As you will all be aware, EU GMP Volume 4 Annex 1 and PIC/S Annex 1 (hereinafter referred to Annex 1) for “the manufacture of sterile medicinal products” was published in August 2022 and the majority of the guidance came into force in August 2023. One of the key elements of the guidance was the introduction of Quality Risk Management (QRM). For me, in terms of sterile medicinal products, the principles of QRM are exemplified by the requirements of the Contamination Control Strategy (CCS). If you search Annex 1 for either the phrase “Contamination Control Strategy” or “CCS,” you will find that these are referenced over fifty times, showing how important this is.
So why do I say that, for me, CCS is the essence of the QRM process? Well, it encapsulates a number of points that you expect to see when using QRM principles; it demonstrates an understanding of the design elements, such as equipment, facility, and process (from the supplier’s to the patient’s point of view). It contains within it a process of assessing the risks inherent in these design elements and then allows for a decision process whereby the user decides whether the inherent risk is acceptable or if further design controls need to be incorporated.
Once the user accepts the residual risk from the design process (and I do not think there is any process that I have seen where there is not a residual risk), there is then a process of creating procedures; these will include several elements of consideration, but one key element will be the mitigation of the design risks. The GMPs would refer to the design controls as “technical measures,” and then the procedural controls would be referred to as organizational controls (see clause 2.3 of Annex 1, but there is further reference to these in Chapter 5 [Production] of the EU and PIC/S GMPs [Chapter 5 for public consultation comments from Commission]). The procedural control measures will then go through a further iteration of the risk acceptance decision process, with some risks being accepted and others not being accepted, resulting in updates until they become acceptable. Again, there will be residual risks, so the final point of the design of the CCS is the monitoring regime. While this does not mitigate risks, it is intended to demonstrate that all of the control measures (technical and organizational) are operating as designed and, if they start to fail or drift, then the monitoring system will detect this drift. I would reiterate here that the monitoring system does not mitigate risk, it just ensures that we become aware of the realization of risk. One of the things I really like about Annex 1 is that it clearly states this, in the second paragraph of clause 2.2:
“In the first instance, QRM priorities should include appropriate design of the facility, equipment and processes, followed by the implementation of well-designed procedures, and finally application of monitoring systems as the element that demonstrates that the design and procedures have been correctly implemented and continue to perform in line with expectations. Monitoring or testing alone does not give assurance of sterility.”
As you can see, the intent is design right first, then monitor to make sure it is working properly. We sometimes see the opposite in the field where the design is not robust but the user chooses to ignore this and rather rely on monitoring (environmental, aseptic process simulation, or sterility testing) to support the poor design. Some of you who know me personally likely know that my opinion of microbial monitoring is that its reliability as an indicator of sterility is limited (and I say this as a trained microbiologist). Furthermore, those of you who know this about me also know that one of my other favourite sayings when discussing micro results is “absence of evidence is not evidence of absence.”
The CCS Key Principles
So where does that leave us? We have a requirement to have a CCS for sterile medicinal products. But, for me, this is not just because a regulatory body is now asking for this, but because it makes good sense, both for the patient and for business. If well designed, the CCS will lead to fewer contamination events, which should result in fewer investigations and fewer rejected products, but also a decrease in the number of product shortages, with a reduced risk to our key stakeholder (the patient).
Often, when talking to people in the pharmaceutical industry who are involved in the manufacture of other product types (e.g., ophthalmic products or low bioburden drug substance), we hear from them, “we do not need a CCS because we are not making sterile products.” My response to this is, “well, actually, the CCS is not a new requirement, it has been referred to in Chapter 3 and Chapter 5 since 2015 for all products.” But my real response to that question, given the business and patient safety benefits, is not, “why would you?” but rather, “why wouldn’t you!”
If you are confused or struggling with your CCS and need help establishing one or ensuring that it is fit for purpose, Lachman can help you! We have seen many different types of CCS, some done well (and some not so well done) so we can help you through the process of designing and implementing a good and effective CCS. Contact us today for a consultation at LCS@LachmanConsultants.com.
