Annex 1: Regulatory Changes Increase Expectations for Pharma
Microbial Solutions
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Rachael Kerr

Annex 1: Regulatory Changes Increase Expectations for Pharma

How can global drug companies prepare to meet Good Manufacturing Practice (GMP) expectations and regulatory changes pertaining to Annex 1?

Dr. Lucia Ceresa head shot.Dr. Lucia Ceresa is the Senior Technology and Market Development Manager for Charles River Microbial Solutions. She is currently serving as Vice President of the PDA Italy Chapter, a member since 2005, and is an active participant of the Steering Committee since 2009.

Dr. Ceresa has more than 25 years of industry experience and a proven track record within pharmaceutical operations, including pharmaceutical aseptic production and all aspects of validation and quality control, with focus on GMPs and alternative microbiological methods.

She has extensive international experience within pharmaceutical operations, microbiology, rapid methods, aseptic processing and methodologies, validation, and QC. After 10 years as a Permanent Qualified Teacher for chemistry and microbiology, she started her career initially within the life sciences industry at Millipore Corporation, followed by Gelman Sciences Corporation, Pall Corporation, and Particle Measuring Systems. She graduated from the University of Milan in 1981 and specialized in microbiology.​

Rachael: What are the biggest challenges currently facing the pharmaceutical industry in understanding the requirements needed to maintain a quality-controlled facility?

Lucia: Production of sterile products is a complex activity that requires in-depth knowledge of each of the products and their required production processes. The quality and integrity of the products is only as good as the processes, documented data, and understanding and control of your production facility. Regulatory requirements should be considered the minimum, and the quality management team should be applying a risk-based approach, and quality risk management (QRM) that is specifically designed for their facility. Production facilities manage processes for so many products, it is hard to maintain one standard baseline. There is extreme value and need for applying the QRM but it is equally important to remember that requalification of the processes, every 6 and 12 months, for Class areas A-B and C-D, respectively, is a minimum requirement. Generally, these approaches are designed with guidance based on ISO 14614, which defines the critical and essential points in process and facility mapping.

The FDA’s Current Good Manufacturing Practices (CGMP) has been providing a very good guideline since 2004, whereas CGMP pertaining specifically to Annex 1 now offers more detailed regulatory specifications that must be incorporated. The specifications are causing dramatic enhancements and changes to how facilities perform processes and track their production and product testing data. These new requirements drive need to now implement barriers, air locks, isolators, and aims to remove people from the production cleanroom areas by implementing more automation. Continuous routine environmental monitoring (EM) will be needed during process changes so you understand what microflora the facility currently has and what corrections to production/personnel flow need to be implemented to mitigate and control problematic areas causing a risk of contamination. Rationale will need to be understood, documented, and described to prove knowledge of any issues and needed improvements and changes implemented during the requalification.

Rachael: Given the specific impact on production testing, microbial identification strategies, and having the ability to interpret organism data and track facilities’ microflora, what is the most critical aspect within microbiology? What key changes would you suggest making to ensure GMP and regulatory guidelines are maintained?

Lucia: The most important aspect in good, quality microbiology, for an effective environmental monitoring program, is to verify that the number of samples being collected and tested is enough to fully understand the production environment. Maintaining compliance requires maintaining confidence in data integrity. Currently, there is a strong push for all laboratory testing methods utilized to introduce and prove data integrity and rapid, scientific-based methods. For example, there are still many identification methods, such as phenotypic technologies, that involve more manual testing, introducing subjectivity in the resulting data. As a comparison, genotypic identification methods, in general, can achieve strong data integrity through the technology and advanced automated systems and reliable databases used. Many warning letters are related to the lack of correct EM programs, inadequate sample collection, gaps, or weak data reported. Chapter 9 in the Annex 1 guidance as well as the ICHQ9 guideline represent qualified references for microbiology laboratories and quality control programs related to EM expectations, where increased funding for these programs will be required to gather the expected test samples and product samples needed. If these expectations are not met, many facilities could expose themselves to risks of warning letters, 483, and even, in worst cases, production shutdown.  

Rachael: How should manufacturers determine what organisms are objectionable?

Lucia: Class C and D areas are where the contamination is initially being introduced within the cleanroom environment, so it is extremely important to be tracking organisms within these areas to determine what a facility’s or product’s objectionable organisms are.

The expectation in the revised Annex 1 guidelines is for all isolates to be identified to the species level in areas classified A and B and to understand the potential impact of such microorganisms on product quality (for each batch implicated), and the facility’s overall state-of-control should be continually evaluated.

Considerations should also be given to the identification of microorganisms to the species level for isolates detected in Class C and D areas (for example where action and/or alert limits are exceeded or where atypical or potentially objectionable microorganisms are recovered). The approach to organism identification and any investigations should always document known risk and mitigation, showing proper disinfectant and cleaning protocols were followed.

During an investigation, you need to be able to trace back to the specific area and operator to determine root cause and correct or mitigate the situation and point of contamination, to prevent reoccurrences. Maintaining control of the environment and production facility, requires a lot of planning, preparation, and observation through constant monitoring of all classes, whether during startup or requalification. If you are unable to provide robust data from the start of production, it is impossible to determine an accurate root cause and determine how to mitigate the risk. Maintaining control of the product is absolutely mandatory to ensure final product testing will confirm that products are free of contamination and safe for the patients. In-process water testing of the entire facility is becoming more important to provide knowledge and traceability of naturally occurring microorganisms present within the facility to facilitate the determination of the objectionable organisms. We cannot rely alone on testing only the final product, contamination needs to be actively as well as proactively prevented throughout production and not reactively handled if it presents in the final product. In-process control proves you are producing by continuously reducing and mitigating all risk to the final product, in turn mitigating any risk to patient safety.

Annex 1 affects not only pharmaceuticals manufactured in the EU, but those imported by its member nations as well. By understanding the potential industry impact these revisions will have, global pharmaceutical manufacturers can prepare in advance to meet these upcoming regulatory changes.

Charles River hosted a three-part webinar series; Keeping Up With Annex 1 Revisions to provide a comprehensive overview of the proposed changes, with a focus on Environmental Monitoring and Quality Control. This complementary series is now available on-demand.