PIC/S – New Draft Annex 1 – Part 3 of 8

Quality Risk Assessment

PIC/S – New Draft Annex 1 – Part 3 of 8

In Part 3 of the blog series on the draft revision of Annex 1, we look at chapters 5 and 6, on the subjects of Premises and Equipment respectively.

Readers may also wish to view the Initial BlogPart 1 and Part 2 of this series for context.

Draft Annex 1 – Chapter 5 – Premises

The new Premises chapter is significantly expanded. It contains 34 clauses, compared with 10 in the 2007 version. 10 clauses are brand new, meaning a significant number (14) have been relocated from other sections in the previous version.

DraftSubjectPotential impact
5.14Encouragement to design facilities with consideration to line of sight (windows)Minor – Most facilities are designed with this in mind but the clause is ambiguous in intent – see point of contention below.
5.18Background environment and airflow visualization requirement for RABSMinor – the type of visualization studies required are commonly performed under interpretation of the 2007 Annex. Grade B background is universally applied. This clause has a redundant “and” in the second sentence.
5.20QRM considerations for isolator background. (To be read in conjunction with 5.19)Significant – Spells out the considerations for determining isolator background, and makes it clear that Grade D cannot be the default position. Effectively states that where items are introduced to the isolator by means other than a validated sterilization cycle, Grade D is not appropriate.
5.22Requirements for RABS/Isolator decontaminationNegligible – Provides instruction in line with normal cleaning validation expectations.
5.23Basis for qualification of clean rooms and clean air devices.Minor – This is an explicit stating of information that was previously implied. It provides clarity of the link between classification and qualification for clean rooms. It may require some formal assessment of activities vs environment for some manufacturers.
5.24Reference standards for qualification and classification of clean rooms and clean air devices (Annex 15 and ISO 14644)Minor – linking the qualification of clean rooms to Annex 15 may result in some increased rigor for some less mature organisations.
5.27The microbial load in clean rooms is required to be assessed during qualification of clean roomsModerate – not universally performed as part of qualification currently. Now mandated.
5.28Distinction made between qualification/classification and monitoringNegligible – This concept is well understood
5.29Expectations for determination of classification frequencies. QRM referenced as decision basis for both change management and for the standard frequencyModerate – For most organisations, changes as described in the clause would generate a QRM effort. Some organisations may not base their standard frequency on risk, and therefore may not currently be able to justify why they employ the maximum frequency (which is the current default)
5.33Specific instructions on demonstration of disinfectant efficacyModerate – some less mature organisations may not currently have evidence to demonstrate efficacy on their facilities, equipment and processes as required by the clause


Point of Contention: Clause 5.14 is written almost as design guideline rather than a regulatory requirement. If it is suggested practice, it is arguable that Annex 1 is not the appropriate place for it. If it is intended as an enforceable GMP, it raises several questions: is the clause adequately described? What are the consequences for legacy facilities? Which areas require observation without entry – all clean areas, or just A/B or some subset of areas? Is it the practice of observation without entry or just the ability to do so?


Clauses with Negligible Change in Chapter 5

Draft2007SubjectExplanation of “Negligible Change” Status
5.11Description of processing areas for sterile manufactureExact copy
5.22Concept of separation of unit operationsAlmost exact copy. New clause deletes sentence relating to differentiation of terminal sterilsation and aseptic processing. The deleted statement offered little value and is effectively covered elsewhere in the Annex.
5.446Surface finish expectations for clean roomsExact copy
5.547Concept of facility design to avoid accumulation of particlesAlmost exact copy. New clause deletes reference to “undesirable” sliding doors. Presumably sliding doors could be acceptable provided they meet the other statements within the clause.
5.748Requirements for false ceilings, if present, in clean roomsAlmost exact copy. New clause adds the requirement that false ceilings be “designed” to prevent contamination from above, not just sealed. The practical implication for this seems negligible.
5.1522Transfer of materials in and out of isolators/RABSSignificant enhancement of detail and clarity of the first sentence of clause 22. The intent, however, has not changed and the enhancements are unlikely to be surprising to operators of isolators/RABS.
5.1624Considerations given to the implementation of isolatorsThe statement is a significant enhancement in clarity and focus, with the inclusion of RABS and deletion of self-evident validation statements, but the intent is effectively identical.
5.3016Environmental monitoring of parameters apart from particles and microbiological contaminationExact copy
5.3262Monitoring and management of disinfectants and detergentsExact copy
5.3463FumigationAlmost exact copy. Adds VHP as an example, potentially at the inadvertent exclusion of other methods (refer to point of contention below)

