This is the final part of a three part article on the new PIC/S Recommendation (PI 032). The Recommendation interprets the changes to Annex 1 of the PIC/S GMP Guide. In this part, we look a few minor issues arising from the publication.
There are a few other points in the interpretation which I feel have the potential to cause confusion. These aren’t so significant, but warrant a mention to raise awareness.
- In section 12 the Annex confirms that sample sizes for monitoring do not need to be the same as for classification. The PI 032 interpretation quite rightly points out that needing to sample a full cubic metre before activating an alarm is problematic, especially in Grade A zones. The implication, of course, is that significantly smaller sample sizes are appropriate where fast response is required.
With that in mind, the use of the phrase “sampling of 1 m3 … could be inadequate” is potentially misleading, insofar as the word “inadequate” implies not enough, when really it is too much. A more suitable term to avoid confusion would have been “inappropriate”.
- The inconsistency between sections 34 and 116 was raised in part 2 of this article. If you are unsure about which section to follow, obviously the safer and more advisable route is to stick to section 116 and avoid the use of sealed transfer trays.
In itself this issue is barely worth mentioning, but with PI 032 implying that section 12 is now superseded, it seems that the carryover of section 34 has not been noticed by the reviewers or interpreters.
Additionally, the interpretation states that section 116 is “basically equivalent” to the old section 12, yet there is a very important distinction. There is no provision in the new section for transfer in sealed containers, and it would be impossible to meet this stated requirement using sealed containers, as Grade A airflows cannot be met.
- On a positive note, I should mention that I had some issues with the PI 032 interpretation of clause 121, however, the revision PI 032-2 has largely addressed those concerns. Originally the document could be interpreted to suggest that you could mitigate an ineffective rejection system by improving the quality of the background environment. The revision clarified these comments to put the emphasis on monitoring and the degree of human intervention required in the rejection system.
Finally, it should be noted that there are 20 or so interpretations in the PIC/S recommendation and I have highlighted 4 or 5 which I think could be reworked to varying degrees. The remainder generally provide sound advice, clarity and definitions that the user can employ with confidence.
However, the issues raised should be addressed by PIC/S – especially those covered in parts 1 and 2 of this article. Given that PIC/S was prepared to issue version 2 only a month after version 1, let’s hope that version 3 may not be too far away.PIC/S Interpretation of Annex 1 – Clarifying or Confusing? Pt 2
January 18th, 2010
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:
- 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?
- 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.
January 18th, 2010