Quality Risk Assessment

New draft PIC/S Annex 1 – Part 5 of 8

Parts 5 & 6 of the blog series on the draft revision of Annex 1 looks at Chapter 8 (Production & Specific Technologies). The chapter has been separated into two blog posts due to size, as it is by far the longest chapter in the draft Annex. At 123 clauses, Chapter 8 represents about 46% of the total clauses in the Annex.

It features 15 sub-headings, 4 of which (Form-Fill-Seal, Lyophilisation, Closed Systems and Single Use Systems) are not explicitly covered in the 2007 Annex. Almost exactly half of the clauses in the chapter (62) are brand new, including all 27 clauses under the new topic sub-headings.

With such a significant rewrite and re-development of requirements, this chapter will be a key focus for manufacturers assessing gaps compared with existing practice. Part 5 focusses on terminal sterilisation of products and related sterilisation processes.

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

Chapter 8, Part A – Sterilised Products & Sterilising Processes (Clauses 1-5 & 30-77)

In this first of two looks at Chapter 8, we focus on sterilised products (clauses 1-5) and sterilising processes (clauses 30-77). All of the topics covered under the 7 related sub-headings are also covered in the 2007 Annex. However the 30 clauses from the previous version have been combined with 4 clauses from other parts of the 2007 version and expanded to 53 in the draft revision.

The sub-headings from the draft revision covered in Part 5 are:

  • Terminally sterilised products (clauses 1-5)
  • Sterilisation (30-46)
  • Sterilisation by heat (47-53)
  • Moist heat sterilisation (54-63)
  • Dry heat sterilisation (64-68)
  • Sterlisation by radiation (69-71)
  • Sterilisation with ethylene oxide (72-77)

Brand New Clauses in Chapter 8

DraftSubjectPotential impact
8.4Bioburden reduction filtration of bulk solutions prior to terminal sterilizationMinor to Moderate – Most terminal sterilization processes are likely to include a bioburden reduction filtration step, but it has not previously been mandated. Such a change is considerable if required.
8.31Steriliser and program decisions based on QRMMinor – The use of QRM in critical decision making is appropriate and generally well applied. A literal interpretation of this clause may be problematic, however (see point of contention below). The existence of risk assessments that comply with this clause may not be universal.


Point of Contention: Clause 8.31 requires the application of QRM principles to certain sterilizer decisions. Some of those decisions are understandable (e.g. selection, design and location of a steriliser), however, the use of QRM as the primary tool to select cycle programs appears unnecessary and possibly inappropriate.


It is more common, and arguably better practice that cycle selection be based on scientific principles and data which demonstrate repeatable, reliable sterilisation. QRM should be a secondary consideration for cycle selection.


Brand New Clauses in Chapter 8 continued

DraftSubjectPotential impact
8.43Expectations for disinfection of materials into aseptic process.Moderate– Clear expectations for a common practice that was previously not described in the annex. Most manufacturers who perform this practice will have some form of verification, but this clause provides specific expectations that may exceed the scope of some exercises.
8.46Specific requirement to perform validation on depyrogenation processesNegligible to Minor– Validation is commonly performed on depyrogenation processes, although some less mature manufacturers may overlook it. This clause is also notable because the requirement to demonstrate sterilization is explicitly omitted for depyrogenation studies.
8.47Explanatory note on the difference in science and purpose of dry heat and moist heatNegligible – Not a compliance requirement and well understood in any case. Arguable that this type of information is better placed as one or multiple entries in the glossary.
8.50Location of controlling and recording temperature sensors for heat sterilisationMinor to Moderate - Requires locations to be “determined” during validation and verified against and independent sensor at the same location. Many manufacturers would perform validations similar to those described, but it would not be universal.

The concept of “determining” sensor locations during validation is counter to the concept of validation as a confirmation of pre-determined criteria. Possibly an alternative term such as “confirmed” or “verified” is more appropriate.
8.59Requirement to assure removal of air from sterilisation process that purge with airNegligible to Minor – this is already performed by the vast majority of manufacturers affected. Some manufacturers may need to assess if their “assurance” is appropriate.
8.61Prevention of distortion and damage to BFS containers for terminal sterilisationNegligible – Distortion and damage to containers is important for several reasons, not just for GMP. It is hard to imagine a BFS process which does not have such measures included.
8.62Maintenance of sterility in sterilisers by excluding non-sterile airNegligible - This requirement appears self evident
8.63Expectations for SIP systemsNegligible 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.
8.64Basic principle of dry heat sterilisationNegligible - This requirement appears self-evident,
8.65Expectations for dry heat tunnelsNegligible 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.
8.66Handling and managing endotoxin indicatorsNegligible– Most of this information is well understood and implemented.
8.67Expectations for dry heat ovensNegligible 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.

