Expediting the Technical Transfer of Biopharmaceutical Products - Proper infrastructure ensures equivalent analytical results at all laboratories for a successful simultaneous commercial release from


Expediting the Technical Transfer of Biopharmaceutical Products
Proper infrastructure ensures equivalent analytical results at all laboratories for a successful simultaneous commercial release from various sites.

BioPharm International

Methodology. The limits of parameter variability discovered during method validation for a given analytical test are de facto verified during the technical transfer. The design of a high-quality analytical variability matrix during method development and subsequent validation is essential to provide satisfactory outcomes in parameters such as robustness and reproducibility at the time of method transfer. This kind of expertise is challenging to transfer to the downstream laboratories in a limited time frame. Side-by-side training is highly recommended to acquire all pertinent method details and the proper criteria to identify and correctly attribute the source of parameter variation results, to ensure minimal interlaboratory result variations, or to accommodate the use of equivalent, but nonidentical, analytical instrumentation. Additional considerations taken for the establishment of equivalence of compendial methods between countries include, for example, content uniformity and moisture. The United States Pharmacopeia (USP) has three compendial methods for water determination <921> 1a, 1b and 1c, whereas the European Union uses mostly method EP (2.5.12), which is equivalent to USP <921> 1c8; determination of content uniformity in JP General Test 109, even if it is considered an equivalent method to USP <905>, has differences in the way the results are calculated and reported.

Case Studies. Acquisition of truly equivalent instruments might mitigate potential variability in results later on. In one case, negotiations to acquire equivalent instrumentation were not productive and equivalency between two instruments had to be established relative to a third standard instrument. Eventually, the receiving laboratory agreed to consider purchasing an equivalent instrument.

Acceptance Criteria. The decision to set up acceptance criteria should be based on the receiving laboratory's ability to perform the method successfully. The criteria for interlaboratory variability during method transfer should not be confused with method variability and must be weighed against the precision of the instrumentation used for the particular method and biopharmaceutical drug specifications. Interlaboratory variability acceptance criteria are method dependent and require careful examination of each individual method documented in the transfer protocol. The handling of potential deviations from the acceptance criteria should be clearly defined in the transfer protocol and a remediation plan should be instituted prior to initiation of transfer testing. All deviations must be reported and documented as an addendum to the original transfer protocol.

In our experience, the preset acceptance criteria for one analytical method resulted in an out-of-specification (OOS) investigation by the receiving laboratory. This situation could have been avoided if adequate acceptance criteria accounted for a realistic analyst-to-analyst variability.

Drug Specifications. Specifications for a given biopharmaceutical might be considered too broad for the receiving regulatory agencies at the time of product release. Specifications are intrinsically associated with the nature of the biopharmaceutical product and the precision and sensitivity of the analytical method and instrumentation used; specifications also should be independent of analyst variability. Suitable specifications are typically refined during the development of the drug product candidate and finalized before its commercial launch; their acceptable ranges must be narrowed to meet or surpass acceptable ranges in accordance with the International Conference on Harmonization (ICH) guidelines, in addition to those specified by the intended market regulatory agencies.

Analytical Reagents. Reference standards and critical reagents should be provided to the receiving laboratory to cover transfer protocol testing and should include additional material for practice testing. For biopharmaceuticals, analytical reagents may not be commercially available. A reasonable inventory supply tracking system must be established by the transferring laboratory to maintain a log of critical reagents supply required to cover the needs of all release laboratories for long-term release testing. Additionally, a regular supply chain must be established to the receiving laboratories. Not to be forgotten are valid import permits to allow customs release of the shipped materials. Chain of custody procedures and environmental monitoring are customary for all shipped critical reagents used for testing under a Current Good Practices cGXP setting (i.e., cGMP, cGLP, cGCP).

In our experience, unexpected situations have occurred and one must be prepared to handle them decisively. As an example of critical reagent transfer surprises, the establishment of a good working relationship with the contracted international courier was instrumental in preventing the loss of a dry ice shipment during a particularly hot summer week at a European port of entry. To compensate for an unexpected delay in shipment relays caused by an airport controller strike, the courier contacted its local office, rented a truck, and drove the shipment overnight through two countries to deliver the critical reagents safely.

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