Analytical method transfer protocol

Since the aim of the protocol is to ensure the mitigation of problems, the essential elements of the protocol consists of sections that include (a) an Introduction, (b) treatment and disposition of data, (c) types of methods being transferred, (d) materials, reference standards, and reagents being used, (e) recommended type of equipment, (f) sample handling, (g) predetermined acceptance criteria, and (h) an Acknowledgment section. An example of a typical table of contents (TOC) of an analytical methods transfer protocol is discussed in Table 16-2. 

The process of method transfer must follow a method-transfer protocol which defines the experiments and acceptance criteria necessary to demonstrate the analysts proficiency, equipment s suitability, and true ruggedness of the analytical method. If we assume that any quality analytical laboratory has proficient analysts who operate suitable equipment, then the method transfer stands as an ongoing means to substantiate the suitability of the original method validation. Example 5 contains an example of a method-transfer protocol for a chromatographic procedure. 

The methods transfer protocol is the main driver that governs the conduct of the experiments and ensures that assessment of results generated is not unduly influenced by biases due to either (a) the analytical method or (b) inherent batch-to-batch variability of the active pharmaceutical ingredient or pharmaceutical dosage form. The methods transfer protocol establishes the predetermined acceptance criteria by which results will be judged to have either passed or failed the methods transfer. The criteria for assessment of success or failure contained in the methods transfer protocol is achieved through an iterative... 

This chapter highlights the important aspects of the analytical transfer processes as they relate to process, compliance, analytical data, and documentation. Types of method transfers and the timeline of transfer activities are discussed. The risk assessment prior to initiation of transfer activities is also described. The chapter describes content and utility of the transfer protocol and final report, as well as documents that govern analytical method transfers (i.e., SOPs and master plan). The importance of selecting appropriate method transfer acceptance criteria and use of statistical methods to evaluate results are described. The significance of the inclusion of an adequate level of detail in the methods, protocol(s), and other documents cannot be overly stressed. Last of all, the process for transfer of technical ownership of the analytical methods is discussed. Other chapters in this text should be consulted for elaboration on the various important facets of technical transfer, including method development, method validation, documentation, and stability. 

Partial or complete re-validation is another precedented approach to method transfer. Those variables described in method validation guidance documents (ICH Q2B, 1996 USP, 2012c) that are likely to be impacted by method transfer, should be assessed and documented (transfer or validation protocol). Agut et al. (2011) indicated that, in the changing industry model with the increased outsourcing of R and D activities (alliances, outsourcing, etc.), method re-validation may constitute, in some cases, an efficient approach when the transfer is performed from the Analytical Development Laboratory of an external partner who does not share exactly the same environment (validation standards, analytical culture or traditions , equipment, etc.). ... 

Eventually the point will be reached at which the development of a product is complete the formulation is finalized, the equipment has been selected, the analytical methods are validated, the development transfer report has been issued, and the Preapproval Inspection (PAI) is anticipated. Now is the time to consider validation of both the manufacturing and cleaning processes. Although some process validation may have also been completed or a process validation protocol may have been prepared and approved, it is likely that very little has been finished that would enable us to state that the cleaning process is fully validated. 

However, the problem of analytical transferability remains. The optimal, but usually very unrealistic, situation assumes that the analytical methods, including their calibration and quality assurance, are identical in the laboratories. A more pragmatic approach involves standardization of analytical protocols, common calibration, design of a sufficiently efficient external quality control scheme, and the use of mathematical transfer functions if the results still are not directly comparable. 

Method Transfer. Method transfer is the process of collecting documented evidence that the receiving laboratories (customers) are capable of running the method. This is based on analytical experiments showing the equivalence of the analytical results obtained in the development and receiving laboratories. These experiments are set up according to the transfer protocol that should contain preapproved acceptance criteria. 

The transfer protocol must include suitable acceptance criteria relevant to the tests and specific dosage forms. It should be noted that giving hard and fast specifications for such criteria is not possible. There would surely be more exceptions than norms. At the recent PhRMA ARDSC workshop on method transfer, individuals gave answers that spanned a variety of approaches. Table 1 summarizes some of the responses to questions about acceptance criteria for analytical methods. 

In the case that qualification is included in the method transfer, the contract should contain an agreed list of all analytical characteristics to be addressed. Specific criteria for success and failure of qualification experiments should be agreed upon and described in a protocol. Responsibility for the cost of experimental repeats that are caused by suspicious Vaberrant/anomalous results should be clarified. The criteria for defining anomalous results and how they would trigger repeat analysis should be well documented. 

The analytical procedures which have been developed especially to control and to monitor the efficacy of each bio-pro-cess step need also to be defined and to be transferred (see Part VII, Chapter 1). Protocols must be written that describe each in-process-control (IPC) step from the analysis of the WCB cell line, the (on-line) monitoring of the cultivation to the analysis of the purification need to be established. Due to the complexity of bioprocesses, the need for good biochemical analytical methods and capabilities cannot be overemphasized. 

At the conclusion of development, when methods are locked, it is becoming more common for the analysts to ask the quality unit for input and comment on the proposed method package before final validation. Such a method test drive can avoid problems with the formal transfer taking place later. This process has been termed an analytical method evaluation ring test (AMERT) by Crowther and associates and was presented and described elsewhere. In brief, this process allows the quality unit to make comments and suggestions to their R D colleagues before the final validation of the method. It is also becoming more common for the quality unit to approve method validation protocols. This provides the quality unit with an opportunity to ensure that the method meets the performance expectations to enable routine use in the quality environment. In some cases, covalidation by the R D and Quality Units (discussed below) replaces formal method transfer. Thus, the frequently seen throw the method over the fence syndrome is avoided. 

Carryover is defined as the unintended transfer of a quantity of analyte or reagent by an analytical system from one specimen reaction into a subsequent one. Because carryover introduces error into the analytical results from the subsequent reaction, it should be minimized. Details for determining the extent of analyte carryover are described in the NCCLS document EP 10-A2, Preliminary Evaluation of Quantitative Clinical Laboratory Methods Approved Guideline Second Edition. More elaborate protocols are required to evaluate the extent of reagent carryover. Most... 

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