Causes 8.65 and 8.67 are differentiated only by a small amount of unique information for tunnels (8.65) and ovens (8.67). It may have been more succinct to have a common clause, and two much shorter unique clauses.
8.68Consistency of dry heat principles regardless of material type or stageNegligible – the clause is possibly present only because of statements in 8.65 and 8.67 which describe typical scope for each equipment type. This clause effectively states that the same principles apply for non-typical applications.
8.69Direct reference to Annex 12 for guidance on irradiation.Negligible – as it refers to a pre-existing guidance. This is the 4th and final reference to “EU GMP” to define the parent GMP guide at the apparent exclusion of PIC/S. Arguably a more inclusive term can be found given that all 4 references apply equally to the PIC/S version.

Clauses with Negligible Change in Chapter 8

Draft2007SubjectExplanation of “Negligible Change” Status
8.128Preparation of components and products for terminal sterilisationAlmost exact copy, minor corrections of grammar and improved clarity. Intent is identical.
8.229Filling of products for terminal sterilisationExact copy
8.517Examples of operations in various grades for terminally sterilized productAlmost exact copy of ther terminal sterilization section of 2007 Clause 17.
8.30110Sterilisation methodology in order of preferenceSignificant rewording of 2007 clause 110, with some information also separated out into 8.78. The intent of the clause remains the same, however, that terminal sterilization is preferred, then heat treatment, then aseptic processing as product allows.
8.3383Validation of sterilization processes (general)Almost exact copy. The minor changes are for clarity and should not cause any new actions for previously compliant manufacturers
8.3484Validation of sterilization loads (general)Almost exact copy of the first sentence of 2007 clause 84. Adds “equipment” to “product” as subject of assessment, but this should not create compliance issues.
8.3685Effective sterilization requires whole of material to be subject to processAlmost exact copy. Previously stated “material” now states “material and equipment”. Intent identical
8.3786Establishment of parameters for sterilization loads Terminology is changed from “validation” to establishment of routine operating parameters. No practical difference in expectation, however.
8.3988Segregation of sterilised and non-sterilised items.Almost exact copy, with minor clarity improvements.
8.4089Sterilisation recordsAlmost exact copy, with minor clarity improvement
8.48126Considerations for parametric releaseAdds periodic review and lifecycle considerations. Organisations that have made the effort to obtain authorization for parametric release will inevitably have appropriate review processes.
8.5191Use of indicators in heat sterilisationExact copy
8.5292Heat sterilisation time requirementsExact copy
8.5393Prevention of contamination during cooling of heat sterilisationExact copy
8.7098Overview of sterilization by radiationExact copy
8.71101Density of packages must be considered during irradiation validationExact copy
8.72104Overview of Ethylene Oxide (EtOH) sterilizationAlmost exact copy. Dated phrasing (three words) have been removed in the interest of clarity, but should have been replaced with alternative phrasing, as the sentence is no longer grammatically complete.
8.73105Mechanism of Ethylene Oxide (EtOH) sterilizationExact copy
8.74106Importance of environmental equilibrium in EtOH sterilizationExact copy
8.76108Critical process variables for EtOH sterilization.Information which is covered elsewhere has been removed from 2007 clause 108, and the remainder reworded for clarity, but intent is identical.
8.77109Post-sterilisation activities for EtOH sterilisationAlmost exact copy, with minor clarity improvement

Clauses with Minor Change in Chapter 8

Draft2007SubjectChangeExplanation of “Minor Change” Status
8.3584Validation of sterilisation loads (frequency)Almost exact copy of second sentence of 2007 clause 84, but adds examples of revalidation triggersMost manufacturers will be compliant with the additional information, however, some of the specific (e.g. product packaging changes) might not be fully covered by all manufacturers
8.3887Use of biological indicators to monitor sterilization processesSignificantly more detail in the management and handling of BIsThe clause has been significantly enhanced with more detail,
8.4177Protection of materials after sterilization2007 clause 77 was specific to cleaning, and 8.41 is an enhancement of that clause, specific to sterlisation.While there is a large amount of detail in 8.41 that is not present in the 2007 version, it is largely information that is well understood and implemented. Because of the volume of new information, it is possible that some manufacturers do not meet all aspects of the clause currently.
8.4478Sterilisation hold timesThe requirement to validate hold time between washing/drying and sterilisation is removed. The requirement to validate hold time between sterilisation and use is enhanced to include package integrity checksThe new clause describes the subject matter as sterilised in sealed containers. The focus is on the package integrity rather than the just the ability to remain sterile, which may have impact on the way some validations have been performed.

