Comments on updated EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use; Manufacture of Sterile Medicinal Products

On February 20, 2020, a second stakeholder targeted consultation to Annex 1 of the EU GMP guidelines for manufacturing of sterile medicinal products was released. Certain sections specific to water systems are included, which overall, are largely inconsequential and consistent with current industry standards for Water for Injection (#WFI).

Our review of these sections on water systems includes the following comments:

6.7 Water treatment plant and distribution systems should be designed, constructed and maintained to minimize the risk of particulates, microbial contamination/proliferation and pyrogens (e.g. sloping of piping to provide complete drainage and the avoidance of dead legs), and prevent the formation of biofilms to ensure a reliable source of water of an appropriate quality. Where filters are included in the system, special attention should be given to the monitoring and maintenance of these filters. Water produced should comply with the current monograph of the relevant Pharmacopeia.

Comments on Section 6.7:

To avoid confusion, water treatment plant and distribution systems should be replaced with water treatment generation, storage, and distribution systems. The example citing sloped piping should be qualified.

Current industry consensus is that there is no value-added for sloped piping, unless required for draining condensate after steam sanitization or to facilitate draining. It is hard to justify the statement that sloped piping aids in minimizing contamination. It would be impossible to design a system void of some type of deadlegs. Deadlegs should always be minimized, but it would be impractical to eliminate deadlegs altogether on instrument connection points.

6.8 Water systems should be qualified to maintain the appropriate levels of physical, chemical and microbial control, taking seasonal variation into account.

Comments on Section 6.8:

This is consistent with current industry standards. It is important that quality attributes are monitored throughout the system, and not only at points-of-use.

6.9 Water flow should remain turbulent through the pipes to minimize the risk of microbial adhesion, and subsequent biofilm formation.

Comments on Section 6.9:

We do recommend that turbulent and positive pressure are always maintained.

6.10 Water for injections (WFI) should be produced from water meeting specifications that have been defined during the qualification process, stored and distributed in a manner which minimizes the risk of microbial growth (for example, by constant circulation at a temperature above70°C). Where the WFI is produced by methods other than distillation, further techniques such as nanofiltration and ultra-filtration as well as electrodeionization (EDI) should be considered in conjunction with reverse osmosis (RO) membranes.

Comments on Section 6.10:

In general, the use of examples in regulatory documents is discouraged, because they can easily be interpreted as the sole or recommended method, process, or procedure. By using elevated temperature as an example of a means to minimize microbial growth, it could be interpreted as the preferred method of microbial control, therefore limiting other technologies such as periodic ozonation.

The section does not mention two pass RO. Certainly, there have been many membrane-based WFI systems installed and validated which do not use two pass RO.

6.11 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should be sterilized and the integrity of the filter tested before installation and after removal following use.

Comments on Section 6.11:

It is rare that WFI tank vent filters are sterilized prior to use or integrity tested pre and post-use. It is also interesting that the language specifically does not mention that the vent filters be integrity tested in place, as is suggested for sterilizing filters elsewhere in the document.

6.12 To minimize the risk of biofilm formation, sterilization or disinfection or regeneration of water systems should be carried out according to a predetermined schedule and when microbial counts exceed action limits. Disinfection of a water system with chemicals should be followed by a validated rinsing/flushing procedure. Water should be tested after disinfection/regeneration. The results should be approved before the water system is returned to use.

Comments on Section 6.12:

It is never suggested that a claim of sterility be made for a WFI system. Sterilization should be changed to sanitization.

It is preferred to have sanitizations carried out based on a validated frequency, rather than on a predetermined schedule.

Section 6.13 below correctly refers to Alert Levels and not Alert Limits. Action Limits in this section should be changed to Action Levels.

Water can be tested on-line in real time for chemical impurities immediately after sanitization, but it may not be possible to have microbial results before water is returned to use.

6.13 Regular, ongoing chemical and microbial monitoring of water systems should be performed. Alert levels should be based on the qualification or a review of ongoing monitoring data that will identify an adverse trend in system performance. Sampling programs should reflect the requirements of the CCS and include:

i. All points of use, at a specified interval, to ensure that representative water samples are obtained for analysis on a regular basis.

ii. Potential worst case sampling locations.

iii. A sample from the point at the end of the distribution loop each day that the water is used.

Breaches of alert levels should be documented and reviewed, and include investigation of system trends to determine whether the breach is a single (isolated) event or if results are indicative of loss of control or system deterioration. Each breach of action limits should be investigated to determine the root cause of the issue and any impact on the quality of products and manufacturing processes as a result of the potential use of the water.

WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, (unless justified otherwise) as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk and the outcome of qualification.

Comments on Section 6.13:

Sampling programs should also include inter-component sampling of the generation system. While this sampling may be less frequent than use-points, it is critical to maintain a state of control for the entire system.

We suggest a sample from the distribution point each day the water is used, but this does not necessarily have to be at the end (return) of the distribution loop.

Continuous monitoring of conductivity and TOC should be supplemented with grab sampling if there is an increased risk of contamination at the use-point (e.g. if point-of-use heat exchangers are used).