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Established, fully validated methodology and SOPs are required prior to initiation of any training activities.
One of the challenges faced by the pharmaceutical industry in today's global economy is the successful release of commercial drug products in multiple markets.
When the commercial release of a drug has to be accomplished simultaneously from different sites, the establishment of the proper infrastructure ensures equivalent analytical results across the various laboratories.
Thoughtful coordination and implementation of the highest quality standards involves expert training, compliance with established standard operating procedures, analytical methodology, validated instrumentation, availability of critical reagents and reference standards, and a uniform materials and documentation practice across analytical laboratories. The result is a successful technical transfer of products.
Particularly challenging is product release of commercial biopharmaceuticals. Careful planning and preliminary considerations ensure a successful technical transfer.1-6 In the case of biopharmaceuticals, analytical methods are often quite complex. For commercial product, the methods are fully validated and the biopharmaceutical product has been well characterized by the originating laboratory.7
As a case study, the experience of Wyeth Research in the successful technical transfer of bioanalytical product release methodology to the Japanese and European markets is discussed.
Analytical Training. The goal is to provide adequate training to the receiving laboratory analysts and ensure compliance with procedures established by the originating laboratory while minimizing variability in analytical results. This will likely entail direct training by the transferring laboratory. Established, fully validated methodology and SOPs are required before initiation of any training activities. Coordination of training requirements among sites must include verification of equivalent training practices while considering each site's unique needs. Additionally, qualifications of the analysts to be trained must be documented.
In our own experience, a visual training presentation was instrumental in overcoming unexpected language barriers.
Regulatory and Compliance. All documentation encompassing validation of analytical methods, SOPs, reagents, certificates of analysis/origins of materials, instrumentation equivalence, equipment qualification status, personnel training, and facilities certificates must be reviewed and compiled in compliance with regulatory agencies from both ends of the transfer. In the case of biologicals, additional safety parameters, such as biohazard exposure and adequate training of personnel in biomaterials handling, are essential. Regulations pertaining to the licensing permits and qualifications of the receiving laboratory in handling items such as radioactive materials or biohazard or pathogenic materials also must be examined and may vary on a case-by-case basis. Procedures must be verified to meet compliance requirements with national regulatory agencies governing the receiving laboratory.
Safety. The primary responsibility of the releasing analytical laboratory is to produce the highest quality data and corroborate product integrity, thereby ensuring the safety of patients receiving a drug product. It is essential that the releasing laboratory acquire not only pertinent analytical methodology, but also develop scientific expertise and become fully acquainted with all aspects of the drug characteristics prior to release to the public. Open communication channels must be established to ensure that adequate knowledge about the drug product is transferred from the originating laboratory to the receiving laboratory during and following completion of the technology transfer training activities.
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.
Communication. Direct communication among all parties involved in the technical transfer before and during preparation of the draft protocol document should be encouraged. Prior expertise in the technology transfer process facilitates the inclusion of well-defined responsibilities, organization of the transfer program, and lessening of avoidable protocol amendments. Communication may include both the transfer and receiving laboratories, the technical transfer officer, and the quality units from both sites. Whenever possible, teleconferences should be scheduled (taking into account time differences) to allow for direct discussions to clarify any issues. The transferring laboratory's expertise should be openly disclosed to discuss any questions or expectations by the receiving laboratory during protocol preparation. Sensitivity to different cultural backgrounds and potential language barriers may need to be addressed.
As an example, due to language subtleties, the receiving laboratory may erroneously interpret a procedure described in a method. This situation can be avoided with side-by-side training and clarification of any statements perceived as vague.
