Follow
1. After marketing, the stability of the medicinal product should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package.
2. The purpose of the on-going stability programme is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labelled storage conditions.
3. This mainly applies to the medicinal product in the package in which it is sold, but consideration should also be given to the inclusion in the programme of bulk product. For example, when the bulk product isstored for a long period before being packaged and/or shipped from a manufacturing site to a packaging site, the impact on the stability ofthe packaged product should be evaluated and studied under ambient conditions. In addition, consideration should be given to intermediatesthat are stored and used over prolonged periods. Stability studies on reconstituted product are performed during product development andneed not be monitored on an on-going basis. However, when relevant, the stability of reconstituted product can also be monitored.
4. The on-going stability programme should be described in a written protocol following the general rules of Chapter 4 and results formalised as a report. The equipment used for the on-going stability programme (stability chambers among others) should be qualified and maintained.
5. The protocol for an on-going stability programme should extend to the end of the shelf life period and should include, but not be limited to, the following parameters:
=> number of batch(es) per strength and different batch sizes, if applicable;
=> relevant physical, chemical, microbiological and biological test methods;
=> acceptance criteria;
=> reference to test methods;
=> description of the container closure system(s);
=> testing intervals (time points);
=> description of the conditions of storage (standardised ICH conditions for long-term testing, consistent with the product labelling, should be used);
=> other applicable parameters specific to the medicinal product.
6. The protocol for the on-going stability programme can be different from that of the initial long-term stability study as submitted in the marketing authorisation dossier provided that this is justified and documented in the protocol (for example the frequency of testing, or when updating to ICH recommendations).
7. The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none are produced during that year). For products where on-going stability monitoring would normally require testing using animals and no appropriate alternative, validated techniques are available, the frequency of testing may take account of a risk-benefit approach. The principle of bracketing and matrixing designs may be applied if scientifically justified in the protocol.
8. In certain situations, additional batches should be included in the on-going stability programme. For example, an on-going stability study should be conducted after any significant change or significant deviation to the process or package. Any reworking, reprocessing or recovery operation should also be considered for inclusion.
9. Results of on-going stability studies should be made available to key personnel and, in particular, to the Qualified Person(s). Where on-going stability studies are carried out at a site other than the site of manufacture of the bulk or finished product, there should be a written agreement between the parties concerned. Results of on-going stability studies should be available at the site of manufacture for review by the competent authority.
10. Out of specification or significant atypical trends should be investigated. Any confirmed out of specification result, or significant negative trend, should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered in accordance with Chapter 8 of the GMP Guide and in consultation with the relevant competent authorities.
11. A summary of all the data generated, including any interim conclusions on the programme, should be written and maintained. This summary should be subjected to periodic review.
