Introduction to the MHRA
The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health in the UK. The MHRA is responsible for the regulation of medicines and medical devices, equipment used in healthcare, and the investigation of harmful incidents. The MHRA is also the competent authority for blood and blood components. The principal aims of the Agency are to protect, promote and improve the public’s health.
The MHRA has a team of over 50 Inspectors within the Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) Inspectorate which is part of its Inspection, Enforcement and Standards (IE&S) Division.
Companies that manufacture or wholesale medicinal products may only do so if they hold the appropriate license, which is granted after a GMP or GDP inspection shows that their operations comply with EU GMP or GDP guidelines. Inspections of UK sites are carried out whenever a company has applied for or been named on a manufacturing or distribution license and re inspection occurs periodically on a risk- based frequency thereafter to maintain the license. Manufacturing sites are also issued GMP certificates.
Fees are charged for inspections and there is no legal requirement to notify the license holder of an intention to visit and therefore inspections may be pre-notified or unannounced. Additional inspections that may be required to be performed are, for example, to follow up significant deficiencies raised previously, following reports of defective products, or to follow up information received from external sources, for example "whistleblowers". Applications to vary details of the manufacturing or distribution license may also trigger an inspection.
Overseas manufacturing sites supplying the UK, or possibly another EU Member State, are inspected by MHRA when named on specific marketing authorizations and are issued with GMP certificates only and not manufacturer's licenses. Overseas inspections focus on the products to be imported and the standards applied, EU GMP, are the same as those applied in the UK. Additionally, sites manufacturing Active Pharmaceutical Ingredients are not issued manufacturer licenses, but may be inspected.
The GMP Inspectorate carries out regular inspections in a number of countries, including USA, India, China and Japan both in connection with national requirements and on behalf of the European Medicines Agency’s (EMA), the World Health Organization (WHO) and the European Directorate for the Quality of Medicines (EDQM).
International co-operation has been an important part of the Inspectorate's activities for many years. The GMP/GDP Inspectorate provides significant resources to the EMA’s GMP/GDP Inspectors Working Group and among this Group’s responsibilities are those for the maintenance of EU GMP and GDP. The Inspectorate was a founding member of the Pharmaceutical Inspection Convention and is an active participant in the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The IE&S Division was involved in the drafting group at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) for Q7, Q8, Q9 & Q10.
Introduction to the Sterility Test
The sterility test is a key microbiological test that is required to be performed to support the release of sterile products. A sterility test failure is a time consuming, stressful event often involving a great deal of extra work for a number of people under severe time pressures. It is essential that companies plan for these events prior to them happening so individuals are aware of their roles and responsibilities.
Fig. 1
The method for conducting the sterility test is documented in the European Pharmacopoeia (2.6.1). and United States Pharmacopoeia (<71>). Occasionally this test will produce a positive result. In the event of such a result, thorough investigation of the production activities and the laboratory process is required to identify if the positive test is due to a contamination event during the manufacturing process, or an invalid sterility test due to a laboratory error.
Much is made in industry of the ‘statistical relevance’, of a failing (or indeed passing), sterility test on a batch of medicinal product [1]. The fact remains, for all major regulatory bodies; the sterility test remains a primary release criterion for sterile products. It is recognized by the regulators that just because a batch had passed the sterility test, it does not mean that it is sterile. Sterility is assured by the battery of contamination controls that are employed throughout the manufacturing process. It is these controls that will need to be the focus of your investigation to determine the potential cause of the positive sterility test.
The Investigation Process
One of the key challenges faced in the event of a positive sterility test is time. The sterility test is often the final result received to support release of the batch, and delivery schedules are often structured around its completion. Any additional investigation will often involve numerous incubation steps and identifications of organisms, all of which add to the delay. To ensure this is carried out in the most efficient way, it is essential that an investigation procedure is in place and understood before the event.
For the purposes of such an investigation, the standard Laboratory Out of Specification Procedure (as applied to analytical chemical testing) is often inappropriate. A procedure that considers the process of investigating microbiological data deviations should be in place. This may make use of tools such as a proposed investigation protocol/ checklist and a reporting proforma. It should clearly state which department is responsible for each part of the investigation, what is required to invalidate the sterility test and justify a retest, and a communication plan for the concerned parties.
