Pharmaceutical products microbial contamination

Packaging Similarly, information on the closure/packaging systems must be provided in terms of material specification, suitability/compatibility with the pharmaceutical product, dimensional specifications, water impermeability, and so on. Defence against microbial contamination should be discussed in the context of either packaging of sterile product or use of preservatives as appropriate. 

The first chapter in this section provides a unique account of the ecology, i.e. distribution, survival and life-style, of microorganisms in the factory environment, and should enable process designers, controllers and quality control personnel to comprehend, trace and eradicate the sources of failure due to extraneous microbial contaminants in the finished product. Much of the information given here is applicable to hospital manufacture also, and this is extended in a contribution (Chapter 19) dealing with contamination in hospital pharmaceutical products and in the home. 

Pharmaceutical products are used in a variety of ways in the prevention, treatment and diagnosis of disease, hi recent years, manufacturers of pharmaceuticals have improved the quality of non-sterile products such that today the majority contain only a minimal microbial population. Nevertheless, a few rogue products with an unacceptable level and type of contamination will occasionally escape the quality control net and when used may, ironically, contribute to the spread of disease in patients. 

It has been known for many years that microbial contaminants may effect the spoilage of pharmaceutical products through chemical, ply sical or aesthetic changes in the nature of the product, thereby rendering it unfit for use (see Chapter 18). Active drug constituents may be metabolized to less potent or chemically inactive forms. Physical changes commonly seen are the breakdown of emulsions, visible surface growth on solids and the formahon of slimes, pellicles or sediments in hquids, sometimes... 

Baird R.M. (1985) Microbial contamination of non-sterile pharmaceutical products made in hospitals in the North East Regional Health Authority. J Clin Hasp Pharm, 10, 95-100. 

The greatest risk of contamination of a pharmaceutical product comes from its immediate environment. Additional protection from particulate and microbial contamination is therefore essential in both the filling area of the clean room and in the aseptic unit. This can be provided by a protective work station supplied with a unidirectional flow of filtered sterile air. Such a facility is known as a laminar airflow unit in which the displacement of air is either horizontal (i.e. from back to front) or vertical (i.e. from top to bottom) with a minimum homogenous airflow rate of 0.45 ms" at the working position. Thus, airborne contamination is not added to the work space and any generated by manipulations within that area is swept away by the laminar air currents. 

Ringertz O. Ringertz S.H. (1982) The clinical significance of microbial contamination in pharmaceutical and allied products. Sci, 5, 201-226. 

The types of microorganisms found in various products are Pseudomonas species, including Pseudomonas aeruginosa, Salmonella, species, Staphylococcus aureus, and Escherichia coli. The USP and other pharmacopoeias recommend certain classes of products to be tested for specified microbial contaminants, e.g., natural plant, animal, and some mineral products for the absence of Salmonella species, suspensions for the absence of E. coli, and topically administered products for the absence of P. aeruginosa and S. aureus. Emulsions are especially susceptible to contamination by fungi and yeasts. Consumer use may also result in the introduction of microorganisms. For aqueous-based products, it is therefore mandatory to include a preservative in the formulation in order to provide further assurance that the product retains its pharmaceutically acceptable characteristics until it is used by the patient. 

As with traditional aseptic filling, in order to comply with pharmaceutical GMP, it is important to minimize contamination at all stages of manufacture. Raw materials should be of a high quality and tested for microbial contamination. Water used for product manufacture should be of low bioburden and high purity (preferably water-for-injection quality, although this requirement is dependent upon the nature of the product being manufactured). 

The tests for microbial limits and recommendations for microbial quality criteria of raw materials, excipients, drug substances, and pharmaceutical products have been established in pharmacopoeial compendia for over 30 years. These tests are listed in the USP 24 Chapter (61) Microbial Limits Tests and in the Ph. Eur. 3rd ed.. Biological Tests 2.6.12 and 2.6.13, Microbial Contamination of Products Not Required to Comply with the Test for Sterility (total viable count, tests for specified microorganisms) and the JP XIII 30 Microbial Limit Test. 

Monitoring pharmaceutical ingredients, water for pharmaceuhcal purposes, the manufacturing environment, and finished products submitted to the laboratory to demonstrate control of microbial contamination of the pharmaceutical products manufactured... 

