5.1.4. MICROBIOLOGICAL QUALITY OF …

1 EUROPEAN PHARMACOPOEIA MICROBIOLOGICAL QUALITY of pharmaceutical preparations Table - Parenteral and ophthalmic preparations Category 1. Log reduction Preparations required to be sterile by the relevant 6h 24 h 7d 14 d 28 d monograph on the dosage form and other preparations labelled sterile. Bacteria A 2 3 - - NR*. - - Test for sterility ( ). B 1 3 NI**. - - - Category 2. Fungi A 2 NI. - - - Preparations for topical use and for use in the respiratory B 1 NI. tract, except where required to be sterile, and transdermal *NR : no recover patches. **NI : no increase Total viable aerobic count ( ). Not more than The A criteria express the recommended efficacy to be 102 micro-organisms (aerobic bacteria plus fungi) per achieved. In justified cases where the A criteria cannot be gram, per millilitre or per patch (including the adhesive attained, for example for reasons of an increased risk of and backing layer). adverse reactions, the B criteria must be satisfied. Transdermal patches : absence of enterobacteria and Table - Topical preparations certain other gram-negative bacteria, determined on Log reduction 1 patch (including the adhesive and backing layer).

2 Other preparations : not more than 101 enterobacteria and 2d 7d 14 d 28 d certain other gram-negative bacteria per gram or per Bacteria A 2 3 - NI millilitre ( ). B - - 3 NI Absence of Pseudomonas aeruginosa, determined on - - 1 g, 1 ml or 1 patch (including the adhesive and backing Fungi A 2 NI layer) ( ). B - - 1 NI. Absence of Staphylococcus aureus, determined on 1 g, The A criteria express the recommended efficacy to be 1 ml or 1 patch (including the adhesive and backing achieved. In justified cases where the A criteria cannot be layer) ( ). attained, for example for reasons of an increased risk of Category 3. adverse reactions, the B criteria must be satisfied. A. Preparations for oral and rectal administration. Table - Oral preparations Total viable aerobic count ( ). Not more than Log reduction 103 bacteria and not more than 102 fungi per gram or 14 d 28 d per millilitre. Bacteria 3 NI Absence of Escherichia coli (1 g or 1 ml) ( ). Fungi 1 B. Preparations for oral administration containing raw NI.

3 Materials of natural (animal, vegetable or mineral). The above criteria express the recommended efficacy to be origin for which antimicrobial pretreatment is not achieved. feasible and for which the competent authority accepts microbial contamination of the raw material exceeding 103 viable micro-organisms per gram or per millilitre. 01/2008:50104 herbal medicinal products described in category 4 are excluded. MICROBIOLOGICAL Total viable aerobic count ( ). Not more than QUALITY OF pharmaceutical 104 bacteria and not more than 102 fungi per gram or per millilitre. PREPARATIONS. Not more than 102 enterobacteria and certain other The following chapter is published for information. gram-negative bacteria per gram or per millilitre This general chapter presents 2 sets of recommended ( ). acceptance criteria for MICROBIOLOGICAL QUALITY . The 1st set Absence of Salmonella (10 g or 10 ml) ( ). of criteria corresponds to the 1st sets of methods in general chapters and In the same way that the 1st Absence of Escherichia coli (1 g or 1 ml) ( ).

4 Sets of tests in chapters and are to be replaced Absence of Staphylococcus aureus (1 g or 1 ml). in future by the 2nd sets, so the 1st set of criteria in this ( ). chapter will be replaced by the 2nd set. Where authorised, the 2nd set of criteria may be used instead of the 1st set Category 4. before replacement of the latter. The 2nd set presents herbal medicinal products consisting solely of one or more criteria developed in co-operation with the Japanese herbal drugs (whole, reduced or powdered). Pharmacopoeia and the United States Pharmacopeia to achieve harmonised requirements. A. herbal medicinal products to which boiling water is added before use. A. METHOD OF THE EUROPEAN PHARMACOPOEIA. In the manufacture, packaging, storage and distribution Total viable aerobic count ( ). Not more than of pharmaceutical preparations, suitable measures must 107 bacteria and not more than 105 fungi per gram or be taken to ensure their MICROBIOLOGICAL QUALITY . The per millilitre. pharmaceutical preparations should comply with the criteria Not more than 102 Escherichia coli per gram or per given below.

5 Millilitre (see Appendix). General Notices (1) apply to all monographs and other texts 529. MICROBIOLOGICAL QUALITY of pharmaceutical preparations EUROPEAN PHARMACOPOEIA B. herbal medicinal products to which boiling water is not yeasts/moulds count (TYMC) are given in Tables and added before use. Acceptance criteria are based on individual results Total viable aerobic count ( ). Not more than or on the average of replicate counts when replicate counts 105 bacteria and not more than 104 fungi per gram or are performed ( direct plating methods). per millilitre. When an acceptance criterion for MICROBIOLOGICAL QUALITY is Not more than 103 enterobacteria and certain other prescribed it is interpreted as follows: gram-negative bacteria per gram or per millilitre 101 CFU : maximum acceptable count = 20 ;. ( ). 102 CFU : maximum acceptable count = 200 ;. Absence of Escherichia coli (1 g or 1 ml) ( ). 103 CFU : maximum acceptable count = 2000, and so forth. Absence of Salmonella (10 g or 10 ml) ( ).

