Pharmaceutical manufacturers in the EU may have to approach the manufacturing of sterile drugs a little differently under the EU’s Annex 1 covering good manufacturing practices (GMPs), which goes into effect soon. For example, regulators may be asking to see whether firms have a documented contamination control strategy (CCS) and may require firms to conduct pre- and post-sterilization integrity testing (PUPSIT) on filters used in sterile drug manufacturing.
In the meantime, regulators from the US Food and Drug Administration (FDA) said that while they will not be enforcing Annex 1, inspectors will be looking into similar areas as their counterparts in the EU.
These assertions were made by regulators and members of the pharmaceutical industry from the US and EU at two panel discussions on Annex 1 implementation at the International Society for Pharmaceutical Engineering’s annual aseptic conference in Bethesda, MD this week.
Panelists addressed a range of questions concerning filter testing under PUPSIT, implementation of the new CCS, and whether existing lines should be retrofitted to meet the new requirements of Annex 1.
The revised Annex 1, which was released in August 2022 after 14 years of development, governs the manufacturing of sterile drugs made in the EU and imported products, is set to take effect on 25 August 2023. The section on 8.123 on lyophilizer sterilization will take effect one year later, on 25 August 2024.
Panelists at the meeting also agreed that PUPSIT continues to be problematic.
A panel on industry implementation issues delved into specific areas that manufacturers must address by the August deadline.
The session’s moderator, Nidhi Shah, director of aseptic processing SME for Sanofi, asked the panel to address what manufacturers should prepare to implement the CCS.
The CCS is a high-level document that addresses how manufacturers plan to address and mitigate the risk of contamination to their products.
Christa Myers, a senior fellow of aseptic and sterile products and vertical market leader at CRB, said the CCS is not anything new, but rather formalizes efforts to get manufacturers to set out a plan for controlling contamination.
“Most of the elements of the CCS have always there. It’s all of the airflows that we deal with and all of the room pressurizations that that we have all been working at for a long time. It’s our cleaning protocols and the way that operators gown,” said Myers. “What is different about Annex 1 is that they have made it a little more prescriptive so that when they walk in your facility they can tell you what they want and what chapter it’s in. It makes it easier for them to work through your facility.”
Lingering problems with PUPSIT
At this session, Shah asked Jörg Zimmermann, vice president of external affairs at Vetter Pharma, to explain the purpose of PUPSIT testing and whether such testing will be required or is a hypothetical requirement.
Zimmermann responded that PUPSIT is “trying to address a situation where a filter may be slightly failing” allowing contaminants to pass through the filter and into the drug.
Yet Zimmerman is not a fan of PUPSIT. He said that there is no need for conducting such testing if manufacturers are already validating and testing product filters. He added that the risk of testing filters used in the sterilization process, could introduce the contamination that it is designed to prevent.
“All in all, we have to look at the risk benefit ratio and I am still very much convinced that the risk associated with this process are higher than the benefits,” he said. “I have seen it as a kind of myth and some people in the regulatory agencies don’t want to get away from it. That has been one of the pain points that I have.”
He did not address whether regulators will be requiring PUPSIT.
US will not be enforcing Annex 1
At the regulator session the next day, FDA officials were asked to address Annex 1 implementation in the US.
FDA’s Richard Friedman, deputy director of the Center for Drug Evaluation and Research’s Office of Manufacturing Quality said there are no plans to enforce EU’s GMPs Annex 1 in the US, though FDA’s existing guidance for sterile drug manufacturing is largely aligned with Annex 1.
Friedman said each country in the Pharmaceutical Inspection Co-operation Scheme (PIC/S), of which FDA is a member, “has sovereignty and has their own national laws and guidances” and are not obligated to comply with Annex 1. Instead, these laws and guidances are only supposed to be harmonized with Annex 1.
FDA officials also said that for similar reasons, they will not be enforcing PUPSIT, yet said that PUPSIT was largely aligned with FDA’s existing guidance.
“Our guidance does say that integrity testing can be done prior to processing, and it can be performed post-sterilization” so the language is similar to Annex 1, said FDA’s Brooke Higgins, senior policy advisor for CDER’s global compliance branch.
Do manufacturers need to retrofit filling lines
Regulators were also asked to address whether manufacturers should retrofit or supplement their existing lines with new restricted access barrier systems (RABS) and isolators, or whether they should build entirely new lines with these technologies to more closely align with Annex 1, which encourages the adoption of RABS and isolators for making sterile drugs.
Higgins said some of the responses she has received from manufacturers with older lines who have received warning letters is they are going to try to retrofit the lines with the new technologies. She said, “it has not been an easy road for these firms, so there’s a lot to consider when you’re talking about the line and trying to retrofit it and trying to put a RABS around it.”
Higgins said that these discussions about whether to retrofit older manufacturing lines are similar to the decision on whether to replace an old car with a new car.
“At some point you have to say to yourself, ‘I am putting all this money in an older car, maybe I should have gotten a new car instead.’ So, I kind of think about that with the older lines. Investing in one that is more stable that will not require as many interventions and maintenance as these older lines.”
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