Practical Training. Once the technical transfer protocol has been prepared and approved, it is desirable to provide direct training to the receiving laboratory before protocol execution. The complexity of the training for release testing may vary according to the complexity of the analytical methods involved. There are no perfect methods, and often, direct visual demonstration of procedures such as sample preparation, handling, and sample application can avoid erroneous method interpretations arising from language nuances. In addition, training on specialized software for data analysis may be included as needed. Analytical data analysis templates should be prepared ahead of time for the receiving laboratory, as well as accompanying examples of representative data. Simultaneous training of two analysts is preferred, although we have successfully transferred multiple methods to a single analyst. The transferring laboratory must carefully coordinate side-by-side training activities to allow sufficient time for completion of all methods by trainees. Contingency plans for repetition of side-by-side training in case of technical failures are not required, but highly recommended. Our policy requires that all original training records of the receiving laboratory analysts must be documented and retained according to the practices of the transferring laboratory regardless of the documentation practices for training at the receiving laboratory.
Protocol Execution. Once preliminary training is completed, execution of the preapproved technical transfer protocol may take place at the transferring and receiving laboratory sites. Each method will dictate the need for equivalencies in instrumentation between laboratories. Parameters to consider in addition to system suitability include instrument performance tests, lot-to-lot, and interlaboratory variation at the time of data review. In the case of commercial product, the analytical release method needs to be fully validated per ICH guidelines2,3; thus, transfer of commercial release methods must comply with guidelines and be reflected in the transfer protocol document. Samples used for method transfer testing need not be from commercial lots, and may be representative samples. The advantage of using freshly manufactured and released batches as the choice for technical transfer protocol execution obviates the need of retesting at the time of transfer by the transferring laboratory. The transfer training measures the ability of the receiving laboratory to perform the testing from the transfer laboratory within the preset acceptable criteria limits.
Data Analysis. Analytical data should include tabulated values from each laboratory, standard deviations, and coefficients of variance to establish meaningful statistical correlations in interlaboratory or instrument-to-instrument variations, for instance. Free exchange of analytical results should be encouraged to facilitate satisfactory completion of the protocol. If commercial lots are used for analysis, the transferring laboratory may provide the original results from the product release certificate of analysis. The choice of sample lots should be considered carefully to include samples whose analytical values are representative of the entire range of specifications. For example, results in the average range should be used along with lots trending towards high and low ends of the specifications. This practice might be more challenging, given the expected higher analyst variability during initial tests at the time of training, but it will ensure better consistency at the time of true product release. On completion of data analysis, conclusions of the successful completion of transfer should be documented and included in the protocol for final review and approval.
Investigative Procedure Failures. Procedures detailing the handling of laboratory test result failures should be compared between both transfer sites and a common remediation practice procedure should be established and included in the transfer protocol. In the case of simultaneous commercial product release from multiple sites, procedures for handling result discrepancies should be established prior to the initiation of release testing. In the case of biopharmaceutical sample preparation, handling, storage, and stability are critical parameters for correct analytical testing.
The complexity of the technology transfer analytical methodology dictates most of the aspects of design and acceptance criteria for the transfer protocol. As a reminder, the length of timing between technology transfer training and authentic product release testing must be taken into account and communication continued to provide training refresher support as needed.
The authors are members of the Analytical and Quality Sciences Laboratory, Preclinical Development department, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, 845.602.4981, firstname.lastname@example.org
1. Bioanalytical Method Validation, guidance for industry, USD-HHS, FDA-CDER, FDA-CVM, May 2001.
2. Text on Validation of Analytical Procedures, ICH guidelines Q2A, 27 Oct 1994.
3. Validation of Analytical Procedures: Methodology, ICH guidelines Q2B, 6 November 1996.
4. Specifications: Test Procedures and acceptance criteria for Biotechnological/Biological Products, ICH guidelines Q6B, 10 March 1999.
5. Scypinski S, Roberts D, Oates M, Etse J. Analytical Method Transfer, draft guideline, Pharmaceutical Research and Manufacturers Association (PhRMA) Acceptable Analytical Practices, Pharmaceutical Technology Europe, March 2002.
6. Krause SO. A guide for testing biopharmaceuticals-Part 1: general strategies for validation extensions. Pharmaceutical Technology Europe, May 2006.
7. Lutz H. Introduction to Validation of Biopharmaceuticals, BioPharm International, March 2005.
8. European Pharmacopoeia, 5th Ed. 5.5, Assay Method 2.5.12
9. The Japanese Pharmacopoeia, 14th Ed. Part 1, General Test 10.