Risk Considerations for Installation of a New Autoclave in a Pharmaceutical Manufacturing Facility

Tim Sandle

May 6, 2015 11:00 pm EDT

ABSTRACT

This paper addresses some of the risk considerations that must be evaluated when replacing a steam sterilizing autoclave within a pharmaceutical processing facility. It demonstrates the application of Failure Modes and Effects Analysis (FMEA) for assessment of risk as part of quality risk management. Formal risk approaches normally share four basic concepts including risk assessment, risk control, risk review, and risk communication. Risk management is fundamentally about understanding what is most important for the control of equipment or design quality and then focusing resources on managing and controlling these aspects. Before risks can be managed, they need to be assessed. FMEA is a widely used risk assessment tools. Steps to perform FMEA are identified; questions to be asked are listed. Criteria for risk assessment must be defined. Either a numerical scoring system or marker phrases such as “high,” “medium,” “low” may be utilized. Three areas are evaluated: Severity of the hazard, likelihood of occurrence, and likelihood of detection. Tables for classifying these aspects are provided. A team approach to risk assessment is recommended. The risk assessment process is demonstrated using the example of a steam sterilizing autoclave replacement.

INTRODUCTION

This paper addresses some of the risk considerations that must be evaluated when replacing a steam sterilization autoclave within a pharmaceutical processing facility. A cast study format is utilized. In outlining the key risk considerations, the paper demonstrates a risk assessment approach – Failure Modes and Effects Analysis (FMEA).

An autoclave is a pressure chamber used to sterilize equipment and supplies by subjecting them to high pressure saturated steam (1). Autoclaves are used within pharmaceutical facilities to eliminate microbial cells and spores from within a given device. Autoclaves commonly use steam heated to 115–134°C (250 273°F). To achieve sterility, a holding time of at least 30 minutes at 115°C, 15 minutes at 121°C (250°F) or 3 minutes at 134°C (273°F) is required (2).

The validation and verification of the sterilization process is well monitored in the pharmaceutical industry. Operators must ensure that autoclaves comply with various regulatory guidances and regulations. Nonetheless, the purchase of a new autoclave and the assessment requires evaluation. An additional dimension is added when one autoclave is being used to replace another, as with the case study discussed here. To make such an evaluation, a formal risk assessment is required under the auspices of quality risk management.

Risk management and risk assessment principles should be applied as early as possible during the design and construction of steam sterilization devices. The most critical functions in a steam sterilization device are the steam sterilization of direct and indirect the product contact parts. A second important aspect relates to air removal. All of the trapped air must be removed from the autoclave before activation. Trapped air is a very poor medium for achieving sterility during the sterilization cycle.

Formal risk approaches normally share four basic concepts, which are listed below:

Risk assessment
Risk control
Risk review
Risk communication.

This paper considers the application of FMEA, failure modes and effects analysis, to the replacement of a steam-sterilizing autoclave in a pharmaceutical manufacturing facility.

FAILURE MODES AND EFFECTS ANALYSIS (FMEA)

Risk management is fundamentally about understanding what is most important for the control of equipment or design quality and then focusing resources on managing and controlling these aspects to ensure that risks are reduced and contained. Risks relate to a situation, event or scenario where a recognized hazard may result in harm. Before risks can be managed, they need to be assessed (3).

Risk assessment involves identifying risk scenarios. In relation to cleanroom and clean air design, this should ideally be a prospective exercise rather than in reaction to a failure. This process involves determining what can go wrong in the system and all the associated consequences and likelihoods. To achieve this, some kind of risk assessment tool is required (4).

Three key definitions are outlined in ICH Q9(5). These help to contextualize what is meant by “risks.”

Risk: The combination of the probability of occurrence of harm and the severity of that harm
Harm: Damage to health, including the damage that can occur from loss of product quality or availability
Hazard: The potential source of harm.

For engineering systems, one of the most widely used tools for risk assessment is Failure Modes and Effects Analysis (FMEA) (6).

FMEA is a highly structured approach and can be undertaken through the following steps:

a) Setting the scope

b) Defining the problem

c) Setting scales for factors of severity, occurrence and detection (see below)

d) Process mapping

e) Defining failure modes

f) Listing the potential effects of each failure mode

g) Assigning severity ratings to each process step

h) Listing potential causes of each failure mode

i) Assigning and occurrence rating for each failure mode

j) Examining current controls

k) Examining mechanisms for detection

l) Calculating the risk

m) Examining outcomes and proposing actions to minimize risks.

