The Medicines and Healthcare Products Regulatory Agency, MHRA, has released an article written by senior GMP inspector, Andrew Hopkins, which provides guidance around the use of vaporised hydrogen peroxide (VHP) for sterilisation purposes.
Hopkins has 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. One particular topic that has come up as a discussion point is around how to sterilise direct and indirect product contact items in an isolator. In the article, Hopkins unveils the agency’s view.
He said that it is great to hear that a number of manufacturers are looking at isolator technology in new or existing facilities, 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.
Hopkins explained: “Indirect product contact parts 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.”
According to Hopkins, the arising issue 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 VHP cannot be used for “sterilisation” of these direct and indirect product contact parts. Hopkins explained: “Pharmacopoeias 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.
Regulatory background
Hopkins pointed out to the time when VHP was 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, he said, to a number of papers being written 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 means of sterilisation.
Hopkins also said that taking into consideration the design of some of the indirect and direct product contact parts, they find it is difficult to achieve VHP penetration with a number of them, or damage and wear and tear can leave difficult-to-clean surfaces hence potential occlusion. He explained: “When well controlled and validated, VHP is a useful method for the decontamination of the surrounding workspace, e.g. an isolator environment. Given the above concerns, the Agency’s 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, Hopkins said, 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.
MHRA expectations
According to Hopkins, the MHRA 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 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.
- 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.
According to Hopkins, the MHRA also expects 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.
Looking ahead
Hopkins concluded that as industry continues to move increasingly into a pharmaceutical world governed by the principles of quality risk management, the agency is unable to say that VHP will never be an acceptable approach.
He recommended manufacturers who are considering a different approach to sterilisation, or to any other GMP requirement, to 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!” he concluded.The original article is available on the MHRA website.
