Microbiology plays an important role in FDA inspections, whether it is in sterile manufacturing or non-sterile manufacturing because problems with microbial control systems will affect product quality and patient safety.
Throughout my years of working with pharmaceutical companies to prepare for inspections and respond to remediation-related issues, I've noticed common microbiology issues that come up repeatedly due to a failure to understand these issues. Therefore, by learning about these issues, you can improve your processes, avoid receiving citations during an inspection and remain prepared for an FDA inspection.
In this post, I will segregate the primary microbiological issues encountered during FDA inspections and detail how they develop, why they are significant and strategies for effectively addressing each of these.
Some of the biggest problems that FDA encounters when reviewing environmental monitoring plans include the following examples:
A. Number of sample locations and frequency of sampling: Companies may create a plan that does not include places that are at risk or sometimes will cut back on sampling frequency or the number of sample locations to conserve time and money.
B. Lack of data trend assessment and investigation of nonconformances: FDA wants to see historical data trends and statistical investigations into out-of-trend or deviated sample results.
C. Inaccurate alert and action limits: These limits should be based on scientific principles and risk assessment, If an action limit is determined to be arbitrary or too broad, it will result in the inspector not having the necessary confidence that you can detect real risk.
A poorly designed environmental monitoring plan that does not provide inspectors with quality data will be viewed as an area of weakness for the contamination control of your product.
Some common problems that occur within aseptic processing are as follows:
- Not consistently following the appropriate gowning practices will increase the overall-risk associated with bioburden.
- Touch contamination by the operator during aseptic transfers or device setup is a common finding during aseptic transfers or when conducting aseptic operations.
- Media fills that do not appropriately simulate worst-case scenarios in regards to contamination.
When FDA inspectors are conducting site inspections, they do not just review your documentation. They also observe your operators during-site operations to ensure that what they see and observe a comparison between how operators are performing those aseptic actions, in addition to how they have documented that performance on paper.
Examples of common problems are:
- Sampling/testing plans that are not supported by scientific rationale for selection of sites, sampling frequency, etc. That means that without having sound scientific data to justify why certain sites were selected or how frequently samples were taken (or will be taken), the plan appears arbitrary.
- There is also a lack of validation of microbiological testing methodologies for each product/matrix, where the methodology used may work for one product/matrix but not another.
- In addition, due to delays in time between sample collection and analysis or a lack of appropriate storage conditions prior to sample collection/analysis, it is not unusual for testing to yield a false positive and/or a false negative result.
The testing process is not intended to simply "check boxes" but provides FDA an assurance that both sampling and testing methods accurately represent the true microbial condition of a facility/product environment.
Some examples are:
- Temperature fluctuations in Incubators or being noncompliant for the manufacturer specifications. If the temperature of an incubator deviates from the set ranges, then any data generated from that incubator could be incorrect.
- Microbial contamination monitoring is not performed on the Water used for media & reagents. All water used to prepare media and reagents must be held to acceptable Quality Standards and routine analysis must be performed.
- The Incubators and/or Hoods must be clean; build-up of biological material, rust and dust is unacceptable.
If an inspector observes any neglect in the maintenance of an instrument, this raises a flag about the validity of the results obtained using that instrument.
Some of the most common findings made by inspectors relative to microbial excursion investigations include:
1. Incomplete Investigations: Root causes of issues were not identified and excusatory conclusions were made that doesn’t have supporting data.
2. Lack of Corrective Action: No corrective action was taken to fix the cause of the initial contamination then investigation will continue to circle back to the same contamination.
3. No Verification of Corrective Actions: Investigations should be able to suggest corrective action and it should work and must be effective otherwise, implementing a change without verifying effectiveness is inadequate.
The FDA expects companies to drill down on the actual root cause of an excursion and will take action based on this root cause to ensure prevention of the recurrence of the excursion.
Some common reasons for concern are:
- The validation of the RMM has not been performed at all or at least not fully verified for its intended use nor has it been done quicker than the traditional microbiological tests.
- Operators and/or the quality team often trust these RMM without understanding how to interpret the atypical results.
- Most importantly, RMM has no contingency plan for what to do if the system fails, i.e. what is your fallback test?
