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Poonam Kushwaha et al. / Journal of Pharmacy Research 2010, 3(1),124-131
Available online through www.jpronline.info
Microbial Contamination: A Regulatory Perspective
Poonam Kushwaha Faculty of Pharmacy, Integral University;Lucknow-226026 (India) Received on: 10-09-2009; Revised on: 17-10-2009; Accepted on:05-12-2009 ABSTRACT The microbiological attributes of pharmaceutical ingredients are often critical to final product quality. FDA expects from the manufacturers to measure and characterize the bioburden of their products. The concern of FDA and compendia towods microbial contamination described in this article. This article also describes the source, methods of detection, and methods of elimination of microbial contamination. Keywords: Microbial contamination; source of contamination; control of microbial contamination; FDA concern; USP concern; microbial limit test. INTRODUCTION Pharmaceutically active products (drug products) are expected to be efficacious, however; the presence of microorganisms in these products may have adverse effects on their efficacy. The severity of the effects that microorganisms may have on any particular drug product is a function of the nature of the product, its intended use, and the nature of the microorganism concerned. At one end of the spectrum, microbial contamination of a sterile parenteral product may, on injection into a debilitated patient, result in fatality; at the other, patients may refuse to begin or continue a course of medication because of aromas, off-flavors, or discolorations of microbial origin. In either situation, or in any related situation, the presence of microorganisms ought to be avoided in drug products . Manufacturers of human and veterinary products, medical devices, processed food and cosmetics are required to establish quality systems to help ensure that their products consistently meet applicable requirements and specifications. In the United States, current Good Manufacturing Practice (cGMP) regulations are issued by the U.S. Food and Drug Administration (FDA) as the minimum requirements for quality systems for FDA-regulated products such as food, drugs, biologics and devices. One requirement of cGMP regulations is the monitoring of microbiological contamination. Microorganisms can be transferred into an aseptically-filled product directly by contaminated raw ingredients or indirectly through condensation, aerosols, lubricants, packaging materials or workers . *Corresponding author.
Poonam Kushwaha Faculty of Pharmacy, Integral University;Lucknow-226026 (India) Tel.: + 91-9451144299 E-mail: email@example.com
Incoming raw materials from pharmaceutical ingredients, chemical compounds, vitamins, minerals, herbs and even food ingredients are tested for the presence of undesirable microbes according to the current USP (United States Pharmacopeias) methods. All finished products have to be tested for the presence of undesirable microbes as well. This ensures that all processes are clean and micro free . The pharmacopoeial requirement of sterility test for all products intended for parental administration and ophthalmic preparation, irrespective of whether they are prepare by end -sterilization process or produced under conditions, provides an adequate level of control for such preparation. Many other products, especially liquid preparations and creams for topical application to severely injured skin, large open wounds or mucus membrane which are liable to bacterial, mould and fungal contamination from the atmosphere ( or less frequently from the contaminated equipments during manufacture) should be controlled for microbial contamination. Few materials are self sterilizing but many products capable of supporting microbial growth requires the addition of suitable antibacterial or antifungal agents, if microbiological spoilage of the product is to be completely avoided. Certain materials, which are particularly prone to microbial contamination, may constitute a health hazard unless they are carefully controlled. These are mainly substances of natural origin, which are known to be liable to contamination usually with specific organisms. The most satisfactory control therefore is one which set a requirement for freedom from specified microbial contamination. This is the preferred method of control in the United Kingdom. In some countries reliance is place on a limit of total viable count of microorganism present. This method of control, is however, is less satisfactory as growth of contaminating micro-organisms may occur on storage of the product .
