SC I M. Microbial Contamination

This section of Supplementary Chapter I provides information on the status and application of the texts on microbial contamination included in Appendix XVI. These texts, which are taken from the European Pharmacopoeia (Ph Eur), are used both to satisfy mandatory requirements of the Pharmacopoeia and as guidelines for the purposes of microbiological monitoring. This chapter provides clarification on the application and interpretation of the test methods and criteria in the different situations.

1. Appendix XVI B and Appendix XVI F comprise several sub-sections describing tests for detecting different types of microbial contamination and Appendix XVI DAppendix XVI G

2. The tests for specified micro-organisms, included as Appendix XVI B1, are those included as method 2.6.13 of the Ph Eur. These tests describe the methods used to set mandatory requirements in monographs for certain bulk materials of natural origin. For example, the monograph for Dried Aluminium Hydroxide specifies the absence of Escherichia coli and from bile-tolerant gram-negative bacteria and that for Pancreatin specifies 1 g is free from Escherichia coli and 10 g is free from Salmonella. These methods are also used to support the relevant non-mandatory recommendations made within the guidelines on the microbiological quality of pharmaceutical preparations and herbal medicinal products (see paragraph 9 below).

3. The tests for total viable aerobic count, included as Appendix XVI B2, are those included as method 2.6.12 of the Ph Eur. These quantitative tests are used in two contexts within the Ph Eur. In addition to being invoked to set mandatory limits for a range of bulk materials of natural origin, the methods are also used to support the non-mandatory guidelines on the quality of pharmaceutical preparations and herbal medicinal products (see paragraph 9 below).

4. In Appendix XVI B2 of the British Pharmacopoeia (BP), an introductory paragraph states that the tests are designed primarily to determine whether a substance or preparation complies with an established specification for microbiological quality. For example, the monographs for Agar and for Dried Aluminium Hydroxide specify total aerobic microbial counts of not more than 10³ micro-organisms per gram and total combined yeast/mould counts of not more than 10² micro-organisms per gram. The method indicates that, when used for such purposes, it is to be carried out in accordance with the instructions in the general text, including the number of samples to be taken, and the results are to be interpreted as stated.

5. When the tests are used by a manufacturer for monitoring raw materials and/or finished products or for process validation, the sampling plans for microbiological examination and the method of interpretation of the results are matters for agreement between the manufacturer and the competent authority. (See also Basis of Pharmacopoeial Requirements in the Introduction to Supplementary Chapter I.)

6. The test for absence of mycoplasmas, included as Appendix XVI B3, is method 2.6.7 of the Ph Eur as applied to vaccines for human use. This test is invoked as a mandatory requirement in the relevant parts of the Production section of certain monographs for viral vaccines produced in cell cultures or in eggs, for example, Inactivated Influenza Vaccine (Surface Antigen). (The test as applied to veterinary vaccines is reproduced in the BP (Veterinary).)

7. The test for mycobacteria, included as Appendix XVI B4, is method 2.6.2 of the Ph Eur. Reference to this method is made under the tests for extraneous agents in viral vaccines (see paragraph 8 below).

8. The tests for extraneous agents in viral vaccines, included as Appendix XVI B5, are those included as method 2.6.16 of the Ph Eur. These tests are invoked as mandatory requirements in the relevant parts of the Production section of certain monographs for viral vaccines.

9. As indicated in the general monograph for Pharmaceutical preparations, recommendations on the microbiological quality of non-sterile pharmaceutical preparations are provided in Appendix XVI DAppendix XVI G

The text on Microbiological Quality of Non-sterile Pharmaceutical Preparations, included as Appendix XVI D, is general text 5.1.4 of the Ph Eur. As described in the General Notices: ‘General chapters become mandatory when referred to in a monograph, unless such reference is made in a way that indicates that it is not the intention to make the text referred to mandatory but rather to cite it for information’. Where general text 5.1.4 is referred to in a general monograph as giving recommendations on microbiological quality, different acceptance criteria may be justified.

The general monograph for Oral Liquids, for example, has a mandatory Production requirement that ‘In the manufacture, packaging, storage and distribution of liquid preparations for oral use, suitable measures are taken to ensure their microbial quality’ the following statement ‘recommendations on this aspect are provided in the text on Microbial Quality of Pharmaceutical Preparations (5.1.4)’ clearly constitutes a non-mandatory recommendation.

The text on Microbiological Quality of Herbal Medicinal Products for Oral UseAppendix XVI G

10. The texts of Appendix XVI DAppendix XVI G