Transfer Methods

When a separation is transferred to a column with a different inner diameter d, the flow rate F needs to be adapted in order to get identical retention times  

The only parameter to be considered is the ratio of the squared diameters. If the particle diameter d is altered too, then the flow rate should also be corrected with regard to the van Deemter curve because the transferred separation should run at the same reduced velocity v as before (preferably at the optimum). Smaller particles allow faster runs because v is proportional to their diameter in Section 8.5 we saw that 

If column and particle diameters are changed simultaneously the following equation yields the necessary change in flow rate  

The old method required a 4.6 mm column with 5 )Xm packing, used at a flow rate of 

5 ml min . Now a 2.0 mm column with 3 (tm packing is planned to be used. Which flow rate is needed  

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The responsibihties of the quahty assurance unit generally fall into two categories support for or improvement of the existing quahty system (31). The support activities of QA often include employee training, quahty system documentation, method vahdation and method transfer, audit, and customer complaints. 

Method Transfer. Method transfer involves the implementation of a method developed at another laboratory. Typically the method is prepared in an analytical R D department and then transferred to quahty control at the plant. Method transfer demonstrates that the test method, as mn at the plant, provides results equivalent to that reported in R D. A vaUdated method containing documentation eases the transfer process by providing the recipient lab with detailed method instmctions, accuracy and precision, limits of detection, quantitation, and linearity. 

Encapsulation of semiconductors. The usual material is epoxide resin (see Chapter 26) and the preferred method transfer moulding. It has been estimated that by 1980 annual production of such encapsulated parts exceeded 10 billion units. 

Van Nederkassel, A. M., Aerts, A., Dierick, A., Massart, D. L, Vander Heyden, Y. Fast separations on monolithic silica columns method transfer, robusmess and column ageing for some case smdies. /. Pharm. Biomed. Anal. 2003, 32, 233-249. 

Chemical precipitation/coagulation methods transfer the target substances (mainly metals) in solution into a solid phase. Many heavy metal hydroxides and sulfides have very low solubility (within a certain pH range) and are therefore insoluble. The metal sulfides have significantly lower solubility than their hydroxide counterparts over a broad range of pH.26 Precipitation/coagulation is also applicable for removing certain anionic species such as phosphate, sulfate, and fluoride. 

Section 5.2 introduced the subject of metrological traceability and calibration and the use of pure chemical substances and reference materials in achieving trace-ability. Reference materials are used as transfer standards. Transfer standards are used when it is not possible to have access to national or international standards or primary methods. Transfer standards carry measurement values and can be... 

Short column with small particles (2 to 3 flm) Use of conventional HPLC with minimal or no equipment modifications Greatest diversity of column chemistry Easy method transfer Best reproducibility and ruggedness... 

Short column with STM particles (< 400 bar) Potential use with conventional HPLC Significant reduction in analysis time Easy method transfer Higher efficiency Relatively good variety of column chemistry Two-fold increase in speed for SIM... 

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. 

For any new excipients, APIs or drug products (where new does not necessarily mean novel, but new to the receiving site) there are additional testing criteria, e.g. supplier audits, third-party contract laboratory audits, analytical method transfers, sample management/tracking, etc. For those key excipients, where there is on-site historical experience, it still behoves both parties to check whether the local grade/supplier used by the CMO is equivalent to that used by the supplier (Worsham, 2010). There are many examples of differences in excipient physical properties, e.g. particle size, which have been attributed to different excipient sources that could ultimately impact on the performance of those excipients in formulated products (Frattini and Simioni, 1984 Dansereau and Peck, 1987 Phadke et al., 1994 Lin and Peck, 1994). 

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.). ... 

Table 1. Pre-defined Analytical Method Transfer Acceptance Criteria for API and Drug Product (adapted from Agut et al., 2011)...

Figure 1. Structure of method transfer for Case Study 2 showing the number of replicates per site required for a power of 95% and a pre-defined acceptance criteria (9) of 4.0.

In these cases, it is not uncommon for Targe numbers (200-400) of methods to be simultaneously transferred, far exceeding the scope of traditional analytical transfer. (Raska et al., 2010). The resource implications of these traditional method transfer approaches (given the requirements for... 

Raska et al. (2010) introduced the concept of a risk based method transfer process (which is similar to USP transfer waiver approach). This involves assessing the risk that the sites involved in method transfer could generate non-comparable data either at transfer or subsequently thereafter and assessing the probability of that risk occurring. Thus with constrained resource it is more sensible to focus that resource on either avoidance or mitigation of high risk transfers, whilst accepting the limited risk inherent with a low probability risk scenario. 

On the basis of this risk assessment the transfer strategy is evaluated. For those transfers with lowest risk, method transfer will be limited to simple knowledge transfer as there is no added value in performing any practical transfer exercises i.e. transfer waiver. 

Gradient HPLC No Complex High Receiving site has no familiarity of the compound or method. Transferring site have indicated that resolution of two impurities is critical. Comparable performance... 

This is a similar approach to that articulated by USP, where transfer waivers can be utilised if the receiving site is considered to be qualified to use the method(s), without comparison or generation of inter-laboratory comparative data. The different types of testing associated with the different types of method transfer, together with acceptance criteria are summarised in Table 5 (Raska et al., 2010). 

Table 5. Typical Analytical Testing and Acceptance Criteria for Different Types of Method Transfer (adapted from Raska et al., 2012)...

De Fontenay, G. Analytical method transfer New descriptive approach for acceptance criteria definition. J. Pharm. Biomed. Anal., 46, 2008, 104-112. 

Raska, C. S., Bennett, T. S., Goodberlet, S. A. Risk based analytical method transfer Application to large multi-product transfers. Anal. Chem., 82, 2010, 5932-5936. 

Scypinski, S., Roberts, D., Oates, M., Etse, J. Pharmaceutical research and manufacturers association acceptable anbalytical practice for analytical method transfer. Pharm.Technol., 28, 2004, 84-88.2004... 

Manufacturers publish their product s performance characteristics as specifications, which are often used by the customer for comparison during the selection process. Table 1 shows the specifications of an Agilent 1100 Series Quaternary Pump, which is quite representative of other high-end analytical pumps. Note pulsation is particularly detrimental to the performance of flow-sensitive detectors (e.g., mass spectrometer, refractive index detector). Differences in dwell volumes and composition accuracy between HPLC systems might cause problems during method transfers. 

While method transfer remains a formal process to demonstrate equal method performance between the development and the application laboratories, the continuous involvement of the customers during method development greatly facilitates the process. The final method is not new for the application laboratories at the time of transfer and the transfer process is not the primary challenge of the method. 

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