Journal of Pharmacy Research Vol.3.Issue 1.January 2010
dust. These factors determine what microorganism(s) would be the dominant contaminant(s) and the level of spoilage of the product or raw material. soil q Fungi yeast personnel q Mold (filamentous Environment. senna.i. / Journal of Pharmacy Research 2010. improper handling by the workers. The goal of the investigation could be to determine the nature of primary contamination and the causes. dried aluminum phosphate. of raw materials or Extrinsic.Equipment and process Design Material/Surface Unprotected storage tanks Back flow Perforated heat exchangers Unsanitary pumps Carbon filters Membrane filters Valves Seals/gaskets 3-Environment/Facility Undesirable facility design Inadequate air handling systems Inadequate construction materials Inadequate sanitization procedures Inadequate maintenance (standing water.e. The primary contamination may be: Intrinsic. Generally.e. in each manufacturing environment a unique microbial community “natural-micro flora” will be present since the local conditions tend to select for a particular assemblage of microorganisms. Various sources of microbial contamination include [6. The significance of contamination in a processing industry is determined by a number of factors as well as properties of the microorganism(s) concerned. soil Sources of Microbial Contamination: Micro-organisms will contaminate formulations from a wide variety of sources.Freedom from pseudomonas: dried AlOH3. equipment or even the workers handling the product/raw materials. Environmental factors may include pH and water activity of the product or raw material. microbiological analysis of the product/raw material and the air within the processing area is recommended. For non-sterile products it is a balance between the cost of reducing contamination against possible risk to the consumer and product .3.. it is then easy to design suitable sampling strategies to trace the source of contamination . The first thing is to have a walkthrough of the plant and analyze in detail the stages of processing or production and using microbiological knowledge identify the stage(s) in the entire production process where possible contamination is likely to occur. water used in the processing.Freedom from escheria coli: sterculia . 3(1). Once the contaminating organism has been identified. the “natural-flora”). and the ambient temperature.January 2010 124-131 . the product and environmental factors. available nutrients (e. All aspects of formulation and manufacture should try to minimize contamination.e..i.. Similarly.Raw materials/ excipients a) Components Natural vs.Poonam Kushwaha et al. samples of the contaminated material should be sent to a reputable laboratory for analyses. Recommended control of microbial contamination in natural pharmaceutical substances:  Types of microbial contamination  If contamination involves the product or raw material. likely sources of contamination and the stages in the processing where contamination of the product or raw material is most likely to occur. The source or the cause of primary contamination requires to be identified for appropriate action to be taken.Issue 1.124-131 Contamination from microorganisms is a big problem for all formulations containing moisture but it can be a bother in solid dosage forms also if some natural polymers are used because many natural polymers are fertile sources of microorganisms . during or after processing Since contamination of raw materials or the product may originate from contaminated air.) Ineffective EM Program 4-Personnel (Major potential source of microbial contamination) Journal of Pharmacy Research Vol. q Bacteria fungi) Gram (+) rods -environment. synthetic products Water activity level Containers (cardboard boxes) b) Water Systems (Purified Water. WFI) Biofilm 2. it is important to have an idea of the possible contaminants (i. This is critical for sterile products. rust. tregacanth . When investigating microbial contamination in an industrial setting. soil Gram (+) cocci –personnel Gram (-) rods -water.. 7]: 1. aerosolized product).g. Contamination originating from raw materials can contaminate hands of workers and then be transferred to the product and equipment. etc. . Factors contributing to multiplication of microorganisms to unacceptable levels may include improper storage conditions. microorganisms of concern are often present in small numbers as part of the natural micro flora of raw materials and could not be totally eliminated.Freedom from salmonellae: acacia.
3.50 IU/mg NMT 0. Detection of Microbial Contamination in Biological/ Sterile Products: Many tests can be used to detect microbial contamination of biological products. Commonly-known microbial contaminants are well-known to frequently cause contamination in biological products . Environmental contaminants are micro-organisms that are present in the production facility. The composition of these media is sometimes modified to limit or inhibit the growth of biological products. Other media support the growth of specific micro-organisms (referred to as selective media). and strains of the microbial contaminants are known. For selective media. species. microbial contaminants are detected by the formation of colonies.e. The internationally harmonized chapters provide a strong framework for this assurance . and commonlyknown microbial contaminants. The manufacturer is responsible for the quality and safety of the product marketed.124-131 Microbial Contamination in Nonsterile Products: Exposed skin (flakes.0 IU/mg Microbiological testing