Although RMM is a very effective tool, it needs to be properly integrated into the overall Quality System to achieve the maximum benefit.
The most commonly cited items by inspectors are:
1. Lack of raw data: Only summary reports are available with no traceable links to the original observation.
2. Logbooks not completely filled out: Handwritten entries that can't be read or contain no dates or are crossed out.
3. Inconsistencies in electronic records: Analytical data altered, deleted or available without an audit trail.
Without data integrity, you have lost the trust of the FDA. If the FDA cannot trust your records, you cannot expect them to trust the quality of your system.
Microbiological inspections from the FDA can be challenging. The reason is that they address essentially every area of contamination control. You should take everything from environmental monitoring to sampling to paperwork and ensure that every area is risk-based and well-documented.
Most of these common problems that we’ve outlined are not surprises to experienced inspectors; however, they continue to arise because every time they do, they indicate that there’s an ongoing issue in some area of the design, execution and oversight of programmes. Therefore, if you can address them before the inspection through a solid scientific rationale, a disciplined approach to your programs, and thorough documentation, you will be able to significantly lower your chances of receiving a citation and improve the quality of the product.
If you are preparing for an inspection, begin to conduct a gap analysis in relation to the major areas mentioned above. Include your microbiologists, quality assurance and production teams because a well prepared and united team can defend effectively during the FDA inspection process.
Throughout my years of working with pharmaceutical companies to prepare for inspections and respond to remediation-related issues, I've noticed common microbiology issues that come up repeatedly due to a failure to understand these issues. Therefore, by learning about these issues, you can improve your processes, avoid receiving citations during an inspection and remain prepared for an FDA inspection.
1. Inadequate Environmental Monitoring Programs
An environment is the backbone of any microbiological control strategy and consists of two types of experiments: viable air sampling, surface contact plates and personnel monitoring, etc., along with follow up these results so they can be used. Environmental monitoring is also essential to the microbiological control of product quality.Some of the biggest problems that FDA encounters when reviewing environmental monitoring plans include the following examples:
A. Number of sample locations and frequency of sampling: Companies may create a plan that does not include places that are at risk or sometimes will cut back on sampling frequency or the number of sample locations to conserve time and money.
B. Lack of data trend assessment and investigation of nonconformances: FDA wants to see historical data trends and statistical investigations into out-of-trend or deviated sample results.
C. Inaccurate alert and action limits: These limits should be based on scientific principles and risk assessment, If an action limit is determined to be arbitrary or too broad, it will result in the inspector not having the necessary confidence that you can detect real risk.
A poorly designed environmental monitoring plan that does not provide inspectors with quality data will be viewed as an area of weakness for the contamination control of your product.
How to Solve These Issues
Create a risk based environmental monitoring plan. This should include: adequately validated sample site locations and frequency of sample collection, use of control charts for data trend analysis and ways to investigate trend deviations with changes made to the system.2. Improper Aseptic Processing Practices
Maximum contamination prevention is necessary in aseptic processing areas because even very small errors can result in entire shipment batches being rendered unusable or, in some cases, worse. FDA inspections often reveal accidental, unplanned procedural errors, as well as poor gowning practices and insufficient media fills.Some common problems that occur within aseptic processing are as follows:
- Not consistently following the appropriate gowning practices will increase the overall-risk associated with bioburden.
- Touch contamination by the operator during aseptic transfers or device setup is a common finding during aseptic transfers or when conducting aseptic operations.
- Media fills that do not appropriately simulate worst-case scenarios in regards to contamination.
When FDA inspectors are conducting site inspections, they do not just review your documentation. They also observe your operators during-site operations to ensure that what they see and observe a comparison between how operators are performing those aseptic actions, in addition to how they have documented that performance on paper.
