Annex 1 to Volume 4 of the EU Guidelines for Good Manufacturing Practice for Medical Products for Human and Veterinary Use is legally binding for the manufacture of sterile products bound for the European Union.  A primary focus of the mandate is to minimize the risk of microbial contamination during the production of sterile drugs.  It presents a requirement for a contamination control strategy (CCS) to be developed for these processes.  The CCS formalizes a holistic approach to contamination control and should include contamination control in critical utility systems such as those which produce pharmaceutical grade waters.

The goal of a CCS is to identify potential sources of contamination and document the approach to mitigating the associated risk to the greatest extent possible or practical.  Many control mechanisms and procedures may already exist in practice, however, the CCS catalogs the strategies and tactics in one common document.  The criticality of the water, how it is used in manufacturing, and the degree of purity may all influence the expansiveness of a CCS.  This formal process for documenting contamination control measures, which relies on risk assessments and the use of subject matter experts for technical input, should logically extend to water used in non-sterile manufacturing processes as well.

Types and Sources of Contamination

Any contamination of pharmaceutical waters for sterile process manufacturing should be scrutinized as the amount of tolerable impurities is dependent on the product and application.  Risk assessment tools are used to determine acceptable impurity levels for product waters, in particular for those impurities identified as Critical Quality Attributes (CQAs).  Extraneous contamination may be considered an Added Substance, the presence of which is strictly impermissible per compendial water monographs.  However, pharmaceutical waters, including Water for Injection (WFI) are not pure.  Sterility, or an absence of all viable microbial impurities, is never implied for pharmaceutical waters produced in bulk.

Annex 1 specifically mentions microbial, particulate, and endotoxin contamination.  Additional types of contamination in pharmaceutical waters may include dissolved organic matter, ionic impurities, colloidal material, non-viable submicron particles, weakly ionized substances and dissolved gasses.  Contamination from chemical impurities such as conductivity and TOC is easily identified by in-line or on-line process analyzers.  Microbial contamination, including total viable bacteria and endotoxin is more challenging to monitor, predict, and identify as these species are not homogeneous throughout the system.  Potential sources of contamination in a pharmaceutical water system include:

• Feed Water (inconsistent quality due to variable nature)
• Failure of System Integrity Controls (vent filters, pump seals, double tube heat exchangers)
• Consumable Replacement or Routine Maintenance (system boundary is compromised)
• Chemical Cleaning and Sanitization Process (system boundary compromised and chemicals introduced)
• External Sources (sampling, points-of-use, back contamination)

Contamination sources should be evaluated at points throughout the pharmaceutical water treatment system, and not exclusively in storage and distribution.  Some impurities (e.g. dissolved gasses) may be permissible if not identified as a CQA nor present at concentrations or levels above those specified.

Design Considerations

There are a few specific requirements for water systems mentioned in Annex 1.  A review of their impact on system design, operation, and maintenance is summarized here.   In addition to critical material attributes for product contact surfaces, operational controls for pharmaceutical water systems must be established and verified.  Specific to utilities, Annex 1 states:

The nature and extent of controls applied to utility systems should be commensurate with the risk to product quality associated with the utility. The impact should be determined via a risk assessment documented as part of the CCS. 

After identification of the CQAs that define the product water purity, Critical Design Elements (CDEs) are established based on a hazard analysis that identifies critical control points throughout the process. CDEs are design features and system operational functions.  They ensure process parameters are maintained within their design ranges such that the specified values for CQAs are consistently achieved.  For pharmaceutical water systems, CDEs should be established, tested or verified, and optimized to ensure a validated state of operation that produces minimal contamination risk.

For purification of water, removal of feed water impurities is achieved by more than one process.  Many operations work in conjunction or succession to achieve final product quality.  Removal of specific impurities may be essential for ongoing operation of downstream components.  For instance, removal of residual feed water disinfectant is crucial for long term operation of a downstream reverse osmosis unit, which in turn removes additional impurities.  When developing a CCS for a multi-unit process, where many operations are interdependent, a technical process review is imperative.  A properly prepared CCS, should outline these system and functional interdependencies.

Of note, design features should be purposeful; implemented to minimize product risk and contamination control.  Features and functions which are not based on sound engineering principles or scientific logic should be specifically excluded.  For example, if sloped piping does not provide an engineering or maintenance benefit to the system design or operation, implementation should be questioned.  Eliminating certain design elements or material attributes, regardless of perceived regulatory mandates, is justified using risk assessment tools.

Pharmaceutical Water System CCS Development

There is no recommended structure or format defined in Annex 1 for a CCS document.  A specific CCS document for pharmaceutical water or other critical utilities is not required as it can be a section in the overall CCS for a manufacturing process.  It may also be a collection of design development and qualification documents consolidated into a single volume.  Again, for existing systems, information required for a CCS may already exist for water systems and it is just a process of consolidating all of the material.

For a pharmaceutical water system, a risk assessment should be the initial step of the CCS development process.  For existing systems, gaps in control points, monitoring, excursion analysis (including CAPA), and training should be identified and addressed.  For new systems, the risk assessment can be used to confirm process design, control logic, and confirm proper CDEs.  All phases of the development process should be documented.  A summary report, similar to those used in the qualification process, should be included.

Operating data and control hierarchy should be periodically reviewed,  This can be coupled with or included as part of the Periodic Performance Review recommended for validated pharmaceutical water systems.  The CCS document should be dynamic in nature, and updated based on review of system performance.  Variable feed water composition, aging consumables such as membranes and filters, temperature fluctuations, and many other variables can affect long term system performance and operation.  Control points associated with less frequent maintenance such as gasket and elastomer replacement, derouging and re-passivation, instrument calibration, etc. may be difficult to predict and require reassessment throughout the system life cycle.  Reviews and updates of the control strategy should be integral to ongoing operation.

Path Forward

Many of the current Good Manufacturing Practices for pharmaceutical water systems used to control contamination have likely already been identified, implemented, and verified during process validation for existing systems.  Hopefully, widespread adoption of a formalized CCS requirement will expand the risk and science based approach to design, operation, validation, and maintenance of pharmaceutical water systems in the future.