of nonsterile pharmaceuticals has thus far been performed only in special cases.. such as by Polymerase Chain Reaction (PCR). Cross contaminants are biological products that are manufactured at the same manufacturing facility. Harmonized Chapter (1 11 1) recommends the determination of the risk associated with “other organisms.25 IU/mg NMT 4. consideration must be given to the promotion of hygiene and safety as well as to the feasibility of application in GMP .” which is in agreement with the FDA expectation for absence of “objectionable” organisms [11. environmental contaminants.00 IU/mg NMT 55. In formulating such regulations.0 IU/mg NMT 0. and their growth in the presence of a large quantity of biological product can be limited or inhibited. resulting in false negative results.” It must be stressed that FDA’s concern about objectionable organisms” is not the same as the compendial tests for “specified” organisms. The suspected colonies can be further evaluated.0 IU/mg NMT 05. The harmonized microbial limits tests only address the “absence of specified microorganisms” and leave the determination of the “absence of objectionable microorganisms” in the capable hands of each company’s appropriately educated and well-trained microbiology group .25 IU/mg NMT 1. Accordingly. The introduction of these three harmonized chapters is likely to require some revalidation of existing methodologies. 15]. the “absence of objectionable microorganisms”) from the product. 12]. For rich media.083IU/mg NMT 0. Components that are sometimes used to limit or inhibit the growth of the biological products can be specific antibiotics. 124-131 Journal of Pharmacy Research Vol. Companies should put plans in place immediately for this work and show consistent progress toward this goal. The US Pharmacopoeia and the US Food and Drug Administration are in agreement about the question of the microbial quality of nonsterile pharmaceuticals: the product must be safe for use.01 IU/mg NMT 10.Issue 1. and can detect relatively low levels of microbial contaminants. This is because the amount of microbial contamination in the biological product can be very low. oils) Exposed Hair Exposed Clothing Dirt Cosmetics Tobacco smoke Behavior Types of Microbial Contamination in Biological / Sterile Products: There are three possible origins of microbial contaminants: cross contaminants. Differential media uses specific media for the detection of microbial contaminants. An immunofluorescence assay can be used to determine the presence of microbial contamination. Nonsterile products are subject to process controls from a microbiological perspective. in order to improve the sensitivity of detecting microbial contamination. microbial contaminants are detected by the presence of colonies that have different morphologies from those of the biological products.0 IU/mg NMT 0. / Journal of Pharmacy Research 2010. Microbiological control of such products is necessary until now. regulations concerning the permissible level of nonpathogenic microorganism in non sterile drugs exist in only a few countries.Poonam Kushwaha et al. the US Code of Federal Regulations (21 CFR) clearly requires the manufacturer to produce products free of” objectionable organisms. and so the finished product should also be evaluated for the presence of “objectionable” while in quarantine (costing money for warehousing and not being sold. This method is especially useful. The National Formulary monograph requirement for the absence of specific organisms is a minimal requirement and should not be taken as proof that the product is suitable for sale from a microbiological perspective. this assay should be validated to detect cross contaminants and commonly-known contaminants. when the type.January 2010 . and it is FDA’s clear expectation (as described in CFR) that this will include a determination of the microbial safety (i.0IU/mg NMT 300. Some of these tests are described in subsequent paragraphs .5 IU/mg NMT 500. Some of the specific media support the growth of essentially all micro-organisms (referred to as rich media). 3(1). which the sponsor is aware of in these microorganisms prior to production . ) [14. List of some Drugs containing Endotoxin and their Limit  Drug Amoxicillin sodium buserelin Carbenicillin sodium desmopressin fosfomycin Heparin sodium insulin oxytocin somatropin Tetracyclin hydrochloride Vanomycin xylitol Limit NMT 0. or other specific chemicals or nutrients . specific amino acids. Though these controls are not as stringent as those for aseptic manufacture.
Finished product testing is at best confirmatory and in some cases may be dispensed with when manufacturing controls ensure that products are highly unlikely to become microbiologically contaminated (parametric release in its broadest sense) . manufacturing processes. and processes from sources of microbiological contamination. inactivation. Environmental monitoring should be performed before. by individual air supply and exclusion of air flow from laboratory to production. 