By Peter H. Calcott, Ph.D., president and CEO, Calcott Consulting LLC
Released in late August 2022,1 the EMA’s revised Annex 1 “Manufacture of Sterile Medicinal Products” gives us until August 2023 to be in compliance with the bulk of the annex, with an extra 12 months to become compliant on manually loaded lyophilizers (Section 8.123), where the deadline is Aug. 25, 2024. That does not leave much time to complete all the work.
This annex applies to sterile products, whether manufactured by terminal sterilization in its many forms, and to aseptically filled products that cannot be terminally sterilized. But the principles included apply elsewhere. It can also apply to areas where contamination control is critical, such as cell culture techniques, preparation of oral liquid products, and many others. The principles apply and should be documented. If you claim a process meets the tenets of Annex 1, you had better be able to prove it and document it.
The good news is that many of the ambiguities in the old 2009 version of the annex were removed in the revised version. The new annex is in line with the rest of the EMA regulations and annexes as well as other international regulations, e.g., ICH and PIC/S. It also references the need to keep current with new technology, but more about that later.
Many of my clients are still pondering what to do and want checklists to help them assess and remedy their systems. We are fortunate that the new Annex 1 does contain many checklists to get you started. But I always counsel caution when using checklists. They should be viewed as a tool to get you thinking rather than lists etched on stone tablets. In this article, I will point out areas where I see my clients stumble in their implementations and where checklists can be found (I will not be going line by line in the annex). I’ll also focus on what is new and what I see as glimpses into the future.
First, Let’s Get Into The Proper Global Mindset
Many of you might be thinking, “Why should I worry about an EMA Annex? I make products in the U.S. where the FDA rules.” That thinking is dinosaurian. We all make products for worldwide markets, so many products made in the U.S. (and elsewhere) end up being sold in the EU. Further, the EMA did not write this guidance in a vacuum. The FDA, PIC/S, WHO, and other country regulators were involved in the writing and deliberations. Thus, this end product will be not only accepted by EMA but by PIC/S as well, and FDA is a member of PIC/S. The FDA involvement is a clear indication that the contents will be the FDA position in general terms, although we know FDA regulations are notoriously vague and their interpretation changes. So, think globally and act locally, as the saying goes.
As pointed out in another review of the annex,2 ICH Q9 (QRM) and Q10 (New PQS) are fully embedded in this new annex: they are integrated not just into the contamination control strategy (CCS) but literally everywhere. For an overview on how to implement an effective QRM, review the articles in references 3 and 4. While the concept of CCS is not new, the new approach in the annex is that it should be developed in a holistic manner. That means not in a piecemeal manner but as an overarching strategy to combat contamination in its many forms. That is, microbial (bacteria, mold, virus, mycoplasma) contamination, particulates (glass, carbohydrate, resin, plastics), and endotoxin/pyrogen/lipopolysaccharide should be considered together. And we should examine every element of their potential causes.
What Are The Most Important “Checklists” And Discussions In The Annex?
Contamination Control Strategy (CCS): One of the first checklists presented in the annex is in section 2.5, which describes elements you need to consider in your CCS:
- Design of both the plant and processes, including documentation
- Premises and equipment
- Raw material controls, including in-process controls
- Product containers and closures
- Vendor approval, such as key component suppliers and critical service providers
- Management of outsourced activities and availability/transfer of critical information
- Process risk management
- Process validation
- Validation of sterilization processes
- Preventive maintenance – maintaining equipment, utilities, and premises (planned and unplanned maintenance)
- Cleaning and disinfection
- Monitoring systems, including introduction of scientifically sound alternative methods
- Prevention mechanisms – trend analysis, detailed investigations and tools, root cause determination, corrective and preventive actions (CAPA)
- Continuous improvement based on information derived from the above
The EMA stresses that the CCS is not a one-time event but rather it should be revised periodically as circumstances change to assure its appropriateness. The PQS systems should be developed to maximize the use of QRM to full advantage. A checklist is supplied in section 3.1. Sections 4, 5, and 6 describe the elements of facilities, utilities, and equipment. Again, checklists are available. Examples include 4.25 and 4.32 on cleanroom and air qualification and requalification.
Using New Technologies: Hidden in in Section 4, there is a discussion of the usefulness of restricted access barrier systems (RABS) and isolators (these are the new technologies I alluded to earlier). Their use is encouraged simply because they get the contamination away from the product better than more historic approaches that are still in place in many facilities. Robotics can do a similar thing. While the annex encourages their use, it does indicate that if you choose to not use these technologies, you must justify their non-use. In other words, the onus is on you to justify your actions. One of the few reasons I can think of to not implement these types of technological improvements is that they cost more. But I fear that reason will not fly. Are we seeing the beginning of a requirement being implemented?
