Antimicrobial preservative

Liquid Dosage Forms. Simple aqueous solutions, symps, elixirs, and tinctures are prepared by dissolution of solutes in the appropriate solvent systems. Adjunct formulation ingredients include certified dyes, flavors, sweeteners, and antimicrobial preservatives. These solutions are filtered under pressure, often using selected filtering aid materials. The products are stored in large tanks, ready for filling into containers. QuaUty control analysis is then performed. 

Solutions for external or oral use do not require sterilization but generally contain antimicrobial preservatives. Ophthalmic solutions and parenteral solutions require sterilization (qv). 

Mineral oil and paraffins should not be used, because these are not metabolized and may irritate tissue. Various other additives are needed for stabiUty, stefihty, and isotonicity antimicrobial preservatives, antioxidants (qv), chelating agents (qv), and buffers. No parenteral container material is completely inert to parenteral solvent systems. 

Single-dose preparations intended for use in eye surgery do not contain excipient ingredients, in order to avoid tissue irritation. However, multiple-dose containers may require antioxidants (qv), antimicrobial preservatives, or buffers to maintain stabiHty and stefiHty. Such solutions are packaged in polyethylene flexible dropper units called droptainers or in glass dropper botdes. 

An antimicrobial preservative serves to protect materials and products from the deleterious consequences of microbial growth and activities. 

Sulfur dioxide, sulfites, and metabisulfites have had extensive use as antimicrobial preservatives in the food industry. In pharmaceuticals they have had a dual role, acting as preservatives and antioxidants. The sulfa dmgs, or sulfonamides, the first effective chemotherapeutic agents to be employed... 

Benzyl alcohol (C6H5CH2OH). This has antibacterial and weak local anaesthetic properties and is used as an antimicrobial preservative at a concentration of 2%, although its use in cosmetics is restricted. 

British Pharmacopoeia (1993) Appendix KV C Efficacy of Antimicrobial Preservation, A191-A192, (and BP 1993, 1995 Addendum Appendix XVIIF, A407). London HMSO. (3.2)... 

Substances that have been used as preservatives for disperse systems include chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, parabens, and others [76,77]. The use of cationic antimicrobial agents such as quaternary ammonium compounds (e.g., benzalkonium chloride) is contraindicated in many cases because they may be inactivated by other formulation components and/or they may alter the charge of the dispersed phase. Clay suspensions and gels should be adequately preserved with nonionic antimicrobial preservatives. The use of preservatives is generally limited to products that are not intended for parenteral use. Intravenous injectable... 

Large-volume parenterals (LVPs) and small-volume parenterals (SVPs) containing no antimicrobial agent should be terminally sterilized. It is common practice to include an antimicrobial agent in SVPs that cannot be terminally sterilized or are intended for multiple-dose use. The general exceptions are products that pass the USP Antimicrobial Preservative Effectiveness Test [1] because of the antimicrobial activity of the active... 

Multidose Packaging of Unpreserved Topical Drops. In some cases it may be desirable to provide a product without an antimicrobial preservative for patients who exhibit sensitivity to various preservatives. This can be accomplished with the use of unit dose containers, but these usually contain more than that... 

The choice of the excipients and their concentration, including their function (e.g., antimicrobial preservatives, antioxidants. ..). In the case of antimicrobial preservatives, data are expected on the preservative efficacy in products on storage, including after reconstitution or dilution and during the period of use. 

Microbiological aspects will need to be discussed, but the amount of information will depend on the type of product. For nonsterile products there will need to be a description of the microbiological attributes of the product and, if appropriate, a rationale for not performing microbial limit tests. For preserved products the selection of the antimicrobial preservatives will need to be discussed and the effectiveness of the selected system demonstrated. For sterile products there will need to be appropriate process validation data and information on the integrity of the container-closure system. 