Removal of the requirement to validate pre-sterilisation clean hold time will have little effect.
8.4577Handling of aseptic processing components which cannot be sterilisedNearly considered an entirely new clause, but the intent of this clause is captured in 2007 clause 77. The new clause provides considerable additional detail on the concepts of contamination prevention. Importantly, it requires that disinfection transfer processes be validated.The requirement to validate disinfection processes for aseptic processing components was not explicit in the 2007 version, but has been common practice for most manufacturers. This will, however, require additional work for some.
8.4990, 94Monitoring and recording of heat sterilization cyclesClarifies that monitoring and recording systems should be independent of the controllerWhile this principle has been part of guidance documents in the past, this is an important clarification in the regulations which may have impact on some manufacturers.
8.5594Requirements for heat sterilization cycle/system faultsSimilar to part of 2007 clause 94, but with the added instruction that appropriate action must be taken in response to the faults prior to process acceptanceGenerally well implemented already, but the lack of specific instruction for managing such faults in the 2007 version may have led to less timely assessment of faults in some cases.
8.5694Requirements for temperature monitoring in SIP/sterilizer drainsClause correlates closely to part of 2007 clause 94 with respect to monitoring sterilizer drains. New clause adds equivalent expectation for SIP systemsGenerally, this principle is applied to SIP systems, but it is conceivable that some have not considered this expectation in the absence of specific instruction.
8.5894Leak testing of moist heat sterilisersSimilar to part of 2007 clause 94. Adds circumstances under which leak testing is expected, and the determination of frequency through QRM Leak testing is generally well implemented. The application of QRM for frequency may not be.
8.75107Use of BIs in ethylene oxide (EtOH) sterilization cyclesRemoves the explicit requirement to include BI results in the batch record. Exempts parametric release from the use of BIs.The changes are a relaxation, but could still impact relevant manufacturers.

Clauses with Moderate Change in Chapter 8

Draft2007SubjectChangeExplanation of “Moderate Change” Status
8.330Definition of unusual risk for filling of terminally sterilized productsAdds product “held for extended periods of time before sterilization” to the list of unusual risks.As this requirement was absent from the previous version, universal application of a Grade A filling zone in such circumstances is unlikely. As a result, this may have considerable impact for some manufacturers.

The concept of “extended periods of time” is not defined and would need to be the subject of QRM.
  1. Parameters to monitor during heat sterilization
  2. Sterilised package integrity confirmation
Adds “time” to subject 1.

Subject 2 is entirely new
The addition of time has little impact, if any, as it would be routinely monitored. The new clause requires assessment of package and seal integrity on unloading and prior to use. While logical and good practice, this may not be universal practice.

It is difficult to understand why these two subjects have been combined into one requirement, instead of two.
8.5794Validation requirements for moist heat sterilisationComprehensive expansion of principle described in part of 2007 clause 94. The new clause has significantly more detail and specific requirementsThese validation requirements are generally well understood, but the level of detail far exceeds what had been prescribed previously, and may not be wholly universally adopted.

Clauses with Significant Change in Chapter 8

Draft2007SubjectChangeExplanation of “Significant Change” Status
8.4281Mechanisms for transferring materials into an aseptic processing areaIs specific regarding means other than a double ended autoclave. Adds the term “unidirectional” to describe the transferAlternative means are generally well understood. Disinfection is the method which poses the greatest compliance risk and will be the most heavily scrutinized. The term “effective” indicates that the process must be evidence based.

The use of unidirectional possibly means that bi-directional pass-through into Grade A is no longer permitted, which may be significant for some smaller manufacturers.
8.6095Steam sterilizing load considerationsAdds requirement to confirm load dryness as part of sterilization process acceptanceThe new clause implies that the load dryness confirmation is required for every load, which may be different than some manufacturer’s process, where the parameter has been considered as part of validation.

Point to Consider: For moist heat sterilization (e.g. autoclaves) 8.60 requires load dryness to be an acceptance criterion for sterilization process acceptance (except for sealed container sterilization). Is this current practice at your facility, or do you rely on load pattern validations?


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 (this post)

Draft Annex 1 – Part 6

Draft Annex 1 – Part 7

Draft Annex 1 – Part 8