The pharmaceutical world, particularly those involved with the manufacture of sterile products, is anxiously anticipating publication of the final approved revision of the EU GMP Annex 1: Manufacture of Sterile Medicinal Products. The latest information received is that this is expected this summer, which could be sometime between June and September. Organizations must prepare for changes based on the text of the latest draft of the revision (the twelfth draft), published in February 2020.
To support this preparation, PDA organized a number of workshops on the twelfth revision. The 2022 PDA Annex 1 Workshop, held 16-17 May in Dublin, was the second of a series of four and the first held on European soil. Based on the feedback received, the event was a great success.
The Workshop was characterized by a mix of presentations and interactive discussion sessions based on specific topics in the draft guidance. Participants had the opportunity to ask a panel of experts about the presented subject and, above all, delegates had the opportunity to discuss their interpretation, challenges and possible solutions with peers from the industry. The following key takeaways were distilled from these discussions.
In the run up to the final publication, there has already been much debate about the allowed implementation period. The industry requested an implementation period of 12 months for standard topics, with an extended implementation period up to 36 months for more complex matters that would require facility or process updates.
Former regulatory representatives reemphasized that the draft guidance is based on what regulators have already seen as industry practice and is, in essence, not new. The new revision puts more emphasis on these practices, and it will now be important for industry to formalize these practices in a presentable format. As such, during a 2021 meeting among EU member states, a period of 6 months for standard implementation was proposed, with a 24-month period for more sophisticated and intricate changes, such as automated loading/unloading systems for lyophilization or implementation of pre-use post-sterilization integrity testing (PUPSIT).
As the draft text has already been out for discussion and consultation for some time, organizations know what is coming. Where a company believes it will not be fully compliant within the timeframes agreed, a gap analysis with a clear and realistic remediation program is expected to be in place and demonstrated adherence to the plan will be key.
Pre-Use Post-Sterilization Integrity Testing
A robustly discussed topic concerned the benefit or, more importantly, the risks related to the expected implementation of PUPSIT. It is expected to remain the norm in and outside of the EU.
According to the regulators, PUPSIT will increase the level of aseptic assurance of the final product, and, consequently, patient safety. In addition, they said, PUPSIT makes sense from a business perspective, as it prevents the rejection of products because of failing filters.
There may be situations where PUPSIT can be omitted, but these must be rigorously scientifically justified with supporting data. The use of preassembled and presterilized single-use systems is not deemed a reason in itself to omit PUPSIT.
PDA performed masking test studies and published Points to Consider for Risks Associated with Sterilizing Grade Filters and Sterilizing Filtration for implementation of PUPSIT.
Quality Risk Management
The scope of Draft Annex 1 makes clear that quality risk management (QRM) applies to the document in its entirety, not only to specific paragraphs. QRM is to be used proactively based on a scientific approach, and data will be expected to be seen to support QRM.
Risk experts often work with an extremely in-depth risk assessment tool, which is not always required. Selecting the most appropriate tool, based on system knowledge and the complexity and the criticality of the system, is important. Having meaningful assessments that are data driven and scientifically sound is the key purpose, not the number of risk assessments completed to come to a justification.
A common pitfall is when the endpoint of a risk assessment is predetermined, and the people involved work their way to this assumed or desired endpoint. Good risk management requires an experienced risk facilitator guiding the process with a multidisciplinary team. This can present a challenge for small organizations.
Contamination Control Strategy
Although not entirely new within the regulations, Draft Annex 1 makes it clear that organizations are expected to have a contamination control strategy (CCS) implemented across the facility defining all critical control points present with an assessment of their effectiveness. The CCS should be risk-based and should evaluate the end-to-end process in a holistic manner to prevent contamination. Hence, CCS and QRM go hand in hand.