Point of Contention: Clause 5.34 singles out vapourised hydrogen peroxide (VHP) as a useful fumigant. While VHP is currently the most widely used method of vapour disinfection, it is hard to understand why it has been singled out, when several other methods have been shown to be comparably effective (e.g. NO2, Cl2, O3 and ionized hydrogen peroxide, which is distinct from VHP). The singling out of VHP is unnecessary and risks creating industry bias toward that technology. In time, it may also appear outdated if other technologies surpass VHP.


Clauses with Minor Change in Chapter 5

Draft2007SubjectChangeExplanation of “Minor Change” Status
5.675Items which generate fibresFormerly stated such items should be minimized, now states they should not be permitted in clean roomsA clear change of expectation, but unlikely to create new non-conformance.
5.850Sinks and drains in clean areasThe term “in aseptic areas” has been removed and a requirement to clean and disinfect regularly for drains in lower grade areas is includedThe term “aseptic area” implied that if Grade A/B was required for a terminally sterilised process (e.g. when unusually at risk), that floor drains or sinks were permissible. This was not the intention and was probably rarely implemented so has little impact. The requirement to clean and disinfect regularly may, in some cases, require procedural updates.
5.1722Uni-directional airflow in isolatorsPreviously acknowledged that uni-directional flow may not exist in an isolator.New clause confines exemption to closed isolators when proven to have no negative product impact.Unlikely to be an issue for most, as uni-directional flow is likely to be present in most installations. May require some manufacturers to revisit their air-flow studies in isolators, and prepare risk-based discussions if uni-directional flow is not present.
5.263, 5, 7, 14Qualification and classification of clean rooms and clean air devicesMultiple existing clauses have been combined into 1 clause with 6 sub-parts. The most significant changes are:“Typically” expected that aseptic processing rooms (Grade B) will have more sample locations and higher sample volumes for classification than prescribed in ISO 14644.The clean up period prior to at-rest conditions being achieved is no longer specified (formally 15-20 minutes). Instead, the manufacturer should determine during initial classificationFor some manufacturers, the increased expectation for Grade B may require some adjustment to procedure. Future recovery rate testing criteria can be based on design capability rather than the arbitrary 15-20 minutes.


Clauses with Moderate Change in Chapter 5

Draft2007SubjectChangeExplanation of “Moderate Change” Status
5.1052Prevention of simultaneous airlock door openingAirlocks leading to Grade A and B areas must be interlocked, where previously alarms had been permissible. Additional consideration to time delays included (physical locks or procedural delay)While interlocks are typically favoured over alarms, the new requirement for interlocks may require modifications in certain circumstances.
5.1254Air flow visualization studiesPreviously, air flow visualization was referenced only with respect to unidirectional flow. Now a risk assessment is required to determine if air flow studies are required in non-unidirectional flow zones.The clause provides little information to aid in determining how extensive such risk assessments may be.While non-unidirectional studies may have been performed in the past, they would usually be in response to risks identified through process improvement or regulatory exercises. The new clause appears to expect comprehensive, pro-active assessment of all such areas, which may be a significant impost for some
5.1355Air pressure warning systemsPrevious clause required waring of supply failure, and indication of differential where important.New clause adds requirement for warning for low pressure differential where importantFor facilities (mostly older facilities) that do not have continuous monitoring systems and have relied on intermittent observation of the indicators, the new requirement for low pressure warning will likely require facility modification.Little impact for facilities with existing automated pressure monitoring.
5.1923Background environment for isolatorsPreviously a blanket “minimum” of Grade D.New clause specifies limitations (albeit broad) under which the Grade D “minimum” is permissible.(This clause should be read in conjunction with 5.20)The obvious inference is that some isolator installations do not meet the requirements to be sited in the minimum (Grade D) background (e.g. closed systems without sporicidal decontamination, or any installation with unusually high risks for contamination). This could be a significant compliance risk for some older isolator installations and require update to decontamination regimes, or even background environments
5.3161Disinfectant effectivenessClause enhanced significantly with a strong emphasis on demonstration of effectiveness for the shelf life and use (surfaces, method) of disinfectants.Also includes reference to ongoing effectiveness of disinfectant program.While there is much in the clause that was not previously present, this updated clause appears to be a consolidation of long-held regulatory views.If the concepts in the updated clause are new to a manufacturer, there is significant work involved in achieving compliance. For most though, it may be just an opportunity to check current practices against the formalized requirements.


