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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: firstname.lastname@example.org
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
and the ambient temperature. dried aluminum phosphate. water used in the processing. soil Gram (+) cocci –personnel Gram (-) rods -water. Once the contaminating organism has been identified.3. Recommended control of microbial contamination in natural pharmaceutical substances:  Types of microbial contamination  If contamination involves the product or raw material. 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. it is important to have an idea of the possible contaminants (i.e. of raw materials or Extrinsic. microbiological analysis of the product/raw material and the air within the processing area is recommended. samples of the contaminated material should be sent to a reputable laboratory for analyses.. For non-sterile products it is a balance between the cost of reducing contamination against possible risk to the consumer and product .. etc. equipment or even the workers handling the product/raw materials. Various sources of microbial contamination include [6.g.Freedom from salmonellae: acacia. rust.January 2010 124-131 . The primary contamination may be: Intrinsic. synthetic products Water activity level Containers (cardboard boxes) b) Water Systems (Purified Water. The goal of the investigation could be to determine the nature of primary contamination and the causes. Generally.Issue 1. All aspects of formulation and manufacture should try to minimize contamination. . soil Sources of Microbial Contamination: Micro-organisms will contaminate formulations from a wide variety of sources. the product and environmental factors. during or after processing Since contamination of raw materials or the product may originate from contaminated air. Environmental factors may include pH and water activity of the product or raw material. 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.Raw materials/ excipients a) Components Natural vs. improper handling by the workers. The significance of contamination in a processing industry is determined by a number of factors as well as properties of the microorganism(s) concerned.e. The source or the cause of primary contamination requires to be identified for appropriate action to be taken. senna. dust.Freedom from escheria coli: sterculia .. Similarly. This is critical for sterile products.e. soil q Fungi yeast personnel q Mold (filamentous Environment.i. aerosolized product). tregacanth . q Bacteria fungi) Gram (+) rods -environment. WFI) Biofilm 2. / Journal of Pharmacy Research 2010. When investigating microbial contamination in an industrial setting.i. 7]: 1. 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. Factors contributing to multiplication of microorganisms to unacceptable levels may include improper storage conditions.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. 3(1).Freedom from pseudomonas: dried AlOH3.) Ineffective EM Program 4-Personnel (Major potential source of microbial contamination) Journal of Pharmacy Research Vol. available nutrients (e. Contamination originating from raw materials can contaminate hands of workers and then be transferred to the product and equipment. likely sources of contamination and the stages in the processing where contamination of the product or raw material is most likely to occur. it is then easy to design suitable sampling strategies to trace the source of contamination . These factors determine what microorganism(s) would be the dominant contaminant(s) and the level of spoilage of the product or raw material..Poonam Kushwaha et al. the “natural-flora”).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 .
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. Environmental contaminants are micro-organisms that are present in the production facility. 3(1).0 IU/mg NMT 05. This method is especially useful. The suspected colonies can be further evaluated. 12]. 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 .124-131 Microbial Contamination in Nonsterile Products: Exposed skin (flakes. 15]. Accordingly. 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. specific amino acids. resulting in false negative results. the “absence of objectionable microorganisms”) from the product. Some of the specific media support the growth of essentially all micro-organisms (referred to as rich media). Differential media uses specific media for the detection of microbial contaminants. Companies should put plans in place immediately for this work and show consistent progress toward this goal. which the sponsor is aware of in these microorganisms prior to production .0 IU/mg NMT 0. This is because the amount of microbial contamination in the biological product can be very low. in order to improve the sensitivity of detecting microbial contamination. The composition of these media is sometimes modified to limit or inhibit the growth of biological products. Components that are sometimes used to limit or inhibit the growth of the biological products can be specific antibiotics. For selective media. and it is FDA’s clear expectation (as described in CFR) that this will include a determination of the microbial safety (i. and strains of the microbial contaminants are known. The internationally harmonized chapters provide a strong framework for this assurance . The introduction of these three harmonized chapters is likely to require some revalidation of existing methodologies. microbial contaminants are detected by the formation of colonies. the US Code of Federal Regulations (21 