The European Union’s Annex 1, which specifies the GMP requirements for the manufacture of sterile medicinal products was originally issued in 1989, with partial updates in 1996, 2003, and 2007 (Anonymous, 2018b). In the years since the issuance, there have been many changes in regulatory influence and guidance, e.g., issuance of ICH Q9 for Quality Risk Management and ICH Q10, which describes the Pharmaceutical Quality System. Many of these changes in regulatory expectations have not been incorporated into Annex 1. There were also some issues of ambiguities and confusion in the requirements as issued. Another major area of change is regarding the production of Water for Injection. Recently, Pharm Europa was changed, and it now allows methods other than distillation. (Lyons, 2018) While these revisions have been anticipated for a long time, the draft was published in December 2017. (Anonymous, 2018)
One of the most notable changes is the total change of the order of sections in the Annex. (Anonymous, 2018)
This article discusses some of the changes and clarifications that have been made to the document. There are separate sections identified corresponding to the sections in the Annex.
This section is a typical description of where this document is applicable. However, it also contains some wording about various topics, e.g., contamination control, room qualification, classification, monitoring and gowning (lines 18-20) that would be appropriate to apply to non-sterile manufacturing processes. While true that these topics are useful to other types of manufacturing processes, why would non-sterile manufacturers review this document? Wouldn’t it be better to place this type of comment in a document for non-sterile manufacturing, referencing them back to this document?
This section opens with a variety of “special requirements,” which include references to Annex 11 and Annex 15 of the European GMPs as the requirements for qualification and validation; requirements for personnel to have appropriate training, skills and abilities; and that there must be appropriate processes and monitoring using qualified/validated systems and monitoring by personnel with appropriate process, engineering and microbiological knowledge. (lines 30-41)
It also references the appropriateness of management of the processes, equipment, facilities and manufacturing activities using quality risk management procedures proactively. (Lines 44-45)
The document highlights the importance of Quality Assurance and its responsibilities. One of those is the need to ensure that a contamination control strategy is implemented across the facility. Included in the strategy should be:
- Design of both the plant and the process
- Equipment and facilities
- Raw Materials Control - including in-process controls
- Product containers and closures
- Vendor approval – such as key component suppliers, sterilization of components and single use systems, and services
- For outsources services, such as sterilization, sufficient evidence should be provided to the contract giver to ensure the process is operating correctly
- Process risk assessment
- Process validation
- Preventative maintenance – maintaining equipment and premises (planned and unplanned maintenance) to a standard that will not add significant risk of contamination
- Cleaning and Disinfection
- Monitoring Systems – including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination.
- Prevention – Trending, investigations, corrective and preventive actions (CAPA), root cause determination and the need for more robust investigational tools.
- Continuous improvement based on information from the above systems (lines 50-54 and 69-106).
The key to this program is the minimization of the risk of contamination (lines 59-62). Another important feature of this program is that it should have a life-cycle approach with ongoing and periodic review and update (lines 56-57). The program should include potential sources of contamination like microorganisms, cellular debris (like pyrogens and endotoxin) and particulate matter (line 64-67).
The document clarifies that sterility testing alone (final product test) does not ensure product sterility (lines 108-110)
Pharmaceutical Quality System (PQS)
There is a significant section that has been prepared on the Pharmaceutical Quality System (PQS). It describes that this is in addition to the requirements specified in the EU GMPs chapter 1 (Lines 126-132). Several of the items listed in addition to the Chapter 1 requirements include:
- requirements for an effective risk management system in the product life cycle,
- the manufacturer has sufficient knowledge and expertise in relation,
- expectations to identify, assess and eliminate (where applicable) contamination control risks,
- conducting regular review and periodic product reviews including change control and risks,
- protection of container closure integrity during finishing and transport of sterile products,
- personnel responsible for quality release are appropriately knowledgeable and have access to required records and information (lines 134 – 164)
There is a section that describes the need for investigations for non-conformities, and it specifically talks about sterility test failures and environmental monitoring excursions as it relates as the potential impact to sterility. This statement may change the policies for companies that do not routinely perform investigations for each environmental excursion (lines 166-171)
This section provides guidance on the appropriate number of personnel that should be present, and when we should be using the minimum number of people versus the maximum number of people. It also addresses the need for training, qualification and monitoring of personnel. Within this section there are specific details for where personnel should be monitored and how they should be gowned for different stages of the process. There should also be written procedures that include how to disqualify individuals from working in aseptic areas. (lines 175 – 301)
While we are used to the wording about prohibition of jewelry, wristwatches, and make-up, there is a specific new wording about the prohibition of mobile phones. In some companies the use of mobile phones in cleanrooms and throughout the manufacturing process is excessive. This change could have a significant impact on many companies, if it is in the final issuance of the Annex (lines 236-237).
