PharmOut – GMP and Validation Blog

Annex 1 Capping Environments – A Pleasant Surprise?

After my recent three part blog on the PIC/S interpretation of Annex 1, I’ve had reason to revisit the recommendation at some length. During this process I had a moment of clarity regarding capping environments that had escaped me previously.

Section 120 of the Annex states that capping can be performed as either an aseptic process, or as a clean process outside the aseptic core. However, if uncapped vials are to be removed from the aseptic core, the Annex specifies that a “Grade A air supply” must be maintained until the vials are capped.

While the original intention for this section undoubtedly was in consideration of transfer tunnels and similar apparatus which connect the aseptic core to a separate capping area, it starts to become ambiguous when applied to transfer by hand or on open conveyers.

Remarkably, the Annex provides no definition of “Grade A” air supply, making the interpretation even more difficult. Thankfully, the revision of the PIC/S interpretation (PI032-2), defines a Grade A air supply as:

“a supply of air which is HEPA filtered, and at the point of supply meets when tested, the non-viable particulate requirements of a grade A area, as defined in paragraph 4 of the revised Annex 1.”

Additionally, it provides qualification and monitoring requirements for such areas:

· Qualified “at-rest” only. No requirement for “in-operation” qualification

· Qualification requires non-viable counts only

· Particle counts to be conducted “at the point of supply of the filtered air”

· Unidirectional (laminar) air flow is not required, but smoke tests should demonstrate absence of air entrainment from surrounds

· Air velocity limits should be justified (but don’t need to meet Grade A conditions)

· Monitoring for both viable and non-viables should be defined through risk assessment.

The wording of the interpretation refers to transfer tunnels, and it is clear that most, if not all of the thinking for this subject has focussed on this type of arrangement.

So that still leaves the issue “what does this requirement mean for (for example) a small company who transfers fully stoppered vials from an aseptic filling station to a “clean” capping station manually?

Well, on review, it turns out that Grade A air supply is perhaps not as big an issue as it may have seemed. Applying the definition and qualification requirements, it seems clear that any well designed Grade B zone (and probably most Grade C zones) will meet the requirements of a Grade A air supply! Remember, Grade B non-viables limits at rest are almost identical to Grade A.

So don’t panic, you may not need to spend thousands of dollars upgrading air systems after all. Having said that, there are still two significant implications which manufacturers need to consider.

· Have you fully validated your stoppering process so that you can be confident that 100% of your vials are fully stoppered? If you cannot be certain that every vial coming out of your aseptic area is fully stoppered, you are likely to require not only grade A air supply, but fully Grade A and aseptic conditions until the completion of crimping.

· And whatever your transfer process, you need to be able to prove that it does not pose additional risk to your products, so the method of transfer will come into question just as much as the environment in which it is conducted.

Now, transferring a tray full of stoppered vials through a Grade B area from filling to capping; that seems like an excellent candidate for Grade B continuous monitoring … but that’s another blog!

Add comment February 4th, 2010

PIC/S Interpretation of Annex 1 – Clarifying or Confusing? Pt 2

Following on from my previous blog entry, this article looks at a second significant issue with the PIC/S Recommendation (PI-032) which interprets the changes to Annex 1 of the PIC/S GMP Guide.

The second, less critical issue I have relates to section 120 on capping environments. The Annex states that capping can be performed as either an aseptic process, or as a clean process outside the aseptic core. However, if uncapped vials are to be removed from the aseptic core, the Annex specifies that a “Grade A air supply” must be maintained until the vials are capped. The definition of Grade A air supply has been helpfully clarified in the revision of PI 032.

While this requirement no doubt creates a significant cost impost for new facilities and where the requirement is currently not met, the reasons for it are understandable. There are, however, two areas for concern:

1. The requirement for Grade A air supply has presumably come about because uncapped vials are considered non-integral, and therefore potentially at risk of being contaminated. Grade A air supply rather than “Grade A conditions” have been specified, perhaps because of the difficulty and expense in installing, maintaining and qualifying such systems couldn’t be justified in light of the risk. Even so, a risk has been identified and measures provided to mitigate that risk.

With this is mind, why would the interpretation advocate the use of unsterilized caps on these non-integral vials? Yes, it’s understood that the process at this stage is not aseptic, but after having deemed the risk high enough to mandate that manufacturers spend many thousands of dollars on maximising air quality, why is PI 032 prepared to expose these same ‘non-integral’ vials to potential contamination from unsterilized caps?

1. Another area of confusion is related more to the Annex than the interpretation. section 34 states that partially stoppered vials may be transferred to a freeze dryer either under GradeA conditions, or in sealed transfer trays in a Grade B environment. section116 covers the same topic, but omits the sealed transfer trays. section 120, on the transfer of fully stoppered vials to a capping station also does not provide scope for transfer in sealed trays.

If these sections are taken at their word, the Annex allows the transfer of partially stoppered vials in sealed transfer trays, but does not allow the same for fully stoppered vials. Logically, this doesn’t make sense. (The section 34/116 inconsistency is discussed further in part 3)

To sum up, I would expect that caps on aseptically filled vials would be sterilised before introduction into the capping process, regardless of whether the process is truly aseptic, or simply ‘clean’. The impost of sending a bag through the autoclave is surely next to nothing compared with that of complying with the environmental requirements of the Annex, but maintains a consistent approach to protection of ‘non-integral’ vials.

Similarly, despite the retention of section 34, it seems clear that the intention of the guide is to move manufacturers away from sealed containers and I would recommend against their use. It would surprise to see section 34 modified or removed from future revisions.

The final part of this article will discuss some minor issues in the interpretation.

1 comment January 18th, 2010