Quality Risk Assessment

PIC/S – New Draft Annex 1 – Part 8 of 8

The final part of the blog series looks at Chapter 10 (Quality Control) and the glossary. In addition, we say goodbye to small number of clauses which have been removed between the 2007 and 2017 versions of Annex 1.

Readers may also wish to view the Initial BlogPart 1, Part 2,Part 3, Part 4, Part 5, Part 6 and Part 7 of this series for context.

Chapter 10 – Quality Control

Chapter 10 contains only 11 clauses, although this is up from 3 in the previous version. Most of the clauses have little new impact, which may disappoint some hoping for greater clarity for sterility and other microbiological testing requirements.

Brand New Clauses in Chapter 10

Clauses with Negligible Change in Chapter 10

Point of Contention: Clause 10.2 carries forward from 2007, the statement that bioburden limits should relate to the efficiency of the sterilisation method. If this were taken to its logical conclusion, bioburden limits would typically be significantly greater than are commonly applied.

For example, sterilising grade filters are usually validated to retain 107 cfu/cm2 of effective surface area. When considering common batch/filter size combinations, it would be typical that a sterilising filter could easily cope with bioburden exceeding 104/mL in a bulk solution. Bioburden specifications for aseptically prepared products are often as low as 10cfu/10mL and are rarely in excess of 100cfu/10 mL.

Trying to justify higher limits because of sterilising method capability is theoretically possible with this clause, but likely to meet with regulator resistance. Consequently, the value of the statement is questionable.

Of more value would be a statement suggesting that bioburden limits should consider the efficiency of the sterilisation method, and be reflective of a process with an effective contamination control strategy.

Clauses with Minor Change in Chapter 10

Chapter 11 – Glossary

58 terms are defined in the glossary, including 3 that do not appear in the document, and another that is only present in the glossary itself.

Most of the definitions could be improved with varying degrees of modification, however, this review is not intended to be a comprehensive, term by term analysis. Instead, the review highlights the terms that are most in need of improvement, as well as identifying some terms which are not present, but would help with interpretation of the Annex.

A full, term-by-term analysis will be available in PharmOut’s response document to be published after March 20.

Point of Contention: Neither “aseptic manufacturing area, nor “aseptic processing facility” are used within the draft revision. However, the term “aseptic processing area” is, and probably should be defined with a reworking of both definitions.

Several terms are used within the draft revision that are potentially ambiguous, or at least subjective. The draft revision could be improved by elaborating on (or rationalising) such terms as:

  • Appropriate/appropriately
  • Suitable/suitably
  • Generally
  • Grade A conditions (when compared with Grade A or Grade A air supply)
  • Medicines vs medicinal products
  • Zone vs area vs environment
  • Requirement imperatives – (the terms desirable, recommended, may, should, shall and must are all used to describe the significance of different requirements)

This is not a comprehensive review, and there is no doubt other terms which could benefit from rationalisation or elaboration.

Clauses Removed from the 2007 Revision

The following clauses are present in the current (2007) version of Annex 1, but have no equivalent clause in the draft revision. Some of the clauses have been made redundant by new clarity in related clauses, while some have been removed in favour of external reference, and at least one has been removed because of erroneous content.

And so, we have reached the end of the draft revision. If this series has been useful to you, or you are looking for more specific detail, please look out for PharmOut’s official response to the draft revision, which will be published shortly after the final submission date on March 20, 2018.

Initial Blog

Draft Annex 1 – Part 1

Draft Annex 1 – Part 2

Draft Annex 1 – Part 3

Draft Annex 1 – Part 4

Draft Annex 1 – Part 5

Draft Annex 1 – Part 6

Draft Annex 1 – Part 7

Draft Annex 1 – Part 8 (this post)