom Liquid- Warming Honey Lemon were manufactured on 06/26/2010 (batch OF227B), 07/08/2010 (batch OG150B), and 10/28/2010 (batch OK90B). Two batches of this product were made prior to the first validation batch; OF227B. The first validation batch – OF227B – was then followed sequentially by the second validation batch –OG150B, but [REDACTION] batches were manufactured between this batch and the third validation batch; OK90B. Per the QA Manager, all of the lots of product manufactured prior to the first validation batch and between the second and third validation batches were released.

b. The packaging process validation on the [REDACTION] packaging line, used to package oral liquid products including [REDACTION] Night Time Cough and Cold Syrup, [REDACTION] Guaifenesin and Phenylephrine Oral Pediatric, [REDACTION] Cold Syrup, and [REDACTION] Sore Throat Spray Menthol Liquid, did not include critical elements of the process and the affect on the drug products including:

  1. The use of a [REDACTION] filter, these filters were not included in the packaging validation but have been used on subsequent batches of product. The use of the filters was not always documented in the subsequent batch records. No studies have been done to show that these filters are appropriate for use with these products.
  2. The pre-filter and final filter are changed during packaging if the filters are clogged with product. The affect of the filter change on the packaging process was not part of the packaging validation.
  3. The conveyor speed during the packaging validation was not recorded and was not deemed important to the process. A subsequent batch of product had a deviation due to convey or speed problems i.e DEV-10-INT-063
  4. Oven temperature for the tamper evident seal around the neck of the bottle was not part of the packaging validation and was not deemed important to the process.

[H & P Industries, Inc., Date Issued: 01/07/2011]


Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristic of in-process material and the drug product.

a. The written procedure (SOP v-029) for your Statistical Process Control (SPC) systems is deficient because incorrect application of statistical process control is being used. For example:

  • The sigma (8.14) estimation used for the control charts is incorrect. This erroneous estimation could lead to inappropriate control limits on the respective statistical process control charts. Inappropriate control limits could lead to either an over controlled or under controlled process.
  • Step 9.1.4 is incorrect due to the fact that the constant A can only be used if both sigma and µ are known and not estimated. According to section 8.1.3, your firm will be “estimating sigma and µ on no less then [REDACTION] data points.” This contradicts the usage of constant A.
  • The calculation of the control limits for tablets greater than [REDACTION] mg is incorrect as stated in 9.2.2. The value of A for a sample size of [REDACTION] cannot be determined by dividing the value of A for a sample size of [REDACTION] Not only is the calculation of control limits incorrect, the usage of constant A is inappropriate.

b. No investigation and or/assessment was performed for low % yield during granulation of [REDACTION] drug-layered pellets for lots [REDACTION] (93.0%) [REDACTION] (89.0%), and [REDACTION] (88.2%) as required by your Computation of Yields and Material Reconciliation SOP, G-017 version 2.0 effective June 15, 2010. The specified range is NLT [REDACTION] NMT [REDACTION] These lots were used in process validation of [REDACTION] capsules. [REDACTION] is pending FDA approval.

c. During your process validation of [REDACTION] Capsules [REDACTION] you failed to achieve blend homogeneity for final blend of batches [REDACTION] due to agglomeration of talc. This product is pending FDA approval.

d. During your process validation of [REDACTION] Capsules [REDACTION] you did not achieved acceptable % usable yield according to your specification [REDACTION] for the following process validation lots during encapsulation process...

Due [REDACTION] agglomeration and low % yield observed during your execution of profess validation batches, your firm has recommended that [REDACTION] Capsule is not to be considered validated. These batches will be designated for developmental/clinical purposes only and further evaluation will be conducted.

e. Your manufacturing process during process validation drug product [REDACTION] Capsules [REDACTION] (pending FDA approval) is not the same as what was submitted to the FDA. [REDACTION] Pellets blend lot [REDACTION] required mixing the following ingredients in the order listed below... 

This blend lot [REDACTION] was used to make submission batches of [REDACTION] Capsules [REDACTION] However, during the execution of your process validation of [REDACTION] the order of adding the above ingredients were changed as follow...

