Focus on Aseptic Processing: A Report from the September 2022 PDA Annex 1 Event in Amsterdam

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The European Medicines Agency (EMA) was true to its word in 2022. While pharmaceutical companies involved in manufacturing sterile products were assessing the text of Draft Revision 12 of Annex 1 to the European Union’s good manufacturing practice (GMP) regulations, the final approved revision was published on 25 August 2022 (1), bringing an end to speculations about what it would include.

The Parenteral Drug Association (PDA) has organized a series of four workshops, the third of which took place in Amsterdam, The Netherlands, on 22–23 September 2022. The draft revision was covered at the previous two events — in Dallas, TX, and Dublin, Ireland — but this time all participants could refer to the effective version of Annex 1.

Similar to the previous events, this meeting combined presentations based on specific Annex 1 topics with interactive workshops in which participants could ask panels of experts about the topics on which they had presented. Above all, the meeting provided opportunities to discuss interpretations, challenges, and possible solutions for compliant implementation of the new Annex 1 revision among industry peers. Many questions were asked during the panel and roundtable discussions, with much interaction among presenters and attendees.

Implementation Period and Readiness
Following publication of the final version of Annex 1, companies need to comply with it no later than 25 August 2023, except for a sterilization requirement before each loading of manually loaded/unloaded lyophilizers. For that requirement, companies are expected to comply with point 8.123 of the annex before 25 August 2024, with an implementation period of two years after its publication.

As regulatory representatives indicated during previous PDA Annex 1 workshops, the final text was not expected to deviate much from that in the draft version that was published in February 2020. In fact, the body of the text has remained unchanged except for some added clarification. Thus, companies had the opportunity to begin preparing and familiarizing themselves with the text over two years and generally knew what to expect. That was one reason why the EMA gave a deadline of one year for implementation, reemphasizing that the final published Annex 1 text is based on what regulators already have seen practiced in the industry and thus is, in essence, not new.

It was surprising to learn that some organizations still had limited familiarity with the draft document. Multisite facilities expect difficulty in implementing all requirements within the expected timeframe. Companies working with contract manufacturing organizations (CMOs) depend on their readiness and willingness to implement the required changes. A lack thereof could lead to serious financial costs and time constraints in seeking regulatory approval of updated drug master files (DMFs).

Knowing that the clock is ticking and that implementation is expected within half a year from publication of this report, companies are urged to familiarize themselves with the final text, to perform gap assessments, and to create realistic remediation plans with tangible actions to assure compliance from 25 August 2023 onward.

Quality Risk Management
Quality risk management (QRM) applies to the final Annex 1 document in its entirety. The EMA expects companies to use QRM in a proactive scientific approach, making data available to support their assumptions and decision-making processes. QRM is not in place to “risk-out” good practices or expectations, nor is it intended to justify bad practices or predetermined outcomes. Proper QRM demonstrates that an organization understands the characteristics of its products and processes used to manufacture them within the facilities and with the utilities that support those activities. Potential risks are identified, and controls are put into place to mitigate those risks. The point of a solid risk assessment (RA) is to prioritize and mitigate the identified risks. Besides benefiting companies, those actions give regulators an impression of how well the organization understands its processes, how those are controlled, and how potential issues are detected.

The maturity of QRM implementation varies across the biopharmaceutical industry, with some companies having it already embedded in their day-to-day operations even as others explore how to apply its principles. The latter companies will face difficulty in adding a structured and formalized quality risk assessment (QRA) process for areas that had not been mentioned in the previous version of Annex 1. Selecting the best risk tool to apply will be key to finding the right answers. Many company leaders default to the tools that they are most familiar with, whether or not those present the optimal choice. Like using a hammer to drive in a screw, applying some tools could work but not ideally. The PDA and American National Standards Institute (ANSI) have collaborated to develop a specific tool for aseptic processing RA (2).

Good QRAs often are led by experienced risk facilitators who are familiar with QRM concepts and can help in planning to ensure that the scope and risk questions being asked are fully agreed upon and documented before selection of the most appropriate QRA tools. A risk facilitator guides the QRA process with a multidisciplinary team to keep progress on track to avoid “scope creep.” Difficulty can arise in determining where the responsibility for ownership lies for completion of RAs and identifying who contributes and takes actions — potentially leading to delays or even incompletion of QRAs. For smaller companies, such efforts can be a challenge because they require support from team members who could be needed elsewhere. A responsible, accountable, consulted, and informed (RACI) matrix can help to provide a solution (3).