STARTING THE RISK ASSESSMENT PROCESS

Before commencing a risk assessment, it is important to define the size and the scope of the assessment while remaining focused on what is to be achieved, to select the appropriate team (often an interdisciplinary team is best); selecting and reviewing the appropriate risk management tool; deciding upon any numerical scale to be used, and prioritizing the different problems to be addressed.

These steps can be broke down as follows:

Gathering data through an audit and analysis
Constructing diagrams of work flows
Pin-pointing areas of greatest risk
Examining potential sources of contamination
Deciding on the most appropriate sample methods
Helping to establish alert and action levels
Taking into account changes to the work process / seasonal activities
Using some type of scoring system so that the risk can be ranked and the level of risk determined.

In doing so the following questions should be asked:

What is the function of the equipment?
What are its performance requirements?
How can it fail to fulfill these functions?
What can cause each failure?
What happens when each failure occurs?
How much does each failure matter? What are its consequences?
What can be done to predict or prevent each failure?
What should be done if a suitable proactive task cannot be found?

These reflective questions help to structure the risk assessment activity.

RISK CRITERIA

It is important to establish the risk assessment criteria as part of the risk assessment exercise. This is necessary in order to place risks in proportion to one another and against a universal scale. Without this, it cannot be determined whether one risk is a greater or lesser problem compared with another, or if a given risk could potentially result in patient harm.

FMEA may utilitze either a numerical scoring system or marker phrases such as “high,” “medium,” “low’ for quantitation. Marker terms are used in the following case study.

These terms are applied to three aspects. These are the severity of the hazard; how likely the hazard is to occur; and whether there are any mechanisms in place to detect the hazard should it occur. Here:

Severity is the consequence of a failure, should it occur
Occurrence is the likelihood of the failure happening based on past experience
Detection is based on the monitoring systems in place and on how likely a failure can be detected. Sometimes, a good detection system is described as one that can detect a failure before it occurs.

When these three are cross-compared, the overall risk can be established. The best means to do this is through the use of risk filters. These are illustrated in Tables 1 and 2 below.

Before looking at the risk filter tables, it is necessary to define each of the terms used to establish the overall risk.

Severity of Impact

High = Patients safety will be impacted
Medium = Potential patient safety issues
Low = No impact on patient

Likelihood of Occurrence

High = 1 failure per year
Medium = 1 failure every 5 years
Low = 1 failure every 10 years

For documentation, the likelihood is as follows:

High = No Documentation
Medium = Incorrect Documentation
Low = Documentation present and correct

Probability of Detection

Low = Will not be detected by in-place systems
Medium = Only one mechanism for detection by existing systems
High = More than one mechanism for detection by existing systems

RISK CLASSIFICATION AND RISK FILTERING

Record the risk classification based upon the impact and likelihood from the table (Table 1). This is established through the use of a filter (or matrix).

CLASSIFICATION OF RISK
Impact	Likelihood
		Low	Medium	High
	Low	LOW	LOW	MEDIUM
	Medium	LOW	MEDIUM	HIGH
	High	MEDIUM	HIGH	HIGH

TABLE 1: CLASSIFICATION OF RISK

Risk Priority

Record the risk priority based upon the risk classification and probability of detection from the table.

RISK PRIORITY
Risk Classification	Probability Of Detection
Risk Classification	High	Medium	Low
Low	LOW	LOW	MEDIUM
Medium	LOW	MEDIUM	HIGH
High	MEDIUM	HIGH	HIGH

TABLE 2: RISK PRIORITY

Risk Process

In formulating the risk assessment a group was assembled consisting of engineering, validation, microbiology, and the end-users. The process began by identifying the key risk factors and potential failure modes. These were described as “functional details.” Once these were defined, these primary categories were broken down into sub-steps that are termed “sub-functional details.”

Once these were selected and agreed, the steps were grouped together. The group then proceeded to assess the risk for each step, using the FMEA schema outlined above. This consisted of:

a) Considering the relevance of each sub-functional detail. For example, whether it could potentially impact upon product quality
b) The possible risk scenarios were considered
c) The severity of impact was then assessed as either “high”, “medium” or “low”, using the definitions outlined above
d) The likelihood of impact was then assessed, using the same descriptors
e) With the severity and likelihood assessed, the risk class was determined using Table 1 above.
f) The probability of detection was assessed next
g) Knowing the probability of detection allowed the overall risk priority to be determined using Table 2 above.
h) The penultimate step was to consider whether any controls or risk mitigation factors were in place
i) The final step was to reach a conclusion in relation to risk management.