Your Regulatory Affairs has determined this change to be annual reporting. 

f. The spray rate specification during granulation for [REDACTION] pellets I II was changed from [REDACTION] min to [REDACTION] min without adequate justification. Your firm submitted in submission batches [REDACTION] and [REDACTION] with specified spray rate of [REDACTION] min. However, during process validation for lot [REDACTION] and [REDACTION] your firm changed the specification to [REDACTION] min due to peristaltic pump not capable of being set below [REDACTION] therefore, could not achieve lower g/min rate limit of [REDACTION] min as specified in the Formulation Manufacturing Record (FMR) during pump set-up according to your Deviation investigation (WDEV-09-0472). However, contrary to your investigation finding, the submission FMR for batches [REDACTION] and [REDACTION] indicated your firm was able to achieve spray rate of [REDACTION] min. 

[Sandoz Inc., Date Issued: 06/22/2011] 


Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

Specifically,

Benadryl Allergy Fast Melts Process Validation Report 20-VAL-RPT-0166

A. The firm’s SOP titled Site Validation Requirements Procedure indicates that the Process Validation Protocol regarding the Critical Process Parameters (CPP)must provide a detailed description of the Critical Process Parameters including the set points and ranges, how they are monitored according to the batch records, and equipment controls. The protocol did not include a detailed explanation for the chosen CPP as required by the firm’s procedures.

Validation Protocol Report No,: VAL PRO-0166 explained that the [REDACTION] Critical Process Parameters (CPP) are [REDACTION] For example:

1a) Validation protocol indicates that the CPPs were established and justified based on developmental batches. The protocol did not have a detailed description for the scientific rational for choosing these CPPs. The protocol did not discuss the assessment conducted regarding the developmental batches.

2a) [REDACTION] was identified was [REDACTION] of the [REDACTION] CPPs. The protocol report indicated that [REDACTION] duration would be [REDACTION] as specified in the VMR. The protocol did not explain the scientific rational used to determine [REDACTION] Additionally, the protocol did not describe in detail how the [REDACTION] would be monitored. For example machine and product settings that could impact end product quality. There was no discussion for the CPP regarding the VMR in the protocol

3a) [REDACTION] was identified as the [REDACTION] CPP in the protocol. The target speed is identified to be [REDACTION] specified as listed in the VMR. The protocol did not explain the scientific rational for identifying the target speed. Additionally, the protocol did not describe in detail how the target speed would be monitored for example machine and product settings that could impact end product quality. There was no discussion concerning the VMR as it related to the CPP in the protocol.

B. The firm has [REDACTION] for [REDACTION] The [REDACTION] is then [REDACTION] Concerning the validation, there were no hold time studies discussed in the process validation report to assure that the final blend (in-process material) maintains uniformity and does not exhibit segregation during storage or transfer to the second [REDACTION] which is [REDACTION] Additionally, there were no hold time studies discussed in the process validation for the Coated Granulated Diphenhydramine HCL to assure that segregation does not occur and it maintains uniformity over time.

C. Per the Process Validation Protocol 20-Val-Protocol 20-VAL-PRO-0166 and Validation Report the initial batch matrix consists of [REDACTION] batches of formula [REDACTION] Grape Flavor and [REDACTION] batches [REDACTION] Cherry Flavor. Additionally, the report specifies batches [REDACTION](for Grape Flavor) and batches [REDACTION] (for Cherry Flavor) Validation Batches [REDACTION] and [REDACTION] were destroyed because they did not meet the product specifications [REDACTION] additional Grape Flavor batches were produced in replacement, batches [REDACTION] to meet the requirements of the validation matrix. A portion of the replacement validation batch [REDACTION] was rejected because the in-process tablet weight variability was greater relative to the other process validation batches. This portion of the batch was rejected without being fully tested and evaluated to see if the weight variations had any effects on the tablet content uniformity results, DPH assay or dissolution.

D. During process validation materials that did not meet their predetermined specifications were used in the process validation batches. Specifically, the Coated Diphenhydramine [REDACTION] did not meet the specification requirements of white to off white granules because dark specks were found in the materials. This material was placed on blocked status, not approved for use. However, the materials were released from the blocked status in order to allow them to be used in the process validation batches prior to the investigation being completed

[McNeil Consumer Heathcare, Div of McNeil-PPC, Inc., Date Issued: 12/09/2012]


Part 211 Subpart F – Production and Process Controls, Sec 211.113 Control of microbiological contamination

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Specifically,

a. The Sterile technique qualification (media fills) do not represent your routine operating conditions and does not evaluate worst-case activities that can provide a challenge to manual aseptic operations. Specifically,