There is also specific wording that for sterilized gowning must be changed at least for every working session in Grade A and B areas (lines 281-284). For some companies this can be a major change to their processes.
This section provides specific guidance on the use of classified areas, including where airlocks should be used. It further describes the qualification and requalification of these areas. There are similar sections wording the design of cleanrooms as in the FDA GMPs, 21CFR §211.42. It also prohibits sinks and drains from Grade A/B areas (lines 305 – 398).
There is a requirement for the visualization of air flow patterns in Grade A/B areas to determine if the flow is unidirectional. It also discusses that visualization studies may be necessary in other areas based upon risk assessment. Lastly it indicates that the airflow studies should be consulted in determining the environmental monitoring program (lines 412-421).
Sections are included for barrier technologies (lines 435 – 483), Clean room and clean air device qualification (lines 487- 565), which includes all of the tables for particulate levels in each room Grade. One of the interesting things in this section is that although many expected the removal of requirements for monitoring of 5µm particles. However, this did not occur in the draft. There is a new useful column that describes the ISO classification both in operation and at rest (Table 1 starting at line 505).
There is also specific information provided for the initial classification of the minimum number of sampling locations as in ISO 14644-1. While stating this, it also indicates that a higher number of samples and sample volumes are typically required in the aseptic processing room and the immediately adjacent environment (Lines 51—517).
Clarifications are provided in lines 519 – 530 of what specifically is meant by “in operation” and “at rest.”
Starting at line 544, there is Table 2, which describes the “Recommended limits for microbial contamination in operation.” This table previously had a footnote that allowed for an average of >1 cfu before an investigation be conducted. This footnote (lines 550-551) has been changed to state: “It should be noted that for grade A the expected result should be 0 cfu recovered; any recovery of 1 cfu or greater should result in an investigation.” This new wording is consistent with the USA FDA requirements but it a significant change in interpretation for European companies.
Another interesting comment is provided in section 5.30 (lines 563-565). Regarding temperature and humidity, it discusses that these parameters should not interfere with the defined cleanliness standard.
A subsection on Disinfection is included in this section. In section 5.31 (lines 569-578) there is some interesting wording. It says that “more than one type of disinfecting agent should be employed, and should include the periodic use of a sporicidal agent.” It is not clear whether this section is stating that rotation of disinfectants is required or if it is sufficient to use a routine disinfectant along with a sporicidal agent. In line 576 it also talks about the “ability to detect the development of resistant and/or spore forming strains.” This section is not clear as to whether a specific test method is required or whether monitoring trend analysis to see if so-called sensitive organisms are showing up in the monitoring program. It would be good to have some clarification in this section.
In section 5.32 (lines 580-583) there is wording describing the need to monitor disinfectants and detergents for microbial contamination. It is not clear whether this applies only to non-sterile preparations or also requires monitoring of sterile formulations.
This section requires detailed descriptions of the equipment design, that should be kept up to date (lines 593-595). There is no provision for systems that may not have had been implemented prior to this requirement. As such, it would necessitate companies to “create” these documents for systems that would likely be treated “as built” designs. The design document specifically needs to describe the product, and other critical gas and fluid pathways and controls.
Conveyor belts are discussed in section 6.8 (lines 625-627). This section requires that the belt “cannot go through from a Grade A to Grade B area or other area of lower air cleanliness, unless the belt itself is continuously sterilized (e.g., in a sterilizing tunnel). This wording can be confusing, as it is not clear if the belt must go through the sterilizing tunnel immediately before passing to a lower-class area or not. Additionally, if it must be “immediately” sterilized this could be burdensome for companies to find appropriate systems.
