- 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. |