Personnel Requirements: Sections 7 and 10 describe personnel requirements in operations and QC, respectively. Again, there are some interesting checklists in these sections for you to gauge how well your programs are operating. They emphasize that the training and systems in the sterility suite are as important as those in the aseptic core. After all, a rugged sterility suite program may be your only defense when encountering a sterility test failure.
Operations: Section 8 on operations is where the largest number of checklists resides:
8.18 Aseptic processes
8.67 Dry heat sterilizations
8.70 Dry Heat ovens
8.77 Ethylene oxide sterilization
8.82 Filtration systems
8.85 Filtration validation parameters
8.100 Form fill seal
8.101 Equipment qualification critical control parameters
8.114 Blow fill seal (BFS) validation
8.115 BFS critical control factors
8.132 Single use systems risks
Not every one of these applies in all cases, but you can tailor your assessment to include those that do apply.
Process And Environmental Monitoring: Section 9 on process and environmental monitoring describes in detail the expectations for setting up systems. While it is common knowledge that a risk-based approach should be used to choose sampling sites and frequencies and methodologies, too many clients of mine simply dig out an old sampling plan from an older facility and shoehorn it into the new facility without assessing the validity of doing so. A more progressive organization will start from scratch and perform a true risk assessment using knowledge from previous experience as well as asking the risk questions again. The annex advises that we should be examining all data in a holistic manner rather than treating the non-viable, surface viable, and the air viable data and other data piecemeal. After all, we gather the complex range of data to ask the questions “Are my facilities in control?” and “Is the environment acceptable?” Add this to your checklist.
It seems to me that the areas of aseptic process simulations (APS) or media fills are always front and center in warning letters, and I see so many problems in the design and execution of them in my own consulting work. Section 9 does provide some good checklists to consider (9.33, 34, 36).
So, what is expected to be done by the deadline in August 2023? Obviously, any new construction contemplated should incorporate any changes to the annex. And if you choose not to abide by the annex, a justification must be put in place, but that might be risky. However, preexisting systems, although grandfathered in, should still be examined and remedies instituted or, at least, defense strategies need to be formulated to justify gaps.
The annex is comprehensive, embeds QRM and CCS into the thought processes, and advocates a holistic approach to the design and operation of processes that have tremendous potential to contaminate our products. It clearly advocates for modern approaches to help solve these issues using RABS, isolators, and robots. But will we get where we need to be by the agency encouraging their use rather than requiring them? Hopefully the checklists described above might make your task of being in compliance a little less onerous.
For additional articles related to the revised Annex 1 on cleanroom gowning and working with CDMOs, check out references 5-7 below.
- Manufacture of Sterile Medicinal Products 2022 https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en#annexes
- A Practical Guide to navigate the EU revised GMP Annex 1 2022 https://www.outsourcedpharma.com/doc/a-practical-guide-to-navigate-the-eu-s-revised-gmp-annex-0001
- How to set up an Effective Quality Risk Management Program 2022 https://www.outsourcedpharma.com/doc/how-to-set-up-an-effective-quality-risk-management-program-0001
- What’s the role of Intuition when making QRM decisions 2022 https://www.outsourcedpharma.com/doc/what-s-the-role-of-intuition-when-making-qrm-decisions-0001
- Cleanroom Gowning Compliant with EU GMP Annex 1 an overview 2022 https://www.bioprocessonline.com/doc/cleanroom-gowning-compliant-with-eu-gmp-annex-an-overview-0001
- Cleanroom Gowning Compliant with EU GMP Annex 1 2022 https://www.bioprocessonline.com/doc/cleanroom-gowning-programs-compliant-with-eu-gmp-annex-0001
- CDMOs and Contamination Control Strategy the span pf oversight in the EU GMP Annex 1 2022 https://www.outsourcedpharma.com/doc/cdmos-and-contamination-control-strategy-the-span-of-oversight-in-eu-gmp-annex-compliance-0001
About The Author:
Peter H. Calcott, D.Phil., is president and CEO of Calcott Consulting LLC, which delivers solutions to pharmaceutical and biotechnology companies in the areas of corporate strategy, supply chain, quality, clinical development, regulatory affairs, corporate compliance, and enterprise e-solutions. He has also served as an expert witness. He also teaches at the University of California, Berkeley in the biotechnology and pharmaceutics postgraduate programs. Previously, he was executive VP at PDL BioPharma, chief quality officer at Chiron and Immunex Corporations, and director of quality assurance for SmithKline Beecham and for Bayer. He has also held positions in R&D, regulatory affairs, process development, and manufacturing at other major pharmaceutical companies. He has successfully licensed products in the biologics, drugs, and device sectors on all six continents. Calcott holds a doctorate in microbial physiology and biochemistry from the University of Sussex in England. He has been a consultant for more than 20 years to government, industry, and academia.