Where a large pack size is provided, it might be necessary to undertake more extensive in-use testing and/ or to restrict the in-use shelf life once the container has been opened. In addition to preservative efficacy testing the chemical stability of antimicrobial preservatives should also be investigated over the unopened and in-use shelf lives of the product. 

With the exception of antimicrobial preservatives and antioxidants (see below) and coloring matter (for which an identity test should be available), it is not normally necessary to test for the presence of excipients in finished products. 

Antioxidants and antimicrobial preservatives are the subject of a further specific guideline (CPMP/CVMP/QWP/115/95, adopted July 1997). These materials are designed to be aggressive, and there are certain risks associated with their use. They are used, respectively, to (a) reduce the rate or extent of oxidation of active ingredients or other ingredients or... 

Where antioxidants or antimicrobial preservatives are used, the finished product release specification will need to include identification tests and assays for these two types of excipient. The shelf life specification should also include a specification for assay for antimicrobial preservatives. Stability data will be required for both antioxidants and antimicrobial preservatives in the finished product, and in addition the preservative efficacy of the formulated product should be examined over its shelf life and by means of appropriate in-use stability tests. Preservative efficacy data should also be presented at the lower limit of the preservative assay. 

Aqueous products that are at greatest risk from microbial spoilage include solutions, suspensions, and emulsions for repeated oral, parenteral, or external use and include critical products such as multidose injections and eye drops. Unpreserved products without adequate antimicrobial efficacy should not be presented in containers intended for use on more than one occasion unless justified. When antimicrobial preservatives are used, their efficacy has to be demonstrated using the Ph Eur test for antimicrobial preservative efficacy. Factors to be taken into account in designing a preserved product include the nature of the preservative, its concentration in the product, the... 

The purpose of in-use stability studies is to establish the period for which a product intended to be used on more than one occasion may be used after reconstitution or dilution or the withdrawal of the first dose from the container without adversely affecting the integrity of the product and with the product retaining acceptable quality characteristics. This type of test can be applied to any multiple use product (e.g., sterile products in multiple-use containers, powders or granules including those used to produce oral solutions or suspensions) but is likely to be of particular importance in the case of products that are manufactured with an inert headspace gas, for products containing antioxidants to protect an active ingredient that is liable to oxidative decomposition, and for products that contain a volatile antimicrobial preservative. 

The availability of unpreserved and preserved dosage forms is considered. Mention is made of formulation changes necessitated by multidose products. The need for adequate antimicrobial preservative efficacy can be discussed if this was an issue during product development. 

CPMP/CVMP/QWP/115/95 Note for guidance on inclusion of antioxidants and antimicrobial preservatives in medicinal products (July 1997)... 

Preservative/antimicrobial preservative, antimycotic agent, bacteriophage control agent, chemosterilant/wine maturing agent, disinfection agent... 

Although some types of pharmaceutical products, like ophthalmic and injectable preparations, are sterilized by physical methods, including autoclaving, dry heat, or by bacterial filtration during their manufacture, many of them additionally require the presence of an antimicrobial preservative to maintain their aseptic condition throughout the period of their storage and use. Other types of preparations that are not sterilized during their... 

The ICH-EWG-Q developed a list of 12 general chapters (tests and assays) that were deemed critical to new product registration and urged the PDG to concentrate on prompt harmonization (Table 3), The Antimicrobial Preservatives Effec-... 

Antimicrobial preservatives are added to multiuse nonsterile liquids, ointments, and ereams, and sterile injectable products to protect them from microbial contamination that may be introduced inadvertently during use of the product (postmanufacturing). 

The test for antimicrobial effectiveness is used to demonstrate the effectiveness of any added antimicrobial preservative(s). Compendial referenees include USP 24 Chapter (51) Antimicrobial Effectiveness Test JP XIII General Information 3, Pre-servatives-Effeetiveness Tests and the Ph. Eur. 3rd ed., Biologieal Tests, 5.1.3. Effi-eacy of Antimierobial Preservation. 

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