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.
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
|7.1||Risk based determination of equipment controls||Minor 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.|
|7.2||Explanation of what constitutes higher risk utilities||Negligible to Minor – the concepts described are well understood and unlikely to require action by manufacturers.|
|7.3||Requirement 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.|
|7.4||Trending of critical parameters from high risk utilities||Minor 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.|
|7.5||Availability of current drawings||Minor 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
|7.9||Validation of water systems||Minor – 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”?
|7.10||Turbulent flow in water pipework||Negligible – 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|
|7.11||Sanitary water system design||Negligible – as for turbulent flow, the concepts sloping pipework, minimal deadlegs and monitoring of system filtration are long established and documented in relevant design guidance.|
|7.12||WFI tank vent filters||Minor - 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)|
|7.13||Periodic sterilization / disinfection / regeneration of water systems||Moderate – 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
|7.14||Water sampling program||Negligible – 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.|
|7.15||Specific water sampling requirements||Probably 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.
|7.16||WFI should have TOC and conductivity continuous monitoring||Moderate – 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.|
|7.17||Purified water is mandated as the minimum feed quality for pure steam||Negligible – purified water is the minimum feedwater standard for pure steam across the pharmaceutical sector,|
|7.19||Quality of gases that are product or critical surface contact||Minor – 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.|
|7.20||Backflow prevention for vacuum systems||Negligible – this is a standard design practice.|
|7.21||Cooling system locations||Negligible – 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”|
|7.22||Cooling system leaks||Minor – 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.|
|7.23||Cooling circuit leak testing||Minor – leak testing of cooling circuits is common practice. The formal implementation of periodic testing and testing after maintenance may require action from some manufacturers.|
|7.24||Periodic cleaning of vacuum and cooling systems||Moderate – cleaning/disinfection may be commonplace for vacuum systems, but would not necessarily be routine for cooling circuits,|
Clauses with Negligible Change in Chapter 7
|-||Draft||2007||Subject||Explanation of “Negligible Change” Status|
|7.6||49||Installation of pipes, ducts and recesses in clean areas||Exact copy|
Clauses with Minor Change in Chapter 7
|-||Draft||2007||Subject||Change||Explanation of “Minor Change” Status|
|7.7||59||Water treatment plant design shall ensure reliable water quality||Very similar to first part of 2007 clause 59. Adds specific reference to microbial proliferation and compendial compliance||The basis of design for process water systems is almost always the compendial specification, which necessitates minimization of microbial contamination.|
|7.8||59||Requirements for WFI production||Similar 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 distillation||PW 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
|-||Draft||2007||Subject||Change||Explanation of “Moderate Change” Status|
|7.18||96||Steam quality||Adds specific testing requirements for steam quality||Most 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.
Draft Annex 1 – Part 4 (this post)