Contamination Control Strategy
The requirements for organizations to design their processes and premises for minimizing contamination risk date back to 2015 (4–6). The revised Annex 1 emphasizes those requirements with an expectation that each company has implemented a contamination control strategy (CCS) across its facility, focusing specifically on microbiological, pyrogen/endotoxin, and particulate contamination. As listed in the “Elements” box, the annex summarizes a minimum of 15 elements to consider when defining and creating a CCS. The document defines all critical control points (CCPs) present and provides an assessment of their effectiveness. It serves as a repository of such elements and control measures for holistically evaluating an end-to-end process to prevent contamination.

Because a CCS should be risk based, it is closely related to QRM. So the points described in the QRM section above also apply to the development and maintenance of an effective CCS. Strategy documents often describe a company’s activities but do not explain its reasoning, which too often is based on undocumented historical knowledge. A CCS must be based on the outcome of the QRA process for assessing contamination risks at each point in a process flow.

A CCS must drive continuous improvement; therefore, it must periodically be reevaluated and adjusted where necessary, particularly when an underpinning RA has been revised based on a company’s change-management and deviation processes. Trending of process, utility, and environmental monitoring (EM) data also provides valuable information about the effectiveness of a company’s CCS — and thus warrants periodic revisiting.

For CMOs and their customers, it can be difficult to agree on what information should be included in a CCS when some information might be proprietary to a CMO or common across several clients. Risks and proposed mitigation actions or changes must be communicated to clients, so it is important to understand risks associated with a process, including those related to an active pharmaceutical ingredient (API) or drug substance, consumables, and other materials. One potential solution is for CMOs to have a general CCS in place covering their overall strategies, then augment those with product/process-specific strategies for each client. That would enable customers to focus on their own product-specific elements without a risk of sharing confidential information.

The PDA’s technical report 90 covers development of a CCS in pharmaceutical manufacturing that should provide guidance for effectively establishing such strategies (2).

Preuse Poststerilization Integrity Testing
It was no surprise that preuse poststerilization integrity testing (PUPSIT) remained a highly debated topic during the workshop in Amsterdam. Although US Food and Drug Administration (FDA) regulators are not enforcing PUPSIT, it will be required in Europe going forward. In some situations, PUPSIT can be omitted — such as for small-volume radiopharmaceuticals — but such omissions have to be justified scientifically with rigorous supporting data. It will be difficult for companies to justify a rationale for not performing PUPSIT, so that could be a major compliance issue for companies that have not considered integrating it into their final sterile-filtration processes.

For processes that involve single-use systems (SUS), CCSs should be designed such to allow for PUPSIT. Early engagement with SUS suppliers will be paramount to ensuring that those systems are designed correctly and can meet supply demands for quality and quantity.

Note that the PDA has performed masking studies and demonstrated that some drug products can foul and clog damaged filters, causing “pass” results in postuse filter-integrity tests. Such findings strengthen the position of regulators that PUPSIT reduces the risk of using nonintegral filters without detecting the problem. As one former regulator rightfully commented during the workshop: There is no question as to whether PUPSIT should be implemented into drug-product operations; the only question is how to do so.

Container–Closure Integrity Testing
Compared with the draft revision published in February 2020, the effective revision of Annex 1 has added a key adjustment regarding the requirement for 100% container–closure integrity testing (CCIT) of units that are closed by a fusion method. Whereas the draft revision required that containers of all volumes be subjected to a 100% integrity test using a validated method, the final requirement is exclusive to containers of ≤100-mL volume. The test frequency may be reduced for larger containers, but only if doing so is justified and based on scientific data. However, it is more important to focus on a robust process with adequate controls in place to prevent container–closure integrity failures than to define a test strategy that confirms compliance of drug products but doesn’t actually control failure levels.

