- The objective of this exercise is to qualify XYZ Limited, to use the analytical test method for the testing of Ezetimibe. The Ezetimibe test method will be used for this testing.
- For this exercise, Quality Control, ABC Ltd. will be considered as the originating or transferring laboratory (OL) and XYZ Limited will be considered as the receiving site (RL).
- The method transfer protocol is designed to demonstrate that the receiving site is qualified to perform the test procedures. The selected procedures and the acceptance criteria are included in this document. The agreement will be obtained between the originating and receiving sites prior to the execution of any deviations from this protocol or the test procedures. Deviations will be formally documented and explained in the analytical method transfer report generated upon completion of laboratory testing. Results generated as a part of the routine release will be reported as the results for ABC Ltd.
- After completion of method transfer activity, final report will be compiled and prepared by receiving laboratory. The analytical method transfer report will be approved if it is acceptable by both RL and OL.
- The exhibit batches of Ezetimibe and Simvastatin Tablets were manufactured by ABC Limited. This product is now being transferred from ABC Limited to XYZ Limited. The Ezetimibe API will be used in the manufacturing of Ezetimibe and Simvastatin Tablets. The methodology adopted for transfer of analytical methods will be 'Indirect Transfer'.
- This protocol represents the consensus reached between the two sites for this method transfer. Assay, Impurity Profile, Determination of EZT Des-Fluoro-A and Des-Fluoro-B impurities, Residual solvents tests will be performed as part of the method transfer of this Raw Material. Problems and questions that are by the receiving laboratory during testing will be resolved through with the originating laboratory.
- Two API lots of Ezetimibe will be tested. Testing performed by each laboratory will be within 30 days. Testing that extends beyond 30 days will be explained in final report. The following table summarizes the method transfer testing to be for Ezetimibe.
|
Test |
Method Transfer Testing Required (Yes/No) |
Comment |
|
Description |
No |
No
special technique required |
|
Identification
by IR |
No |
No
special technique required |
|
Identification
by HPLC |
No |
No
special technique required |
|
Water
(by KF) |
No |
No
special technique required |
|
Heavy
metals |
No |
No
special technique required |
|
Specific
rotation (25℃)
(3% in methanol) |
No |
No
special technique required |
|
Sulphated
ash |
No |
No
special technique required |
|
Assay
(By HPLC) (on anhydrous basis) |
Yes |
Requirement |
|
Impurity
Profile by HPLC |
Yes |
Requirement |
|
Determination
of EZT Des-Fluoro-A and EZT Des-Fluoro-B impurities by HPLC |
Yes |
Requirement |
|
Residual
solvents (by GC) |
Yes |
Requirement |
|
Particle
size distribution (by Malvern D90 |
No |
Analytical
method validation will be performed at XYZ Ltd. |
|
Test |
Receiving Laboratory No. of replicate analysis |
Acceptance criteria for individual Laboratory results |
Acceptance criteria tor Method Transfer |
|
Assay (By HPLC) (On anhydrous Basis) |
6 |
98.0% to 102.0% |
Difference
between the average results from the two laboratories should not be more than
2.0 % (absolute). The RSD of the
% Assay obtained from six sample preparations at receiving laboratory should
be NMT 2.0%. |
|
Impurity Profile
by HPLC |
2 |
a. 3'R, 3R, 4S isomer- NMT 0.15% w/w
b. EZT-Cyclic ether- NMT 0.15% w/w
c. EZT—Keto- NMT 0.15% w/w
d. Any other unspecified impurity – NMT 0.10% w/w
e. Total Impurities (Including EZT Des Fluoro-A
and EZT Des Fluoro-B except 3'R,3R,4S isomer)- NMT 1.0% w/w |
Known
Impurities 1. If either lab has (or both labs
have) the result greater than 0.1 % for given impurity, the differences
between each result for a given impurity/degradant from the OL and RL must
not be more than the largest of 25 % of the specification or 0.05 %(absolute) 2. If both labs obtain a result of 0.1%
or less for a given impurity/degradant, the labs are considered comparable
with regard to the determination of that impurity/degradant, regardless of
the numerical difference between the results when additional sufficient
figures are considered. However, the impurity must be detected by both labs.
Maximum
unknown impurity: 1. Identification of a different
maximum unknown impurity by both labs is acceptable if the maximum unknown
impurity identified by the OL is present in the receiving labs chromatogram(s)
and the maximum unknown identified by the RL is present in the OL chromatograms. 2. For those cases where both labs
identify the same maximum unknown impurity, if either lab has (or both labs
have) the maximum impurity greater than 0.1%, the difference between each
result from the originating and receiving labs must not be more than the larger
of 25% of the specification or 0.05% (absolute). 3. If both labs obtain a result of
0.1%, or less, for the maximum unknown impurity, the labs are considered
comparable, regardless of the numerical difference between the results, when
additional significant figures are considered, and regardless of which unknown
peak was identified as the maximum unknown impurity.
Total
impurities: The difference between each calculated total (sum) of impurities / degradants (known and / or unknown) from the originating and receiving labs must not be more than the larger of 25% of the specification or 0.1% (absolute). Test solutions
at both laboratories should exhibit a similar impurity profile as determined
by visual inspection of chromatograms and evaluation of quantitative results. |
|
Determination of EZT Des-Fluoro-A and EZT Des-Fluoro-B impurities byHPLC |
2 |
a.
EZT Des-Fluoro-A NMT 0.15% b.
EZT Des-Fluoro-B NMT 0.15% |
Known
Impurities 1. If either lab has (or both labs have)
the result greater than 0.1 % for given impurity, the differences between
each result for a given impurity/degradant from the OL and RL must not be
more than the largest of 25 % of the specification or 0.05 %(absolute) 2. If both labs obtain a result of
0.1% or less for a given impurity/degradant, the labs are considered
comparable with regard to the determination of that impurity/degradant, regardless
of the numerical difference between the results when additional sufficient
figures are considered. However, the impurity must be detected by both labs. |
|
Residual solvents (By GC) |
2 |
a.
Methanol: NMT 3000 ppm b.
Acetone: NMT 5000 ppm c.
2-Propanol: NMT 5000 d. Methylene chloride: NMT 600 ppm e.
Toluene: NMT 890 ppm |
1.
The difference between each result
for a given residual solvent from the OL and RL must be less than or equal to
the larger of 25% of the specification, or LOQ of the method. 2. If RL does not detect a given
residual solvent ppm and the OL obtains a result less than or equal to the
larger of 25% of the specification, or LOQ of the method for same residual
solvent, the observed difference between the two labs is acceptable. 3. If the RL detects a residual solvent
and OL does not, the difference should be evaluated in regards to the
reporting level to determine further corrective actions, as necessary. 4. If both labs do not detect a given residual solvent, the labs are considered comparable with regard to that residual solvent. |
The data generated from the method transfer will only be used within the scope of the purpose of this protocol and not used to re-evaluate the release status of the lot or to extend their re-test period.
If any OOS value(s) are observed, an investigation will be conducted. This investigation will include typical Phase 1 OOS investigative steps as well as any additional testing agreed upon between the originating and receiving sites and will be documented in the final report.
Upon successful completion of this protocol, the Quality Control department of XYZ Ltd. will be qualified to execute these methods.
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