The risk assessment process is outlined in Appendix I using the example of a steam sterilizing autoclave replacement.

Equipment preparation

The defined loading of the autoclave with equipment to be sterilized in an important sub-functional detail is in autoclave operation. The relevance of loading an autoclave incorrectly significantly impacts product quality. Here the risk scenario is an incorrect sterilization of the load. In this case:

a) The severity of impact would be high;
b) The likelihood of impact could be medium.

This produces, according to Table 1, a high risk class.

The probability of detection would be low, because the activity is operator dependent and there are no system aspects that prevent an incorrect load from being prepared. Therefore, using Table 2, the risk priority is high.

However, in terms of risk mitigation and risk management, a clear SOP can be put in place and operators can be trained in order to lower the possibility of an incorrect load being prepared. In addition:

Photos of the loads can be prepared during the Operational Qualification
Schematics may be included in the SOP
Worst-case loads can be verified during both the Operational Qualification and Performance Qualification.

This example is included in Appendix I. Other sub-functional steps were derived using similar processes.

RISK EXAMPLE

Appendix I contains an example of risk assessment for a replacement steam-sterilizing autoclave. The table is arranged in a fashion to facilitate the risk assessment steps described above where functional and sub-functional steps are outlined. The case study was designed around a particular device and should be regarded as illustrative. Users embarking on a similar process may take note of the items covered. However, they should construct their own risk schematic and reach conclusions that are relevant to their own particular circumstances.

CONCLUSION

The final assessment of the FMEA risk exercise was that the new autoclave can be fitted and that the risks are adequately controlled. It was noted that although the new autoclave has newer control systems technology, the steam sterilization principles together with the load/ test cycles remain in line with the autoclave that is being replaced.

The FMEA risk assessment methodology was appropriate to the task. An alternative approach could have been to use a numerical risk assessment. However, the use of descriptor words like “high,” “medium,” and “low” proved adequate in relation to the activity.

REFERENCES

Sandle, T. (2013). Sterility, Sterilisation and Sterility Assurance for Pharmaceuticals: Technology, Validation and Current Regulations, Woodhead Publishing Ltd.: Cambridge, UK, pp93-110
Hugo WB (1991). A brief history of heat and chemical preservation and disinfection. J. Appl. Bacteriol. 71 (1): 9–18
Sandle, T. (2011): Risk Management in Pharmaceutical Microbiology. In Saghee, M.R., Sandle, T. and Tidswell, E.C. (Eds.) (2011): Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices, New Delhi: Business Horizons, pp553-588
Sandle, T. and Lamba, S. S. (2012) Effectively Incorporating Quality Risk Management into Quality Systems. In Saghee, M.R. Achieving Quality and Compliance Excellence in Pharmaceuticals: A Master Class GMP Guide, New Delhi: Business Horizons, pp89-128
ICH Q9: Quality risk management. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH, Geneva (November 2005)
Sandle, T. (2003). The use of a risk assessment in the pharmaceutical industry – the application of FMEA to a sterility testing isolator: a case study, European Journal of Parenteral and Pharmaceutical Sciences; 8(2): 43-49

