The term “holistic” often has a pseudoscientific connotation. Catherine Jomary, Ph.D., ATMP Technical Lead at Integrated Project Services (IPS), uses holistic in the purest sense. She reframes the understanding of contamination control under the EU GMP Annex 1 regulatory revision, which takes effect in August 2023, to fully encompass the human and technological processes involved in the interconnected nature of modern pharmaceutical manufacturing.
As we prepare for Annex 1 to take effect, it is important to understand the big picture and recognize the benefits of this regulatory revision. I tell clients that, in many ways, this is an excellent tool for us. Previously, the regulatory strategy of GMP (good manufacturing practices) was deliberately vague and open for interpretation which allowed the industry to excuse certain practices as “good enough.”
In terms of contamination control, “good enough” seemed to achieve good customer safety results. Over time, the nature of the pharmaceutical product required more attention to contamination control. In this age of cell and gene therapy (or Advanced Therapeutic Medical Products, as they are commonly known outside of the US), the call for purity in our products is even more critical because the consequences of failing to act are more dire.
Annex 1 is built on mitigating risk. It is a compilation of the best contamination control practices currently in operation in facilities across the globe. Since the release of the first drafted Annex 1 revisions, I have worked with clients across the industry to understand how these regulations might impact their operations.
Annex 1 calls for a holistic understanding of the manufacturing process. Under Annex 1 regulations, we must thoroughly understand the relative risks involved in introducing contamination into any aspect of our facilities, from the flow of raw materials and personnel throughout the facility to air handling, the cleaning of manufacturing surfaces, and the egress of waste materials. Nothing is left to interpretation, and everything must be accounted for in your risk-assessment analysis.
This analysis extends to every corridor and every room across the facility. It impacts the worker experience from the moment they enter the building.
What Does it Really Mean to Holistically Assess Your Facility?
It is important to read the Annex 1 revisions and understand what is being asked of the industry. Many companies often skim these revisions and believe that they are already compliant and no changes will be needed before August. Many often fail to realize the inherent risk of that line of thinking.
It all returns to the notion of a holistic approach to understanding risk across the facility. Without a thorough facility audit regarding Annex 1, you simply do not know what process needs to be reconfigured to come into compliance or what technological changes need to be incorporated (and tested and re-validated). Wise organizations will employ a diverse team to audit their facilities, with experts from inside and outside their company to leverage their expertise and challenge each other’s assertions.
To regulators under Annex 1, the safety of patients has no cost. There is no economic argument for excusing risk, and with contamination risk for potential patients comes greater financial risk for pharmaceutical manufacturers.
Contamination control is a combination of human procedures and facility technology. Technical solutions should complement procedural changes. There is often a technical solution that will reduce risk in certain aspects of manufacturing. However, we can also evaluate human behavior, activity, and traffic flow within a facility to make simple changes in process design that complies with GMP.
These two elements work in tandem. Workers can follow the processes and procedures to the letter, but it won’t matter if your ventilation system, for example, is substandard or if there is no way to remove waste without interacting with the manufacturing line.
For example, I worked with a company that had developed an impeccable mitigation strategy against cross-contamination. On paper, they did everything correctly regarding procedures and the flow of materials and workers throughout the facility, except for one big thing: a waste pipe along the side of a corridor built at about knee height. It would only take a small seal failure or an accidental stumble to cause a small, barely perceptible leak to begin, which could then be tracked across the facility.
Modernizing your production facilities could cost time and capital expenses. However, few things may cost a manufacturer more than a regulatory shutdown, whether that is the loss of a batch or the losses that accrue every moment a production line is closed.
Come August, Annex 1 regulators want to see you have done your work. They want to know that you have read the regulations and evaluated your facility. They want to see what you have done to mitigate contamination and that you have generated the numbers to back your assertions.
Your greatest asset to meet this challenge is a simple spreadsheet.
Evaluating Your Facility by Room
A modern facility is a wonder of science and engineering. It is, of course, complicated and difficult to perceive in its entirety. Breaking the process down into smaller steps makes evaluation manageable.
Take any given room in your facility. It is a tab in your spreadsheet. What is the purpose of the room? What is the flow of people, and how do they get in or out? Is it bi-directional or unidirectional? The risk is different for each scenario, of course. Is there an airlock? How does raw material flow into the room? How about utilities? How do you clean it? How often is it cleaned? What is the cleaning process? How do you manage the waste? Where does the waste go? Does it conflict with the flow of people? Is there a potential for risk there?
Asking these questions will achieve a complete, holistic understanding of this room’s problem. Then you solve these problems where conflict occurs. That might be procedural – a bi-directional hallway becomes unidirectional – or a technological solution might be achieved by rerouting pipes or exchanging machinery for something that can be put through an autoclave.
Then, this process is repeated for every room and corridor in your facility. It does not end there, however, as now you have multiple tabs on this spreadsheet, and you must make sure your contamination strategy for one tab does not conflict with another.
Good Enough Will Never Be
The EU GMP Annex 1 revisions will dominate the regulatory world come August. This is a tremendous opportunity to conduct a risk assessment and either improve your production techniques or gather evidence to support your contamination strategy to regulators.
At this stage, hesitancy to act will have dramatic consequences, and many small manufacturers might be gambling on whether their assumptions will be enough to convince regulators. For Annex 1, “good enough” will never be enough, and your only defense will be a global, holistic understanding of your contamination risks.