  1. Your media fills do not challenge the maximum number of times drug product lots can be filled from sterile stock solutions or the maximum number of units filled without increasing the risk of contamination of the manufactured sterile drug product. For example stock solutions can be stored and used to fill over a curse of [REDACTION] days. Stock solution of Ropivacaine 0.2% lot S09132012@312 was used to fill approximately [REDACTION] final products lots in 09/2012
  2. Your aseptic process validation does not challenge representative container closure systems currently used at your facility that represents a worst case challenge. For example, your firm performs media fill studies with [REDACTION] bags when the following sizes: 25mL, 50mL, 150mL, 250mL, 500mL, 1000mL, 3000mL, and 4000,mL, bags are used during routine production.
  3. Your media fills do not simulate aseptic manufacturing operations that incorporate worst-case activities and conditions that provide a challenge to aseptic operations. For example; maximum number of personnel and their activities, and an evaluation of critical routine and non-routine interventions (e.g the continuous entering and exiting of the class 100 hoods used in the manufacture of sterile drug products.)

b. Sterile Filtration has not been validated for its intended use. For example:

  1. Bacterial retention challenge has not been performed for product contact [REDACTION] filters used to sterile filter injectable drug products intended for patient use for patient use for exampleFentanyl, Ropivacaine, etc. 
  2. [REDACTION] recommended to be use for general laboratory use and not intended for direct patient care applications
  3. The firm does not have the data, procedures, and controls to assure that additional rounds of filtration do not adversely impact product. Your firm re-filtered, at least one time, all sterile stock solutions lots involved in the sterility failures before releasing final drug product lots for patient use.

[Ameridose, LLc., Date Issued: 11/09/2012]


Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process. 

Specifically, 

1. The validation protocol for Media Fill Validation for the 5mL & 100mL vials in Rooms AH/AJ(Lyo Area) utilizing Lyophilize [REDACTION] listed key issues under the study design section that were not followed in the execution of the protocol. Therefore, the protocol requirements for the validation were not met. The following are the examples of requirements that were not followed in the execution of the protocol.

a. The fill volume requirement for the 5mL vial was [REDACTION] The fill volume was only [REDACTION] or [REDACTION] % for the [REDACTION] mL vial.

b. The protocol included a fill speed rate of [REDACTION] vpm (vials per minute) for the [REDACTION] mL vial. The fill speed rate for the [REDACTION] mL vial was run at a rate of [REDACTION] 

c. The protocol stated that duration of post-sterilization hold time for the pre-sterilized parts and components was to be NLT [REDACTION] hours. The hold time was less than [REDACTION] hours for the majority of the hold times.

d. The protocol stated that chamber for the lyophilizer must be held under slight vacuum conditions to simulate the process. The slight vacuum conditions were not created during the hold time when the media filled vials were in the lyophilizer chamber.

2. Failure to thoroughly investigate Media Fill Batch [REDACTION] Code [REDACTION] 100mL vials, performed in filling area AH and lyophilisation in room AJ on 7-28-08 when it was invalidated. The batch was invalidated because batch [REDACTION] failed to support the growth promotion test for Micrococcus luteus at the [REDACTION] incubation temperature for Tray [REDACTION] 

3. Lack of assurance that the microbiological growth media does in fact contact all of the interior surfaces of the LDPE bottles as well as the dispensing tip for the aseptic media fill process for ophthalmic finished products. The white color LDPE bottles does not allow for visually observing microbial growth that may be present in the inside of the finished product container. The dispenser tips are also made of opaque material which also does not allow for visually observing microbial growth that may be present. THIS IS A REPEAT OBSERVATION 

4. Failure of the have an adequate preventive action for the storage of integral reject (intervention integral rejects)for Media Fill Batch [REDACTION] for Code [REDACTION] 100mL vials performed in filling Area AH and lyophilisation in room AJ on 1/23/-24/08. After filling, batch [REDACTION] had 75 integral rejects (intervention integral rejects). The integral rejects were accidently disposed of by a production employee along with non-integral rejects while awaiting transfer to the incubator at another facility. This media fill was used to support the validation of filling area AH and Lophilizer [REDACTION]  

5. The initial review of the media fill batch records did not identify unauthorized pen amendment changes made by a production employee for the following Media Fill batches [REDACTION] and [REDACTION] A production employee crossed out the non-braided tubing, part number [REDACTION] listed in the batch record and made handwritten changes using a pen for the purpose of using a similar tubing, part number [REDACTION] without Quality Assurance approval at the time it was actually used in the media fills. This tubing is not listed in the master batch record for Media Fill Code [REDACTION] for Xylazine, Code [REDACTION] for Media Fills using 5 mL vials in filling area AH, Code [REDACTION] for Sarapin Injection, and Code [REDACTION] for Orphenadrine Citrate injection USP. The pen amendments were not identified until the final review by a second QA official.