CFR) clearly requires the manufacturer to produce products free of” objectionable organisms. An immunofluorescence assay can be used to determine the presence of microbial contamination. when the type.083IU/mg NMT 0. The manufacturer is responsible for the quality and safety of the product marketed. and their growth in the presence of a large quantity of biological product can be limited or inhibited. species. In formulating such regulations. and commonlyknown microbial contaminants.. such as by Polymerase Chain Reaction (PCR).0 IU/mg Microbiological testing of nonsterile pharmaceuticals has thus far been performed only in special cases.0IU/mg NMT 300. / Journal of Pharmacy Research 2010. or other specific chemicals or nutrients . For rich media. Detection of Microbial Contamination in Biological/ Sterile Products: Many tests can be used to detect microbial contamination of biological products. Harmonized Chapter (1 11 1) recommends the determination of the risk associated with “other organisms.3. regulations concerning the permissible level of nonpathogenic microorganism in non sterile drugs exist in only a few countries. this assay should be validated to detect cross contaminants and commonly-known contaminants. Microbiological control of such products is necessary until now.Issue 1. Other media support the growth of specific micro-organisms (referred to as selective media).00 IU/mg NMT 55. 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. 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.25 IU/mg NMT 4. environmental contaminants. 124-131 Journal of Pharmacy Research Vol.25 IU/mg NMT 1.50 IU/mg NMT 0.e.” It must be stressed that FDA’s concern about objectionable organisms” is not the same as the compendial tests for “specified” organisms.0 IU/mg NMT 0. 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.01 IU/mg NMT 10. Commonly-known microbial contaminants are well-known to frequently cause contamination in biological products .5 IU/mg NMT 500. and can detect relatively low levels of microbial contaminants.Poonam Kushwaha et al. ) [14. consideration must be given to the promotion of hygiene and safety as well as to the feasibility of application in GMP . Nonsterile products are subject to process controls from a microbiological perspective. microbial contaminants are detected by the presence of colonies that have different morphologies from those of the biological products. Cross contaminants are biological products that are manufactured at the same manufacturing facility. Some of these tests are described in subsequent paragraphs . Though these controls are not as stringent as those for aseptic manufacture.January 2010 .” which is in agreement with the FDA expectation for absence of “objectionable” organisms [11.
A variety of tests. This may involve obtaining samples at each stage of production for the presence of micro-organisms unrelated to the biological products. that contamination of protected areas and materials (production) is excluded. 211. Environmental monitoring should be performed before. Laboratory waste must be disposed of such. performance in a Laminar-Air-Flow Cabinet to reduce the contamination risk .Issue 1. and so forth. microbiological contaminants are also routinely controlled by removal. The execution of testing such as on growth promotion or on the efficacy of antimicrobial preservation in a given room. these findings have been in the Top Ten List of FDA Warning Letters. manufacturing processes. The growth medium and other components related to fermentation and production should be tested (eg. The overall goal of such a system is to prevent microbiological contamination of the pharmaceutical product [18. and processes from sources of microbiological contamination. designed to prevent objectionable microorganisms in drug products not required to be sterile. The testing of product samples for compliance with microbiological standards is only one small part of this. All microbial examinations must be performed under conditions designed to avoid accidental contamination of the product and of the product sample to be examined. with rinse and swab samples fully analyzed for confirmation according to validated cleaning procedures. and equipment thoroughly cleaned and sterilized. By and large. food (including dairy) have microbial contamination control procedures in place.113). or destruction . The control of microbiological contamination is an outstanding integral part of inspection findings. shall be established and followed. All downstream production processes (eg. 21CFR Sec.3. product-contact packaging components. In 2005. In-process controls should be performed to prevent and identify contaminants. designed to prevent microbio124-131 Journal of Pharmacy Research Vol. formulation. sterility test. microbiological test methods are product-destructive and. By and large. and after each production . Minimizing the risk of microbiological contamination of drug products is assured by the application of microbiological and physical standards and controls to starting materials. growth medium. manufacturing facilities. (b) Appropriate written procedures. Further measures include dedicated gowns and other protective clothing. All equipment (fermentor. these assurances are obtained by applying controls that protect materials. 3(1). Such conditions include examination to take place in a dedicated room i. during. an air pressure cascade system. physically and logistically separated from production areas by various means: by location and by restriction of access. e. 