Quality Risk Assessment

PIC/S – New Draft Annex 1 – Part 6 of 8

As noted in Part 5 of the blog series on the draft revision of Annex 1, Parts 5 & 6 look at Chapter 8 (Production & Specific Technologies).
Part 5 focussed on terminal sterilisation of products and related sterilising processes. “PIC/S – New Draft Annex 1 – Part 6 of 8” looks at the remainder of Chapter 8, and discusses aseptic processing, finishing of products and specific production technologies.
Readers may also wish to view the Initial BlogPart 1Part 2Part 3Part 4 and Part 5 of this series for context.

Chapter 8, Part B – Aseptic Processing, Finishing Sterile Products and Specific Technologies (Clauses 6-29 & 78-123)

In this second look at Chapter 8, we explore not only 4 topics carried over from the 2007 version, but also all 4 new production related topics. Part 6 covers mostly information new to the Annex – of the 70 clauses looked at this this part, 46 are brand new (including 22 from the new sections).

The sub-headings from the draft revision covered in Part 6 are:

  • Aseptic processing (clauses 6-16)
  • Finishing of sterile products (17-29)
  • Filtration of medicinal products which cannot be sterilized in their final container (78-89)
  • Form-Fill-Seal (90-92)
  • Blow-Fill-Seal (93-104)
  • Lyophilisation (105-111)
  • Closed systems (112-116)
  • Single use systems (117-123)

Brand New Clauses in Chapter 8

-DraftSubjectPotential impact
8.6New description of aseptic processing. Negligible – Not a requirement, more of a definition and its presence in the requirement clauses instead of the glossary is questionable. The definition provided in the clause is arguably not as suitable as the definition of asepsis in the glossary.
8.7Considerations for aseptic processing contamination control strategyModerate to Significant – Contains specific instruction which aids in the development of a contamination control strategy. Important for those yet to develop such a strategy, but also helpful guidance for those who wish to confirm the level of compliance of their existing strategy.
8.11Preparation and handling of aseptic product when not sterile-filteredNegligible – Reflects standard current practices.
8.13Specific requirements for aseptic connectionsMinor – Generally reflects standard practices, although the requirement that aseptic connections be “appropriately assessed” is a little ambiguous and could lead to differing interpretations and expectations.
8.15Minimisation of aseptic manipulationsNegligible to Minor – Generally consistent with standard practices. However, small volume, manual operations may need to demonstrate that manipulations have been minimized.
8.16Definition of maximum hold times for various operationsSignificant – Considerable expansion of the types of hold times previously discussed in the annex. It is likely that many manufacturers will not comply with every aspect of this clause and will require further studies and procedural update to be compliant.
8.20Container closure validation should consider transportMinor to Moderate – The clause lacks detail and therefore has some ambiguity. While it apparently refers to ensuring that the transport does not have a negative impact on container closure integrity, the potential methods or basis for acceptance are not discussed. Similar activities are widely performed, but are not universal, so this will likely require some manufacturers to undertake further studies.
8.24Manual capping to employ techniques to avoid human contact with componentsNegligible – Consistent with standard practice
8.25RABS/isolators considered for cappingMinor – As a “may be” statement, it is unlikely to influence most manufacturers. However, it may be used as leverage to encourage manufacturers to adopt improved technologies.
8.29Visual defects should be recorded and trended by defectModerate to Significant – Such programs are not universally adopted currently, and while they are important improvements to knowledge management, they may require significant efforts to implement for those who currently do not perform them.
8.80Details of sterilising filter systemsMinor – mostly well understood and implemented. The clause, however, clearly attempts to define the requirements for filtration systems within the concept of pre-use, post-sterilisation integrity testing (PUPSIT) as an expectation, and appears to place a strong preference on SIP as the sterilization method. This clause should be read with consideration to 8.84 which provides limited exception for PUPSIT.
8.81Information on product/filter validationNegligible – this concept is well understood, especially by filter vendors, who most commonly perform the validations.
8.82Product should be used for bacterial retention testing where possible Negligible – as for above, commonly performed by filter vendors, who are highly experienced. Where product is not a suitable test medium (which is not uncommon, due to the bacteriostatic (or stronger) nature of many pharmaceuticals) substitutes are permitted
8.83Expectations for filter parameters.Negligible to Minor - Most of this information is well understood and implemented. The specific detail of some requirements may not be fully implemented at all affected manufacturers.

Although these concepts are generally well implemented, this is a useful summary of the relevant considerations.

