All those can prohibit validation and lead to lost opportunities for potentially important production process improvements.
Such problems affect many companies in the biopharmaceutical industry regardless of the scale of their production bioreactors (ranging from ~20 L to >20,000 L), modes of production (lasting from days, as in fed-batch mode, to months in the case of perfusion bioreactors), and the number of units available for manufacturing.
It may be impossible in many organizations to use commercial facilities for installation and operation of a scale-down platform to be qualified.
In such cases, use of development-stage or pilot facilities should be permissible in alignment with internal quality assurance (QA) standards.
Moreover, when a production unit is devoted to a validation study for a proposed process change, the resulting drug product manufactured often must not be released but rather kept on hold until stability and all predetermined acceptance criteria have been met and verified.
Such implementation can be driven by product safety, purity, and stability enhancement opportunities as well as by cost-reduction pressures.
Our approach aligns with the US Food and Drug Administration’s (FDA’s) product life-cycle concept (6) and the expectations of “prospective” validation (based on a preplanned protocol).
The study plan should specify criteria for concluding whether a process consistently makes acceptable quality product as well as provisions for addressing deviations from expected results and handling nonconforming data.
For instance, Genentech has reported using good laboratory practice (GLP) compliant pilot-plant facilities equipped with 400-L bioreactors to aid validation programs for implementation at the 12,000-L scale (8).
The company further demonstrated product comparability for its TNKase product.