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