How to Solve These Issues
Invest in consistent and thorough operator training, assessment and conduct media fills that accurately challenge the product and develop a culture of rigorous discipline (in terms of gowning and in terms of maintaining aseptic practices).3. Lack of Proper Microbiological Sampling and Testing
Although sampling/testing tasks may appear routine, they consistently uncover larger underlying issues associated with facility/system/plant operations. For example, the FDA finds problems with microbiological sampling/testing associated with a lack of risk-based sampling/testing plans, with using unvalidated testing methodologies for a particular product matrix etc. or a lack of adherence to the recommended sample holding times (or timeframes) before analysis.Examples of common problems are:
- Sampling/testing plans that are not supported by scientific rationale for selection of sites, sampling frequency, etc. That means that without having sound scientific data to justify why certain sites were selected or how frequently samples were taken (or will be taken), the plan appears arbitrary.
- There is also a lack of validation of microbiological testing methodologies for each product/matrix, where the methodology used may work for one product/matrix but not another.
- In addition, due to delays in time between sample collection and analysis or a lack of appropriate storage conditions prior to sample collection/analysis, it is not unusual for testing to yield a false positive and/or a false negative result.
The testing process is not intended to simply "check boxes" but provides FDA an assurance that both sampling and testing methods accurately represent the true microbial condition of a facility/product environment.
How to Solve These Issues
Create your sampling/testing plan based on the results of risk assessments, validate all methods using appropriate product matrices and maintain strict control of the holding conditions and times for all samples. Document the scientific basis for the development of sampling/test plans and maintain documentation for each sampling/test plan to provide the FDA with a written rationale for the selection of sites, sampling frequency and other supporting documentation.4. Outdated or Poorly Maintained Lab Equipment
Microbiology laboratories put considerable emphasis on instrument performance and rely on dependable instrumentation. Inspectors frequently observe issues with incubators, water systems, biosafety cabinets and plate readers; most issues found by Inspectors involve calibration, documentation of maintenance history and cleaning status.Some examples are:
- Temperature fluctuations in Incubators or being noncompliant for the manufacturer specifications. If the temperature of an incubator deviates from the set ranges, then any data generated from that incubator could be incorrect.
- Microbial contamination monitoring is not performed on the Water used for media & reagents. All water used to prepare media and reagents must be held to acceptable Quality Standards and routine analysis must be performed.
- The Incubators and/or Hoods must be clean; build-up of biological material, rust and dust is unacceptable.
If an inspector observes any neglect in the maintenance of an instrument, this raises a flag about the validity of the results obtained using that instrument.
How to Solve These Issues
Set up and maintain a comprehensive Calibration and Maintenance Programme. Make use of logs to document Schedule Dates, Performance Checks, Maintenance Records and Indication of Responsibility. Provide regular cleaning and organisation of the laboratory and document all deep-cleaned activities.5. Inadequate Investigation of Microbial Excursions
Microbial excursions are going to happen. It is not what happened but how you handle the situation that matters. Many deficiencies noted during inspections are not due to the finding of contamination but rather due to the incomplete and ineffective investigations and corrective actions.Some of the most common findings made by inspectors relative to microbial excursion investigations include:
1. Incomplete Investigations: Root causes of issues were not identified and excusatory conclusions were made that doesn’t have supporting data.
2. Lack of Corrective Action: No corrective action was taken to fix the cause of the initial contamination then investigation will continue to circle back to the same contamination.
3. No Verification of Corrective Actions: Investigations should be able to suggest corrective action and it should work and must be effective otherwise, implementing a change without verifying effectiveness is inadequate.
The FDA expects companies to drill down on the actual root cause of an excursion and will take action based on this root cause to ensure prevention of the recurrence of the excursion.
How to Solve These Issues
Ways to fix the inadequacies of investigations include using structured investigation tools like fishbone diagrams and the 5 Whys and validating that the corrective action(s) taken were effective using data over time. Finally, both accountability and documentation must be clear and readily available to confirm accountability.6. Limited Understanding of Rapid Microbiological Methods
Many companies choose to adopt Rapid Microbiological Methods (RMM) to speed up the time it takes to perform a microbiological test. However, the FDA sees a lot of poor implementation and validation, along with a misunderstanding of how to use these methods.Some common reasons for concern are:
- The validation of the RMM has not been performed at all or at least not fully verified for its intended use nor has it been done quicker than the traditional microbiological tests.
- Operators and/or the quality team often trust these RMM without understanding how to interpret the atypical results.