Point to Consider
: Do you currently justify execution (or absence) of air flow visualization studies in non uni-directional flow zones on QRM principles?


Clauses with Significant Change in Chapter 5

Draft2007SubjectChangeExplanation of “Significant Change” Status
5.33Definition and requirements for graded clean areasGrade A definition has clarity and detail enhancements,  including the minimization of personnel in the zone and expectations for uni-directional air velocity measurementGrade B definition has been changed to define “interface” rooms as Grade C onlyGrade C and D definition is unchangedGrade A changes may have some impact where velocity measurement requirements have been interpreted differently, but the change improves what was previously ambiguous.The Grade B change adds ambiguity, as “interface” is not defined (refer to point of contention below)
5.951Personnel and material airlocksThe clause is significantly expanded, especially with regard to material movement, and now includes new expectations, such as:a) Personnel and material movement should “typically” be through separate areas.b) Separate entry and exit changing rooms imperative has changed from “sometimes desirable” to “generally desirable.”c) On entry, personnel must not skip grades.d) Pass-throughs be actively ventilated, with exceptions risk assessed and mitigated.e)Materials entering Grade A/B shall have been qualified and listed as authorized. Unauthorized material should enter only by a documented exception procedure.f) Movement of material from unclassified to Grade C (without transition through Grade D) should be risk assessed and mitigatedSome of the changes have long been inferred, even in the absence of clear instruction in the previous version. However, most of these changes will have some impact to some manufacturers.The entry and exit changing room expectation in particular, may have impact on smaller manufacturers where the decision to use a common entry/exit is often based on available floor space.Many facilities have non-active pass-throughs installed, especially in lower graded areas, and the impact of this change will depend on regulator interpretation for existing installations.
5.1153Air supply requirements to graded areasThe new clause is almost an exact copy of the 2007 clause, but the change is significant.The words “a filtered air supply ..” have been replaced with “a HEPA or ULPA filtered air supply …” when referring to the air supplied to graded areas.For Grades A, B and C, this change has little or no impact, but it is very significant if this is intended to apply to Grade D areas.Grade D areas with HEPA filtration are increasingly preferred for new installations, but Grade D areas without HEPAs are common and successfully operated world-wide.Retrospective application of this clause as currently written could have severe implications for many.
5.2125Isolator glove testingThe requirements for integrity testing of gloves has changed from “frequent” to “… at a minimum of the (sic) beginning and end of each batch, and following any intervention that may affect the integrity of the unit”Some manufacturers have been lobbying for a reduction in the expectations around glove integrity testing. This statement makes it clear that glove testing is seen as critical to sterility assurance. Some manufacturers may not be compliant with the expectation as written and may need to update procedures.Additionally, this clause does not mention RABS and it is unclear whether the same frequency is required for RABS, or if not, what the expectation for RABS may be.
5.254Limits table for clean room classificationThe table no longer includes ³5.0 µm particles for assessment.The footnote requires manufacturer definition of Grade D “in operation” conditionsThe change is significant in that all Annex 1 compliant manufacturers can alter their procedures to delete classification against the ³5.0 µm particle limits.This will have little real effect, apart from slightly reducing the effort required for reporting and reviewing classification events.The expectation for defining Grade D ‘in operation’ limits was set in the PIC/S interpretation document of the previous Annex 1 revision, but is new as an explicit requirement. Some manufacturers may be deficient as a result.