FMEA KEY

BI - Biological Indicator

IQ - Installation Qualification

O&M - Operation and Maintenance

OQ - Operational Qualification

PQ - Performance Qualification

PC - Personal Computer

SOP - Standard Operating Procedure

SAT - Site Acceptance Test

UPS - Uninterruptable Power Supply

APPENDIX 1

Project: Replacement of the Steam Sterilizing Autoclave - Risk Assessment
Function Details	Sub-Functions Details		Assessment of Risk							Controls In Place	Risk Management
Function Details	Sub-Functions Details		Relevance	Risk Scenarios	Severity of Impact	Likelihood of Impact	Class	Probability of Detection	Overall Priority	Controls In Place	Risk Management
Equipment	Autoclave Operation And Maintenance Manuals		cGMP	Incorrect documentation supplied	High	Medium	High	High	Medium	SAT	Documentation check during IQ.
Equipment	Autoclave Operation And Maintenance Manuals		cGMP	No documentation supplied	High	Medium	High	High	Medium	SAT	Documentation check during IQ.
Equipment	Drawings And Schematics (Including P&ID and General Assembly drawings)		cGMP	Drawings not the latest revision	High	Medium	High	High	Medium	Functional Specification	Documentation review and approval of Functional Specification.
Equipment			cGMP	No drawings supplied	High	Medium	High	High	Medium	Functional Specification	Documentation review and approval of Functional Specification.
Equipment	Equipment Inspection		cGMP	Poor Design and construction. Components not securely installed	High	Medium	High	High	Medium	SAT	Equipment inspection during commissioning & IQ checks.
Equipment	Equipment Inspection		cGMP	Poor construction. Components damaged	High	Medium	High	High	Medium	SAT/ EN285	Equipment inspection during commissioning & IQ checks.
Equipment	Equipment Inspection		cGMP	Manufacture not performed according to a recognized standard	High	Low	Medium	High	Low	SAT	Documentation check to confirm that manufacturing according to BS5750 or equivalent.
Control System	Standard Operating Procedures		cGMP	SOP not in place	High	Low	Medium	High	Low	SAT/ Training	To be created/ Approved post supplier training.
Control System	Standard Operating Procedures		cGMP	SOP followed incorrectly	High	Low	Medium	Medium	Medium	Training	Supplier/ Training and SOP sign off.
Equipment	Maintenance Programme		cGMP	Maintenance requirements not identified	High	Low	Medium	High	Low	Asset register	Asset Registration Form
Equipment	Maintenance Programme		cGMP	Maintenance procedure not produced	High	Low	Medium	High	Low	Asset register	Asset Registration Form
Operations	Equipment Logbook		cGMP	Logbook not present	High	Low	Medium	High	Low	SOP	Equipment Registration and Assessment
Operations	Equipment Identification		cGMP	Incorrect labeling	High	Medium	High	High	Medium	SOP	Equipment Registration and Assessment
Operations	Equipment Identification		cGMP	No identification	High	Medium	High	High	Medium	SOP	Asset Number check during IQ.
Operations	Spare Parts And Consumables		Business Critical	Spare Parts List not available	High	Low	Medium	Medium	Medium	SOP	Documentation check during IQ.
Operations	Spare Parts And Consumables		Business Critical	Consumables not identified so not in stock	High	Low	Medium	Medium	Medium	SOP	Equipment Registration and Assessment
Equipment	Materials In Product Contact		cGMP	Materials not suitable	High	Low	Medium	High	Low	SAT	Documentation check during IQ.
Equipment	Materials In Product Contact		cGMP	Documentation not available	High	Low	Medium	High	Low	SAT	Documentation check during IQ.
Equipment	Lubricants		cGMP	Incorrect lubricants supplied	High	Low	Medium	High	Low	SAT	Documentation check during IQ.
Equipment	Lubricants		cGMP	Lubricants not pharmaceutical grade	High	Low	Medium	High	Low	SAT	Documentation check during IQ.
Equipment	Filters		Business Critical	Filters not available	High	Low	Medium	High	Low	SAT	Documentation check during IQ.
Equipment	Filters		Business Critical	Incorrect filters supplied	High	Low	Medium	High	Low	SAT	Documentation check during IQ. Engineering Stores to stock critical filters.
Equipment	Control System Hardware		cGMP	Incorrect components supplied	High	Low	Medium	High	Low	SAT	Documentation and Hardware check during IQ.
Equipment	Control System Software		Business Critical	Incorrect version of the software supplied	High	Low	Medium	High	Low	SAT	Documentation and Software check during IQ.
Equipment	Control System Software		Business Critical	EPROM failure	High	Low	Medium	High	Low	SAT	Documentation and Hardware check during IQ.