6. Specifically, the validation protocol, V1904-08-00, entitled Process Simulation (Media Fill) Media Fill Validation for the 5mL & 100mL vials in Rooms AH/AJ (Lyo Area) utilizing Lyophilizer [REDACTION] included specific procedural requirements referenced in SOP AA204, the Media Fill Process Simulation Program. The protocol was approved by Quality Assurance even though some of the necessary requirements referenced in SOP AA204 were not correctly included in the original or executed protocol. Some requirements were also listed in the master batch record for the media fill and some were not referenced in the batch record. Because the requirements were incorrectly included in the original and executed protocol, several deviations occurred during the validation. The following are some of the deviations listed in the summary report for the validation.

a. The fill volume requirement for the 5mL vial was [REDACTION] mL or [REDACTION] %. The fill volume was only [REDACTION] g or [REDACTION] for the 5 mL vial. The root cause of the protocol deviation was that the protocol was different than what was required in the batch record.

b. The fill speed for the 100mL vial was run at a fill rate of [REDACTION] vpm (vial per minute). The protocol included a fill speed rate of [REDACTION] vpm. The root cause of the protocol deviation was that the protocol was different that what was required in the batch record 

c. The protocol stated that chamber for the lyophilizer must be held under slight vacuum conditions to simulate the process. The slight vacuum conditions were not created during the hold time when the media filled vials were in the lyophilizer chamber.

[Akorn, Inc., Date, Issued: 06/30/2009]

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process

Specifically,

a. The periodic performance qualification protocols for the [REDACTION] used to terminally sterilize 500ml and 1000ml drug products do not require that biological indicator D-values be comparable to those previously used to qualify the terminal sterilization process. Written procedure 90.M-0330, “D-values Associated with Microorganisms used for Sterilization Validation”, effective 7/20/12, allows for the stipulated biological indicator organism,  [REDACTION] to possess D-values ranging from[REDACTION]

b. There is no written procedure requiring that sporulation counts of the biological indicator organisms used to validate the performance of the [REDACTION]  are compared against each other and against scientifically justified specifications prior to heat shock processing, after health shock processing, and with the positive controls. Personnel at this currently utilize a non-proceduralized requirement that the post-heat shock sporulation counts must be within [REDACTION] % of the pre heat shock counts.

[Hospira, Inc., Date Issued: 03/01/2013] 


Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed. 

Specifically,

The Validation Change Request (VCR) 9799 dated 12/1/10 concerns the establishment of a unidirectional airflow zone above the [REDACTION] Line [REDACTION] (room) [REDACTION] capper operation via the installation of [REDACTION] self-contained, HEPA filtered air recirculation units and associated laminar flow curtains. The VCR concludes,” ...the combines system (HEPA recirculation units and associated laminar curtains) has proven capable of meeting the requirements of QPO.29.002, Microbiological and Environmental Control of Aseptic Process Operations Procedure, and has proven capable of maintaining an ISO Class 5 HEPA air supply until the product’s final cap seal has been applied.” However, there is no non-viable particulate monitoring performed to assure that the laminar flow curtained area is “capable of maintaining an ISO Class 5 HEPA air supply until the product’s final cap seal has been applied.” In addition;

1. The aforementioned corporate procedure “defines the minimum control limits and monitoring requirements for all Hospira manufacturing environments involved with sterile parenterals products produced by aseptic processing.” The following 30ml tear top vial type finished products are aseptically filled and capped with the use of the [REDACTION] Capper, 

  1. Acetylcysteine 20% Solution, USP, list #3308-04-13
  2. 2% Chloroprocaine T Hydrochloride Injection USP, list #4169-04-86
  3. 3% Chloroprocaine T Hydrochloride Injection USP, list#4170-04-86
  4. Bupivacaine HCL 0.25% EPI 1:200,000, list#9042-04-17
  5. Bupivacaine HCL 0.25% EPI 1:200,000, list#9042-04-87
  6. Bupivacaine HCL 0.25% EPI 1:200,000, list#9045-04-17
  7. Bupivacaine HCL 0.25% EPI 1:200,000, list#9045-0487 