Point of Contention
: Clause 5.3 states that “only grade C cleanrooms should interface with the grade B aseptic processing area”. This could be interpreted as:1) rooms with a direct air passage to Grade B, where material or personnel may enter Grade B (e.g. via a door) shall be Grade C; or 2) rooms from which Grade B is accessed in any way (including, for example, via an actively ventilated pass-through) shall be Grade C). If interpretation 2 is correct, it may result in significant physical and/or operational modifications for some facilities. Not only where Grade B and Grade D may interface via an adtive pass-through, but also where Grade A or B areas interface with Grade D or lower classified areas in an”exit only” manner (e.g. where a high pressure differential through a wall opening and a conveyor system allows the transfer of fully integral containers for inspection and/or labelling operations)



Draft Annex 1 – Chapter 6 – Equipment

The new Equipment chapter features 10 clauses, up from 5 in the 2007 version. There are 5 brand new clauses. This section is arguably the least impactful new section with few clauses of notable impact.

Brand New Clauses in Chapter 6

DraftSubjectPotential impact
6.1Equipment Design DescriptionUndetermined - The clause is somewhat ambiguously written, so the impact is hard to gauge. There is lack of clarity regarding whether this is required for all GMP equipment (from small, simple units to large, complex equipment), or whether is it an overall description by system or process, or some hybrid approach.In many cases, such a description can be found in equipment qualification documentation, but the ambiguity about the scope makes it difficult to determine if such existing work is sufficient, or whether this is a new expectation over and above common existing practice.
6.2Requirements for equipment monitoringModerate - states that ongoing monitoring requirements should be determined during qualification and that process alarms relating to these requirements should be reviewed and trended. Monitoring and trending of equipment parameters is not universal practice, especially as smaller organisations and this may require some procedural update and additional ongoing effort for compliance.
6.5Cleaning validationNegligible - This clause highlights an apparent disconnect between the specifics of its intent (product contact equipment requiring disinfection and/or sterilization) and the subject matter of the section (“equipment”).Additional context is required in this section so that the reader can understand clearly which clauses apply to given equipment types (e.g product contact vs non-product contact).Notwithstanding the lack of context, the new cleaning validation clause adds little that is not currently understood as a requirement for sterile processes
6.6Sterility of product contact surfacesNegligible - Requires sterility of equipment surfaces that contact sterile materials. The intent is relatively clear and is well understood.
6.10Sterility assessment for unplanned maintenance on sterility critical equipmentMinor - A documented impact assessment is required when unplanned maintenance is carried out on equipment which is critical to product sterility.This assessment would be commonly done through most organisations existing unplanned maintenance and/or change management systems. However, some manufacturer’s systems may not be mature enough to identify and link the equipment and its criticality to product  sterility, and such systems will require update.


Clauses with Negligible Change in Chapter 6

Draft2007SubjectExplanation of “Negligible Change” Status
6.458Equipment maintenance in clean areasExact copy
6.760Validation and maintenance requirements for common sterile manufacturing equipmentAlmost exact copy. Air vent and gas filters have been deleted (requirements are documented elsewhere), and the concept of equipment monitoring is included, but overall intent is the same.
6.856Conveyors which transition out of Grade AExact copy
6.96Particle counter requirementsSmall modifications to require qualification of particle counters as well as remove explanation for short tube requirements. Impact is negligible.


Clauses with Minor Change in Chapter 6

Draft2007SubjectChangeExplanation of “Minor Change” Status
6.357Equipment maintenanceAlmost exact copy, however adds suggestion that additional monitoring or disinfection above routine levels may be required when maintenance has been conducted within the clean areaGenerally well understood, although may require procedural update in some instances.Arguably the discussion around maintenance within clean areas (including the small change in section 6.3) should be confined to section 6.4.


The new draft Annex 1 Chapter 5 brings some long-awaited clarity around certain issues for premises, and spells out some requirements that have only been implicit historically.

The new draft Annex 1 Chapter 6 poses minimal change or cause for concern, but in both chapters, there is still room for improvement when it comes to limiting interpretation.

Initial Blog

Draft Annex 1 – Part 1

Draft Annex 1 – Part 2

Draft Annex 1 – Part 3 (this post)

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

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