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1224 TRANSFER OF ANALYTICAL PROCEDURES
Testing to the specification of an ancillary material, intermediate, and/or ingredient and product is critical in establishing the quality of a finished dosage form. The transfer of analytical procedures (TAP), also referred to as method transfer, is the documented process that qualifies a laboratory (the receiving unit) to use an analytical test procedure that originated in another laboratory (the transferring unit), thus ensuring that the receiving unit has the procedural knowledge and ability to perform the transferred analytical procedure as intended.
The purpose of this general information chapter is to summarize the types of transfers that may occur, including the possibility of waiver of any transfer, and to outline the potential components of a transfer protocol. The chapter does not provide statistical methods and does not encompass the transfer of microbiological or biological procedures.
TYPES OF TRANSFERS OF ANALYTICAL PROCEDURES
TAP can be performed and demonstrated by several approaches. The most common is comparative testing performed on homogeneous lots of the target material from standard production batches or samples intentionally prepared for the test (e.g., by spiking relevant accurate amounts of known impurities into samples). Other approaches include covalidation between laboratories, the complete or partial validation of the analytical procedures by the receiving unit, and the transfer waiver, which is an appropriately justified omission of the transfer process. The tests that will be transferred, the extent of the transfer activities, and the implementation strategy should be based on a risk analysis that considers the previous experience and knowledge of the receiving unit, the complexity and specifications of the product, and the procedure.
Comparative testing requires the analysis of a predetermined number of samples of the same lot by both the sending and the receiving units. Other approaches may be valid, e.g., if the receiving unit meets a predetermined acceptance criterion for the recovery of an impurity in a spiked product. Such analysis is based on a preapproved transfer protocol that stipulates the details of the procedure, the samples that will be used, and the predetermined acceptance criteria, including acceptable variability. Meeting the predetermined acceptance criteria is necessary to assure that the receiving unit is qualified to run the procedure.
Covalidation Between Two or More Laboratories
The laboratory that performs the validation of an analytical procedure is qualified to run the procedure. The transferring unit can involve the receiving unit in an interlaboratory covalidation, including them as a part of the validation team at the transferring unit and thereby obtaining data for the assessment of reproducibility. This assessment is made using a preapproved transfer or validation protocol that provides the details of the procedure, the samples to be used, and the predetermined acceptance criteria. The general chapter Validation of Compendial Procedures 1225 provides useful guidance about which characteristics are appropriate for testing.
Revalidation or partial revalidation is another acceptable approach for transfer of a validated procedure. Those characteristics described in 1225, which are anticipated to be affected by the transfer, should be addressed.
The conventional TAP may be omitted under certain circumstances. In such instances, the receiving unit is considered to be qualified to use the analytical test procedures without comparison and generation of interlaboratory comparative data. The following examples give some scenarios that may justify the waiver of TAP:
If eligible for transfer waiver, the receiving receiving unit should document it with appropriate justifications.
ELEMENTS RECOMMENDED FOR THE TRANSFER OF ANAYTICAL PROCEDURES
Several elements, many of which may be interrelated, are recommended for a successful TAP. When appropriate and as a part of pretransfer activities, the transferring unit should provide training to the receiving unit, or the receiving unit should run the procedures and identify any issues that may need to be resolved before the transfer protocol is signed. Training should be documented.
The transferring unit, often the development unit, is responsible for providing the analytical procedure, the reference standards, the validation reports, and any necessary documents, as well as for providing the necessary training and assistance to the receiving unit as needed during the transfer. The receiving unit may be a quality control unit, another intracompany facility, or another company such as a contract research organization. The receiving unit provides qualified staff or properly trains the staff before the transfer, ensures that the facilities and instrumentation are properly calibrated and qualified as needed, and verifies that the laboratory systems are in compliance with applicable regulations and in-house general laboratory procedures. Both the transferring and receiving units should compare and discuss data as well as any deviations from the protocol. This discussion addresses any necessary corrections or updates to the final report and the analytical procedure as necessary to reproduce the procedure.
A single lot of the article may be used for the transfer, because the aim of the transfer is not related to the manufacturing process but rather to the evaluation of the analytical procedures performance at the receiving site.
A well-designed protocol should be discussed, agreed upon, and documented before the implementation of TAP. The document expresses a consensus between the parties, indicating an intended execution strategy, and should include each partys requirements and responsibilities. It is recommended that the protocol contain the following topics as appropriate: objective, scope, responsibilities of the transferring and receiving units, materials and instruments that will be used, analytical procedure, experimental design, and acceptance criteria for all tests and/or methods included in the transfer. Based on the validation data and procedural knowledge, the transfer protocol should identify the specific analytical performance characteristics (see 1225 and 1226) that will be evaluated and the analysis that will be used to evaluate acceptable outcomes of the transfer exercise.
The transfer acceptance criteria, which are based on method performance and historical data from stability and release results, if available, should include the comparability criteria for results from all study sites. These criteria may be derived using statistical principles based on the difference between mean values and established ranges and should be accompanied by an estimation of the variability (e.g., percent relative standard deviation [%RSD] for each site), particularly for the intermediate precision %RSD of the receiving unit and/or a statistical method for the comparison of the means for assay and content uniformity tests. In instances of impurity testing, where precision may be poorer such as in the case of trace impurities, a simple descriptive approach can be used. Dissolution can be evaluated by a comparison of the dissolution profiles using the similarity factor f2 or by comparison of data at the specified time points. The laboratories should provide appropriate rationale for any analytical performance characteristic not included. The materials, reference standards, samples, instruments, and instrumental parameters that will be used should be described.
It is recommended that expired, aged, or spiked samples be carefully chosen and evaluated to identify potential problems related to differences in sample preparation equipment and to evaluate the impact of potential aberrant results on marketed products. The documentation section of the transfer protocol may include report forms to ensure consistent recording of results and to improve consistency between laboratories. This section should contain the additional information that will be included with the results, such as example chromatograms and spectra, along with additional information in case of a deviation. The protocol should also explain how any deviation from the acceptance criteria will be managed. Any changes to the transfer protocol following failure of an acceptance criterion must be approved before collection of additional data.
THE ANALYTICAL PROCEDURE
The procedure should be written with sufficient detail and explicit instructions, so that a trained analyst can perform it without difficulty. A pretransfer meeting between the transferring and receiving units is helpful to clarify any issues and answer any questions regarding the transfer process. If complete or partial validation data exist, they should be available to the receiving unit, along with any technical details required to perform the test in question. In some cases it may be useful for the individuals who were involved with the initial development or validation to be on site during the transfer. The number of replicates and injection sequences in the case of liquid or gas chromatography should be clearly expressed, and, in the case of dissolution testing, the number of individual dosage units should be stipulated.
When the TAP is successfully completed, the receiving unit should prepare a transfer report that describes the results obtained in relation to the acceptance criteria, along with conclusions that confirm that the receiving unit is now qualified to run the procedure. Any deviations should be thoroughly documented and justified. If the acceptance criteria are met, the TAP is successful and the receiving unit is qualified to run the procedure. Otherwise, the procedure cannot be considered transferred until effective remedial steps are adopted in order to meet the acceptance criteria. An investigation may provide guidance about the nature and extent of the remedial steps, which may vary from further training and clarification to more complex approaches, depending on the particular procedure.USP35
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