Equipment	Control System Software		Business Critical	No software backup disk supplied	Medium	Low	Low	High	Low	SAT	Back up disk check during IQ.
Equipment	Monitoring System		cGMP	Back up battery failure in Chart Recorder	Medium	Low	Low	High	Low	SAT	Battery checked during IQ.
Operations	Environmental Requirements		Business Critical	Plant room too hot for Autoclave control system to operate.	High	Low	Medium	High	Low	Preliminary works	Plant room temperature to be controlled via extraction and additional cooling if necessary.
Equipment	Equipment Generated Particles		cGMP	Autoclave sheds dust/ particles into clean rooms.	High	Low	Medium	High	Low	SAT	Material type compliance certs to be checked during IQ.
Operations	Utility Requirements		cGMP	The utilities supplied do not allow sterilisation conditions to be achieved.	High	Low	Medium	High	Low	Utilities to be tested IQ/ SAT	The critical utilities will be designed to be tested at SAT.
Operations	Utility Requirements		cGMP	Services are not satisfactorily connected	High	Low	Medium	High	Low	SAT	Services to be checked during commissioning and SAT.
Equipment	Operating Specifications		cGMP	Autoclave Operating Specifications are set-up incorrectly	High	Low	Medium	High	Low	SAT	To be checked and documented during OQ
Operations	Maintenance works		cGMP	Maintenance work on the steam, water or piped gas services is performed after installation/ operational tests are completed	Medium	Low	Low	High	Low	SAT	Tests must be repeated before commissioning starts.
Equipment	Calibration Information		cGMP	Critical instruments not identified	High	Low	Low	High	Low	SAT/ SOP	Identification and classification of instruments during IQ
Operations	Critical Instruments		cGMP	Critical instruments not calibrated	High	Low	Low	High	Low	SAT/ SOP	Identification and classification of instruments during IQ
Operations	Critical Instruments		cGMP	Calibration Certificates not available	Medium	Low	Low	High	Low	SAT/ SOP	Documentation check during IQ. Calibration schedule updated.
Operations	Critical Instruments		cGMP	Calibration Laboratory not traceable to UKAS	Medium	Low	Low	High	Low	SAT/ SOP	Documentation check during IQ.
Operations	Training		cGMP	Operators not trained	High	Medium	High	High	Medium	Supplier Training/ SOP	Autoclave Supplier Training to be completed on site post commissioning and SOP to created and signed off for training.
Operations	Utility Requirements		cGMP	Equipment operation interferes with other equipment in the same room	Medium	Medium	Medium	High	Low	SOP	Utility Impact Assessment/ Change Control/ SOP
Equipment	Operation		cGMP	Equipment is not safe to operate	High	Medium	High	High	Medium	SAT	Commissioning Safety checks, and SAT checks to ensure safety. PUWER risk assessment.
Operations	Equipment Setup		cGMP	Setup incorrect	Medium	Medium	Medium	High	Low	Training/ SOP	Training & Sign off against SOP.
Equipment	Power Failure Recovery		Business Critical	EPROM does not have the latest version of the software after SAT changes	Medium	Low	Low	High	Low	SAT/ Change Control	Checks made during SAT and any changes/ or deviations noted in change control.
Equipment	Power Failure Recovery		Business Critical	Batch data lost when equipment power restored	Medium	Low	Low	High	Low	Training/ SOP	SOP to train out process for recovery.
Equipment	Power Failure Recovery		Business Critical	Previous version of the software loaded after power restoration	Medium	Low	Low	High	Low	Training and Maintenance SOP	SOP to train out process for recovery.
Equipment Alarms	Safety Devices		cGMP	Steam Valve failure	High	Low	Medium	High	Low	SAT/ Maintenance	Checked during SAT and added to Maintenance schedule
Equipment Alarms	Sensors		cGMP	Temperature sensor failure	High	Low	Medium	High	Low	SAT/ Maintenance	Checked during SAT and added to Maintenance schedule
Equipment	Interlocks		cGMP	Unloading door opens after a Bowie Dick Test	Medium	Low	Low	High	Low	SAT/ SOP	Checked during SAT and regular SOP checks
Equipment	Interlocks		cGMP	Both doors open at the same time	Medium	Low	Low	High	Low	SAT/ SOP	Checked during SAT and regular SOP checks
Equipment	Interlocks		cGMP	Unloading door opens after cycle failure	High	Low	Medium	High	Low	SAT/ SOP	Checked during SAT and regular SOP checks
Control System	Algorithm Verification		cGMP	Algorithms used in the calculation of critical parameters is incorrect	High	Low	Medium	High	Low	Functional Specification/ SAT	Checked at Functional Specification review and SAT
