The European Union’s Good Manufacturing Practice (GMP) Annex 1 Revision is set to take effect on August 25, 2023. Annex 1 will offer a broad-reaching regulatory revamp that will impact any pharmaceuticals manufactured for export to the EU. Kevin Smyth, a biochemical engineer with 30 years of experience in the pharmaceutical industry, offers insights and expertise in working with firms to understand what regulators seek to meet new standards.

The pharmaceutical industry is subject to some of the most rigorous regulatory requirements in the world. The good news for pharmaceutical manufacturing companies is that the regulators who developed Annex 1 are not innovators. They are merely reporters and codifiers. Nothing in this set of thinking involves original research or technology. Instead, they performed due diligence – outstanding due diligence, in fact – in reviewing the best current practices in the industry.

Annex 1 regulators can come from any EU nation and tend to conduct inspections with the same expectations as a facility in their home country. For example, the Irish biopharmaceutical industry is relatively young, and many of the innovations employed in Irish facilities helped inform the drafting of Annex I. Therefore, you could expect an Irish regulator to enter a given facility with certain expectations.

One must keep in mind the notion, however, that inspectors are not in the business of shutting down vital pharmaceutical manufacturing lines, nor are they interested in allowing practices that could put lives at risk. Indeed, regulators may make specific allowances for high-value, low-volume products, such as cell or gene therapy (generally referred to as ATMP – or advanced therapy medicinal products outside the US).

However, they will still carefully examine your risk mitigation procedures.

Good Manufacturing Practices Require Modern Contamination Control

The focus of Annex 1 is heavily weighted on contamination control strategies, with a focus on provable processes that minimize the risk to patients. Each facility – and all the controls and processes put in place – is accountable for ensuring the product is not compromised. Moreover, a thorough strategy should not only be in place, but it should also be verifiable, testable, and provable. Ultimately, a contamination control strategy should be scientific – driven by data, not well-meaning assurances.

To meet contamination control goals, many solutions are a matter of human behavior – improving procedures to mitigate risk effectively, otherwise known as Things You Should Be Doing Now. Still, others might require investment in new manufacturing technologies, with the knowledge that changes to a manufacturing line will require re-validation and product testing procedures to prove there is no contamination in the interim.

One unavoidable manufacturing technology involves PUPSIT or pre-use, post-sterilization integrity testing. When putting drug products into a vial or syringe, you have two options: heating or filtering. Most drug products denature at sterilizing temperatures, so filtering becomes required. This filtering is an expected practice.

Currently, testing the filter before use in the US is not standard practice. Under the PUPSIT norms of Annex 1, however, the integrity of the filter must be verified before and after the filtration process.

The reason is that filters could conceivably develop flaws allowing microbiological contamination to pass. These flaws have the potential to be obscured by other particles, such as inert material or the medicinal product itself, during the filtration process, which might allow contaminated products to go to market even though they have been run through filtration. The pre-use test, therefore, would be expected to detect flaws in the filter before the product is passed through it and into its final container.

It is a simple concept that adds tremendous complexity to the production line, involving complex piping and filter sterilization. Conceivably, a manufacturing line that does not have PUPSIT in place before August 2023 is at risk, particularly if the manufacturers cannot demonstrate they have the plan to mitigate potential contamination while the desired changes to the manufacturing line occur.

Under Pressure (and Heat) to Sterilize

Of course, PUPSIT is not the only potential stumbling point in adapting Annex 1 to American manufacturing norms. Annex 1 requires closely examining every facet of the manufacturing process regarding how the environment interacts with the sterile product.

Take the standard glass vial with a rubber top, for example. The inside of the glass vial and the rubber stopper requires sterilization, and so does everything that comes into contact, directly or indirectly, with the vials and the stoppers. That means the stoppering bowl and the conveyor belt (and anything that encounters the stoppering bowl and conveyor belt) require sterilization to prevent the possibility of transferring contamination. This is an example, but it is emblematic of a common problem seen in working with clients regarding Annex 1 compliance.

In the US and many parts of the world, the most common solution to this problem is to sterilize everything periodically with hydrogen peroxide. Under Annex 1, however, hydrogen peroxide is not considered sufficiently effective. Everything must be autoclaved.

Unfortunately, an existing surface or piece of equipment may not survive autoclaving. Relatively modern manufacturing components can fail to withstand repeated autoclave exposure. This, of course, becomes a problem with a time-intensive solution. In this example, manufacturing components, such as the stoppering bowl, must be re-designed or re-engineered. Even under the rosiest conditions, designing, building, and testing could take a year or 18 months.

The interim solution, meanwhile, is more thorough testing of the final product, which also adds to costs, even temporarily. Of course, anything changed on a filling line is a substantial deal. Once new components are in place, the entire line must be re-validated. This, of course, inevitably leads to unavoidable production stoppages.

With a heavy focus on contamination control strategies, implementing the EU’s Good Manufacturing Practice Annex 1 Revision presents significant global challenges for pharmaceutical manufacturing companies. Companies must take clearly-defined and scientifically-verifiable proactive measures to mitigate risks and ensure product safety. For example, introducing PUPSIT and the accompanying requirement for autoclaving may add unavoidable complexity to the manufacturing process. This could require changes to equipment, re-validation of the production line, and product testing procedures that may be expensive in the interim – but certainly not as costly as the regulatory shutdown of a manufacturing line. Despite the challenges, companies must recognize the importance of complying with Annex 1 to meet regulatory standards, maintain product quality, and protect patient safety.

This white paper was originally published in Cell and Gene.