19]. designed to prevent objectionable microorganisms in drug products not required to be sterile. filling) must be performed aseptically inside a Class 100 laminar flow hood. do require stringent measures i. centrifuge bottles. and equipment. food (including dairy) have microbial contamination control procedures in place. Laboratory waste must be disposed of such. as a consequence.113 Control of microbiological contamination states that: (a) Appropriate written procedures. it is unusual to find valid statistical sampling and testing being done at batch release.3. unless such analyses were carried out in a LaminarAir-Flow Cabinet. The execution of testing such as on growth promotion or on the efficacy of antimicrobial preservation in a given room. and packing materials should be sterilized prior to use. and so forth.Issue 1. microbiological contaminants are also routinely controlled by removal. that contamination of protected areas and materials (production) is excluded. All equipment (fermentor. Minimizing the risk of microbiological contamination of drug products is assured by the application of microbiological and physical standards and controls to starting materials. physically and logistically separated from production areas by various means: by location and by restriction of access. 3(1). The facility should include features for control and containment of environmental and cross contamination of microorganisms. manufacturing facilities. for the detection of micro-organisms unrelated to the biological products. 21CFR Sec. Examples are multiple suites or operations for different products. strict separation of production workflow from laboratory workflow and of flow of personnel and materials etc. The sampling procedure in particular should be designed with special care. a separate heating/ ventilating/air-conditioning system for each suite. and equipment thoroughly cleaned and sterilized. Control of Microbial Contamination: Microbial control of pharmaceuticals is primarily concerned with minimizing the opportunities for drug products to be contaminated by microorganisms. microbial monitoring of samples of purified water. 11 citations in FDA Warning Letters were caused by a lack of control of microbiological contamination (21 CFR 211. / Journal of Pharmacy Research 2010. All downstream production processes (eg. secure containment of biological products. an air pressure cascade system. Further measures include dedicated gowns and other protective clothing. In-process controls should be performed to prevent and identify contaminants. by a bioburden test. e. sterility test. In recognition of the frailty of protective measures in all but the most extreme circumstances. Such conditions include examination to take place in a dedicated room i. microbiological test methods are product-destructive and. The growth medium and other components related to fermentation and production should be tested (eg. during. the production suite should be thoroughly cleaned . All microbial examinations must be performed under conditions designed to avoid accidental contamination of the product and of the product sample to be examined. The overall goal of such a system is to prevent microbiological contamination of the pharmaceutical product [18. these assurances are obtained by applying controls that protect materials. A series of regulations address the subject of microbiological facility control. or destruction . At the end of each production. Contamination especially in food industry can result to not only human morbidity and mortality but also to business losses . shall be established and followed. these findings have been in the Top Ten List of FDA Warning Letters.g. The integrity of the filters used for media sterilization should be tested before and after production. precludes product testing in this particular room.e. The testing of product samples for compliance with microbiological standards is only one small part of this.). laboratory. performance in a Laminar-Air-Flow Cabinet to reduce the contamination risk . (b) Appropriate written procedures. designed to prevent microbio124-131 Journal of Pharmacy Research Vol. It is secondarily concerned with minimizing the potential for any microorganisms that may have contaminated drug products to increase to levels that may risk the efficacy of the product.113).January 2010 . growth medium. In most cases the implementation of appropriate hygiene programmes and measures have been implemented as an essential part for the manufacturing of pharmaceutical products. as well as personnel monitoring. In 2005. etc. Processing industries such as pharmaceutical. By and large. Over the last years. Regular hygiene monitoring of a plant and equipment. washing. A variety of tests.Poonam Kushwaha et al. This may involve obtaining samples at each stage of production for the presence of micro-organisms unrelated to the biological products. or detection of microorganisms after extensive incubation) to ensure a lack of contaminating microorganisms. By and large. product-contact packaging components. and after each production . The laboratory has to be monitored on viable count at appropriate and constant intervals. and microbiological sampling of products and raw materials are invaluable in detecting potential sources and routes of contamination. The control of microbiological contamination is an outstanding integral part of inspection findings. with rinse and swab samples fully analyzed for confirmation according to validated cleaning procedures. equipment. formulation. 211. glassware. The production areas should undergo environmental monitoring. personal hygiene and beauty products.e.124-131 Steps for avoiding Microbial Contamination: There are some steps that should be taken to avoid microbial contamination.