The first part of the investigation is to establish the scope and impact of the investigation. On detection of a positive sterility test, the first assumption must be that it is a potential true failure. The batch in question must immediately be put in quarantine, and a decision must be taken to set the boundaries of the investigation and identify other batches which may also be affected. Considerations should include other batches filled on the same filling line, filled in the same suite, using the same sterilizers, using equipment sterilized in the same manner, sharing the same air handling system, or using the same materials in formulation. In the event of a positive sterility test for only part of a batch, the other parts should also be rigorously assessed. When making these impact assessments, the nature of the failure (catastrophic or isolated), the type of organisms recovered and the potential sources of these organisms will influence the final decision. Whatever the decision taken at this stage, it should be fully documented including all risk assessments, rationale and scientific justification, as this is likely to be a key area of focus in your next regulatory inspection. These decisions may need to be reviewed in the light of further information gained through subsequent investigation.
The main investigation to establish the cause of the positive test should focus equally on manufacturing and filling process, and the microbiological laboratory. For the purposes of speedy identification of the cause, it is recommended that the two areas are investigated concurrently. This will help satisfy the regulator with respect to identifying the scope of the issue and ensuring protection of the patient, and facilitate resumption of normal supply to the market. What follows below should not be viewed as the definitive list. Other factors may be relevant to your product/process/facility.
The Manufacturing and Filling Process
A logical way to approach the investigation is to follow the process flow and consider all the areas/factors which may be a potential source of the contamination detected in the positive sterility test. The nature of the organisms recovered in the sterility test may give some direction to potential source, but care should be taken to ensure that the investigation remains sufficiently broad to include all potential sources. Common risk management tools such as Failure Mode Effects Analysis, or Fault Tree Analysis, may be useful to identify, analyze and evaluate the risks and their potential to have caused the contamination [2]. Due to the potential variability of microbiological results, the investigation should not be limited to information/results relating to the specific batch, but should include a broader review of historical results and trends. Unusual events should be fully investigated to understand their potential impact.
The microbiological testing of the materials that make up the formulated product should be reviewed including the raw materials, process water and interim stages such as the bulk solution most importantly prior to the sterilization step. Test results reviewed should include both bioburden results and contamination indicators such as pyrogen/endotoxin testing. The condition of the raw material containers and the dispensing process should also be reviewed.
The manufacturing process including the hold times, sterilization records and the results of the finished unit inspection should be reviewed. The manufacturing and filling processes are designed to reduce the potential for the introduction of microorganisms into the product. As a consequence they will be central to any investigation into a sterility test failure. Key elements of this are the utilities supporting the manufacturing environment such as steam, water and air, the HEPA filters supplying air to the manufacturing environment and the sterilizers and the sterilization of components, tanks and filling lines. For terminally sterilized products the sterilization process for the finished product will require rigorous scrutiny. Production records, unusual occurrences and validation status should be included in the scope of the investigation.
Another key area of the investigation for aseptically filled products is the filling process, because this usually presents the biggest contamination risk. A thorough review of the environmental monitoring data is essential. This will include both viable and non-viable monitoring results for the filling session and the previous trends. This should not just be limited to the critical filling environment, but should also include the non-critical and support areas. The process simulation history for the filling line is also an important indicator that should be included in the investigation.
Equally important for aseptically filled products are the operators. Considerations here should be the number of operators present during the filling operation, the activities of the operators, their experience, training and history (e.g. personnel monitoring, gowning assessments, and their performance in process simulations). Discussion with the operators regarding potential areas for contamination is essential. Experienced operators can offer insights into occurrences during the filling of the batch which may have a significant impact with respect to contamination events.
Finally for the manufacturing process, the bioburden testing of the disinfectants used in the filling environment along with the cleaning and disinfection records should all be reviewed.