Control System	Operator Panel and Screen Navigation		Operation	Operator panel does not function as specified in the operator manual	Medium	Low	Low	High	Low	SOP/ Maintenance	Checked during SAT and normal operation.
Control System	Security		cGMP	Security levels not set up on the software	Medium	Low	Low	High	Low	SOP/ Training	Checked during SAT and set-up during Training and SOP created.
Control System	Report Generation		cGMP	The results on the printed report do not match the displayed values	Medium	Low	Low	High	Low	Calibration/ Maintenance/ Training/ SOP	Checked during SAT and set-up during system Calibration.
Control System	Report Generation		cGMP	The values used for the display and printed reports are taken at different times in the cycle by the software.	Medium	Low	Low	High	Low	Calibration/ Maintenance/ Training/ SOP	Checked during SAT and set-up during system Calibration.
Control System	Report And Data Archiving		cGMP	The data is lost when archived.	Medium	Low	Low	High	Low	Training/ Maintenance	Checked during SAT and set-up during system maintenance.
Control System	Report And Data Archiving		cGMP	The data is corrupted or changed when retrieved	Medium	Low	Low	High	Low	System Maintenance/ Training	Checked during SAT and set-up during system maintenance training.
Control System	Report And Data Archiving		cGMP	The report batch numbers are changed.	Medium	Low	Low	High	Low	System Maintenance/ Training	Checked during SAT and set-up during system maintenance training.
Control System	Report And Data Archiving		cGMP	The software does not allow the retrieved file to be viewed	Medium	Low	Low	High	Low	System Maintenance/ Training	Checked during SAT and set-up during system maintenance training.
Control System	Report And Data Archiving		cGMP	The software is not available for retrieval of data	Medium	Low	Low	High	Low	System Maintenance/ Training	Checked during SAT and set-up during system maintenance training.
Control System	Recipe Loading		cGMP	The incorrect parameters are loaded in to the cycle	High	Low	Medium	High	Low	Training/ SOP/ O&M’s	Checked during SAT and set-up during Training and SOP created
Control System	Recipe Changes		cGMP	The software does not store changes made to the recipe	Medium	Low	Low	High	Low	Training/ SOP/ O&M’s	Refer to supplier O&M’s and SOP
Control System	Recipe Changes		cGMP	The parameters required to move from one phase to the next cannot be changed on the recipe screen.	Medium	Low	Low	High	Low	Training/ SOP/ O&M’s	Refer to supplier O&M’s and SOP
Control System	Counter/ Sequence Verification		cGMP	The counter does not log all cycles	Medium	Low	Low	High	Low	Training/ SOP/ O&M’s	Refer to supplier O&M’s and SOP
Control System	Counter/ Sequence Verification		cGMP	The counter does not log aborted or failed cycles	High	Low	Medium	High	Low	Training/ SOP/ O&M’s	Refer to supplier O&M’s and SOP
Control System	Counter/ Sequence Verification		cGMP	The clock does not record the correct time (GMT)	High	Low	Medium	High	Low	Training/ SOP/ O&M’s	Refer to supplier O&M’s and SOP
Equipment Operation	Operational Sequence		cGMP	The phase parameters in the software cause the cycle to abort	Medium	Low	Low	High	Low	SAT/ PQ	Checked and documented during SAT and PQ.
Equipment Operation	Temperature Distribution		cGMP	The temperature in the chamber does not meet the specification in EN285 and HTM 2010 for Steam Sterilization.	High	Low	Medium	High	Low	SAT/ PQ	Checked during Autoclave Commissioning, SAT & PQ
Equipment Operation	Temperature Distribution		cGMP	There is uneven heat distribution in the chamber	High	Low	Medium	High	Low	SAT/ PQ (Bowie Dick Tests)	Checked during Autoclave Commissioning, SAT & PQ
Equipment Operation	Air Removal		cGMP	Air is not removed from the equipment	Medium	Low	Low	High	Low	SAT/ PQ	Checked during Autoclave Commissioning, SAT & PQ
Equipment Operation	Air Removal		Operation	There is an air leak in the chamber	Medium	Low	Low	High	Low	SAT/ PQ	Leak Rate Tests during commissioning, SAT & PQ
Equipment Operation	Steam Penetration		cGMP	Steam does not penetrate the equipment	High	Medium	High	High	Medium	Validation -PQ	Checked and documented against current validated load profiles during PQ.
Equipment Operation Equipment Operation	Steam Penetration		cGMP	There are high levels of particulates in the steam supply	High	Medium	High	Medium	High	Clean Steam Quality Testing	Clean Steam to be quality tested
Equipment Operation	Condensate Removal		Operation	The equipment orientation causes drainage problems i.e. Wet Loads	High	High	High	High	Medium	PQ testing and SOP	To be checked and documented during PQ with current validated load profiles.