specifications. in the 1993 instructional guide for inspections of Such validation and documentation may be accomplished in accor.” The USP recommends that certain categories be routinely tested Regulatory Aspects: for total counts and specified indicator microbial contaminants. as necessary. are not “objectionable”) [11. In 1970. such batches may be released prior to comple. sterility.Poonam Kushwaha et al.165 Testing and release for distribution states that: FDA’s concerns are not covered by a USP referee test method. One such situation is with the CFR requirement that medicines be “free of (a) For each batch of drug product. / Journal of Pharmacy Research 2010. This is purely a GMP concern. this test may be required to demonstrate compliance with the mono(c) Any sampling and testing plans shall be described in written pro. and the potential hazard to the user. but it is not sufficient to demonstrate microbial methods employed by the firm shall be established and documented. Such procedures shall include validaFDA has similar. there shall be appropriate labora. sensitivity. shall be established testing are conducted on specific batches of short-lived and followed. and guidance other than “The significance of microorganisms in nonsterile pharmaceutical products should be evaluated in terms of the use of any other relevant criteria . A number of specific monographs tests is not driven by any concern over “Good Manufacturing Pro. of each batch of drug product required to be free of objectionable microorganisms. However. oral liquids for E.also include definitive microbial limits . the Agency has been absolutely clear on the concern over objectionable microoracceptance levels and/or appropriate rejection levels. For USP and FDA frequently are interested in the same thing. 3(1). It is governed by the USP monographs found in the acceptable levels and types of microbiological contamination in prodNational Formulary (NF). of current National Formulary) may require “Absence of Pseudomonas each batch of drug product required to be free of objectionable micro.January 2010 124-131 . ments are identical. quality . the referee chapters in USP (those numbered under <1000>) are enforced. for Aureus [sic]. lowed. The need for these ministration for yeasts and molds. then chapter <51> Antimicrobial Effective. the product. specificity. although organisms.3. urethral. such written procedure shall be fol. The USP monograph for a product (as provided in the (b) There shall be appropriate laboratory testing.” This is reinforced by 21 CFR 211. In fact. there are situations where the 21CFR Sec.” 21CFR 211. here we have pleted as soon as possible. drug products. 211. repro.approval to market submission contained a statement that you would tical quality control criteria as a condition for their approval and re. topicals for P. (b) There shall be appropriate tion of sterility and/or pyrogen testing. 23].” So. Through the literature and through our invesJournal of Pharmacy Research Vol. aeruginosa and S. 211.lems associated with the microbiological contamination of topical tions and any other relevant quality control criteria shall be rejected. and reproducibility of test might be necessary.test the finished product by the Microbial Limits Tests that in fact lease..” There is a test in the Microbial Limits chapter to demonstrate the absence of Pseudomonas aeruginosa.. or vaginal adBacterial Endotoxin. nasal solutions and inhalation products .the target population (i. “For a variety of reasons. and articles intended for rectal. the nature of the product. for Antibiotic/ Vitamin Potency. However.124-131 logical contamination of drug products purporting to be sterile. The statistical quality control criteria shall include appropriate you must do that. as necessary. prior to release. we have seen a number of prob(f) Drug products failing to meet established standards or specifica. there is a need to have a test for nella.165 which states radiopharmaceuticals.on the health hazard.Microbiological Attributes Chapter <1111> provides little specific cessed material must meet appropriate standards. a problem . serious health hazard. Coli [sic].aeruginosa.194 (a) (2). Where sterility and/or pyrogen isms on drug products not required to be sterile. animal and some mineral products for SalmoFrom the vantage point of USP. shall be established and followed.laboratory testing. and that fact that testing to the USP chapter (e) The accuracy.e.113 under the section tory determination of satisfactory conformance to final specifications “Control of microbiological contamination (a)” states “Appropriate for the drug product.QC Microbiology Labs the FDA states: dance with Sec. Dunnigan of the Bureau of Medicine of the FDA commented for antimicrobial efficacy. he said that topical preparations conness Test” is the referee test used to demonstrate that characteristic taminated with gram negative organisms are a probable moderate to . example natural plant. for antimicrobial efficacy. Dr. If there is a monograph that requires a test ucts. for Microbial Limits etc .graph requires as laid out in NF it does not meet the FDA concern that cedures that shall include the method of sampling and the number of any organism in the final product be acceptable to the product and units per batch to be tested.“Testing and release for distribution. However. ganisms in the product. provided such testing is com. Where the requiretion of any sterilization process. The FDA Concern (d) Acceptance criteria for the sampling and testing conducted by the FDA will enforce the GMP requirement that if your product quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statis. As a general guide for cess” (GMP). The USP Reprocessing may be performed. including the identity and strength of each written procedures. designed to prevent objectionable microorganactive ingredient.Issue 1. but separate concerns.objectionable microorganisms. Prior to acceptance and use.
