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

-DraftSubjectPotential impact
10.6Conditions for sterility test definedNegligible to Minor – principles are generally very well understood
10.8Decontamination of sterility samples mustn't cause false negatives for the actual testNegligible to Minor – principles are generally very well understood
10.9Growth promotion testing of media now unambiguously a requirement.Minor – some less mature companies may not have understood the expectations for growth promotion testing.
10.11Rapid microbial methods are acceptable QC methodology, but must be validated for the specific useNegligible – Like any new technology, uptake will be slow, so the issue will affect only a few organisations. The instructions around validation will be helpful for early adopters.


Clauses with Negligible Change in Chapter 10

10.280Bioburden testingThe relevant parts of 2007 clause 80 have been modified slightly, and now include a specific instruction to consider bioburden testing as part of final batch review, but practically, the intent is identical.

The clause continues to make the dubious claim that bioburden limits should relate to the efficiency of the sterilisation method. (see point of contention below)


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.


10.380Overkill sterilisation and bioburden samplingVery slight wording change which suggests that a reduced bioburden testing frequency may be considered, whereas previously, the approach was actively encouraged. There is likely no practical impact in the change.
10.480Parametric release and bioburden samplingExact copy of part of 2007 clause 80
10.5125Sterility testExact Copy


Clauses with Minor Change in Chapter 10

-Draft2007SubjectChangeExplanation of “Minor Change” Status
10.174Microbiological quality of starting materialsAdds contamination control strategy as a mechanism for implementing micro quality limitsThe new, more holistic approach driven by contamination control strategy may result in additional specification limits in some circumstances
10.7127Appropriate sampling for sterility testsAdds two new sub-parts relating to sterility tests for each sub-part of an overall batch (e.g. sterilisation or lyophilisation loads)Likely to be common practice, but some organisations may have sought to minimize testing by rationalizing sterility testing across sub-batches.
10.1018Interpretation of environmental monitoring dataRequires only EM data from Grade A and B for consideration during batch review.

Requires a written methodology for actions arising from EM OOS or OOT.
Some organisations may not have a written plan for actions arising from such results.


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.

Aseptic Manufacturing Area

Not used in the document!
Includes ancillary cleanrooms in the definition, but does not define what constitutes an ancillary cleanroom. States that the term is synonymous with “aseptic processing facility”, but the definition of the processing facility term is significantly different that described for the manufacturing area term.
Aseptic Processing Facility

Not used in the document!
The definition describes any particle/microbial controlled processing area and does not apply specifically to aseptic processing facilities.


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.


Clean Zone

Not used in the document!
Should be removed.
Closed systemThis definition is probably too brief to give meaningful context. More importantly, the limitation of the definition to systems containing “sterile product” unnecessarily limits the value of closed systems.
CommissioningShould be removed.

In the draft body, there is one reference to the term “decommissioning” (unrelated to commissioning) and one to “commissioned” (related). The value of this definition is minimal, given that the term “designed” and “monitored” in the same sentence are not defined.
Critical ZoneIf critical zone is exactly synonymous with “critical area”, then why use both terms? Examining context in the draft implies that “critical area” is a non-specific term, while critical zone refers to a critical area within a barrier system (e.g. RABS, BFS, isolator). If this is intended, it should be stated in the definition.
D ValueUnambiguous, but the term is only used within the glossary, as part of 2 other definitions. There is no use of the term “D value” within the draft revision body.
DynamicUnambiguous, but unclear why this term is necessary, when the term “in-operation” is in common use. The one use of the term “dynamic” in the draft body could effectively be replaced by “in-operation”.
Form Fill SealNeeds improvement.

The definition in 8.90 appears more robust and less vague. Additionally, the term should be “Form-Fill-Seal” for consistency.
Grade A AirNeeds improvement.

Grade A, B and C typically use identical filter types. So passing air “through a filter qualified as capable of producing grade A non-viable quality air” is not very meaningful. Just the filter needs qualifying? How should measurements be taken?
Laminar flowUnambiguous, however the value of the definition is highly questionable given that the only references to laminar flow in the draft body are in the context of describing “laminar flow work stations”, and laminar flow is not a requirement or recommendation for any condition.

Suggest removal of term.
OperatorThe use of the term “aseptic” is incorrect. The term “operator” is used within the draft body to describe personnel performing non-aseptic activities (e.g. visual inspection).
Pass through hatchIt is nonsensical to define pass-through hatches by referring to the definition of airlocks. While much of the definition is useful to describe pass-through hatches, there are problematic differences. A pass-through hatch, for example, should not be described as a “small room”.


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.

-2007 ClauseContentComment
11Guidance on airborne particulate monitoring systemsGuidance on what the system should be comprised of has been abandoned. It simply must comply with the other related clauses.
31Environments for handling materialsWas redundant in previous code. Remains integrated into table at 8.10 (previously clause 17)
32Environments for preparing solutionsWas redundant in previous code. Remains integrated into table at 8.10 (previously clause 17)
33Environments for aseptic processesWas redundant in previous code. Expanded in table 8.10 (previously clause 17)
34Environments for transferring partially closed containers (legacy error clause)This was the contradictory clause to previous clause 116. 116 has been clarified as new 8.17
65Segregation of production based on live/dead microbiological materials Probably considered too specific and generally covered by QRM on other subjects
70How to interpret low level vs gross microbial contaminationAn unnecessary, self-evident clause
71Statement of care regarding validationunnecessary, self-evident
82New procedures should be validated and monitoredNew code has about 70 references to validation, including reference to Annex 15 in the principle, compared with 28 for old code. This is probably redundant as a result
97Air circulation requirements for dry heatNew section written with 5 extensive clauses. Most of this clause is integrated within those clauses and it is difficult to correlate any clause to the limited intent of the old clause
99Dosimetry in irradiation processes.References Annex 12 to cover detail involved sterilisation by radiation
100Use of biological indicators in irradiation processesCovered under general sterilisation clauses
103Time limits on sterilisation by radiationReferences Annex 12 to cover detail involved sterilisation by radiation
118Statement that container is not fully integral until crimped.Perhaps it is deemed that that the previous clause 120/new 8.22 is sufficient (stoppered vial should remain in Grade A or Grade A air supply until capped)


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)