Annex 1 implementation strategies: Experts say manufacturers must grapple with PUPSIT

Regulatory NewsRegulatory News | 12 September 2022 |  By 

Correction: This article was edited on 15 September 2022 to correct Jorg Zimmermann's title. 

Sterile drug manufacturers should start preparing a gap analysis to identify what needs to be done to comply with the EU’s GMP Annex 1 revision to prepare for when these new requirements take effect on 25 August 2023, said experts who spoke to Regulatory Focus.
They should also start preparing a contamination control strategy (CCS), a high-level document that addresses how manufactures plan to address and mitigate the risk of contamination to the quality of the products.
The experts also cited improvements in the revision, such as better differentiation between restricted access barrier systems (RABS) and isolators yet said that the requirement for manufacturers to test filters remains problematic.
The revised annex, released last month after 14 years of development, governs the manufacturing of sterile drugs made in the EU and imported products. (RELATED: EU issues long-awaited GMP Annex 1 revision, Regulatory Focus 25 August 2022)
Experts were asked to comment on what manufacturers can start doing now to comply with the new annex and to comment on some of the more challenging aspects of Annex 1.
The revision has a new section on pharmaceutical quality systems, which incorporates the principles of quality risk management (QRM) into sterile drug manufacturing. There is also a new section addressing the concept of a CCS in reducing contamination, as well as new sections adopting recent advances in sterile processing technology in manufacturing, such as RABS and isolators.
New, but not really new
Experts stressed there should be no surprises for manufacturers that have been paying attention to the Annex 1 revision while it was a work in progress.
Jorg Zimmermann, vice president of external affairs for Vetter Development Services*, a contract manufacturer of sterile injectables, told Focus that the recently published Annex 1 “is not really a new system. There are a lot of things that are described in more detail that we as industry have been doing for years. At the same time, the discussion has been going on for such a long time already that it is unacceptable to only start thinking about implementation now.” 
Richard Denk, senior consultant of aseptic processing and containment at SKAN AG, and a board member of the ISPE’s Germany/Austria/Switzerland affiliate said that for companies that have done their homework, there should be no surprises, and that certain changes should have been anticipated since the last proposed revision in 2017.
Experts advise gap analyses
Hal Baseman, chief operating officer, ValSource, advised companies to prepare a gap analysis to bridge what needs to happen to make sterile manufacturing compliant with Annex 1.
“Companies should perform gap analysis to determine where changes related to the requirements in Annex 1 will be needed. They should determine how long those changes will take. If these changes exceed the one-year implementation expectation, then they should prepare a plan for addressing or controlling any risk associated with manufacturing during this delay,” he said.
Baseman is the former chair of the Parenteral Drug Association’s (PDA) Board of Directors, and a co-leader of the PDA Points to Consider for Aseptic Processing Task Force and Annex 1 Commenting Task Force.
Others suggested that firms start putting together a CCS, if they have not already done so.
“There are some items and principles that have been very clear from the beginning that they are coming. For example, contamination control strategy is something that companies should have in place in the form of a high-level strategy document that describes the approach to avoiding particulate and microbial contamination of sterile products,” said Zimmermann, who also chairs the International Society of Pharmaceutical Engineering’s (ISPE) international board of directors.
The problem with PUPSIT
Experts also cited some of the improvements made since the last revision, while complaining about some of the more problematic aspects of the annex.
Zimmermann said that placing RABS and isolators in two separate sections was a step in the right direction. The former revision had combined these two barrier systems, when they should be treated separately because each system is different.
Yet the requirement to test filters used to sterilize products is a problem under a system called PUPSIT (pre-use, post-sterilization integrity testing) as the risk of testing filters could introduce the very contamination it is designed to prevent.
“The good thing is that RABS and isolators are now separate, not so good is PUPSIT, it doesn’t make sense,” said Zimmermann.
Zimmermann added that “if you do product-specific filter validation properly, then there is really no need for PUPSIT and the risk of doing such testing may exceed the benefits.”
He added that “there are also those agencies, you either do it and you are compliance and or you don’t do it and you are not compliance, I have not seen good set up for it yet.”
Zimmermann said that filters have gotten better over the years, and there is no need to do such testing. “Using single-membrane filters, manually fitted into stainless-steel housings was commonplace in the 1980s, but now we use filter cartridges and capsules that are 100% pre-tested by the manufacturer. There were problems with in-line-sterilization in the early days, but that has also been resolved.”
His colleagues agreed that PUPSIT was one of the more controversial new requirements. “I was part of the ISPE Annex 1 commenting group and PUPSIT created the most of discussion,” said Denk.
Baseman views PUPSIT as a challenge, creating additional stresses on sterilized filters, assemblies and lines, and added that “this will be especially true for companies with less experience or understanding of the relative risk associated with filtration and use of the PUPSIT systems. It will be important for these companies using PUPSIT to make the effort to understand the risk and designs and use PUPSIT accordingly.”
Gabriele Gori, site quality head for Thermo Fisher Scientific and co-chair of PDA’s Annex 1 commenting task force, said, “If not properly designed and executed, this significantly increases the contamination risk, with very little controls downstream to detect any introduced contamination.”


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