Likewise. 27].e. The USP and the European Pharmacopoeia (EP. The health hazard evaluation commented that the risk of pulmonary infection is especially serious and potentially life-threatening to patients with chronic obstructive airway disease. cystic fibrosis. there are no test methods provided in the USP that will enable the identification of the presence of this microorganism .124-131 tigations. it has been shown that a variety of infections have been traced to the gram negative contamination of topical products. In the late 1960’s several outbreaks of disease were traced back to pathogen contaminated medications.12 Microbiological Examination Of Nonsterile Products: Microbial Enumeration Tests 2. and so we will use those drafts as the description of the finalized test [15. USP 2003b.6. the signed-off versions have yet to be published. The USP Concern The USP is on record as early as 1982 verifying that the demonstration of “absence of objectionable microorganisms” is not the intent of the chapter. Why is this concern? To understand this we have to go back to the 1970’s. and immuno. Again. each company is expected to develop microbial specifications for their nonsterile products . The agency classified this as a Class I recall because the product was contaminated with Pseudomonas gladioli/cepacia.13 Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms 5. It includes tests for total viable count (bacteria and fungi) and coliform test to determine Escherichia coli. The procedures in USP were designed to detect the presence of specific “index” or “indicator” organisms. Later in the 1980’s there was a series of articles appearing in the literature describing contamination by P.. The care must be taken in performing these tests. However. The chapter on Microbial Limits Tests provides methods to assure that one may test for those microbial requirements in the individual monographs. 27]. 2005 meeting of the Pharmacopeial Discussion Group (PDG) held in Chicago.compromised patients. For example. Pharm Eur) Microbial Limits Tests are in the final stages of harmonization. but not all objectionable organisms. the USP Microbial Limits Chapter <61> provides methodology for selected indicator organisms. it may be acceptable to identify isolates when testing shows high levels. Microbial Limit Tests: The microbial limit Tests are designed to perform the qualitative and quantitative estimations of specific viable microorganisms present in samples.6. and the final. the present chapter does not preclude the detection of Ps.3. However. Therefore. isolates from plate counts. However.. The Microbial Limits Tests are actually two chapters in the Journal of Pharmacy Research Vol. it is widely recognized that Pseudomonas cepacia is objectionable if found in a topical product or nasal solution in high numbers.1. harmonized test is not yet Table 1: harmonized chapter numbering scheme: [11. as well as enrichment testing. The importance of identifying all isolates from either or both Total Plate Count testing and enrichment testing will depend upon the product and its intended use. 25]. we do know that the harmonized tests do not differ greatly from the drafts published in 2003 (USP 2003a. A relevant example of this problem is the recall of Metaproterenol Sulfate Inhalation Solution. so that microbial contamination from the outside can be avoided . nor does it provide procedures for detecting thousands of other potentially pathogenic organisms. should be identified” [26. if an oral solid dosage form such as a tablet is tested. the identification should not merely be limited to the USP indicator organisms. / Journal of Pharmacy Research 2010. Obviously.4 Microbiological Quality of Nonsterile Pharmaceutical Products public knowledge. and this prompted increased attention to microbial content of non-sterile drugs. The USP XXII monograph requires no microbial testing for this product. In a one page Stimuli to the Revision Process the microbiology committee of the time states : “The tests described in the Microbial Limits Tests <61> were not designed to be all-inclusive. Microbial testing may include an identification of colonies found during the Total Aerobic Plate Count test. 29]. an extensive text on laboratory detection of microorganisms would be required.Poonam Kushwaha et al. to detect all potential pathogens. for other products such as topicals. as the current tests will be disappearing. [26. 3(1). The chapter does not provide specific methods for this. Additionally. They were signed off to Stage 6A at the November. USP 2003c).January 2010 124-131 . However. and 25].Issue 1. most non-sterile medications in the US were not required to assay for microbiological quality attributes until the introduction of the Microbial Limits Tests in 1970. Cepacia – the organism requires subsequent differentiation. This lead to the addition of requirements in the 21 CFR to ensure that there are not objectionable organisms in product released to market [11. cepacia (currently Burkholderia cepacia) and its survival in disinfectants. Nevertheless. these organisms would not have been identified by testing procedures delineated in the general Microbial Limits section of the Compendia . 21. 23] USP <61> Microbiological Examination Of Nonsterile Products: Microbial Enumeration Tests <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms <1111> Microbiological Quality of Nonsterile Pharmaceutical Products EP 2.. yet. The classical example being the Pseudomonas cepacia contamination of Povidone Iodine products reported by a hospital in Massachusetts several years ago [24. i. USP had a test for the “Bacteriological Examination of Gelatin” as early as 1942. To accomplish this. Individual monographs include requirements for limits on total aerobic counts and/or absence of one or more of the four selected “indicator” organisms. This makes the description of the test a bit difficult. IL USA (USP 2006a). inhalants or nasal solutions where there is a major concern for microbiological contamination.