Equipment Operation	Bio-burden		cGMP	High levels of bioburden on the equipment.	High	Medium	High	High	Medium	PQ – BI testing	To be checked and documented during PQ with current validated load profiles.
Equipment Operation	121°C Cycle		cGMP	Sanitization Load cycle failure	High	Low	Medium	High	Low	SAT/ PQ	To be checked and documented during PQ
				Loading conditions change each time	High	Low	Medium	High	Low	PQ testing	PQ Testing to use worst case load on all cycles.
				Sterilization Load cycle failure	High	Low	Medium	High	Low	SAT/ PQ	PQ Testing to use worst case load on all cycles.
				Sterilization Load does not sterilize	High	Low	Medium	High	Low	PQ testing	PQ Testing to use worst case load on all cycles.
				Sterilization conditions not achieved throughout the load	High	Low	Medium	High	Low	PQ testing	PQ Testing to include thermometric testing and microbiological indicators
				Cycle phase time out due to insufficient air removal	High	Low	Medium	High	Low	PQ testing	To be checked and documented during PQ
Equipment Operation	134°C Cycle		cGMP	Sanitization Load cycle failure	High	Low	Medium	High	Low	SAT/ PQ	To be checked and documented during PQ
				Sterilization Load cycle failure	High	Low	Medium	High	Low	SAT/ PQ	PQ Testing to use worst case load on all cycles.
				Sterilization Load does not sterilize	High	Low	Medium	High	Low	PQ testing	PQ Testing to use worst case load on all cycles.
				Cycle phase time out due to insufficient air removal	High	Low	Medium	High	Low	PQ testing	To be checked and documented during PQ
				Cycle phase time out due to insufficient steam penetration	Medium	Medium	Medium	High	Low	PQ testing/ Bowie Dick test	To be checked and documented during PQ
Equipment Operation	Bowie Dick Test		Quality Assurance	Test cycle fails	High	Low	Medium	High	Low	Maintenance/ O&M	To be tested and documented at SAT/ PQ. SOP to refer to trouble shooting and Supplier to provide technical support for new Autoclave
Equipment Operation	Water Intrusion Test		Quality Assurance	Test cycle fails	Medium	Low	Medium	High	Low	Maintenance/ O&M	To be tested and documented at SAT/ PQ. SOP to refer to trouble shooting and Supplier to provide technical support for new Autoclave
Step 1 Equipment Preparation	Equipment Loading		Product Quality	Incorrect sterilization loads	High	Medium	High	Low	High	SOP Training	Photos of the loads (OQ). Schematics to be included in the SOP. Worst-case loads to be verified in the OQ and PQ.
			Product Quality	Incorrect sanitization loads	High	Medium	High	Low	High	SOP Training	Photos of the loads (OQ). Schematics to be included in the SOP. Worst-case load to be verified in the OQ and PQ.
			Equipment Critical	Chamber size incorrect	Low	Low	Low	Low	Medium	SAT	Dimensional checks (IQ).
			Product Quality	Maximum load weight exceeded	High	Medium	High	Low	High	SAT	Worst case loads to be verified in the OQ.
Step 1 Equipment Preparation	Equipment Loading		Product Quality	Loading pattern incorrect	High	Medium	High	Low	High	None	Photos of the loads (OQ). Schematics to be included in the SOP. Temperature Mapping Of The Loads.
	Equipment Loading	Product Quality		Equipment orientation incorrect causing ineffective air removal and condensate drainage	High (Cycle failure)	Medium	High	Low	High	None	Photos of the loads (OQ). Schematics to be included in the SOP. B.Is to be put into the load to verify that there is sufficient air removal and steam penetration
	Equipment Loading	Process Critical		Wrong autoclave used	Medium (Not the final sterilizing step)	Medium	Medium	Low	High	None	SOP and training.
Step 2 Equipment Operation	Cycle selection	Product Quality		Wrong cycle selected	Medium (Not the final sterilizing step)	Low	Low	Low	Medium	None	SOP and training. The sterilization and sanitization cycles will be the same.
Step 2 Equipment Operation	Utilities	Equipment Critical		Compressed air failure	Low	Low	Low	Low	Medium	None	The system aborts the cycle with critical alarms. Alarms will be verified in the OQ
Step 2 Equipment Operation	Utilities	Equipment Critical		Failure of modified steam supply	Low	Low	Low	Low	Medium	None	The system aborts the cycle with critical alarms. Alarms will be verified in the OQ
		Equipment Critical		Failure of new Steam valve	High	Low	Low	Low	Medium	None	The system aborts the cycle with critical alarms. Alarms will be verified in the OQ
		Equipment Critical		Demineralized Water failure affecting the jacket temperature	Low	Low	Low	Low	Medium	None	The system aborts the cycle with critical alarms. Alarms will be verified in the OQ
