Method transfer issues

Method transfer issues aside, HPLC offers less separation efficiency than observed in other separation techniques such as capillary electrophoresis (CE), GC, and SFC. In fact, it is typically difficult to separate more than 15-20 compounds in a single HPLC run, necessitating the use of two or more runs for complex samples. As a result, other techniques continue to receive considerable interest. It is, however, safe to say that there are no emerging techniques that will significantly reduce the utilization of HPLC in the short term. 

A thorough understanding of the injection system and tight calibration tolerances are what is required to avoid method transfer issues due to the injector. 

To minimize unacceptable interruptions in highly regulated work flows, the smooth transfer of legacy methods from conventional to fast LC methods (via geometric transfer or method redevelopment) is a critical issue for implementing fast LC for pharmaceutical applications. Method transfer from HPLC to UPLC is discussed in detail in the literature.52,53 Moreover, method transfer software that provides parameter conversion between UHPLC and conventional HPLC is available from instrument vendors. 

Ideally, an on-line analyzer will be calibrated before it is installed in the process. It may be possible to accomplish this by calibrating it off-line with process grab samples and/or synthetic samples. It may be possible to install the analyzer in a lab-scale reactor, or in a semi-works or pilot plant. It may be possible to transfer to the on-line analyzer a method developed on an off-line analyzer or on another on-line analyzer (e.g. at a different plant site). However, sometimes none of these are possible and the analyzer will need to be calibrated on-line. The challenges of on-line model development (calibration) and validation, as well as approaches to dealing with them, are discussed below. For information related to calibration transfer issues, please see Chapter 12 of this book. 

Another issue is that of transferability of the calibration model among instruments. This has been a significant obstacle to more widespread use of NIR methods. Transferability is especially important to multisite facilities, because it is needed to avoid time-consuming recalibration procedures. Calibration errors may occur among instruments because of slight differences in instrument response, especially if full-spectrum multivariate models are used. Shenk and Westerhaus addressed the problem and proposed a standardization algorithm, which was modified by others. ... 

The designated laboratory is responsible for issuing and following SOPs that define their criteria for accepting an analytical method. The method transfer report includes data generated in accordance with those SOPs. 

The sending and receiving labs are jointly responsible for issuing the final report relating to acceptability of the method transfer. 

If method transfers between partners are happening frequently, the design of the protocol and follow-up report may follow a routine format and be relatively minimal. However, for a first transfer between parties, such protocols and reports will be valuable for evaluating the efficiency of the process and potential issues that may occur during method transfer and will help alleviate problems in future method transfer projects. 

As part of the process of method transfer and troubleshooting methods, the production of some form of checklist or aide-memoire of historical issues should be... 

There is no requirement as to whether separate protocols are written for each test or all tests to be transferred are included in the same protocol. One protocol can be effectively used and will likely be more efficient in that many of the general points (e.g., samples to be used, OOS procedures, etc) will not need to be repeated in several protocols and review and approval will be streamlined. However, a difficult issue with one test that needs substantial investigation and problem resolution could hold up approval of the entire method transfer and delay testing by the receiving lab which could negatively impact the overall transfer team s timeline. 

Novel mechanical or bubble-induced flow designs are not trendsetters nor do they solve many of the and gas-liquid mass transfer problems. Miniaturized reactors, however, could decrease process design and implementation signiflcantly. The numbering-up method for these reactors reduces the time and amount of work necessary for scale-up the process is determined for one experimental unit and then the unit is copied multiple times. The rest of the work is spent on the industrial and economic problems rather than hydrodynamic and gas-liquid mass transfer issues commonly found in scale-up issues for other bioreactors. 

The transfer protocol must include suitable acceptance criteria relevant to the tests and specific dosage forms. Selection of the acceptance criteria is a critical element of the method transfer. Criteria that are too tight could lead to rejection of acceptable results, thereby causing delays in the transfer process. On the other hand, if criteria are too loose, the receiving laboratory may pass the transfer but be unable to appropriately test the actual product s), leading to poor decision making with respect to approval of marketed product. Of the two risks, the latter is more critical since, approving a laboratory that is truly not qualified could affect marketed product safety and/or efficacy and ultimately patient safety. This could lead to recalls and severe quality and compliance issues. 

The old adage if it isn t written, it isn t done certainly applies to analytical transfer. The expectation of the health authorities is that a final report will be issued documenting the analytical method transfer process and associated results. Two types of records are subject to PAI Primary records that demonstrate safety, purity, and efficacy of the drug (e.g., batch records, test data) and supporting documentation such as equipment verification records, change control and development and validation reports that demonstrate the cGMP compliance status of the facility. The method transfer report is categorized vmder the latter set of documentation. 

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