However, during the capping process, the aforementioned finished products are not maintained within an ISO -5 environment in that they are exposed to an unclassified manufacturing environment in room [REDACTION]  

a. All materials, fill room equipment parts and utensils that are used for the manufacturing operations that are not subject to a sterilization process are decontaminated via a [REDACTION]process in the [REDACTION] #RMFJ-0477 [REDACTION] feet, room [REDACTION] The following provide a brief summary of observations;

  1. The engineer (Engineer-I) explained some of the key [REDACTION] process parameters, e.g, [REDACTION] The process parameters were evaluated during the [REDACTION] Cycle development and ultimately used to establish the [REDACTION] process. The Engineer-I confirmed that there exists no record of the cycle development studies to support the current [REDACTION] process,
  2. The manufacture’s cycle development guide defines the validation process to include [REDACTION] study, [REDACTION] distribution with[REDACTION] and a challenge with [REDACTION] For example, a[REDACTION]must be determined to establish the present sterilant concentration and the [REDACTION] via the use of [REDACTION] “are useful for assuring homogenous [REDACTION] patterns”. The Engineer-I confirmed that they have not performed a [REDACTION] profile or a [REDACTION] evaluation via an [REDACTION] evaluation for the [REDACTION] 
  3. The [REDACTION] process validation includes the use of [REDACTION] monitoring probes positioned at defined locations, each with a corresponding[REDACTION] on the [REDACTION] However, as previously note, there exists no [REDACTION] evaluation to assure a homogenous distribution within the [REDACTION] which will identify and establish the worst case [REDACTION] challenge locations of the [REDACTION] load configurations, which will in turn assists to assure that all materials are appropriately decontaminated prior to being transfer into the manufacturing controlled and classified area;
  4. The process validations included evaluations with various material load configurations on the [REDACTION] Regarding routine production opera tions, the QA Project Specialist confirmed, excluding the language noted in the aforementioned procedures, they do not have any specific load configurations for the [REDACTION]
  5. There is no record to document that the routine production load configurations do not exceed the validated load configurations established via the [REDACTION] process;
  6. The “Aseptic Sterilization Operations and Procedures” document #B5340_2023, and [REDACTION] Work Order” document #W5300_342, establish the routine production operations, for example, “Do not stack  items or allow other items to remain in contact with each other” and “Items loaded into the [REDACTION] most be loaded in a configuration that allows no contact with other items or cart”, respectively. The aforementioned standard procedures are silent with respect to defining and establishing the routine load configurations
  7. The Enginner-1 confirmed that the is no [REDACTION] profile performed or a [REDACTION] for the [REDACTION] Line [REDACTION] production[REDACTION] the [REDACTION] and the [REDACTION] that is used for Sterility Tests.

b. For fill line [REDACTION], we observed non-viable particulate (NVP) monitoring that is performed in close proximity to the aseptic filling zone. However, NVP measurements are not taken from other ISO-5 areas (e.g., [REDACTION] ) during the aseptic filling process.

c. The “Aseptic Gowning and Technique Procedure”, document #B5350_0996, establishes the “proper aseptic techniques” when engaged in the aseptic filling operations, which includes to “move slowly and avoid excessive body movements”. However, we observed fill room personnel movements and activities being performed in fill lines [REDACTION] that were inconsistent with the established standard operating procedure.

d. Senior Purchasing Agent explained that all of the gowning attire (e.g, personnel scrubs, clean room gowning/coverall, over shoe covers and goggles) used by personnel that enter into the manufacturing areas have an established minimum and maximum life of a garment, that is in terms of the number of laundry cycles. For example, the clean room gowning, coverall and overshoe covers have a life cycle of [REDACTION] laundry cycles, respectfully. The Senior Purchasing Agent confirmed that there is no standard procedure that defines and establishes the minimum and maximum life of a garment. In addition,

1. There exists no record to document the life cycle of the aforementioned gowning attire, which would assure that the garments and personnel attire are fit for use. 