Qualification of particle counters is discussed in section 6.9 (Lines 629-631). This is interesting as many currently believe that calibration alone is sufficient. The Annex does not provide any guidance on what is expected as part of the qualification.
This section describes the requirements for utilities and includes risk assessment, drawings (that are current) and periodic reevaluation of risks.
There is a subsection on water systems starting at line 665. Some of the changes in this part of the annex is an update to talk about the allowances for production of water for injection that is not manufactured utilizing distillation. This is consistent with the changes to the pharmacopeia that make this same allowance.
Section 7.10 (lines 682) is interesting, in that it says: “Water flow should remain turbulent through the pipes to prevent microbial adhesion.” While continuous flow is desired, some systems have still had biofilms produced even with continuous flow. More information on the prevention of biofilm formation is discussed in section 7.13 (lines 691 – 696). In this section, a concern arises in that the “water should be analyzed after disinfection/regeneration; results should be approved before the start of use of the water system.” For companies that do not use rapid microbiological methods, this could cause a longer shut-down than typically expected awaiting microbiological results to be obtained and approved.
In section 7.15 the annex clearly expects continuous monitoring of total organic carbon (TOC) and conductivity (lines 710-711).
There is a subsection for steam used in sterilization starting on line 713. There are some specific requirements stated for tests that should be conducted for steam in place systems.
Another subsection starts on line 725 covering compressed gases and vacuum systems.
Cooling systems are addressed starting at line 738. This section requires controls to contain spillage and cross-contamination. It also states that: “any leaks for the cooling system must be detectable.” For existing systems, it could be difficult to retrofit the system with these types of leak detection methods.
Production and Specific Technologies
This section specifically describes the requirements for terminally sterilized product, aseptic preparation, finishing of sterile products, sterilization, sterilization by heat, moist heat sterilization, dry heat sterilization, sterilization by radiation, sterilization with ethylene oxide, filtration of medicinal products which cannot be sterilized in their final container, form-fill-seal, blow-fill-seal technology, lyophilization, closed systems, and single-use systems.
This part of the annex contains the bulk of the information.
Some highlights from this major section include:
- The terminal sterilization section (starting at line 754) if very consistent with the previous version.
- The aseptic preparation section (starting on line 785) is consistent with requirements in the FDA’s Aseptic Processing Guidance (2004) and the PIC/s document on Aseptic Processing.
- Finishing of sterile products (starting on line 875) specifically requires partially closed containers need to remain under Grade A conditions until it is in the lyophilizer. There are also some specific requirements stated for the “defect library” used in visual inspection processes. It also indicates that automated inspection systems should be as good as visual inspection or better.
- The sterilization section (starting on line 953) states that if possible, products should be terminally sterilized. This is consistent with the EMEA decision tree on sterilization methods to use. This section highlights some of the ways quality risk management procedures should be used. There are specific requirements for the use of suitable biological indicators and how they should be used.
- Sterilization by heat starts on line 1058. There is a specific section (8.48) which discusses processes for which parametric release is used.
- Moist heat sterilization starts on line 1098.
- Dry heat sterilization starts on line 1155. It is interesting that there is specific wording (lines 1181-1183) that address endotoxin spiked containers. It includes a specific reconciliation of the spiked units, endotoxin quantification and recovery efficiency to be demonstrated.
- Sterilization by radiation starts on line 1206.
- Sterilization with ethylene oxide starts on line 1206. It was sad to see that only gas sterilization using ethylene oxide is discussed. There are other acceptable gas sterilization methods available, e.g., ozone, chlorine dioxide, and nitrogen dioxide. These technologies would be a good inclusion.
- Filtration of medicinal products which cannot be sterilized in their final container begins on line 1249. Interestingly, in lines 1283-1285 it talks about allowing sterilization procedures that have a SAL of 10-6 or better. It is not clear if this is meant to clarify that you can sterilize post aseptic filling or if there is an expectation of this level of sterility assurance on an aseptic process. It is important to remember that there is no way to calculation the SAL of aseptic products that are not subsequently subjected to terminal sterilization. Lines 1360-1362 discuss the need to discard sterilizing filters after processing a single lot. It also says that the filter cannot be used for more than a SINGLE working day. This may cause some concern for producers of long campaign runs and/or identical product that is filled with the same product but may have different labels (as they may be different lot numbers).