Some parts of this clause have correlation to 2007 clause 113, but the new clause is significantly more broad in context and content, and therefore is considered “new”.
8.86Use hydrophobic gas filtersNegligible - This is standard practice
8.87Serial filtration requires all filters to pass integrity testingNegligible - This is standard practice
8.88Redundant filtration requires only one filter to pass, and no need to integrity test redundant filter if primary filter passesNegligible - This is standard practice
8.90Defines Form Fill Seal(FFS)Negligible – This is a definition not a requirement. The one aspect of this clause which may be considered a requirement (100% integrity testing of fusion sealed containers) is fully covered at 8.18. Could be removed and combined with FFS glossary definition
8.91Critical parameters for FFS sealingNegligible– Most of this information is well understood and implemented.
8.92QRM based sampling for visual/performance testing of FFS productsNegligible– Most of this information is well understood and implemented
8.98Environmental monitoring and control in BFS equipment should consider the complex gas flow paths and high heat outputs of such equipmentProbably Minor – For the most part this is well understood by manufacturers. It is conceivable, however, that this sort of vague statement could be used to justify regulatory concerns which are not yet clearly defined.
8.99Shuttle designs should have grade A conditions at the critical (filling) zone between parison cutting and mould sealingNegligible to Minor– While this is a key difference between shuttle and rotary equipment, this concept is generally well understood and applied. It perhaps has been clearly documented to pre-empt attempts to reduce monitoring in shuttle environments to match the lesser requirements for rotary equipment.
8.100Terminally sterilised BFS products can be made with a Grade D backgroundNegligible – Most BFS machines in Australia have been installed with the requirement of flexibility (terminally sterilized or aseptically filled production) and therefore meet the higher standards required for aseptic production. It would be highly unlikely that this requirement represents a challenge against existing conditions.
8.101Avoiding contamination of polymer through appropriate storage and distributionProbably Minor – Manufacturers typically have specific contamination control mechanisms in place for polymer. The regulatory position on “appropriate” is not yet clear, however.
8.102Mid batch re-sterilisation and other interventions if required should only be acceptable if part of routine procedure and process simulationsMinor to Moderate – This principle is not new for aseptic process simulations, however, some interventions required for BFS are unique to the technology. Manufacturers should understand that such procedures should not be performed unless they have been pre-qualified.
8.103Process validation for BFSNegligible – Arguably a redundant statement that process validation in BFS should follow the same basic principle as PV for all processes.
8.104QRM based sampling for visual/ performance testing of BFS productsNegligible – Well understood. Effectively a repeat of clause 8.92, adding the example of wall thickness. Given that 8.92 is a clause which is relevant for both vertical FFS and BFS, it is arguable that this clause is redundant if the wall thickness example were moved into 8.92.
8.105Overarching statement regarding the criticality of lyophilization with respect to sterility and contamination control.Negligible – The concept is well understood and implemented.
8.106Lyophiliser should be sterilised pre-load and protectedNegligible – The concept is well understood and implemented.
8.107Closing systems for partially closed containers shall be sterilizedNegligible – The concept is well understood and implemented.
8.108Lyophiliser trays should be checked for damageMinor –Most manufacturers would check periodically, however, the clause does not provide information regarding frequency – every batch or other frequency?
8.109Manufacturers should define the maximum leakage of air into the lyophiliserNegligible – The concept is well understood and implemented.
8.110System integrity to be monitored along with leak rate testNegligible to Minor – This clause has slightly ambiguous intent. It should be expanded to make monitoring requirements clear.
8.111Loading and unloading lyophilisersNegligible to Minor – This clause represents a good source of information to cross-check against for compliance. Most manufacturers should be implementing all of these, however, some may not have all aspects covered.
8.112Explanation that closed systems is applicable for both single use and fixed systemsNegligible – The concept is well understood.
8.113Explanation of the contamination control benefits of closed systems Negligible – The concept is well understood and the clause does not represent a requirement.
8.114Requirement to ensure sterility of closed system contact surfaces in aseptic processingNegligible to Minor– The concept is well understood and implemented. It is likely that the intent of this clause is to highlight the risks associated with aseptic connections and encourage their minimization.
8.115If a system is intended to be closed, the system integrity must be assured. QRM to be used to determine testing processMinor – The concept is generally well understood and implemented. The use of QRM to determine and justify testing processes may not be universally adopted.
8.116Closed system environments dependent on the risk to integrity. Grade D appears to be minimum acceptableMinor – The concepts described are logical and well understood. The effort which may have been applied to determine the relative risk to integrity, may not universally be sufficient.
8.117Single use systems (SUS) defined Negligible – Clause is not a requirement, but rather a definition. The definition itself is not particularly insightful or helpful. The glossary definition is better, but still imperfect.
8.118Describes “specific risks” associated with SUSNegligible to Minor – The items listed are generally well understood, but their wide array may result in less than universal compliance. Some of the items listed are not risks and are better described as special considerations for SUS.
8.119Product compatibility testing required for SUSNegligible – The concept is well understood and implemented.
8.120Extractable and leachable testing required. May be able to leverage supplier dataNegligible to Minor – The concept is well understood and implemented. The ability to utilize vendor data in certain circumstances is a welcome concession.
8.121System integrity should be assessed at process condition extremes (e.g. freeze/thaw)Moderate – Many manufacturers will have robust integrity assessment which covers processing extremes. It is conceivable that the examples provided may not currently be universally assessed.
8.122Acceptance procedures for SUSNegligible – The requirements appear largely self-evident and no different from any other critical processing material requirements.
8.123Critical manual handling of SUS to be part of media fillNegligible – It would be difficult to envisage how such tasks could be avoided during process simulations without deliberately manipulating the exercise.