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) . The laboratory has to be monitored on viable count at appropriate and constant intervals. personal hygiene and beauty products. / Journal of Pharmacy Research 2010. The production areas should undergo environmental monitoring. Over the last years. etc. The facility should include features for control and containment of environmental and cross contamination of microorganisms. laboratory. strict separation of production workflow from laboratory workflow and of flow of personnel and materials etc. and equipment. washing. Examples are multiple suites or operations for different products. the production suite should be thoroughly cleaned .e. Control of Microbial Contamination: Microbial control of pharmaceuticals is primarily concerned with minimizing the opportunities for drug products to be contaminated by microorganisms. secure containment of biological products. as a consequence. do require stringent measures i. In most cases the implementation of appropriate hygiene programmes and measures have been implemented as an essential part for the manufacturing of pharmaceutical products. At the end of each production. as well as personnel monitoring. by individual air supply and exclusion of air flow from laboratory to production. a separate heating/ ventilating/air-conditioning system for each suite. filling) must be performed aseptically inside a Class 100 laminar flow hood.e. glassware. 11 citations in FDA Warning Letters were caused by a lack of control of microbiological contamination (21 CFR 211. inactivation. The sampling procedure in particular should be designed with special care. precludes product testing in this particular room.January 2010 . and microbiological sampling of products and raw materials are invaluable in detecting potential sources and routes of contamination.124-131 Steps for avoiding Microbial Contamination: There are some steps that should be taken to avoid microbial contamination.g.113 Control of microbiological contamination states that: (a) Appropriate written procedures.). and packing materials should be sterilized prior to use. it is unusual to find valid statistical sampling and testing being done at batch release. 19]. Processing industries such as pharmaceutical. for the detection of micro-organisms unrelated to the biological products. In recognition of the frailty of protective measures in all but the most extreme circumstances. or detection of microorganisms after extensive incubation) to ensure a lack of contaminating microorganisms. unless such analyses were carried out in a LaminarAir-Flow Cabinet. 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. by a bioburden test. equipment. Contamination especially in food industry can result to not only human morbidity and mortality but also to business losses . A series of regulations address the subject of microbiological facility control. centrifuge bottles. Regular hygiene monitoring of a plant and equipment. The integrity of the filters used for media sterilization should be tested before and after production. microbial monitoring of samples of purified water.Poonam Kushwaha et al.
The USP monograph for a product (as provided in the (b) There shall be appropriate laboratory testing. It is governed by the USP monographs found in the acceptable levels and types of microbiological contamination in prodNational Formulary (NF). in the 1993 instructional guide for inspections of Such validation and documentation may be accomplished in accor. (b) There shall be appropriate tion of sterility and/or pyrogen testing. In 1970.Microbiological Attributes Chapter <1111> provides little specific cessed material must meet appropriate standards.194 (a) (2). However.aeruginosa..QC Microbiology Labs the FDA states: dance with Sec. nasal solutions and inhalation products . 23]. The statistical quality control criteria shall include appropriate you must do that. as necessary. Where the requiretion of any sterilization process. 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 . as necessary. Coli [sic]. of each batch of drug product required to be free of objectionable microorganisms. ganisms in the product. In fact. animal and some mineral products for SalmoFrom the vantage point of USP.the target population (i. specificity. However. of current National Formulary) may require “Absence of Pseudomonas each batch of drug product required to be free of objectionable micro. topicals for P.objectionable microorganisms.” 21CFR 211. for Antibiotic/ Vitamin Potency. the product. but separate concerns.laboratory testing. the nature of the product. Dr.January 2010 124-131 . One such situation is with the CFR requirement that medicines be “free of (a) For each batch of drug product. The need for these ministration for yeasts and molds.Issue 1. such written procedure shall be fol.on the health hazard.test the finished product by the Microbial Limits Tests that in fact lease. provided such testing is com.” This is reinforced by 21 CFR 211.” There is a test in the Microbial Limits chapter to demonstrate the absence of Pseudomonas aeruginosa.. Through the literature and through our invesJournal of Pharmacy Research Vol. A number of specific monographs tests is not driven by any concern over “Good Manufacturing Pro. quality . shall be established and followed. The USP Reprocessing may be performed. Prior to acceptance and use. As a general guide for cess” (GMP).” The USP recommends that certain categories be routinely tested Regulatory Aspects: for total counts and specified indicator microbial contaminants. and articles intended for rectal. 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 . for Microbial Limits etc . “For a variety of reasons. 