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Guidelines & Codes Guideline for the transfer of analytical test procedures

10 August 2007

Test method validation overview:

Medsafe expects that all test procedures should be validated in line with ICH guidance as part of method development and validation. This is also a GMP expectation.

Medsafe expects that test method validation reports should be provided as part of a medicine application.

Verification of a test method's acceptability should be performed for all methods even those listed in pharmacopoeial monographs. Verification of a pharmacopoeial method does not necessarily mean full method validation and in general only a cursory review will be made by an evaluator. In addition, partial validation of a pharmacopoeial method may be required under other circumstances, i.e. where a different route of synthesis is employed, or to demonstrate non-interference from a product's excipients.

Regardless, Medsafe does expect that a testing site would verify the acceptability of any test method, if it is to be used on an on-going basis.

When a test method is transferred to an alternative testing site Medsafe requires evidence that the test procedure is functioning correctly. This requirement applies to new medicine applications and changed medicine notifications. Typically this is provided in the form of a test method transfer protocol and report. The protocol and report should be complete and authorised. Meeting system suitability criteria is not considered sufficient evidence of acceptability, as this does not address the consistency of results between sites.

Medsafe's transfer expectations:

Method transfer is the process that qualifies a laboratory to use a certain analytical test procedure developed in another laboratory.

The analytical procedure at the Sending site must be both validated and approved.

The new testing facility should have recent evidence of GMP approval (within the past 2 years).

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Transfer of the test methods is the joint responsibility of the Sending and Receiving sites and this should be reflected in the transfer protocol.

The Transfer protocol/report should describe the objective, scope, responsibilities, procedure and experimental design and state the acceptance criteria for all method procedure transfers. Acceptance criteria should include the comparability of results from either site.

The Transfer report should describe results obtained in relation to the acceptance criteria, contain conclusions and confirm if the Receiving unit is now qualified. Any deviations should be discussed and justified.

The transfer report preferably should include the following information to demonstrate equivalency of qualification batches (although parameters are procedure dependant).

1. Assay

Parallel sample testing of three batches (in triplicate) with quantifiable amounts of impurities, ideally performed by two operators at each site.

Acceptance criteria:

System suitability criteria should be met.

The determined means and the variability of obtained results should be compared. This can be established by direct comparison of results, or statistically (95% confidence level, with an allowable 2% difference in means). In direct comparison a difference of three percent (3%) in means and two percent variability (<2% RSD) would typically be considered acceptable.

For instance, if three batches are tested in triplicate by two analysts at each site (site A and site B) this affords 18 results from each site (n=18). The difference in the means obtained from Lab A (n=18) and Lab B (n=18) should be less than 3%. The RSD of Lab A results (n=18) and the RSD of Lab B results (n=18) should be less than 2%.

2. Content uniformity

The method may be equivalent to assay method and therefore further validation is not required. Otherwise it is suggested that two analysts at each laboratory analyse at least one sample lot. For products with multiple strengths bracketing may be appropriate.

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Acceptance criteria:

The determined means and the variability of obtained results should be compared. This can be established by direct comparison of results, or statistically (2 one-sided T tests, 95% confidence level, with an allowable 3% difference in means). In direct comparison a difference of three percent (3%) in means and two percent variability (<2% RSD) would typically be considered acceptable.

3. Impurities/degradation products/residual solvents

It is suggested that two analysts at each laboratory analyse three sample lots in duplicate on different days.

Samples should be the same, or have similar characteristics of: age, homogeneity, packaging and storage. Spiked samples may be used if samples do not contain impurities above the reporting limit.

The Limit of Quantification (LOQ) and response factors for substances whose amounts are calculated from response relative to drug peak should be confirmed at the Receiving facility.

Accuracy and precision should be generated at the specification limit.

Chromatograms from both laboratories should be compared to ensure a similar impurity profile.

Acceptance criteria

Results must meet release specifications. Comparison of means and variability of results should be included, but will depend on the levels of impurities to be determined. For moderately high levels of impurities the difference in values should typically be NMT 10% at the 95% confidence level. For impurities at lower levels, but above reporting limits, the acceptance criteria may be based on an absolute difference of the means, i.e. the Receiving facility must obtain values within ± 0.05% of the mean value of the Sending facility.

4. Dissolution

For immediate release tablets, or capsules a single six unit dissolution test procedure should be used. For extended release tablets, or capsules a twelve unit dissolution procedure should be used. A twelve unit procedure should also be used if the Receiving unit does not routinely perform this kind of testing. For products with multiple strengths bracketing may be appropriate.

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Results must meet dissolution specifications. Comparison of profiles generated at both sites should be comparable. This can be assessed statistically e.g. F2 statistical comparison, comparison of values at Q timepoints. Alternatively, the acceptance criteria may be based on an absolute difference of the means, i.e. the Receiving unit should obtain values within ± 5% of the mean value of the Sending unit.

5. Identification

Identification tests can vary widely in complexity and techniques used. One determination is usually sufficient to demonstrate equivalence:

ID by HPLC/GC: confirmation of peak retention time ID by interpretation of UV/IR spectra ensure sample preparation and

instrumentation can produce equivalent results ID by chemical reactions or physical property method need not be

qualified as long as technique is well established and staff trained

6. Automated methods

Transfer should focus the ability of equipment to generate equivalent and reproducible results. Critical sample preparation parameters include: weighing, dilutions, dispersing/mixing, filtering/centrifugation and injection/dispensing

Note: Instrumentation used for analyses should be validated and equivalent to that used at both sites. Although instrument qualification (i.e. demonstrated fit for intended purpose) forms part of GMP and if both sites have GMP then 'some' assurance is given. However, this does not validate a specific method on different equipment, e.g. the linearity range for a HPLC detector performing a specific assay should be equivalent for both instruments at the sending and receiving sites. This is particularly important for impurities/degradation product/residual solvent assays (and cleaning validation). Therefore a check on linearity is recommended as well as assay repeatability / accuracy / precision that should demonstrate linearity down to LOQ level at receiving site.

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7. Microbiological testing

On-site validation used for transferring qualitative and quantitative limit tests such as: sterility, antimicrobial effectiveness and microbial contamination. Both Sending and Receiving Units should use identical techniques and materials. Validation to be performed in triplicate

The Sending unit does have responsibilities during the transfer, e.g. creating transfer protocol, training, acceptance criteria. Both the Sending and Receiving Units are jointly responsible for issuing the final report.

http://www.medsafe.govt.nz/regulatory/Guideline/AnalyticalTest.asp