General controls
Article 45
1. All specifications, sampling plans and test procedures shall be scientifically justified and appropriate to ensure that raw materials, intermediates, active substances and labels and packaging materials conform to established standards of quality and purity. 2. Specifications and test procedures shall be in compliance with the terms of the marketing authorisation. There can be specifications in addition to those in the terms of the marketing authorisation. 3. Specifications, sampling plans and test procedures, including changes to them, shall be drafted by the appropriate organisational unit and reviewed and approved by the quality unit. 4. Appropriate specifications shall be established for active substances in accordance with accepted standards and consistent with the manufacturing process. 5. The specifications for the active substance shall include a control of the impurities (e.g. organic impurities, inorganic impurities and residual solvents). If the active substance has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms shall be established and met. If the active substance has a specification for endotoxins, appropriate action limits shall be established and met. 6. Laboratory controls shall be monitored and documented at the time of performance. 7. Procedures shall be established for the investigation and documentation of out-of-specification results. Those procedures shall require analysis of the data, assessment of the criticality of the out-of-specification result, allocation of the tasks for corrective actions and conclusions. Any re-sampling or retesting after out-of-specification results shall be performed according to a documented procedure. 8. Procedures shall be established for the preparation of reagents and standard solutions and the labelling thereof. Expiry dates shall be applied as appropriate for analytical reagents or standard solutions. 9. Primary reference standards shall be suitable for their intended use. The source of each primary reference standard shall be documented. Records shall be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. 10. Primary reference standards obtained from an officially recognised source may be used without testing if stored under conditions consistent with the supplier’s recommendations. 11. Where a primary reference standard is not available from an officially recognised source, an “in-house primary reference standard” shall be established. Appropriate testing shall be performed to establish fully the identity and purity of the in-house primary reference standard. Appropriate documentation of that testing shall be maintained. 12. Secondary reference standards shall be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard shall be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard shall be periodically requalified in accordance with a written protocol.