PIC/S – New Draft Annex 1 – Part 7 of 8

Quality Risk Assessment

PIC/S – New Draft Annex 1 – Part 7 of 8

This chapter contains information which was previously covered under the headings “Clean Room and Clean Air Device Monitoring”, and also clauses 66-69 on Aseptic Process Simulation (APS) which was under the old heading “Processing”. In addition to the 21 clauses from 2007 that have been revised and reallocated to 22 new clauses, there are 27 new requirements that have previously not been stated explicitly. Readers may also wish to view the Initial BlogPart 1Part 2Part 3Part 4, Part 5 and Part 6 of this series for context.

There is some logic in presenting APS alongside the environmental monitoring (EM) requirements in this new chapter, however, the terminology used should be questioned, as per the point of contention below:

Point of Contention: Chapter 9 uses the term “non-viable” when referring to airborne particulate monitoring. Presumably this term was chosen to highlight the contrast and difference between particulate monitoring and viable microbiological monitoring, but this is arguably insufficient reason to use a term which is imprecise at best and erroneous at worst.


Standard light scattering airborne particle counters (LSAPC) are incapable of distinguishing between viable and non-viable particles and, therefore, will include viable particles in any total count provided. The contention may seem semantic, given that the percentage of viable particles in an LSAPC sample will likely be extremely low, but equally there seems no reasonable justification for the inaccuracy given that accurate common use terms (airborne particle monitoring or total particle monitoring) already exist.


To minimise confusion, from this point forward this blog uses the term “non-viable” when describing total airborne particles in accordance with the draft revision.

Brand New Clauses in Chapter 9

DraftSubjectPotential impact
9.1Viable and non-viable environment & process monitoring as part of contamination control strategyMinor – The impact is less about implementing the monitoring requirement and more about the information detailed within the CCS, which most manufacturers will only be developing as a formal document.
9.2The different elements of an EM program definedNegligible – The elements described are well understood.
9.3The use of EM program data in batch release and periodic process reviewMinor – EM is routinely used in batch release, however, it is conceivable that the level of use for periodic review (regular assessment and as a tool for investigations) is not at the level expected by regulators.
9.4Definition of EM program by QRM and regular review of assessments.Moderate – Most manufacturers use QRM to assist in determination of EM elements. The requirement to ensure these risk assessments are regularly reviewed may find some manufacturers deficient against the new clause.
9.5Expectations for scheduling of routine monitoring and how specific monitoring requirements are determined (QRM and qualification) Negligible to Minor – This is the common approach to developing routine monitoring programs. The extent of use of qualification and risk data required has the potential manufacturers deficient
9.6Expectations for additional monitoring to be performed outside of routine operationsModerate – This expectation has not previously been explicit, but many manufacturers are likely to comply already, at least in part. The overall level of compliance with the full expectations and the examples provided is likely to fall short of universal.
9.7Grade A monitoring where highest risk existsNegligible – This is well understood and implemented.
9.8Setting of alert and action limits for particulate and microbiological monitoringNegligible to Minor – Generally well understood. Some manufacturers may not always set alerts based on qualification and trend data, or review regularly.
9.9Specific instruction for setting alert limits for Grade B,C,DMinor – Required to be based on area performance, rather than arbitrary, which may require assessment for some manufacturers.

Self-evident statement that the “… the aim to have (B,C,D alert) limits lower than those specified as action limits.” is of questionable value.
9.10Explanation of what to do for alert and action excursionsMinor – This is a succinct summary of activities, which most manufacturers implement well. Clear instruction for those who currently do not.
9.11Surface and personnel monitoring after critical operationsNegligible – Specific instruction to assess personnel monitoring as part of batch release, but concept is well understood and implemented.
9.13Table specifically for non-viable monitoring, separate from classificationNegligible to Minor – The limits are unchanged from 2007 for monitoring.

The requirement for Grade D in-operation limits to be determined by QRM is new within Annex 1, but has been part of interpretation guidance. There may still be manufacturers who have not implemented this expectation (see also 5.25)
9.20Powdery operations potentially exempt from testing of non-viables during processingNegligible to Minor – Where monitoring has been problematic historically, this issue would already have been addressed.