- Form-fill-seal starts on line 1364. This section is consistent with existing requirements.
- Blow-fill-seal Technology starts on line 1385. This section adds requirements for risk management procedures. It also provides specific guidance for shuttle and rotary type equipment.
- Lyophilization begins on line 1450.
- Closed systems are discussed starting on line 1492.
- Single-use systems are discussed starting on line 1517. It discusses the specific risks associated with this type of system.
Viable and Non-Viable Environmental and Process Monitoring
The document describes that these programs are part of the overall site contamination control program. These programs are important with respect to maintenance of sterility assurance. This is an interesting section that includes viable monitoring, non-viable monitoring and aseptic process simulations. This section starts on line 1580.
Some of the highlights from this section include:
- Clarifies the requirements and expectations for use of risk assessment in these processes.
- Discusses the need for visualization studies (smoke studies) are important considerations in evaluating the effectiveness of the program.
- States “routine monitoring” should be performed in operation, with a few exceptions provided.
- Alert levels should be established based upon data and subject to periodic review.
- If action levels are exceeded, root cause investigations should be conducted including corrective and preventative actions.
- Operational Grade D non-viable particulate levels in operation should be based upon risk assessment.
- Monitoring of 5 µm particles is required for routine monitoring. Some provisions provided for occasional “false” data.
- Continuous monitoring expected for particles in Grade A areas during operation including set-up. Similar monitoring should be conducted in Grade B areas; may have a lesser frequency.
- Continuous monitoring of viable contaminants in Grade A and Grade B areas is expected. For some companies, only periodic monitoring is conducted in these areas.
- Line 1735 describes the use of rapid microbiological methods and how they can be adopted.
- Lines 1753-1754 also identifies the expectation of 0 cfu in Grade A and B areas. It removes the footnote that allowed for averaging of results.
- Lines 1759-1766 provides several specific examples of adverse trends in environmental data. This will be very useful for many companies.
- Section 9.33 (lines 1768- 1772) includes requirements for identification of microorganisms.
- Aseptic Processing Simulation (Media Fills) is discussed starting on line 1774. Most of this section reflects current FDA and PIC/s expectations. One line is disconcerting (line 1845), which states: “ensuring that any contamination is detectable.” Most conventional methods do not have the ability to detect single cells, so it is unlikely that very low levels of contamination are detectable with conventional methods.
- Contaminated units in an aseptic process simulation, even 1, is expected to include a root cause investigation and appropriate corrective and preventative actions (see lines 1911 – 1918). It also provides for use of quality risk management in determining the number of repeat studies required.
This section begins on line 1952.
Much of this section describes a variety of controls that should be used. It describes bioburden testing and the need for monitoring on suitable schedules. This document highlights that the sterility test alone is not sufficient to ensure the sterility assurance of the product. This section also requires review of environmental monitoring data as part of batch release.
A comprehensive glossary begins on line 2011. This section is very useful in understanding the document.
The proposed Annex 1 is open for comment until March 20, 2018. Comments can be submitted at: https://ec.europa.eu/health/human-use/quality/developments/pc_2017_12_sterile_medicinal_products_en. This is the time to note those sections which are of concern to you. Waiting until the final document is issued is not the time to “want it to change.”
Anonymous (2018) Impact of the Annex 1 Revision on Pharmaceutical Water. ECA Academy. Downloaded from: https://www.gmp-compliance.org/gmp-news/impact-of-the-annex-1-revision-o... on February 5, 2017.
Anonymous (2018b) Annex 1: Manufacture of Sterile Medicinal Products. Information. Available Annex 1 is open for comment until March 20, 2018. Comments can be submitted at: https://ec.europa.eu/health/human-use/quality/developments/pc_2017_12_st...
Lyons, J. (2014) Annex 1 (Manufacture of Sterile Medicinal Products) Update. Pharmalex. Downloaded from: https://mcgeepharma.com/eur/annex-1-manufacture-of-sterile-medicinal-pro... on February 5, 2018.