2.2.1.S.4.1 Specification(s)
The specifications, the tests used as well as their acceptance criteria should be specified for the batch(es) of drug substance(s) used in the clinical trial. Tests for identity, impurities and assay are mandatory. Upper limits, taking safety considerations into account, should be set for the impurities. They may need to be reviewed and adjusted during further development. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. If ICH or Ph.Eur. requirements are met, no further limit justification is expected.
Where specifications are set for (potential) mutagenic impurities, the guidance given in relevant guidelines should be taken into consideration.
The microbiological quality for drug substances used in aseptically manufactured products should be specified.
For substances which comply with United States Pharmacopoeia, European Pharmacopoeia, International Pharmacopoeia or the British Pharmacopoeia, reference to the relevant monograph will be sufficient, provided its suitability to adequately control the quality of the active substance from the specific source has been demonstrated. The specification should, however, include acceptance criteria for any relevant residual solvent or catalyst.
For radiopharmaceutical drug substances, the level of radio-nuclidic impurities, radiochemical impurities as well as the chemical impurities should be addressed.
Additional information for phase II and phase III clinical trials
Specifications and acceptance criteria set for previous phase I or phase II trials should be reviewed and, where appropriate, adjusted to the current stage of development.
2.2.1.S.4.2 Analytical procedures
The analytical methods used for the drug substance should be described for all tests included in the specification (e.g. reverse-phase-HPLC-UV, potentiometric titration, head-space-GC-FID, etc.). It is not necessary to provide a detailed description of the analytical procedures (see definition of analytical methods vs. analytical procedures in chapter 1.5 General Considerations).
For radiopharmaceutical substances, the method used for the measurement of radioactivity should be described.
For substances which comply with a monograph of United States Pharmacopoeia, European Pharmacopoeia, International Pharmacopoeia or the British Pharmacopoeia, reference to the relevant monograph will be sufficient.
2.2.1.S.4.3 Validation of analytical procedures
Information for phase I clinical trials
The suitability of the analytical methods used should be confirmed. The acceptance limits (e.g. acceptance limits for the determination of the content of impurities, where relevant) and the parameters (specificity, linearity, range, accuracy, precision, quantification and detection limit, as appropriate) for performing validation of the analytical methods should be presented in a tabulated form.
Information for phase II and III clinical trials
The suitability of the analytical methods used should be demonstrated. A tabulated summary of the results of the validation carried out should be provided (e.g. results or values found for specificity, linearity, range, accuracy, precision, quantification and detection limit, as appropriate). It is not necessary to provide a full validation report.
For substances which comply with a monograph of the United States Pharmacopoeia, European Pharmacopoeia, International Pharmacopoeia or the British Pharmacopoeia, reference to the relevant monograph will be sufficient.
In case of major changes in analytical methods, cross-validation data should be presented especially for specified unknown impurities identified by their relative retention time (RRT) unless otherwise justified. A re-analysis of preclinical batch with the new method should also be considered, where relevant.
2.2.1.S.4.4 Batch analyses
Batch results in a tabulated form or certificate of analysis for batches to be used in the current clinical trial, for batches used in the non-clinical studies and, where needed, for representative batches used in previous clinical trials (e.g. in case the comparable quality of batches manufactured by previous processes has to be demonstrated), should be supplied. If data are not available for the batches to be used in the current clinical trial, data for representative batches for each drug substance manufacturer may be submitted instead. The batch number, batch size, manufacturing site, manufacturing date, control methods, and the test results should be listed.
The manufacturing process used for each batch should be assigned as stated under 2.2.1.S.2.2.
2.2.1.S.4.4 Justification of specification(s)
For substances for which reference to a pharmacopoeial monograph listed under 2.2.1.S.4.1 cannot be made, a brief justification of the specifications and acceptance criteria for impurities and any other parameters which may be relevant to the performance of the drug product should be provided based on safety and toxicity data, as well as the methods used for the control of impurities. The solvents and catalysts used in the synthesis should be taken into consideration.