General controls
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.
Testing
1. Appropriate laboratory tests to determine conformity to specifications shall be conducted for each batch of active substance and intermediates thereof.
2. An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process shall be established for each active substance. The impurity profile shall include:
(a)
the identity of the impurity or some qualitative analytical designation (e.g. retention time);
(b)
the range of each identified impurity;
(c)
a classification of each identified impurity (e.g. inorganic, organic, solvent).
3. By way of derogation from paragraph 2, impurity profiles are not necessary for active substances from herbal or animal tissue origin.
4. The impurity profile shall be compared at appropriate intervals against the impurity profile in the terms of the marketing authorisation or compared against historical data in order to detect changes to the active substance resulting from modifications in raw materials, equipment operating parameters, or the production process.
5. Appropriate microbiological tests shall be conducted on each batch of intermediate and active substance where microbial quality is specified.
Certificates of analysis
1. Upon request, certificates of analysis shall be issued for each batch of intermediate or active substance.
2. The certificate of analysis shall contain at least:
(a)
the name of the intermediate or active substance including, where appropriate, its grade;
(b)
the batch number;
(c)
the date of release;
(d)
the expiry date for intermediates or active substances with an expiry date;
(e)
the retest date for intermediates or active substances with a retest date;
(f)
each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained, if appropriate.
3. Certificates shall be dated and signed by authorised personnel of the quality unit and shall include the name, address and telephone number of the original manufacturer.
4. Where the analysis has been carried out by entities involved in repackaging or reprocessing, the certificate of analysis shall include the name, address and telephone number of the entity involved in repackaging or reprocessing and a reference to the name of the original manufacturer.
5. Whenever new certificates are issued by or on behalf of entities involved in repackaging or reprocessing, those certificates shall include the name, address and telephone number of the laboratory that performed the analysis. They shall also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which shall be attached.
On-going stability monitoring programme
1. Manufacturers shall put in place a documented, on-going stability programme to monitor the stability data of active substances. The results shall be used to confirm appropriate storage conditions and retest or expiry dates.
2. The test procedures used in stability studies shall be appropriate for the active substance and validated.
3. Stability samples shall be stored in containers that simulate the market container.
4. The first three production scale batches shall be placed on the on-going stability programme to confirm the retest or expiry date.
5. By way of derogation from paragraph 4, where data from previous studies show that the active substance is expected to remain stable for at least two years, fewer than three batches may be used.
6. After the first three production scale batches being placed on the on-going stability programme, at least one batch per year of the active substance manufactured shall be included into the on-going stability programme, unless none are produced in a given year or a different frequency is otherwise justified.
7. In case of active substances with short shelf life, stability testing shall be done more frequently. When data exist confirming that the stability of the active substance is not compromised, elimination of specific test intervals may be considered.
8. Where appropriate, the stability testing of active substances shall be performed in accordance with the conditions set out in the Guideline on stability: stability testing of new veterinary drug substances and medicinal products ( 5 ) .
Expiry and retest dating
1. Where an intermediate is intended to be transferred outside the control of the manufacturer and an expiry or retest date is assigned, supporting stability information shall be available (e.g. published data, test results).
2. The expiry or retest date of an active substance shall be based on an evaluation of data derived from stability studies.
3. Preliminary active substance expiry or retest dates may be based on pilot scale batches where the following conditions are fulfilled:
(a)
the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a production scale;
(b)
the quality of the active substance represents the material to be made on a production scale.
Retention of samples
1. Reference samples shall be kept for the purpose of potential future evaluation of the quality of batches of active substance and not for future stability testing purposes.
2. Reference samples of each active substance batch shall be retained for one year after the expiry date of the batch, or for three years after distribution of the batch, whichever is the longest.
3. For active substances with retest dates, reference samples shall be retained for three years after the batch is completely distributed by the manufacturer.
4. Reference samples shall be stored in the same packaging system in which the active substance is stored or in one that is equivalent to or more protective than the marketed packaging system.
5. Sufficient quantities shall be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