- Most importantly, RMM has no contingency plan for what to do if the system fails, i.e. what is your fallback test?
Although RMM is a very effective tool, it needs to be properly integrated into the overall Quality System to achieve the maximum benefit.
How to Solve These Issues
Create detailed RMM validation protocols based on the product and environmental risk; Train Personnel to understand how to interpret and what to expect from RMM and how to handle an unanticipated or atypical result; Use the traditional methods as a back-up when necessary.7. Documentation Gaps and Data Integrity Issues
The final aspect of an inspection that will lead to a fast loss is poor documentation. The nature of microbiology being data-heavy increases the likelihood of errors, taking shortcuts and being dishonest if the controls are not strict.The most commonly cited items by inspectors are:
1. Lack of raw data: Only summary reports are available with no traceable links to the original observation.
2. Logbooks not completely filled out: Handwritten entries that can't be read or contain no dates or are crossed out.
3. Inconsistencies in electronic records: Analytical data altered, deleted or available without an audit trail.
Without data integrity, you have lost the trust of the FDA. If the FDA cannot trust your records, you cannot expect them to trust the quality of your system.
How to Solve These Issues
Follow good documentation practices. All handwritten records should be easy to read, contain date and time and your signature. For electronic records, ensure there are secure audit trails and documented authorized access to records and conduct routine evaluations.Microbiological inspections from the FDA can be challenging. The reason is that they address essentially every area of contamination control. You should take everything from environmental monitoring to sampling to paperwork and ensure that every area is risk-based and well-documented.
Most of these common problems that we’ve outlined are not surprises to experienced inspectors; however, they continue to arise because every time they do, they indicate that there’s an ongoing issue in some area of the design, execution and oversight of programmes. Therefore, if you can address them before the inspection through a solid scientific rationale, a disciplined approach to your programs, and thorough documentation, you will be able to significantly lower your chances of receiving a citation and improve the quality of the product.
If you are preparing for an inspection, begin to conduct a gap analysis in relation to the major areas mentioned above. Include your microbiologists, quality assurance and production teams because a well prepared and united team can defend effectively during the FDA inspection process.
Frequently Asked Questions (FAQs) on Common Microbiology Issues in FDA Inspections
Q1. What are the most common microbiology issues found during FDA inspections?
Answer: FDA inspectors commonly find microbiological problems during their inspections those include poor environmental monitoring, improper aseptic practice, lack of investigation of excursions and improper documentation.Q2. Why does the FDA focus on microbiology during inspections?
Answer: The reasons FDA inspectors concentrate on microbiological issues are that microbial contamination has a significant negative effect on the quality of a product as well as the safety of patients receiving that product.Q3. How can companies improve environmental monitoring programs?
Answer: Companies can enhance their environmental monitoring programs with a risk-based sampling approach, validating all methods of sampling and testing. They should also use statistical trending of results to track control of the sterility of the cleanroom environment and maintain control on deviations.Q4. What are typical aseptic processing issues cited by FDA?
Answer: Common issues with aseptic processing found during FDA inspections include the improper gowning, inadequate application of aseptic techniques and unrealistic media fill simulation.Q5. What steps should companies take to investigate microbial excursions?
Answer: The investigation of a microbial excursion should be based on data. The investigation should be supported and verified by corrective and preventive action (CAPA).Q6. What are FDA expectations for microbiological testing methods?
Answer: The FDA expects that manufacturers use microbiological testing methods that are supported by appropriate scientific justification. Methods are validated for each type of product under validated test conditions and include appropriate sample handling process throughout the manufacturing process.Q7. What role does documentation play in microbiology compliance?
Answer: Accurate and complete documentation of microbiological testing results is very important. If there is any missing information in documentation then there may be questions regarding the integrity of the data and the results of inspections.Q8. How can rapid microbiological methods help reduce inspection findings?
Answer: Rapid microbiological methods help manufacturers conduct microbiology testing to improve their laboratory's ability to analyze their products more quickly than possible with traditional methods. Rapid methods also improve the accuracy of results when they are properly validated by the company and understood by all users.
Get documents for Audit preparation in MS-Word FormatView List
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.