e. 12. These organisms are specified in monographs.. In addition to standards applying to the products themselves. with (at least in the author’s opinion) significant changes from the current USP.” A test in the “Microbial Limits” chapter demonstrates the absence of P. there are also microbial standards applying to the conditions under which drug products are allowed to be manufactured. Non-sterile preparations have less stringent requirements regarding exclusion of microbes. FDA has been concerned about objectionable organisms. But. 21. it does not meet FDA’s concern that all microorganisms in a nonsterile product should be acceptable to the product and the target population (i.” This is reinforced by 21 CFR 211. this is not the major change.” This issue is addressed in the final section of this review because the harmonized Chapter ‹1111› deals with “other organisms. as well as the harmonized document. These manufacturing standards (Good Manufacturing Practices or GMPs) are intended to ensure that finished product standards are being attained consistently. (b) There shall be appropriate laboratory testing. 3(1).113 and 21 CFR 211. The “Control of Microbiological Contamination (a)” section of 21 CFR 211. as necessary. or material filtration and then placing the membrane filter on an agar plate surface. The method of plating can be pour plate. 26. This presents two areas of concern relevant to microbial control: first. the allowance for twice the specification in observed results is significant. designed to prevent objectionable microorganisms on drug products not required to be sterile.January 2010 . A full description of the MPN method is outside the scope of this article. 23. If the product cannot be put into a solution. The membrane filtration method should only be used when few CFUs are expected to be found in the material to be tested.” Thus.” Tables IIIa–c presents the existing “Microbial Limits—Absence of Specified Microorganisms” tests from the current USP and Pharm Eur. But. The preferred method is to put the material into a solution and then plate the aliquots to determine the CFUs/g (or mL) of initial material. that the product should be protected (usually by its packaging) from additional contamination after release to market. spread plate. 28 and 29] USP<61>”Microbial Enumeration” The microbial enumeration test is a basic. Chapter ‹1111› “Microbial Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use” is a relatively short section that has a significant impact. Though membrane filtration is a good method to test a large volume of liquid.113 states. 27.. Before the introduction of the harmonized Chapter ‹1111›. and may assist in determining whether revalidation of method suitability studies is needed. 25. It is presented as an aid to evaluation. aeruginosa. This will be modified in the harmonized version to mirror the European format:  Microbial standards: Microbial standards for drug products are published in the pharmacopoeias and/or are required by regulatory agencies for their registration. They need not be sterile but it has to 124-131 Journal of Pharmacy Research Vol. FDA is bound by the concern expressed in the Code of Federal Regulations (21 CFR 211. are not “objectionable”). industry has had a problem.165 which states in the section “Testing and release for distribution. / Journal of Pharmacy Research 2010. that the product should be formulated to prevent proliferation of any microorganisms that may have been present at tolerable levels at the time of release . and second. shall be established and followed. The microbial standards applying to drug products are expected to be maintained until time of use by the patient (or healthcare professional) and throughout their shelf-lives. There is a significant controversy in the United States over the intent of this evaluation. It should be noted that this harmonized chapter represents a true compromise by all parties. Pharm Eur. and JP chapters. these standards are concerned with the protection of the public from infection by limiting the numbers and types of microorganisms to levels that are unlikely to be harmful.3. but interested readers can refer to the discussion in the US Food and Drug Administration’s Bacterial Analytical Manual. USP <62> “Absence of Specified Microorganisms USP <1111> “Microbial Quality”: a new compendial consideration of “other organisms” current USP: Current USP <61> Microbial Limits Tests (USP 2006b) and <1111> Microbiological Attributes of Nonsterile Pharmaceutical Products (USP 2006c). simple design to count the number of colony-forming units (CFUs) in a nonsterile product or raw material.124-131 USP harmonized chapters: [11. “Appropriate written procedures. it can only count as many as 100 CFUs/membrane.165) relating to the importance of “objectionable microorganisms. the most probable number (MPN) method has several provisions to use. of each batch of drug product required to be free of objectionable microorganisms.. Generally. USP was only interested in specified organisms.Poonam Kushwaha et al.Issue 1. The USP monograph for a product (as provided in the current National Formulary [NF]) may require the “Absence of Pseudomonas aeruginosa. Although this test may be needed to demonstrate compliance with the monograph requirements laid out in the National Formulary. For the US reader.
