New Draft PIC/S Annex 1 – Part 4 of 8

Quality Risk Assessment

New Draft PIC/S Annex 1 – Part 4 of 8

In Part 4 of the blog series on the draft revision of Annex 1. We look at Annex 1 Chapter 7 (Utilities), which provides guidance unique to supporting process services, such as water, vacuum, steam and compressed gas systems. Almost half the clauses in this chapter relate to water systems.

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

Chapter 7 – Utilities

Annex 1 chapter 7 on Utilities for sterile manufacture is largely brand new content (20 of the 24 clauses do not have an obvious related clause in 2007 Annex 1). Despite this, most of the requirements are consistent with current practices and are unlikely to cause major concern for most manufacturers.

Brand New Clauses in Chapter 7

DraftSubjectPotential impact
7.1Risk based determination of equipment controlsMinor to Moderate – the clause specifically requires the level of control for utilities to be commensurate with risk. So, it would stand to reason that WFI or pure steam will require significantly higher levels of control than a vacuum system. This is a well understood principle, but may require some modification to QRM efforts, where the link between level of control and risk has not been made clear.
7.2Explanation of what constitutes higher risk utilitiesNegligible to Minor – the concepts described are well understood and unlikely to require action by manufacturers.
7.3Requirement that utilities be installed, operated and maintained so that they function “as expected”Negligible – it is difficult to imagine what scenarios prompted the authoring of this clause. The concept is long embedded in GMP manufacturing and it appears to be redundant given related statements in the basic requirements.
7.4Trending of critical parameters from high risk utilitiesMinor to Moderate – in many cases, this is probably done routinely, however, with formal QRM efforts now expected around utilities 7.1 & 7.2), it is likely that some manufacturers may find some critical parameters not currently subject to trend analysis.
7.5Availability of current drawingsMinor to Moderate – most organisations would have such drawings of utility systems available, while some less mature organisations may not have up to date versions. This requirement may require some effort to ensure that all drawings are current. See point of contention below regarding some issues with this clause.

 

Point of Contention: Clause 7.5 requires drawings to be “current” but states no explicit requirement for the drawings to be an accurate reflection of the installation. While this concern may appear pedantic, as consultants, we regularly sight drawings that contain important inaccuracies.

Secondly, it is curious that the draft requires drawings to be available for utilities, but does not explicitly require the same for processes, equipment or facilities. It is appropriate that global statement(s) be added to address this

 

DraftSubjectPotential impact
7.9Validation of water systemsMinor – apart from the ambiguity about the scope of this clause (see point of contention below), if it is assumed that this refers to process water systems, the practice of validation consistent with the clause is well understood and implemented.

 

Point of Contention: Several clauses in section 7 use the term “water system” (some refer specifically to Water For Injections (WFI), but no other grades are mentioned). While the intent appears to be that the term “water system” refers to  treatment of water for the distribution to and use directly in the process, the lack of definition could lead to confusion. For example, should a pre-treatment/feedwater plant be considered a “water system”?

 

DraftSubjectPotential impact
7.10Turbulent flow in water pipeworkNegligible – The concept of turbulence in process water pipework to minimize microbial growth has existed for decades and is a key principle of all pharmaceutical water system design guidance
7.11Sanitary water system designNegligible – as for turbulent flow, the concepts sloping pipework, minimal deadlegs and monitoring of system filtration are long established and documented in relevant design guidance.
7.12WFI tank vent filtersMinor - Required to be sterilized and integrity tested pre and post use, which most organisations would do. However, no information is provided on the acceptable duration of use, nor regarding investigational or disposition expectations in the event of a post-use integrity test failure. It appears that this requirement is not intended (thankfully) to require PUPSIT (as per 8.84 for product sterilizing filters)
7.13Periodic sterilization / disinfection / regeneration of water systemsModerate – while the practice of a significant periodic event such as sterilization or disinfection may be common place, the requirement to approve post-event water analysis before the system can be used may cause challenges (refer to point of contention below).

 

Point of Contention: 7.13 states that for post-disinfection/regeneration water samples, “results should be approved before the start of use of the water system”.

