New Challenges to the Cleanroom Paradigm for Multi-Product Facilities - Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a cont


New Challenges to the Cleanroom Paradigm for Multi-Product Facilities
Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a controlled non-classified (CNC) ballroom environment.

BioPharm International
pp. 38-47


Successful development of a strategy for contamination detection and lot disposition requires the application of an overall risk-based control strategy. This application needs to be done to assure process integrity and minimize cross-contamination potential, with quality system, analytical, and advanced process-monitoring concepts integrated into quality assurance (QA) oversight.

Many existing cGMP elements of the lot disposition process for QA will carry over to the new operating paradigm (i.e., CNC ballroom) as per CFR 211 and Eudralex, Volume 4. However, new approaches and additional focus on multi-product control strategies will also need to be designed and implemented to maintain or enhance current levels of oversight and control.

Figure 3: The integration of interacting elements crucial to contamination control.
These control strategies would not require new approaches to the current quality system or QA oversight, assuming a shift to a multi-product operating environment in a traditional, segregated operations space with typical classified areas (ISO/EU Annexes) has already occurred. Similarly, multi-product control strategies generally employed in the industry are a solid foundation to build on for a new CNC ballroom-type operation.

The key elements of a risk-based control are depicted in Figure 3 and are further discussed below:

  • The operating principles around flow path management (e.g., people, equipment, process streams, and waste) via engineering, procedural, and temporal controls (in descending order of preference) will have been established and will require review and adjustment versus invention in an existing facility; these same principles will apply to establishing the controls for the new CNC facility.
  • The facility design and environmental controls will require a more detailed assessment and risk analysis, focused primarily on product quality and cross-contamination risks; special attention on risks associated with concurrent production of two or more products needs to be a crucial part of this risk analysis.
  • Review of cleaning verification must be performed and validation approaches taken for the transition to multi-product operations particularly relating to sampling and testing protocols will be needed. Changes need to be incorporated into the facility cleaning validation documentation, with the data generated providing evidence of contamination control as required for the quality system lot disposition process.
  • It is anticipated that process integrity monitoring, documentation, and subsequent QA review will increase with a change to a CNC, ballroom environment. Little, if any, environmental monitoring data would be available for QA consideration during the disposition process, hence the focus on process integrity and closed systems to support appropriate contamination controls for disposition decision-making.

• It is recommended that environmental monitoring process qualification (PQ) at facility start-up to establish baseline data and identify any environmental isolates that may appear during later in-process monitoring for bioburden be conducted. The baseline data will represent the primary reference and detection mechanism for any process deviations to established microbial limits. This would be consistent with what is expected in a traditional facility. Consideration should be given to the use of hand-held technology alternatives for viable/non-viable monitoring (e.g., Biovigilant) at this stage and a tool to employ in the case of planned or unplanned process integrity breaches.

• Apply integrity testing for closed systems including connections and evidence of expected process volumes and flow rates. The acquisition and review of this data from qualified or validated sources to support product disposition process are new elements that need to be integrated in to the quality system. Here, pressure hold, helium leak testing, or other alternatives should be considered to generate the needed data for review.

  • Process design is expected to incorporate the targeted use of CIP/SIP or sanitization approaches at appropriate post closed-system connection breakage and re-establishment steps, with use of step/material appropriate connection components and technology. CIP/SIP execution completion per qualified or validated recipes would provide for data for QA review, batch record review, and/or batch disposition. Where recipes are automated and alarmed, the application of the review by exception principles, as recommended in GAMP 5 (3), may be integrated into the batch review and disposition process.
  • Enhanced monitoring and control can be achieved via technology advancements.

• In-process control testing for bioburden takes on increased significance in this new operating model especially as traditional bioburden testing is not timely (several days). The incorporation of rapid microbiological analysis technology is a highly recommended element of the control strategy and may mitigate risks associated with timeliness and unexpected results to better support product disposition decisions.

• Consideration might also be given to adopting in-line identification (ID) testing technology to confirm "right product, right container" as real-time data for consideration in the disposition decision.

Integration of the interacting elements of operating principles, cleaning verification and validation, process integrity monitoring and documentation, and process design, monitoring, and control into the quality system and quality assurance oversight process are thus crucial components to achieve the required level of contamination detection and control. Quality-system elements including changeover, campaign, and concurrent manufacturing controls; managing planned (batch record design and change control) and unplanned (deviation or non-conformance) system breaches and the lot-disposition process inclusion of all appropriate criteria will need an intensive review and adjustment to effectively integrate as one moves from single-product, all-classified space to multi-product, CNC ballroom operations.

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