Manufacturers introducing new processes may save themselves some challenges by understanding this exemption.
9.24QRM required to determine non-viable monitoring programNegligible to Minor – Concept is generally well understood, but some may not yet have adequate formal documentation.
9.26Personnel microbiological monitoringNegligible – Concept is well understood and implemented.
9.28Rapid microbiological monitoring methods can be used if demonstrated at least equivalentNegligible to Minor – Specifically allows use of rapid micro methods, but industry likely to be even more conservative than this clause requires.
9.33Organism detected in Grade A and B should be speciated. Consideration given to C and D speciation.Moderate to Significant – Speciation of all organisms detected in Grade B is a new requirement, which some, but not all manufacturers currently perform. The recommendations of speciation for Grade C and D will likely require some QRM activity for many manufacturers and probably requires additional guidance on when it may be considered appropriate.
9.37Approved list of APS interventions is requiredNegligible to Minor – Generally well understood and implemented. Some may require modifications to documentation and/or procedures to be fully compliant.
9.38Comprehensive list of expectations for APSMinor – Generally well understood and implemented, and the acknowledgement of manually intensive operations is important. The significant increase in explicitly stated requirements may result in some non-compliances for some manufacturers.
9.39Sterile active substances requirements. Negligible – The concepts, although new to Annex 1, have been available in supporting guidances previously and are well understood.
9.41Instructions for manual process APS, including when to repeat initial validationNegligible – The concepts are well understood and arguably not specific to manual processes in any case.
9.44Instructions for how to prepare APS units for incubation and management of exclusion and defectsModerate – While these concepts are generally understood, the specific nature of the instructions will necessitate both documented and performed procedure to match the requirement, which may not be the case currently for all manufacturers.
9.45How to incubate APS unitsNegligible to Minor – Incubation parameters are not prescribed, and therefore will not change for most manufacturers. However, there is an expectation that the selected regime is justified by the manufacturer, which may not currently occur in all cases.
9.46Approval of APS before release of subsequent batchesMinor – Clear instruction that product may be manufactured at risk after APS, but may not be released at risk. APS must be formally finalized and approved before release of product. This would be standard practice for most, but not necessarily all. See point of contention below for special cases


Point of Contention: Clause 9.46 provides clear and unambiguous instruction for managing production and release post APS event. However, it appears that this clause only considered those manufacturers whose products can tolerate the hold-release period required to obtain microbiological results of the APS.


Several sterile products cannot be held for such lengths of time (e.g. some pharmacy compounding or radiopharmaceuticals) due to patient requirements or product degradation. Those manufacturers would either need to stop manufacturing while awaiting APS results (usually not a viable option) or will be non-compliant with the requirement as written.


DraftSubjectPotential impact
9.47Expectations for failed APSNegligible – Concept is well understood and implemented.
9.48Expectations for APS indication of failed operator qualificationNegligible – Concept is well understood and implemented.
9.49General documentation requirements for APSNegligible – Concept is well understood and implemented.

Clauses with Negligible Change in Chapter 9

Draft2007SubjectExplanation of “Negligible Change” Status
9.149Duration for particle monitoring in Grade AExact copy of the early part of 2007 clause 9
9.189Consideration of particle monitoring hazards in monitoring design9.18 reflects a part of 2007 clause 9. The ability to modify the monitoring approach due to hazards is unchanged.
9.199Specific particle monitoring requirements where hazards are present Rewording of part of 2007 clause 9. The requirements to monitor when the hazards are not present, and also to perform monitoring during process simulation are unchanged.
9.2112Sampling size for monitoring using automated particle countersExact copy
9.2213Justification for ≥5.0 micron measurementJustification is substantially simplified and limited to monitoring only. The intent has moved from supporting investigation of low level counts to supporting of ≥5.0 micron measurement.

The justification is not supported by evidence despite this being a long-debated point of contention.
9.2313Stray counts in particulate monitoring devicesAlmost exact copy. The concept is well understood.
9.2518Basics of routine viable environmental monitoringAlmost exact copy of the first part of 2007 clause 18. New clause adds glove prints, but this is standard practice in any case.
9.279Continuous monitoring requirements*

* This clause is found in the viable monitoring section but appears only relevant to particulate monitoring
Reworded slightly, but largely the same as information in 2007 clause 9. No change of intent (assuming that the clause is simply incorrectly located in the viable monitoring section).

It is also probably redundant, as the information is effectively duplicated at 9.14, 9.15 and 9.16.

If this is intended, as a viable monitoring clause, it is not possible to comply with using standard, established technology.

See point of contention below.