Clauses with Negligible Change in Chapter 8

-Draft2007SubjectExplanation of “Negligible Change” Status
8.864, 75, 76General precautions to minimize contamination of all typesClosely related to combination of the three 2007 clauses mentioned. Expands detail regarding “all processing stages”, but the concepts are still well understood.

The part of the clause which relates to 2007 clause 75 is a exact copy of clause 5.6, however it appears that this clause is intended for processing materials and equipment, while 5.6 relates to premises infrastructure. Differentiating the wording may help avoid confusion.
8.1235Preparation of sterile products that are not subsequently sterilized or sterile filteredAlmost exact copy, with minor corrections for improved clarity. Intent is identical
8.19123Ongoing testing of vacuum sealed productsAlmost exact copy. Adds that testing should be performed “during shelf-life” which is arguably redundant, given that the requirement already called for an “appropriate” duration. Intent identical.
8.21119Location of capping equipmentExact copy
8.25122Benefits of RABS and isolatorsExact copy
8.79112, 115Information on filters for aseptic processingCombines two previous clauses and there is rewording for clarity. The intent for both clauses remains the same.
8.85113Integrity testing of gas and vent filtersAlmost exact copy, with minor clarity improvement
8.9326Description of Blow Fill SealExact copy of the first sentence of 2007 Clause 26. Clause is a definition, not a requirement.
8.9526Background environment for aseptic BFS productionExpansion to indicate that the Grade C minimum background is applicable to both rotary and shuttle type machines, but no change to requirement.
8.9626Environmental monitoring requirements for shuttle BFS equipmentSeparates out the global requirement from the 2007 clause 26 and makes it specific to shuttle equipment. No change to intent
8.9726Environmental monitoring requirements for rotary BFS equipmentRewrites the formerly global requirement and makes it specific for rotary equipment, giving exemption from in-operation monitoring of the critical zone, with background monitoring based on QRM. This expectation is standard practice for rotary users currently.

Clauses with Minor Change in Chapter 8

-Draft2007SubjectChangeExplanation of “Minor Change” Status
8.921Encouragement to use isolation / RABS / closed systems and automation to minimise interventionsAdds closed systems and specific examples of automation (SIP, DHO, automated loading of lyophilisers) to the list of technologies that are encouraged to reduce human interventionAs clause 21 has been used in the past, this clause will likely continue to be used by regulators to apply gentle pressure to manufacturers to upgrade technologies.
8.1017Examples of operations in various grades for aseptic productThe table is substantially expanded to include several activities which previously were not mentioned, notably in A and B zonesMinor change because of the quantity of expanded text (1 item previously described for A/B has been expanded to 15). The practices described are well understood and implemented.
8.14116, 34Transfer of partially closed containersRemoves ambiguity about use of non-active transfer carts Most manufacturers would not use the 2007 clause 34, but its existence caused some confusion as it apparently contradicted 116. The confusion is removed.

The example of “Grade A conditions” is inadequate and the difference in examples between 8.14 and the related 8.17 creates new confusion.
8.17116Transfer of partially closed containers and pre-filled syringes, not specifically lyophiliser relatedConcise rewording of 2007 clause 116 which includes addition of pre-filled syringes to the descriptionLikely to be well implemented, but may have some implications for PFS manufacturers who had not made the link to partially stoppered vials.