The Laboratory
The laboratory investigation should encompass all of the factors that could have influenced the sterility test result. It should include a review of the media used in the test, whether or not it is prepared in-house or bought pre-prepared, the supplier (of dehydrated or pre-prepared media) history, negative controls run in the session, growth promotion testing and any media sterilization records. The media supplier should be contacted to see if there have been any customer complaints. Sterility tests are relatively difficult to perform due to the number of analytical manipulations required, which may be further increased if the product requires reconstitution and/or mixing. This should be taken into account when reviewing the sterility test history, looking for other sterility test positive results/retests/failures in that session/day, by product, by technique, and by LAF/Isolator. The history of the analyst performing the test should be reviewed, including their experience, testing history, initial and ongoing training.
The environmental monitoring results for the testing session should be reviewed in detail looking at the critical testing environment, the non-critical and support areas. Historical results/trends should also be included and both viable and non-viable testing should be considered.
Finally, the equipment/utilities supporting the testing environment should be reviewed. This review will be similar to that performed on the filling environment and should encompass the sterility testing room, the LAF/Isolator and the equipment sterilization process. If an isolator was used, the leak testing and gassing process should be reviewed. Validation, maintenance and cleaning status will need to be confirmed as part of this review.
Conclusion
At the completion of the initial investigations into both the manufacturing and laboratory areas, it is not unusual to still not have identified a definitive root cause. Additional testing or monitoring may be required to do this. In this event, a documented protocol of this additional activity should be drafted and approved, clearly stating what will be performed, and how the results will be interpreted. At the end of the investigation you will need to ask yourself if you truly have identified the root cause. The contamination source may not actually be the root cause, which may also be influenced by the process. There may be more than one root cause or the best you can come up with will be a probable root cause.
Once you have a root cause(s), you may need to establish if you can invalidate the original test. The European Pharmacopoeia requires you to demonstrate that test was invalid for causes unrelated to the product. For example have you isolated the organisms recovered from the positive sterility test from the negative control or the sterility test environment? The main regulatory bodies have a harmonized approach to this and agree that you must establish unequivocally that the contamination occurred during testing. This will require identification of the organisms recovered to a genetic level (DNA/RNA identification). If this is not possible and the evidence is inconclusive, the sterility test should be regarded as a genuine failure and the batch rejected. The same level of identification should be applied to contamination found in the manufacturing/filling environment when confirming a contamination source.
If the evidence supports the invalidation of the original sterility test, Second Stage sterility testing may be justified requiring double the number of original samples to be tested.
Summary
• Plan ahead – have procedures and protocols in place with staff who know how to use them.
• Communication is key – there will be many stakeholders that will need to be informed promptly when it happens and updated regularly.
• Document everything – at some point, the regulators are going to want to see this and you are going to have to explain your decisions and actions
• Put equal effort into the manufacturing and laboratory investigations – don’t assume that it is an analyst error and that a retest will be acceptable.
• The work does not stop with rejection of the batch – you need to understand the scope of the root cause, other batches that may be impacted, and actions to prevent it occurring again. What will you do if you are unable to establish the root cause?
References
1. Tellez, S. et al. “Unexpected inefficiency of the European Pharmacopoeia Sterility Test for detecting contamination in clostridial vaccines,” Vaccine 2006.
2. ICH Q9 Quality Risk Management
3. FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practice, September 2004.
4. Sandle, T. “Investigating Sterility Test Failures”, GBPR Inc. Newsletter Feb 2011.
Neil Raw is a GMP inspector with the MHRA. He has over 18 years of experience in the pharmaceutical industry, including working as a Qualified Person for a large multi-national company, and joined the MHRA in 2006. Neil is a microbiologist and regularly inspects both large and small scale sterile manufacturing sites in the UK, US and India.
Mark Birse is the Group Manager, Inspections (GMP/GDP) and manages a team of over 50 Inspectors. Mark joined the MHRA in 2002, having previously worked in the pharmaceutical industry for over 10 years in a variety of roles including process technology, new product introduction and quality assurance. Mark is a chemistry graduate with an MSc in pharmaceutical sciences and he is eligible to be named as a Qualified Person under Directive 2001/83/EC.