This case study on facility biocontainment and inactivation is the third of eight in a series put together by the Product
Quality Research Institute Manufacturing Technical Committee (PQRI-MTC) risk-management working group. The series is meant
to advance the understanding and application of the International Conference on Harmonization (ICH) Q9 Quality Risk Management
guideline by providing actual examples of risk-management assessments used by the bio/pharmceutical industry. The introductory
article and first case study, on defining design space, appeared in the July 2011 issue of Pharmaceutical Technology
When a manufacturer produces two or more drug substances in the same manufacturing facility, the facility is considered to
be multiproduct. The facility designs, operations, and controls related to the use for multiple products should provide for
appropriate measures to prevent cross-contamination between products. These controls include the containment procedures used
to prevent the release of hazardous agents within the facility.
There are numerous facility design and operational attributes that may significantly affect the quality of products being
manufactured. These attributes include, but are not limited to, area classifications, open versus closed processing, utility-system
design, cleaning validation/clean-in-place systems, rules regarding equipment sharing, and critical flows throughout the facility.
Facility designs and operations should provide for appropriate segregation of products to prevent cross-contamination. For
facilities with multiple products or processes, the impact of potential process or product failures on the other operations
in the same facility should be evaluated.
The following case study on facility biocontainment and inactivation is the third of eight in a series put together by the
Product Quality Research Institute Manufacturing Technical Committee (PQRI–MTC) risk-management working group. The series
is meant to advance the understanding and application of the International Conference on Harmonization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-management assessments used by the bio/pharmceutical industry. The introductory
article explaining the history and structure of the series, as well as the first case study on defining design space, appeared
in the July 2011 issue of Pharmaceutical Technology (1). The second study addressed functional equivalence for equipment replacement (2).
In the current case study, two existing manufacturing suites were proposed to be remodeled to accommodate and contain manufacturing
operations involving bacterial fermentation through viable cells of Streptococcus pneumoniae, a pathogenic Biosafety Level 2 (BL2) organism. These suites were separate manufacturing areas located adjacent to mammalian
cell culture manufacturing-processing areas. Regulatory guidance requires BL2-Large Scale (LS) waste and residues to be inactivated
prior to exiting the manufacturing area (3). An inactivation autoclave was identified during the initial risk assessment as
one of the primary means of inactivation of BL2 waste and process equipment prior to exiting the fermentation suite. The risk-review
step in the risk-management process identified that there was only one inactivation autoclave in the fermentation suite and
that alternative backup inactivation procedures were desired to maintain continuity of manufacturing operations during autoclave
preventive- and corrective-maintenance activities.
This case study describes the evaluation of various backup inactivation procedures for operational feasibility and includes
a demonstration of an appropriate level of inactivation of the BL2 waste and equipment.
Risk question and risk-assessment method
The risk question developed for the subject case study is: What are the appropriate backup inactivation methods (i.e., procedures) that are operationally feasible and provide an appropriate
level of decontamination capability that can be utilized in the fermentation suite to inactivate BL2 waste and equipment when
the inactivation autoclave is unavailable?
Selection of a backup inactivation procedure is a precise exercise requiring an objective evaluation of the effectiveness
of proposed procedures at inactivating the BL2 organism along with demonstration of consistent execution of these procedures
each time they are performed.
Hazards analysis and critical control points (HACCP) is a risk-assessment tool that can be proactively used to identify and
implement process controls that consistently and effectively prevent hazards from occurring. HACCP involves evaluation of
critical procedural limits and determination of how they will be achieved routinely. Because it is essential that the backup
inactivation procedures prevent the release of the BL2 organism outside of the fermentation suite, HACCP was selected as the
risk-assessment tool to use to determine the appropriate preventative controls.