I have been the chairperson for the revision of Annex 1 of the EU and PIC/S GMPS for the manufacture of sterile medicinal products for a couple of years now. As such I engaged with stakeholders and other regulators to understand their wishes and concerns. One particular topic that has come up as a discussion point at a number of the more recent conferences that gives me great concern, and this is around how to sterilise direct and indirect product contact items in an isolator. I therefore felt it was time to go into print regarding the agency’s view.
A number of manufacturers are looking at isolator technology in new or existing facilities, which is great to hear, but the fly in the ointment, is that the consideration of how to sterilise direct and indirect contact parts does not always form part of the design process. But before I go further I will clarify what I mean by indirect and direct product contact parts:
Indirect product contact parts, as the name implies, are equipment parts that come into contact with items and components, such as stoppers. So, although the equipment itself does not contact the product the items that are “processed” by the equipment do.
Direct contact parts are those that the product passes through, such as filling needles or pumps.
The issue that is arising is that a number of manufacturers are not including robust systems of sterilisation, such as autoclaves, dry heat or offsite irradiation in their facility designs. This leaves a situation where the Agency is being asked, why Vapour Hydrogen Peroxide (VHP) cannot be used for “sterilisation” of these direct and indirect product contact parts. After all, pharmacopeias refer to VHP as a sterilising agent. However, our concern is that although under ideal conditions, VHP can achieve a reduction of biological Indicator spores of up to 6 logs, the process itself is incredibly fragile.
If we cast our minds back a number of years, when VHP was being used to decontaminate the internal surfaces of isolators (not the indirect or direct contact parts) there were a number of issues seen with biological indicators failing the process due to clumping of spores at a microscopic level. This led to a number of papers being written (such as “Biological indicators don’t lie, but in sporicidal gassing disinfection cycles do they sometimes confuse the truth?”, European Journal of Parenteral & Pharmaceutical Sciences 2009; 14(1): 5-10 © 2009 Pharmaceutical and Healthcare Sciences Society) that justified biological indicator failure at one or two locations based on statistical analysis. The papers also recommended that a number of indicators (usually 3) be placed at each location to demonstrate a 3 log reduction (which is not a sterilisation process). This, along with other evidence, such as VHP failure due to very minor occlusion, even to the degree that fatty acids from a fingerprint may “protect” contaminating organisms from the VHP demonstrate the true fragility of the process as a sterilant.
If we then consider the design of some of the indirect and direct product contact parts, we find that a number of them are either difficult to achieve VHP penetration, or, damage and wear and tear can leave surfaces that lead to difficulty to clean and therefore potential occlusion.
VHP, when well controlled and validated, is a useful method for the decontamination of the surrounding workspace, e.g. an isolator environment. However, given the above concerns, our current stance is that VHP cannot be used to sterilise critical items. Even if some of the concerns can be removed by well thought out processes, this still leaves the sterilisation at risk of the vagaries of manual process during set up. For instance, how many of us see ‘human error’ as a high percentage of root cause errors during deviation investigations? Therefore, it would be a high risk option and potentially leave the patient at risk from such a fragile process.
So, what are we expecting?
Our expectation is that the contact parts (direct and indirect) are sterilised using a robust sterilisation method that meets the current requirements of annex 1. This means that:
the sterilising agent reaches all of the critical surfaces in a consistent and repeatable manner, typically requiring processes such as moist or dry heat sterilisation.
the item is unloaded from the sterilisation process either wrapped in integral covering or container, or is transferred under grade A conditions, such as a transfer isolator into the manufacturing isolator.
We also expect that the parts are not exposed to the isolator environment until the isolator has been closed and after completion of the work zone decontamination VHP cycle.
We continue to move increasingly into a pharmaceutical world governed by the principles of quality risk management. We are unable to say that VHP will never be an acceptable approach. However, manufacturers who are considering a different approach to sterilisation, or to any other GMP requirement, seek a dialogue with the agency at an early stage. This may save on costly modification later on in the project and who knows, you may even receive some useful help! The GMP Inspectorate can be approached in a number of ways, one is through the Innovation Office, or by E mail to the GMP Inspectorate directly firstname.lastname@example.org
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