		Equipment Critical		Power failure	Low	Low	Low	Low	Medium	None	The system aborts the cycle with critical alarms. They will be verified in the OQ. No UPS. Machine stops. Data downloaded via Ethernet connection to PC.
Step 2 Equipment Operation	Utilities	Equipment Critical		Vacuum Failure	Low	Low	Low	Low	Medium	None	The system aborts the cycle with critical alarms. Alarms will be verified in the OQ
Step 2 Equipment Operation	Measuring Instruments	Process Critical		Instruments not calibrated	High	High	High	Low	High	None	All measuring instruments will be listed in the IQ and their criticality assessed. In-process Critical instrument calibration will be verified in the IQ.
Step 2 Equipment Operation	Measuring Instruments	Process Critical		Instruments calibrated to the incorrect specification leading to errors in the results	High	Low	Medium	Low	High	None	A Calibration Specification will be prepared based upon the User Requirements. This is used to check for the correct calibration accuracy. controls, maintenance and calibration of instruments.
Step 2 Equipment Operation	Software	Product Quality		Data not logged by the software	High	Medium	Medium	Low	High	An independent chart recorder (cGMP) is attached to the system.	Collection of data will be verified in the OQ. Data will be checked for each batch.
Step 2 Equipment Operation	Software	Product Quality		Software errors causing alarms or incorrect data	High	Low	Medium	Low	High	None	Verified in the OQ
Step 2 Equipment Operation	Hardware	Product Quality		Data not transferred correctly onto the printed report	High	Low	Medium	Low	High	None	Verified in the SAT and OQ. The control system printout cannot be used as evidence of sterilization, it is for information only. The two reports will be compared during OQ. A CFR Part 11 assessment to be performed.
Step 2 Equipment Operation	Software	Equipment/Process Critical		Parameters changed on the cycle	High	Low	Medium	Low	High	None	The software will be password protected with different access levels. Verified in the OQ. These will then be validated cycles and documented in the SOP.
Step 2 Equipment Operation	Software	Equipment Critical		Software not 21 CFR compliant	High	Low	Medium	Low	High	None	A 21 CFR Assessment will be performed.
		Equipment Critical		Software is upgraded during commissioning so parameters are changed.	High	Low	Medium	Low	High	Change Control/ Validation/ HTM 2010	Revision history to be covered under Change Control during the validation.
		Product Quality		Yokogawa Chart Recorder not started at the beginning of the cycle	High	Low	Medium	Low	High	None	The procedure will be verified in the OQ. This will be included in the SOP and training.
Step 2 Equipment Operation	Control System	Product Quality		Incorrect cycle selected	High (Incorrect temperature selected)	Low	Medium (Not the final sterilizing step)	Low	High	None	SOP and training. There is an operator check, a second supervisor check and the cycle traces are also checked.
				Results changed on routine tests, for example, Bowie Dick, by manipulation of instrument readings	High	Low	Medium	Low	High	None	The Engineering department controls access to the instruments, which are inside the unit.
				Critical alarm not logged because of active non-critical alarm	High	Low	Medium	Low	High	None	Verified in the OQ.
				Cycle not aborted with active critical alarm because active non-critical alarm not acknowledged	High	Low	Medium	Low	High	None	Verified in the OQ.
Step 2 Equipment Operation	Filters	Product Quality		Vent Filter damaged causing contamination of the air supply	High	Low	Medium	Low	High	None	This will be included in the Planned Preventative Maintenance System. Integrity Testing Pre-filters in place.
Step 2 Equipment Operation	Filters	Product Quality		Pre-filters damaged causing contamination of the air supply	High	Low	Medium	Low	High	None	Integrity Testing Pre-filters in place.
Step 3 Cycle Completion	Equipment Unloading	Product Quality		Dirty equipment removed from unloading side of autoclave	High	Low	Medium	Low	High	None	SOP and training.

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Ranjeev KUMAR Apr 6, 2017 1:22 pm EDT Reply

Microbiology

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Risk Considerations for Installation of a New Autoclave in a Pharmaceutical Manufacturing Facility | IVT

ABSTRACT

INTRODUCTION

FAILURE MODES AND EFFECTS ANALYSIS (FMEA)

STARTING THE RISK ASSESSMENT PROCESS