For units with stopper seals, integrity testing must be performed using a validated method because visual inspection alone is not deemed sufficient. Apart from the initial validation and product-stability testing, not all companies perform routine CCIT on filled units. Several available technologies can be introduced in-line/on-line, including those for oxygen-headspace measurement, vacuum-leak tests, high-voltage tests, and residual seal-force measurement. But no one solution works in all cases, so organizations are advised to seek expert support. As for other sampling programs, the frequency must be based on risk and justified statistically. A life-cycle approach for vial/stopper filling seems to be the accepted practice.

CCIT verification must be part of transportation of prefilled-syringe products because some transport conditions such as decompression can cause plungers to move inside the syringes. Temperature fluctuations can compromise integrity, as was experienced during some publicized challenges with –80 °C transport and storage of mRNA-based COVID-10 vaccines.

Premises and Barrier Systems
Removing personnel from open aseptic processes is the most effective way to reduce the risk of human-derived contamination. It can be achieved by introducing a physical barrier between the critical grade A zone in the form of restricted-access barrier systems (RABS) or using isolator technology. Hence, the published Annex 1 firmly recommends considering the use of barrier technology.

Barrier technologies and their associated controls differ significantly. For example, frequently opening the doors of a RABS system to perform inherent or corrective interventions classifies it as a grade A–B design by negating its intended purpose of segregating operators from the critical zone during interventions. That already was spelled out in USP <1116> “Microbiological Control and Monitoring of Aseptic Processing Environments” (7).

Regarding the use of isolator technology, whereas the 2009 Annex 1 revision required a minimum classification of grade D as background for isolators, further expectations have been added to the new version. A grade D background is allowed when closed isolator systems are used — that is, there is no infeed from or outfeeds to lower-classified areas. Drug products (including all primary packaging components) must be present in an isolator and the entire aseptic process completed (including sealing of final product containers) within the isolator before it is opened again. In an open-isolator configuration, for example, containers are transferred through a depyrogenation tunnel oven into the critical grade A zone, and units are filled and moved out of the isolator through a mousehole. Such operations require at minimum a grade C background and must be justified for a given CCS.

When a product requires lyophilization, design of the freeze-dryer loading and unloading process plays an important role that will dictate the sterilization frequency of the chamber. According to point 8.123 of the revised Annex 1, manually loaded and unloaded lyophilization processes without barrier technology require sterilization of the chamber before each load. Companies have until 25 August 2024 (two years after the document’s publication) to comply with that requirement. It could have implications for some organizations’ manufacturing capacity and thus potential effects on market supply.

Retrofitting existing freeze-drying setups can be difficult, and financial burden is only one concern. In collaboration with engineering specialists, a workable solution must be found that allows for automatic loading and unloading of an established legacy unit or implementation of barrier technology. Available facility space can be a restricting factor, as can the delivery time for process reengineering, qualification, and validation. Together, meeting those requirements could take longer than the two-year grace period for some companies.

Time Is Running Out
With the final text published in August 2022, time flying by for organizations that need to comply with Annex 1 by 25 August 2023. Companies must ensure that they understand the requirements of the newly published version. A structured gap assessment and realistic remediation plan to address noncompliances as soon as possible will be important to satisfy regulatory inspections and future-proof a company’s compliance for the European market. All of this requires in-depth knowledge of drug-product manufacturing processes and identification of their associated risks, augmented with remediation actions based on correct adoption and successful implementation of QRM.

The final published version of Annex 1 calls on organizations to adopt a new top-down mindset that is holistic and may require cultural changes. Consideration should be given to novel technologies such as barrier technologies, on-line CCIT, and rapid alternative monitoring methods — all with the purpose of improving product quality and, ultimately, patient safety.

References
1 Annex 1: Manufacture of Sterile Medicinal Products. The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. European Commission: Brussels, Belgium, 22 August 2022; https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf.

2 TR 90. Contamination Control Strategy Development in Pharmaceutical Manufacturing. Parenteral Drug Association: Bethesda, MD, 2023.

3 Moon J. Foundations of Quality Risk Management: A Practical Approach to Effective Risk-Based Thinking. American Society for Quality: Milwaukee, WI, 2022.

4 Chapter 3: Premises and Equipment. The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. European Commission: Brussels, Belgium, 13 August 2014; https://health.ec.europa.eu/system/files/2016-11/cap3_en_0.pdf.

