SC I N. Particulate Contamination

This section of Supplementary Chapter I provides information on the status and application of the texts on particulate contamination included in Appendix XIII. Guidance is also offered on limits for visible particles in small-volume injections.

1. Appendix XIII comprises two methods for determining particulate contamination:- Sub-visible particles and Visible particles. Of these two methods, only that for sub-visible particles is currently invoked as a mandatory requirement within the monographs of the Pharmacopoeia.

2. The test for sub-visible particles included as Appendix XIII A is method text 2.9.19 of the European Pharmacopoeia. The criteria are invoked by means of the revised Ph Eur general monograph for Parenteral Preparations. The statements previously included in certain individual monographs of the British Pharmacopoeia such as Sodium Chloride Intravenous Infusion have therefore been deleted and reliance placed on the general monograph.

3. The test for visible particles included as Appendix XIII B is method text 2.9.20 of the European Pharmacopoeia. This text describes standardised viewing conditions but sets no criteria of acceptance. Contamination by visible particles is governed instead by the requirement of the Ph Eur general monograph for Parenteral Preparations that injections and intravenous infusions that are solutions are required to be ‘clear and practically free from particles’. It is recognised that this latter requirement can give rise to problems of interpretation. These problems could, perhaps, be overcome by providing simple criteria for the test for visible particles suitable for application as a pharmacopoeial ‘check-test’, that is, for application by an independent analyst, for example, a hospital quality control pharmacist, as a means of judging the quality of a particular parenteral preparation.

4. The need to set limits is based on the premise that an expectation of total absence of visible particles from all containers from a batch of an injectable preparation is unreasonable and unrealistic. An attributes-based test using a small sample together with simple pass/fail criteria would be consistent with the needs and constraints of a check test. The criteria chosen would need to be capable of detecting a batch that was grossly contaminated while representing an acceptably low chance of condemning batches of satisfactory quality through a small sample being unrepresentative. It would, of course, be unlikely that, if a sample failed such a test, consequent action would be initiated by the competent authority on the result of a single test. In such circumstances the competent authority would investigate the occurrence further with the manufacturer.

5. The following criteria are offered as generally suitable for a check test for small volume injections that are solutions. For guidance, it is suggested that in total 20 containers are examined as described in Appendix XIII B and any particles recorded. It is suggested that the preparation being examined should be considered to have failed the test if one or more particles are found in more than one container.

6. It is emphasised that these criteria are not intended for use by a manufacturer for batch release purposes. It is expected that a manufacturer would obtain assurance of the quality of his product with respect to visible particulate matter by 100% inspection or by other appropriate means in accordance with good pharmaceutical manufacturing practice (GMP).