For microbiological analysis, most organisations would re-commence system use at-risk, while waiting for results which may take several days. Allowance for this appears to be an oversight in the draft. However, if this action is no longer permissible, this requirement has significant impact

 

DraftSubjectPotential impact
7.14Water sampling programNegligible – sampling programs are universal among competent organisations. The clause requires programs to be suitable, representative and regular. No guidance is given on expectations to meet these requirements.
7.15Specific water sampling requirementsProbably negligible – Generally, concepts discussed are well understood, however, the clause contains (probably) a typographical error that infers a sampling rate beyond reason (see point of contention below)

 

Point of Contention: Clause 7.15 includes the sentence “A sample from the worst case sample point, e.g. the end of the distribution loop return, should be included each time the water is used for manufacturing and manufacturing processes.”

If this statement were taken literally, some larger manufacturers would be required to take hundreds of samples each day. Tracking the need for a sample would be nearly impossible and it would likely take multiple additional staff to meet the requirement.

It is much more likely that the clause is supposed to read “… each day the water is used … “ or include another alternative word to “time” which keeps sampling requirements to a more sensible number.

 

DraftSubjectPotential impact
7.16WFI should have TOC and conductivity continuous monitoringModerate – most recently built WFI systems will already have such continuous monitoring systems on line, and many older systems will have had them retrofitted in recent years, However, some older systems may still rely on offline testing, which has been compliant with regulations until now. The capital cost of such equipment is not insignificant.
7.17Purified water is mandated as the minimum feed quality for pure steamNegligible – purified water is the minimum feedwater standard for pure steam across the pharmaceutical sector,
7.19Quality of gases that are product or critical surface contactMinor – most of the requirements are standard practice. A statement about batch review consideration of integrity test results for compressed gas sterilizing filters is added. This may have some impact for manufacturers who don’t currently test gas sterilizing filters every batch.
7.20Backflow prevention for vacuum systemsNegligible – this is a standard design practice.
7.21Cooling system locationsNegligible – expectation that cooling systems be predominantly located remotely from filling rooms, and appropriately managed if this is not possible, a common-sense approach unlikely to cause concern. It is interesting, however, that clauses 7.21-7.24 reference “cooling systems” and not “heat transfer systems”
7.22Cooling system leaksMinor – a requirement that cooling system leaks be detectable via an indication system, which may not always be the case, and may require upgrade to systems in certain circumstances.
7.23Cooling circuit leak testingMinor – leak testing of cooling circuits is common practice. The formal implementation of periodic testing and testing after maintenance may require action from some manufacturers.
7.24Periodic cleaning of vacuum and cooling systemsModerate – cleaning/disinfection may be commonplace for vacuum systems, but would not necessarily be routine for cooling circuits,

 

Clauses with Negligible Change in Chapter 7

Draft2007SubjectExplanation of “Negligible Change” Status
7.649Installation of pipes, ducts and recesses in clean areasExact copy

 

Clauses with Minor Change in Chapter 7

Draft2007SubjectChangeExplanation of “Minor Change” Status
7.759Water treatment plant design shall ensure reliable water qualityVery similar to first part of 2007 clause 59. Adds specific reference to microbial proliferation and compendial complianceThe basis of design for process water systems is almost always the compendial specification, which necessitates minimization of microbial contamination.
7.859Requirements for WFI productionSimilar to second part of 2007 clause 59. Adds requirement for WFI to have PW feedwater, and acknowledges that WFI can be produced by alternative means to distillationPW as feedwater for WFI is standard practice. The challenges associated with implementing WFI by alternative methods will result in limited, and very careful, take up.

 

Clauses with Moderate Change in Chapter 7

Draft2007SubjectChangeExplanation of “Moderate Change” Status
7.1896Steam qualityAdds specific testing requirements for steam qualityMost mature organisations will have been using appropriate international standards to measure steam quality. Some organisations may not have, and still more may not complete the full suite of tests required by the new clause.

 

The new draft Annex 1 Chapter 7 feels a little bit under-developed. In one sense, it appears to be a chapter on WFI, with some small acknowledgement of other utilities. Expectations around some critical utilities (e.g. pure steam or sterile compressed gas) are arguably insufficient, however, further expansion might lead the chapter into design guidance territory.

Its value as a stand-alone chapter will be debated. Alternative approaches (for example, as “utilities” and “process water systems” sub-sections under the Equipment chapter) should be considered.

Initial Blog

Draft Annex 1 – Part 1

Draft Annex 1 – Part 2

Draft Annex 1 – Part 3

Draft Annex 1 – Part 4 (this post)

Draft Annex 1 – Part 5

Draft Annex 1 – Part 6

Draft Annex 1 – Part 7

Draft Annex 1 – Part 8

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