5 Chapter 5: Production. The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. European Commission: Brussels, Belgium, 13 August 2014; https://www.gmp-compliance.org/guidelines/gmp-guideline/eu-gmp-chapter-5-production.

6 Annex 15: Qualification and Validation. EudraLex Volume 4: EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. European Commission: Brussels, Belgium, 30 March 2015; https://health.ec.europa.eu/system/files/2016-11/2015-10_annex15_0.pdf.

7 General Chapter <1116> Microbiological Control and Monitoring of Aseptic Processing Environments. USP–NF. United States Pharmacopeia: Rockville, MD, 2023; https://doi.org/10.31003/USPNF_M99835_01_01.

Further Reading
Camposano D, Mills A, Piton C. A Single-Use, Clinical-Scale Filling System: From Design to Delivery. BioProcess Int. 14(6) 2016: 50–59; https://bioprocessintl.com/manufacturing/single-use/a-single-use-clinical-scale-filling-system-from-design-to-delivery.

Coleman K. The State of Quality Risk Management in the Pharmaceutical Industry: Commentary on the Draft ICH Q9 Revision. BioProcess Int. 20(11–12) 2022: 12–14; https://bioprocessintl.com/2022/november-december-2022/the-state-of-quality-risk-management-in-the-pharmaceutical-industry-commentary-on-the-draft-ich-q9-revision.

Ewan S, et al. Dye Ingress Methods for Container–Closure Integrity Testing: An Industry Position Paper. BioProcess Int. 16(9) 2018: 10–18; https://bioprocessintl.com/analytical/qa-qc/dye-ingress-methods-for-container-closure-integrity-testing-an-industry-position-paper.

Mok Y, et al. Best Practices for Critical Sterile Filter Operation: A Case Study. BioProcess Int. 14(5) 2016: 28–33; https://bioprocessintl.com/downstream-processing/filtration/best-practices-for-critical-sterile-filter-operation-a-case-study.

Nieuwenhuizen P. Aseptic Considerations in Formulation, Fill and Finish: Choosing Between Barrier and Isolator Technologies. BioProcess Int. 19(9) 2021: S1–S5; https://bioprocessintl.com/manufacturing/fill-finish/aseptic-processing-in-formulation-fill-and-finish-choosing-between-barrier-and-isolator-technologies.

Shahrokh Z, et al. Emerging Strategies for Drug Product Comparability and Process Validation: Part 1 — Analytical Tools and Drug Product Comparability. BioProcess Int. 19(3) 2021: 16–22; https://bioprocessintl.com/business/cmc-forums/emerging-strategies-for-drug-product-comparability-and-process-validation-part-1-analytical-tools-and-drug-product-comparability.

Southam L, Drinkwater JL. Formulation, Fill and Finish of Lentiviral Vectors: Part 1 — Case Study in Facility and Process Design. BioProcess Int. 19(10) 2021: S14–S20; https://bioprocessintl.com/manufacturing/facility-design-engineering/formulation-fill-and-finish-of-lentiviral-vectors-part-1-case-study-in-oxbox-facility-and-process-design.

Southam L, Drinkwater JL. Formulation, Fill and Finish of Lentiviral Vectors Part 2: Key Decisions and Risk Management. BioProcess Int. 19(11–12) 2021: 50–54; https://bioprocessintl.com/manufacturing/fill-finish/formulation-fill-and-finish-of-lentiviral-vectors-part-2-key-decisions-and-risk-management.

Stering M. Preuse, Poststerilization Filter Integrity Testing for Single-Use and Stainless-Steel Installations. BioProcess Int. 12(9) 2014: 54–56; https://bioprocessintl.com/downstream-processing/filtration/preusepoststerilization-filter-integrity-testing-single-usestainless-steel-installations.

Vanness B, et al. Response to the Publication of USP ‹1207›. BioProcess Int. 15(1) 2017: 20–21; https://bioprocessintl.com/analytical/qa-qc/bpog-response-publication-usp-1207.

Patrick Nieuwenhuizen is a director and senior consultant at PharmaLex Ireland, Suite 2, Stafford House, Strand Road, Portmarnock, County Dublin D13 H525, Ireland; [email protected].