Point of Contention: Clause 9.27 appears to be providing information on non-viable monitoring requirements, but is located in the viable monitoring section. This leads to 2 possibilities:


a) This clause was intended for the non-viable section, but the mis-location was not identified in editing. If so, this clause should be compared with the updated clauses 9.14, 9.15 and 9.16. 9.27 appears redundant when making the comparison.


b) This clause was intended to establish “continuous” monitoring requirements for viable monitoring, but the clause was not appropriately updated to consider viable monitoring limitations. This seems less likely than a), but either way, the clause needs to be revisited and removed or significantly modified.


Draft2007SubjectExplanation of “Negligible Change” Status
9.2918Risk of viable EM sampling methods to operationsRewording of part of 2007 clause 18, but same intent.
9.3018Additional viable EM sampling required outside of routine.Almost exact copy of last sentence in 2007 clause 18. Same intent.

Clauses with Minor Change in Chapter 9

Draft2007SubjectChangeExplanation of “Minor Change” Status
9.128Purpose of non-viable particulate monitoringClause has moved from the requirement to perform non-viable monitoring to the purpose, (assessing potential contamination risks)While there is no specific new requirement here, the wording in the new clause directs manufacturers to use non-viable monitoring as part of contamination control strategy and assessments.
9.159Non-viable sample size for Grade A.Changed from “suitable size” to “at least 28 litres (a cubic foot) per minute”Intent is the same, and while ≥28lpm is common practice, the specific nature of the new requirement may result in some non-compliances.
9.1610Monitoring non-viables in Grade BRequirements for monitoring system should be based on QRM rather than “effectiveness of segregation”The clauses are very similar apart from the noted change. As a result, documented risk assessment is probably necessary which some may not have.
9.3466Aseptic process simulation (general requirements)Detail added with emphasis on use of surrogate materials and procedures where assessing asepsis may be otherwise difficultMore clarity provided for difficult process simulations which may improve ability to design APS exercises.
9.4068Scheduling of APSAdded information around operators and other events which may trigger APS (e.g. long period of inactivity)Generally well understood, but additional considerations may not previously have been considered by all manufacturers,
9.4269Number of filled APS units requiredThe clause is simplified for batch sizes over 5000 – now “sufficient to simulate all activities representative of process” rather than matching a number.

No change for batch sizes below 5000.
Practically will likely have little difference to the total number of samples, but a justification is now required, which may need to be executed for some manufacturers.
9.4369Acceptance criteria and failure response for APSInstead of allowable contamination, the new clause targets zero growth, with QRM to determine response to positive results.Most do target zero growth + automatic investigation of positives already, but APS procedure may need modification for some to remove information related to 2007 requirement.

Clauses with Moderate Change in Chapter 9

Draft2007SubjectChangeExplanation of “Moderate Change” Status
9.3119Recommended limits for microbiological monitoring.The maximum limit for microbial contamination in Grade A is now 1, when previously it had been <1 cfu/ measurement.

The statement around “average values” has been removed and exposure of settle plates has additional explanation.
The changes are impactful, albeit less stringent (an investigation is still required for any contamination in Grade A, however).

The confusion over averaging is removed. Averaging of results is not permitted.
9.3220Trending, action and alert limitsThe focus has shifted from breach of action and alert to monitoring of trendsIt is a clear change of focus for compliance which may impact some manufacturers and require modifications to procedure and even data acquisition.
9.3567Process simulations – routine inclusionsSignificantly expanded to provide more detailIt is likely that one or more of the specified requirements are not covered in some manufacturer programs.
9.3667Process simulations - interventionsSignificantly expanded to provide more detail and greater clarityThe specific requirements may not be covered by some manufacturer programs

Clauses with Significant Change in Chapter 9

Draft2007SubjectChangeExplanation of “Significant Change” Status
9.1715Determination of monitoring requirements in Grade C & DThe basis for determination has expanded from QRM to QRM + enough data for effective trend analysisFor many manufacturers, this is likely to prompt an increase the necessary frequency of sampling, and in some cases, increase it significantly.

Like many of the chapters before it, chapter 9 is a mixture of improved clarity, explicit confirmation of expectations which have previously been implied, and the occasional hiccup in expression which may cause added confusion.

The separation of the EM and APS topics in a single chapter is probably more logical, but it is also clear that there remains some challenges, particularly for manufacturers of products that are not produced by “traditional” sterile manufacturing techniques.

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 (this post)

Draft Annex 1 – Part 8

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