e. “Smoke Profile for Air Flow Pattern (s) & Curtain Lengths” document #B7100_0003 establishes that the, “Smoke profiling helps determine the effectiveness of the unidirectional air flow, (commonly known as laminar air  flow) within the ISO 5 curtained areas of that cleanroom or class 100 cleanroom itself.” The air flow pattern evaluations include “the smoke profile is done in the operational mode or dynamically” and “the smoke should move down and away from product when introduced at or above product height. There should be no turbulent flow of air in the critical process areas.” The corporate “Facility Qualification Procedure” document #QVO.19.021 establishes the smoke test, “Evaluates the HVAC systems under consideration to determine the effectiveness of the unidirectional airflow under static and dynamic conditions.” The following provide a brief summary of some air flow pattern observations;

  1. For fill room[REDACTION] the evaluations did not include an assessment of the air flow from the HEPA filters that are positioned over the ISO-5 [REDACTION] to assure that the air flow from the ISO-7 surrounding area does not adversely affect the ISO-5 area (Note: the distance between the ceiling (HEPA) and the  [REDACTION] partition is approximately 3 feet);
  2. For fill room [REDACTION] the evaluations id not include an assessment to determine the affects of the air flow when opening and closing the [REDACTION] to assure that “the smoke should move down and away from product when introduced at or above product heights”;
  3. For fill rooms[REDACTION] the simulations of a replacement and/or removal of filling equipment e.g, “Replace fill pump”, “Replace solution tubing (includes from needle to pump and pump manifold)”, “Replace bladder and Stopper head”, the evaluations did not include the routine movements and personnel activities that are commonly performed during routine production operations;
  4. There has been no assessment performed to determine and assure that the air flow from the ISO-7 area does not enter into the ISO-5 area when personnel are performing the various personnel activities next to or when accessing the ISO-5 areas e.g, adjusting the fill equipment/needles, glass vial in feed area in rooms[REDACTION] and [REDACTION] (approximately , respectively), and when accessing the ISO-5 via the [REDACTION] (room) from the ISO-7 surrounding environment;
  5. There are a number of instances when the air flow pattern videos did not demonstrate that “the smoke should move down and away from product when introduced at or above product heights. There should be no turbulent flow of air in the critical process areas”. For example, for line [REDACTION] during [REDACTION] (Please note that the aforementioned simulations and approximate video time stamps are not intended to be an all inclusive or exhaustive list of examples);
  6. The various pieces of fill room equipment and materials used during routine production operations are transferred from the ISO-8 manufacturing support rooms and into the ISO-7 manufacturing areas (surround the ISO-5 critical zones) with the use of [REDACTION] There has been no assessment of the air flow patterns to assure that the air flow of the ISO-7 and ISO-5 areas are not compromised when opening and closing the room doors;
  7. The aforementioned procedure establishes to “allow enough smoke to be introduced to the area to observe the air pattern to the approximate exit of the unidirectional air flow area. If a question arises, introduce additional smoke until the air pattern is determined.” However, the air flow pattern videos for three individual evaluations (approximately 1 minute each) for fill line [REDACTION] (bldg) [REDACTION] documents no visible or distinctly visible smoke;

f. The microbiology department responsibilities include for example, the implementation of the Environmental Monitoring (EM) program and establishment of the microbial alert and action levels for the manufacturing areas (e.g, ISO-5, ISO-7 and ISO-8) and for personnel monitoring. The Biological Quality Supervisor confirmed that they have not performed an evaluation of the air flow pattern evaluations, which for example would assist to determine the appropriate EM site selections for passive and active sampling, the manufacturing areas and personnel activities that may present a degree of microbiological challenge to ultimately assure that the EM program appropriately captures all critical monitoring areas.

[Hospira, Inc., Date Issued: 03/01/2013] 


Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Specifically, the firm’s aseptic filling process simulation runs (media fills) designed to validate the aseptic filling of AmBisome in 20cc molded vials and 20 mm lyo stoppers utilizing the [REDACTION] vial filling and stoppering machine in APA 1079 and lyophilizer in 1077/1077B are deficient in thata: 

a. Modifications to the [REDACTION] vial filler and restricted access barrier (RAB) were made after qualification and media fills on 7/31/08, 8/2/08 were performed and approved without requalification and successful media fills until December 2008. Changes to air velocities and balancing of HEPA filters inside the RAB of the [REDACTION] vial filler were made after performing the media fills and were then set back to the condition (state closest) to that at the time of the media fill on 8/4/08

b. During the media fill performed in March 2009, modifications to the [REDACTION] vial filler and air flow within the RAB were performed between media fill # [REDACTION] and media fill # [REDACTION]

[Gilead Sciences Inc., Date Issued: 02/12/2010]


 




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