Pharm. 4. Worse. These contaminants can lead to unpredictable pharmacological effects or super. Applied microbiology. These techniques share a common goal: to provide a high level of assurance that finished drug products meet their intended and defined specifications. 3(1). 2. 1968. page no. 2002.Look mart find articles. Harmonization of the microbial limit tests.org/PMF News 12. draft guidance. and Arora . USP. Harmonization of US and EUROPEAN Microbial limit tests. 10. 66-73. 55 (5.microbial%20%imp/ controlled%20envirnment%20%20understanding%20contamination. Chatwal.nsf/ 7bd44c20b0dc562649256502001b65e9/146fd852c d5e269049 256f 32001a133e/$FILE/B26. Rockville. Anthony. “guide to inspection of microbiological pharmaceutical quality control laboratories. & Sutton. Chapter ‹1111›. Rockville. Parenteral Drug Association (PDA) Technical Report #13.) 19. Monitoring your production envirnment . Lee.pdf. 12. pp. the FDA. August 2003). Sutton. Scott.microbiol. Scott. Sutton. page no. / Journal of Pharmacy Research 2010. The harmonization of the microbial limit test – Enumeration. requires manufacturers to employ a number of technical and scientific techniques in the manufacturing cycle.pdf ) 29.microbiol. them. pharmaceutical technology. march 2003.January 2010 124-131 .swissmedic.2006.org/docs/ sutton. Joseph. Chapter ‹61›. drug information journal. Sutton. “Antimicrobial effectiveness testing. 28. Microbial limit test. http://www. “Guidance for Industry. Xaver. Vishweshwar.” Pharm Forum. “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests. 3. (http:// www. pp.org/docs/sutton.pdf) 26.R.Sci. Process risk assessment to ensure microbial contamination control.microbiol.M.1.ch/files/ pdf/SMI. 24. US food & drug administration. Compendia also provide harmonized microbial limit tests which helps in their control. (http://www. 29 (5). “Microbial Limits Tests. Dabbah.( http://www. A. (www.2007. 2006. Envirnmental conditions for the microbiological examination of nonsterile products.(http:// www.html) 25.Poonam Kushwaha et al. Scott.” USP 27–NF 22. Grill. ( http://www. vol. vol. pharmaceutical technology. “Microbiological Quality of Nonsterile PharmaCONCLUSION: Unwanted and potentially dangerous microbiological contaminants in pharmaceutical manufacturing have long been an area of concern. 5. (http://www.TI. 2002. (http:// www. Sutton.quality control. 2001 pp.pdf. 2006. Conflict of interest: None Declared Journal of Pharmacy Research Vol. Microbial control of pharmaceuticals. Knapp. 2006. Clontz. 2006 . Pharma Times. USP.3.” (FDA. Gronostajski. Technol. Scott. 7. they may be toxic. Goingtomeet_com Microbial Contamination .0604. Method for microbiological testing of nonsterile pharmaceuticals. viva pharmaceutical. Himalaya publishing house.) 14. Preventive Actions. Stability of drugs: microbiological stability. north carolina biotech centres.124-131 be shown that some specifically named organisms are not present in no.E. 2002.gov/ora/inspect/ _ref/igs/micro. Troubleshooting microbial contamination in an industrial environment.pharmpedia.pharm.Nov 24. 1714–1722. 2004). Nigel. 2005. Suppl.01_01. 2003.2006. FAQ on impurity profile for the bulk drugs. Scott. FDA. FDA. 97-98. Mould & Bacteria Reviews. 27. page no. through its Current Good Manufacturing Practices (cGMP) regulations.”J. Microbial contamination of sterile and nonsterile articles.jp/zaidan/FFCRHOME. Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice. Buhlmann.or sub-potency of the active drug substance.2006. 19191923.4. vol.htm) 20.2001.or. Scott.” USP 29–NF 24 (US Pharmacopeial Convention. 1733–1735.ffcr. MD.pdf. Rockville. And Leyla. Microbiological attributes of nonsterile pharmaceutical products. Because of the potentially dangerous implications of these contaminants on patient safety. Scott. REFERENCES: 1. 21.pda. Roger.technol. General Chapter 51. 1. Activities of the USP microbiology subcommitte of revision during the 1995-2000 rivision cycle.pharm.org/docs/ sutton.pdf) 22.technol.) 15. (http://www.2148– 2150 23.microbiol.Issue 1. the microbiology network. November. March16. King. Source of support: Nil. Microbiology forum. D. “Revised fundamentals of an environmental monitoring program.Corrective Actions. Microbial analysis.Corrective actions. MD. Joseph. Lucia.org/docs/sutton.2001.H. old e –ept.).com/ Stability_Of_Drugs:Microbiological_Stability 6. 2503–2508. Toksoy.technol. 33. 29 (5). GR. Sutton. page no. & Knapp. Chapter ‹61›. 13. no. 34. the difference between ‘’ absence of objectionable microorganism and absence of specified microorganism. 28-71.pdf) 16. Quality control issues related to biological products: microbiological contamination. S & Gupta. 9. (US Pharmacopeial Convention.2. Microbial contamination.M impurities and pharmaceutical substances and their limit test. Pharmaceutical technology. Nov 23. 17. The role of USP in the assessment of microbiological Quality of Pharmaceuticals five-year retrospective leading to the future. Microbial limit tests. pharmaceutical chemistry (inorganics). 18. 2003. (http://www. Judy. Issue: #11. page ceutical Products.pharm. Sutton. 2006. technical interpretation.” Pharm Forum. Understanding control of contamination for process validation. Preventive actions. PMF Newsletter. 1753-1764. Fowler. 16. 8. MD.) 11. vol.
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