19. APIs FOR USE IN CLINICAL TRIALS

19. APIs FOR USE IN CLINICAL TRIALS
19.1 General
19.10 Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new API for investigational use during its development. Section 19 provides specific guidance unique to these circumstances.
19.11 The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.
19.2 Quality
19.20 Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.
19.21 A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.
19.22 Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.
19.23 Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.
19.24 Process and quality problems should be evaluated.
19.25 Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.
19.3 Equipment and Facilities
19.30 During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.
19.31 Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.
19.4 Control of Raw Materials
19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.
19.41 In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone.
19.5 Production
19.50 The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.
19.51 Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.
19.6 Validation
19.60 Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.
19.61 Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.
19.7 Changes
19.70 Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded.
19.8 Laboratory Controls
19.80 While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.
19.81 A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.
19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.
19.9 Documentation
19.90 A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.
19.91 The development and implementation of the analytical methods used to support the release of a batch of API for use in clinical trials should be appropriately documented.
19.92 A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.