Often, companies have scattered, disjointed information that does not consider both CCS and QRM holistically. The CCS brings all this information together and points to the relevant documents for the details. The consensus is that the CCS should be a roadmap-like document, not a tick-box exercise. It must drive continuous improvement and, therefore, requires periodic reevaluation. The Draft Annex 1 summarizes 16 elements to consider, at a minimum, as part of the CCS, which requires a multidisciplinary team with in-depth technical knowledge. The ownership of the CCS is a point of debate, and the availability of resources and getting a team together to create the risk assessment and CCS is often seen as the most difficult task.
The PDA will publish a technical report shortly on the development of a CCS in pharmaceutical manufacturing that will provide guidance about how to establish a CCS in an effective manner.
Direct and Indirect Product Contact Surfaces/HPV Decontamination
Draft Annex 1 clearly states that direct and indirect contact parts are expected to be sterilized. For existing configurations, this can be a challenge as such parts as stopper bowls and tracks can be difficult to remove from their setting, sterilize and reassemble. In some situations, the size of equipment prevents its removal from the enclosure or poses a health and safety risk. Another consideration is how the sterilized parts are handled after sterilization and reassembly, as it is of paramount importance that the equipment not be compromised during transport and installation.
The selected method of sterilization is an important factor to consider. EU regulators do not view hydrogen peroxide vapor (HPV) as a sterilization process, although the target is 6-log reduction of a highly resistant microbial spore. There is some ambiguity between the EMA and the U.S. FDA here, as the latter refers to HPV as a sterilization process. While HPV decontamination is the method of choice for isolator technology, it is not deemed suitable for the sterilization of direct and indirect product-contact parts.
Qualification and Training
Despite all the technology available, the human factor cannot be disregarded. Personnel with the right level of skills and attitude are of paramount importance for a robust and reliable sterile-manufacturing process.
For this reason, training and qualification of personnel is one of the most critical aspects for a company but also one of the most challenging, raising several questions: How can knowledge transfer be measured? And when does one know if training is effective?
There is general agreement that there should be a greater focus on personnel qualifications whereby the “why to do it” is at least as important as how. A good training program is about the education of personnel. It is about the investment in resources, and the likelihood of success is directly related to the investment the company is willing to make to develop effective training programs for its personnel.
Concepts like virtual training allow operators to become familiar with aseptic working environments. It gives them an opportunity to safely gain experience of working in a critical area without being directly thrown into the deep end.
Although Draft Annex 1 was published in February 2020 and organizations have had time to familiarize themselves with the new text and prepare for changes, there are still many points for discussion. The final text is expected to be published before the end of the summer and, despite regulators indicating that the final text will not deviate too much from what is currently published, and guidance given in the Draft Annex 1 is what they already have seen in the industry, companies still have many questions relating to the interpretation and implementation of many aspects of the new draft. For both regulators and industry, understanding and aligning expectations will be important. As such, holding a joint regulator/industry workshop was suggested and, although the idea is welcomed by both parties, no concrete plans have been made.
About the Author
Patrick Nieuwenhuizen, Director Senior Consultant at PharmaLex, has over 25 years of experience in the pharmaceutical industry with a background in microbiology and sterile manufacturing. He has worked for several global pharmaceutical and biotechnology companies, including Genzyme (a Sanofi company) and MedImmune, across a variety of platforms from biologics to sterile fill finish and solid oral dose. Nieuwenhuizen has provided quality, sterility assurance and microbiology oversight for various site and laboratory expansion projects from construction design through to method transfer and operational readiness. Nieuwenhuizen has also been involved in several corporate initiatives, such as a sterility assurance council and the roll-out of corporate standard programs, designed to improve and maintain organizational quality standards. As a lead auditor, he has been involved with audits facing several competent authority inspections, including but not limited to Ireland’s Health Products Regulatory Authority, the U.S. FDA, ANVISA, the Chinese FDA and Health Canada. Acting as a risk facilitator for quality risk management programs, Nieuwenhuizen has gained significant experience with problem-solving and the management of complex investigations.
For more information on Annex 1, the author encourages readers to contact him: [email protected]