EU GMP Annex 1 and Its Importance for High-Purity Media Systems – Part 2

A detailed description and flow diagram should be available and part of the initial qualification package. Monitoring requirements should be defined in the URS and confirmed during qualification. Process and equipment alarms must be validated, and their development/trends should be assessed. The frequency of evaluations should be based on criticality.

For maintenance work that needs to be performed in cleanrooms, special requirements are specified. Cleaning processes must be validated. The equipment (including water systems) must be qualified, monitored, and subjected to regular maintenance. After maintenance, the restart of operation must be approved!

For unplanned maintenance activities, the impact on product sterility must be assessed.

EnviroFALK PharmaWaterSystems Assessment:

The stated requirements for documentation and qualification are already part of the established approach for newly constructed systems. Cleaning and sanitization processes, which are an integral part of water system maintenance, may require intensive coordination with the manufacturer. In addition to process documentation, proof of qualification for the supplier’s executing personnel will be required.

The evaluation of collected data in the form of trending will also need to be carried out in collaboration with qualified supplier personnel.

However, it remains unclear how older existing systems will be handled in this context.

The extent of utility system controls should be determined based on their potential impact on product quality. This impact must be assessed through a risk evaluation and documented within the Contamination Control Strategy (CCS).

As with other critical systems, utilities must be properly designed, installed, qualified, maintained, and monitored.

For high-risk utilities, regular trend analyses should be performed on critical parameters and properties. Additionally, system installation documentation must be retained throughout the entire lifecycle.

EnviroFALK PharmaWaterSystems Assessment:

As outlined in the previous chapters, risk assessment must be applied to all processes that may impact product quality, including utility systems.

For many companies, these requirements may necessitate significant adjustments, as the scope of planning, qualification, maintenance, and monitoring is expected to be considerably more extensive than before.

The water treatment system, including the distribution system, must be designed, constructed, installed, commissioned, qualified, monitored, and maintained to prevent microbial contamination and ensure a reliable water supply. Measures should be implemented to reduce the risk of contamination from particles, microorganisms, and endotoxins/pyrogens. Special attention should be given to the monitoring and maintenance of filters.

The qualification and validation process should consider seasonal variations. Turbulent flow should be maintained within the distribution piping, with the flow rate defined during qualification and routinely monitored.

For WFI storage and distribution systems, measures must be taken to minimize the risk of microbial growth. WFI should be produced by distillation or an equivalent method, such as reverse osmosis combined with other appropriate technologies like electrodeionization, ultrafiltration, or nanofiltration. The integrity of filters should be tested before installation and after use. Measures should also be in place to prevent condensate formation.

To reduce the risk of microbial growth, water systems should be sterilized, disinfected, or regenerated according to a defined schedule or as soon as results exceed limits or specifications. Chemical disinfection must be followed by a validated flushing procedure. System operation should only resume after chemical test results have been confirmed, and batch release should only occur after verifying microbiological and endotoxin test results.

A regular and continuous chemical and microbiological monitoring of the water systems should be conducted. Alarm levels should be based on initial qualification data and periodically reviewed and reassessed. Continuous monitoring data should be analyzed to detect negative performance trends. Sampling programs should comply with CCS requirements and include all sampling points, user points, and exact sampling intervals.

Sampling plans should be based on qualification data, considering potential worst-case sampling points, and ensuring that at least one daily sample is taken from the water used for production.

Exceedances of alarm levels should be documented, reviewed, and analyzed to determine whether a trend indicating system deterioration is present. Exceedances of action limits should be investigated more thoroughly.

For WFI systems, continuous monitoring instruments such as TOC and conductivity measurement should be implemented.

EnviroFALK PharmaWaterSystems Assessment:

Most of the stated requirements are not new and are already standard practice for new installations. However, if existing systems are not granted grandfathering protection—which is likely—many systems will require retrofitting or replacement.

The explicit requirement for dead-space-free design and complete drainage capability, without distinguishing between feed water pretreatment systems and product-quality water systems, is expected to lead to intense discussions regarding its interpretation and technical feasibility.

Additionally, filter monitoring and system maintenance are moving further into focus, likely requiring adjustments in many companies.

The requirement to include turbulence verification in the qualification process and conduct regular reviews is new and will require procedural changes.

The option to produce WFI cold has existed since 2017, and many companies have already adopted this method.

Another new requirement is the validated flushing procedure following chemical disinfection and the confirmation of test results before resuming production.

It remains unclear how this applies to ozonation, which is commonly used for sanitizing WFI storage and distribution systems, or whether this requirement excludes ozonation.

As in previous sections, continuous monitoring, alarm evaluation, and trend analysis play a major role in compliance. It is expected that many companies will need to make significant adjustments or refinements in these areas.

While online measurement systems are now industry standard, there are still older WFI systems where measurements are conducted offline. These companies will likely need to retrofit their systems to comply with the new requirements.

The manufacturer must ensure that there is a sufficient number of qualified personnel with appropriate training and experience in the manufacturing and testing of sterile products, as well as in specific production technologies.

Additionally, personnel should undergo regular training in areas relevant to the proper manufacturing of sterile products.

EnviroFALK PharmaWaterSystems Assessment:

This chapter once again emphasizes the importance of personnel expertise. As previously mentioned, this will likely result in a significantly increased training effort and/or the involvement of service providers with specialized expertise.