We're Going to New Orleans! Let’s Talk about Contamination Control and the Annex 1 Revision A glimpse into the 2023 PDA Annual Meeting

The 2023 PDA Annual Meeting will take place in the good ol’ city of New Orleans, April 3-5. The conference will be filled with networking events and sessions on everything you want and need to know on topics important to PDA members, including biotech, regulations and cybersecurity. One of the hottest topics, contamination control strategies (CCS) as it relates to the August 2022 revision of the revision of the Annex 1, will have sessions on the second day of the annual meeting, which I am extremely excited for, and I think you should be too.

Why is Contamination Control Strategy Important?

CCS is a system of contamination control that takes into account all the significant elements of the manufacturing process for pharmaceutical products. According to the revision of Annex 1, CCS “should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring measures employed to manage risks associated with contamination.”

CCS is the pinnacle of an exercise that aims to uncover new ways of preventing the contamination of products, facilities and supporting processes with microbes, pyrogens and particles. Moreover, manufacturers can create their CCS based on information in the quality target product profile or in the critical quality attributes, in the facility and in the processes that are used to manufacture and transport the product. Now, pertaining to strategy implementation, it involves completing the strategic plan and managing the implementation by priority over time should it be deployed. Additionally, the evaluation of the efficiency and impact of the CCS implemented is confirmed by analyzing various quality performance parameters related to contamination control. The strategy evaluation allows the manufacturer to spot new strategic plans to assist in new measures or controls to achieve the desired result, minimizing the risk of contamination.

Revised Annex 1 and Its Impact on Contamination Control

Mainly, there are two recurring questions that I see among the industry regarding CCS:

• What influence does the revised Annex 1 have on it?
• What impact does the new revision of Annex 1 have on CCS?
• What are organizations doing to successfully implement CCS and what are the challenges?

I had the pleasure of briefly speaking to Kurt Brorson, PhD, Vice President, Paraxel and Siegfried Schmitt, Senior Consultant, Paraxel, who both gave thorough takes on Annex 1 and CCS.

When asked what companies are doing to implement CCS and how they are dealing with challenges, Brorson said, “Virus safety, for instance, is a critical part of the contamination control strategy for biotech and plasma-derived products.”

He said there are unique challenges depending on if firms manufacture cell and gene-therapy products and vaccines. “Each organization takes a different approach toward virus safety, depending on the product. For example, vaccines and cell therapy products rely almost entirely on the testing of cell banks and raw materials to assure safety. On the other hand, biotech and plasma-derived products have the opportunity for downstream removal by the process. These include virus filters, which have evolved over the years to efficiently and robustly remove even very small viruses. New generations of these filters are periodically introduced by the filter companies, each with only a few improvements.”

Schmitt offered some regulatory insight into the uphill battle some organizations are experiencing in their implementation of CCS based on the new Annex 1. “When the regulators put the CCS requirement into Annex 1, they did so based on logic, science and regulatory need,” he said. “However, this is something new. A CCS didn’t really exist as such in the industry. Thus, the challenge is how to do it and how to do it efficiently.”

Schmitt added some additional insight: “Although a lot of the required information will exist for CCS, it is not as simple as putting it all into one folder. Creating the CCS requires a truly multidisciplinary approach under the auspices of top management. The question is, has this message been received? We still see too many companies prevaricating.”

Ryan Murray, a Senior Consultant at ValSource in the advanced therapy medicinal products (ATMPs) space, specifically for gene and cell therapy, would agree with Schmitt that organizations will have difficulty in establishing proper implementation and interpretation of the revised Annex 1 if the document is not read thoroughly by organizations.

He also expounds on other problems companies could possibly face. In an episode of a podcast entitled, “It’s Here! Launching Annex 1,” which he shares with his colleagues on Valsource.com, Ryan addresses CCS and contract manufacturing organizations (time stamp 20:40-21:36). Even before the revision of Annex 1, the industry relied heavily on contract manufacturers (CMOs), he noted. He believes that with the Annex 1 revision putting so much emphasis on risk management in a company’s CCS, clients of CMOs will demand more information, which may be strenuous since CMOs already have the mentality of keeping information on a site’s sterility assurance plans and how they manage it, “close to the chest.”

Ryan further explains that because the revision of Annex 1 will be adopted by PIC/S and the World Health Organization, it could lead to confusion between agencies and industries. At 22:40-23:13, he states, “…If you’re of the opinion that Annex 1 does not apply to ATMPs, then the second challenge will be explaining how both CCS and other elements of Annex 1 shouldn’t apply to your products that are inherently risker by being more manual.”

When I asked Ryan to elaborate on what he meant by this statement, he said, “In the EU, ATMPs are governed by Part IV of the Eudralex Vol. 4—the GMPs for pharmaceutical products. In Part IV, there is a statement that essentially states that the document is a stand-alone document for GMPs concerning ATMPs. In that, all of the other parts and annexes of Vol. 4 do not apply to ATMPs unless they are specifically referenced within Part IV. With Annex 1, the only reference is regarding sterilization processes.

In addition, Ryan asked a fair question about the exclusion of ATMPs in the revision of Annex 1 as it relates to sterility assurance. “Moreover, along with the revision of Annex 1 came the paradigm shift to adopting a risk-based approach to the development of a documented contamination control strategy. The CCS is a key tool to understanding, managing and controlling your aseptic space for sterile drug products. When comparing a typical cell therapy process with a high-speed vial filling line, the number, complexity and the duration of aseptic process interventions are significantly higher in a manual cell therapy process. Given this, if the revision to Annex 1 is ultimately aimed at raising the bar for sterility assurance, why would you exclude ATMPs?”

Although the experts’ responses might seem bleak regarding the revision of Annex 1, along with the document’s implementation and effect on CCS, there is optimism moving forward in the industry.

Onward and Upward

Murray and Brorson do ascertain that this new revision of Annex 1 is not all gloomy and dull. In fact, both believe that this revision is mature and does have its upsides, which they will give more detail at the 2023 PDA Annual Meeting.

Peter Bisp, QA Specialist at Novo Nordisk, will be having another great talk on day two of the annual meeting about evaluating CCS and how his company is handling the implementation of CCS after the revision of Annex 1.

Our industry is constantly evolving; but that is not a bad thing. I am excited to hear the positives that the revision of Annex 1 brings to the industry, and I am going to be front and center listening to what regulators are doing to assist in the implementation process. So, if you want to hear more about what Ryan Murray and Kurt Brorson have to say, register now. Do not wait a second longer!