6 Table includes a list of specified micro-organisms for B. HARMONISED METHOD : MICROBIOLOGICAL which acceptance criteria are set. The list is not necessarily QUALITY OF NON-STERILE pharmaceutical exhaustive and for a given preparation it may be necessary PREPARATIONS AND SUBSTANCES FOR to test for other micro-organisms depending on the nature of pharmaceutical USE the starting materials and the manufacturing process. The presence of certain micro-organisms in non-sterile If it has been shown that none of the prescribed tests will preparations may have the potential to reduce or even allow valid enumeration of micro-organisms at the level inactivate the therapeutic activity of the product and has prescribed, a validated method with a limit of detection as a potential to adversely affect the health of the patient. close as possible to the indicated acceptance criterion is Manufacturers therefore have to ensure a low bioburden of used. finished dosage forms by implementing current guidelines Table Acceptance criteria for MICROBIOLOGICAL on Good Manufacturing Practice during the manufacture, QUALITY of non-sterile substances for pharmaceutical use storage and distribution of pharmaceutical preparations.

7 Microbial examination of non-sterile products is performed TAMC TYMC. according to the methods given in general chapters (CFU/g or CFU/ml) (CFU/g or CFU/ml). and (B. Harmonised method). Acceptance criteria for non-sterile pharmaceutical products based upon the total Substances for 103 102. pharmaceutical use aerobic microbial count (TAMC) and the total combined Table Acceptance criteria for MICROBIOLOGICAL QUALITY of non-sterile dosage forms TAMC TYMC. Route of administration Specified micro-organisms (CFU/g or CFU/ml) (CFU/g or CFU/ml). Non-aqueous preparations for oral use 103 102 Absence of Escherichia coli (1 g or 1 ml). 2 1. Aqueous preparations for oral use 10 10 Absence of Escherichia coli (1 g or 1 ml). Rectal use 103 102 - Oromucosal use Gingival use Absence of Staphylococcus aureus (1 g or 1 ml). Cutaneous use 102 101. Absence of Pseudomonas aeruginosa (1 g or 1 ml). Nasal use Auricular use Absence of Pseudomonas aeruginosa (1 g or 1 ml). Vaginal use 102 101 Absence of Staphylococcus aureus (1 g or 1 ml).

8 Absence of Candida albicans (1 g or 1 ml). Transdermal patches (limits for one patch Absence of Staphylococcus aureus (1 patch). 102 101. including adhesive layer and backing) Absence of Pseudomonas aeruginosa (1 patch). Absence of Staphylococcus aureus (1 g or 1 ml). Inhalation use (special requirements apply to Absence of Pseudomonas aeruginosa (1 g or 1 ml). 102 101. liquid preparations for nebulisation) Absence of bile-tolerant gram-negative bacteria (1 g or 1 ml). Special Ph. Eur. provision for oral dosage forms containing raw materials of natural Not more than 102 CFU of bile-tolerant (animal, vegetal or mineral) origin for which gram-negative bacteria (1 g or 1 ml). antimicrobial pretreatment is not feasible and 104 102 Absence of Salmonella (10 g or 10 ml). for which the competent authority accepts Absence of Escherichia coli (1 g or 1 ml). TAMC of the raw material exceeding 103 CFU Absence of Staphylococcus aureus (1 g or 1 ml). per gram or per millilitre Special Ph. Eur. provision for herbal medicinal products consisting solely of one or more herbal drugs (whole, reduced or powdered) : herbal medicinal products to which boiling Not more than 102 CFU of Escherichia coli 107 105.

9 Water is added before use (see Appendix) (1 g or 1 ml). herbal medicinal products to which boiling Not more than 103 CFU of bile-tolerant 105 104. water is not added before use gram-negative bacteria (1 g or 1 ml). Absence of Escherichia coli (1 g or 1 ml). Absence of Salmonella (10 g or 10 ml). 530 See the information section on general monographs (cover pages). EUROPEAN PHARMACOPOEIA Application of the F0 concept to steam sterilisation In addition to the micro-organisms listed in Table , 01/2008:50105. the significance of other micro-organisms recovered is evaluated in terms of : use of the product : hazard varies according to the route APPLICATION OF THE F0. of administration (eye, nose, respiratory tract) ;. CONCEPT TO STEAM STERILISATION. nature of the product : its ability to support growth, the OF AQUEOUS PREPARATIONS. presence of adequate antimicrobial preservation ;. method of application ; The following chapter is published for information. intended recipient : risk may differ for neonates, infants, The F0 value of a saturated steam sterilisation process is the debilitated ; the lethality expressed in terms of the equivalent time in minutes at a temperature of 121 C delivered by the use of immunosuppressive agents, corticosteroids.

10 Process to the product in its final container with reference to presence of disease, wounds, organ damage. micro-organisms possessing a Z-value of 10. Where warranted, a risk-based assessment of the relevant The total F0 of a process takes account of the heating up and factors is conducted by personnel with specialised training cooling down phases of the cycle and can be calculated by in microbiology and the interpretation of MICROBIOLOGICAL integration of lethal rates with respect to time at discrete data. For raw materials, the assessment takes account of temperature intervals. processing to which the product is subjected, the current technology of testing and the availability of materials of the When a steam sterilisation cycle is chosen on the basis desired QUALITY . of the F0 concept, great care must be taken to ensure that an adequate assurance of sterility is consistently achieved. In addition to validating the process, it may also be necessary to perform continuous, rigorous MICROBIOLOGICAL Appendix : Special Ph.