TABLE 4 Nonsterile Pharmaceutical and OTC Products Recalled by the FDA due to Microbial Contamination Problems, 1991-1998 (n = 46) ... 

A recently published book provides an excellent survey of issues that relate to contamination with endotoxins (present in both viable and nonviable bacteria), their released cell wall constituents, and also viable bacteria in the pharmaceutical industry [1]. It is important to know both the content of the work environment (e.g., indoor air) and the pharmaceutical products themselves. The former provides information on possible sources of microbial contamination and the latter the purity of the final commercial product (or precursors in various stages in its preparation). In some cases it is vital to know the actual bacterial species involved in contamination culture-based methods are standard microbiological techniques which were the focus of Jimenez [1] and thus will not be discussed further. Any contamination (e.g., with endotoxins), regardless of the species of origin, is of utmost of importance (e.g., in determining the safety of a batch of antibiotics to be administered intravenously). This is determined optimally by non-culture-based methods. 

In the general chapter on microbial attributes of nonsterile pharmaceutical products, the guidance suggests that the presence of microbial contaminants in nonsterile products [25] can reduce or inactivate the therapeutic activity of the product and has the potential to adversely effect the health of the patients and recommends manufacturers to ensure that contamination levels are as low as possible for finished dosage forms. Microbial enumeration limits for raw materials (total aerobic microbial count and total combined yeasts and molds count) and finished dosage forms are described. For inhalation, nasal, and topical routes of administration, tests for total aerobic microbial count and total combined and yeast and mold count,... 

Australian Pharmaceutical Manufacturers Association ( ) (1990), The Control of Microbial Contamination in Nonsterile Pharmaceutical Products for Human Use, , Canberra, Australia. 

Fig. 19.3. Representative micro-Raman spectra of single bacterial cells belonging to different species and strains that are predominantly present in pharmaceutical production in case of microbial contamination...

Downstream processing involves employment of a purifying system that can isolate the product in as few steps as possible using the simplest purification technology that will achieve the required purity. While purity is a critical consideration for both small-molecule pharmaceuticals and biopharmaceuticals, the nature of biopharmaceutical administration (typically via injection) and the nature of biotechnology processes require that additional considerations be paid to the purity of biopharmaceuticals. The final product must meet regulatory purity and sterility standards and must be below the maximally acceptable cellular or microbial contamination (Ho and Gibaldi, 2003). 

The manufacture of biological products, unlike that of pharmaceuticals, uses materials that present variability. The active substance is generally produced in small quantities and needs to be separated from complex mixtures containing several types of contaminants. Lots are generally small and quality control tests are usually based on biological techniques that present higher variability than physicochemical assays. The processes are also susceptible to microbial contamination. The in-process controls are of fundamental importance to detect quality deviations that cannot be assessed through assays performed only on the final products. 

The manufacture of sterile products is universally acknowledged to be the most difficult of all pharmaceutical production activities to execute. When these products are manufactured using aseptic processing, poorly controlled processes can expose the patient to an unacceptable level of contamination. In rare instances contaminated products can lead to microbial infection resulting from products intended to hasten the patient s recovery. The production of sterile products requires fastidious design, operation, and maintenance of facilities and equipment. It also requires attention to detail in process development and validation to ensure success. This chapter will review the salient elements of sterile manufacturing necessary to provide acceptable levels of risk regarding sterility assurance. 

Pharmaceutical products can be sterilized by steam sterilization, dry-heat sterilization, filtration sterilization, gas sterilization, and ionizing-radiation sterilization. The USP provides monographs and standards for biological indicators required to test the validity of the sterilization process. These products must also be tested for pyrogens—fever-producing substances that arise from microbial contamination most likely thought to be endotoxins or lipopolysaccharide in the bacterial outer cell membrane. 

During development of the manufacturing process, an experienced microbiologist should be consulted as to the potential for microbial contamination of the product. Issues may include the selection of appropriate pharmaceutical ingredients, the ability of the manufacturing steps to control microbial contamination, the validation of sterilization processes, the cleaning and sanitization of process equipment, the adequacy of... 

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