The example of “Grade A conditions” is a significant improvement on that provided at 8.14 and should be the default explanation.
8.22120Vial capping environmentAlmost exact copy of 2007 clause 120, but limits manual capping to standard Grade A conditionsMay affect some manual capping operations that had applied the lower standard in the old clause.

Fails to take the opportunity to explain the concept of Grade A air supply in more detail.
8.78110, 111Filtration in aseptic processingAdds detail regarding need (potentially) for multiple bioburden reduction filters, and the recommendation for redundant sterilizing filters has strengthened from “may be” to “is” advisable.For the most part, this requirement is well understood and implemented. There may be scope for citation where regulators view bioburden reduction inadequate, or where they see the risk of no redundant sterilizing filters as too high.
8.84113Integrity testing of sterilizing filtersAdds detail on integrity test expectations and provides potential exemption for small batch production.Effectively mandates Pre-Use, Post-Sterilisation Integrity Testing (PUPSIT) for all product sterilizing filters except for small batch production, where risk assessment may justify an alternative.

This is a different approach to the recent European guidance document, and the justifying statement is highly dubious. (see point of contention)
8.89114Usage period for aseptic sterilizing filtersSimilar clauses. New clause adds “single lot” as a limitation of filter useUsing a sterilizing filter only for single lots is common practice,. but may affect some manufacturers who have complied with the letter of the previous requirement.
8.9427Contamination control considerations for BFS The clause has been reworded for clarity and enhanced detail. The control of polymer starting material was not previously mentioned.The requirements are generally well understood and implemented. Some aspects, notably the polymer addition, may require action from some manufacturers.

Point of Contention: Clause 8.84 relates to the highly debated topic of mandatory Pre-Use, Post-Sterilisation Integrity Testing (PUPSIT). In recent years, there has been a strong regulatory push to mandate the requirement in Europe (but not in the USA). There has been similarly strong resistance from both manufacturers and filter vendors, who see PUPSIT primarily as a business risk decision, not a quality enhancement.

The draft revision makes it clear that the authors see the requirement as mandatory, however, the justification provided for PUPSIT:

“ … in case of damage and loss of integrity caused by processing …”

is both confusing and highly questionable. The precise purpose of the post-use test is to assess the filter for damage and loss of integrity caused by processing, and therefore, if this were the true purpose of PUPSIT, then PUPSIT would be redundant. The purpose (and validity) of PUPSIT has been long debated, but the inclusion of this justification is unhelpful at best.

Clauses with Moderate Change in Chapter 8

-Draft2007SubjectChangeExplanation of “Moderate Change” Status
8.18117Sampling requirements for integrity testing of closed containersAdds specific detail regarding inspection of non-fusion sealed containersSome of the new information, for example, use of statistically valid sampling plans or use of QRM for methodology and frequency, are unlikely to be universally applied.
8.27124Visual inspection of filled containers - manualQualification of manual inspection operators is described in detailMost manufacturers have a similar program, which may require enhancement when reviewed against the new clause
8.28124Visual inspection of filled containers - automatedRequirement to benchmark automated visual inspection against manual methodsSome organisations may assume that the automated method is superior without performing the assessment

Clauses with Significant Change in Chapter 8

-Draft2007SubjectChangeExplanation of “Moderate Change” Status
8.23121Considerations for vial capping
  1. Limits automatic rejection of missing/displaced stoppers to when detected in capping events outside the aseptic core.
  2. Requires automated detection for stopper height detection.
  3. Requires microbial ingress studies to determine appropriate maximum stopper height prior to capping
Point 1 arguably allows rework of vials with missing or displaced stoppers inside the aseptic core. A practice which is uncommon.

Point 2 may be problematic for smaller and more manual processes

Point 3 is logical, but is expected to prompt new work, especially for smaller organisations.
8.26124Visual inspection of filled containers - generalSeveral significant additions are present in the new clause:
  • Defect classification and criticality to be based on QRM principles.
  • Defects to be categorised by type and each batch performance analysed.
  • Unusual defect levels compared with routine should result in investigation.
  • Defect library generated and maintained.
Apart from the first item, each of the additions pose likely additional processes and effort for less mature manufacturers.

That concludes the 2-part focus on Chapter 8. The chapter is very broad and could possibly benefit from further sub-division, however, it is understood that this is difficult given the intent for (and benefits of) alignment with Part I of the GMP code.

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  (this post)

Draft Annex 1 – Part 7

Draft Annex 1 – Part 8