Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances - The authors re-examine environmental controls in the context of technical advances in manufacturing. -


Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances
The authors re-examine environmental controls in the context of technical advances in manufacturing.

BioPharm International
Volume 24, Issue 7, pp. 44-60

Critical quality attribute testing

Microbial, biochemical, and adventitious agent testing should be in place for the final BDS with established alert levels and specifications. The alert levels should be indicative of the process capability and the specifications of the quality attributes. Data should be actively trended to identify any shifts or changes in the variability of the process.

Procedural control and compliance

Closed or functionally-closed systems should be considered first when designing connections. If a closed-system design is not practical or possible, temporary breakable connections can be controlled through robust procedural controls that ensure consistency. Biopharmaceutical manufacturers have extensive experience in implementing manual procedures, and ensuring compliance with those procedures through training programs and internal auditing.

Studies to support the control strategy in a CNC environment

There are numerous supporting studies that can be used to support the robustness of processes operating in a CNC environment with respect to microbial and adventitious agent control. Unit operations can be evaluated to assess the impact of planned breaks to process closure using surrogate bacteriostatic buffers or media to quantify impact from the environment. Demonstration and quantification of bioburden reduction through efficacy studies for cleaning, sanitizing, and sterilization processes can eliminate the sources of microbial contamination from the environment.

A review and assessment of historical process contaminants versus environmental isolates can provide evidence that disassociates microorganisms found in the external environment from process contaminations. The qualification and validation of assays ensures that the sensitivity is suitable to detect all levels of microbial contamination.

The most compelling justification for operating under CNC conditions is a full-scale demonstration of the process. Data generated from such a demonstration will most likely address the concerns of internal quality assurance and external regulatory representatives. Such a demonstration is relatively straightforward to organize during engineering or development batches for a new product. Economic and product supply considerations as well as the estimated probability of success would be key variables in the decision to demonstrate CNC operation for currently commercialized products. Small-scale or pilot-scale data may be required to convince internal stakeholders to authorize a full-scale demonstration.


Current good manufacturing practices evolve with new technologies, continuous improvements, and science-based evaluations of the status quo. Regulatory expectations are often slower to evolve. Process improvements are reviewed on a case-by-case basis until sufficient experience is available for a consensus opinion. In the case of BDS manufacturing, the following actions are recommended to advocate for this new industry paradigm of functionally closed manufacturing in a CNC environment:

  • Keep an eye on the leaders—monitor pharmaceutical and regulatory websites and journals for facility information
  • Influence decision-makers and build consensus—attend meetings in industry organizations, particularly those attended by health authority representatives
  • Participate in industry groups and consortia to share and learn from others
  • Design facilities using formal risk assessments specific to processes, validation, and testing
  • Partner with the agencies and actively advocate a scientific, risk-based approach and solicit feedback via design review meetings.


Biopharmaceutical manufacturing in classified cleanrooms is the current status quo across the industry for many BDS process steps. Technologies for processing in closed or functionally closed systems have evolved rapidly in recent years. These technologies were developed to address the risks of open cleanroom operations, and they now call into question the need for classified environments. It is time to rethink the approach for controlling contamination risks in biopharmaceutical processes so that safe operations can be executed at lower cost and with less impact on the external environment. Scientific, risk-based approaches should be employed when determining the required environmental conditions for a particular process step. Significant opportunities are within reach if the industry moves, in concert, away from historical precedent toward a methodical, scientific, risk-based approach for the design and operation of biopharmaceutical manufacturing facilities.

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