211.also include definitive microbial limits . here we have pleted as soon as possible. However.3. sensitivity. there is a need to have a test for nella.165 Testing and release for distribution states that: FDA’s concerns are not covered by a USP referee test method. there shall be appropriate labora.113 under the section tory determination of satisfactory conformance to final specifications “Control of microbiological contamination (a)” states “Appropriate for the drug product. drug products. Such procedures shall include validaFDA has similar. sterility.124-131 logical contamination of drug products purporting to be sterile. although organisms. are not “objectionable”) [11. 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. / Journal of Pharmacy Research 2010. ments are identical. prior to release. designed to prevent objectionable microorganactive ingredient. aeruginosa and S. This is purely a GMP concern. a problem . If there is a monograph that requires a test ucts. the referee chapters in USP (those numbered under <1000>) are enforced. then chapter <51> Antimicrobial Effective. for Aureus [sic]. example natural plant. 211. shall be established testing are conducted on specific batches of short-lived and followed.approval to market submission contained a statement that you would tical quality control criteria as a condition for their approval and re.e. we have seen a number of prob(f) Drug products failing to meet established standards or specifica. Dunnigan of the Bureau of Medicine of the FDA commented for antimicrobial efficacy.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. the Agency has been absolutely clear on the concern over objectionable microoracceptance levels and/or appropriate rejection levels.165 which states radiopharmaceuticals. but it is not sufficient to demonstrate microbial methods employed by the firm shall be established and documented.” So. including the identity and strength of each written procedures. and reproducibility of test might be necessary. oral liquids for E. Where sterility and/or pyrogen isms on drug products not required to be sterile. repro.lems associated with the microbiological contamination of topical tions and any other relevant quality control criteria shall be rejected. and that fact that testing to the USP chapter (e) The accuracy. lowed. specifications. 3(1).“Testing and release for distribution. this test may be required to demonstrate compliance with the mono(c) Any sampling and testing plans shall be described in written pro. such batches may be released prior to comple. or vaginal adBacterial Endotoxin.Poonam Kushwaha et al. for antimicrobial efficacy. there are situations where the 21CFR Sec. and the potential hazard to the user. For USP and FDA frequently are interested in the same thing. urethral. serious health hazard.
[26. it has been shown that a variety of infections have been traced to the gram negative contamination of topical products. for other products such as topicals. For example. and the final. Microbial testing may include an identification of colonies found during the Total Aerobic Plate Count test. and so we will use those drafts as the description of the finalized test [15. 27]. IL USA (USP 2006a). harmonized test is not yet Table 1: harmonized chapter numbering scheme: [11. USP had a test for the “Bacteriological Examination of Gelatin” as early as 1942.13 Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms 5. However. USP 2003c). the USP Microbial Limits Chapter <61> provides methodology for selected indicator organisms. and immuno. 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. Additionally. 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.Issue 1. 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. cystic fibrosis.3. each company is expected to develop microbial specifications for their nonsterile products . the signed-off versions have yet to be published. USP 2003b. but not all objectionable organisms.124-131 tigations.. it is widely recognized that Pseudomonas cepacia is objectionable if found in a topical product or nasal solution in high numbers.. 29]. The USP and the European Pharmacopoeia (EP. The Microbial Limits Tests are actually two chapters in the Journal of Pharmacy Research Vol. However.1. the identification should not merely be limited to the USP indicator organisms. The chapter on Microbial Limits Tests provides methods to assure that one may test for those microbial requirements in the individual monographs. nor does it provide procedures for detecting thousands of other potentially pathogenic organisms. This makes the description of the test a bit difficult.12 Microbiological Examination Of Nonsterile Products: Microbial Enumeration Tests 2. 2005 meeting of the Pharmacopeial Discussion Group (PDG) held in Chicago. Pharm Eur) Microbial Limits Tests are in the final stages of harmonization. 21.compromised patients. It includes tests for total viable count (bacteria and fungi) and coliform test to determine Escherichia coli. if an oral solid dosage form such as a tablet is tested. However. A relevant example of this problem is the recall of Metaproterenol Sulfate Inhalation Solution. Individual monographs include requirements for limits on total aerobic counts and/or absence of one or more of the four selected “indicator” organisms.January 2010 124-131 . 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. The classical example being the Pseudomonas cepacia contamination of Povidone Iodine products reported by a hospital in Massachusetts several years ago [24. an extensive text on laboratory detection of microorganisms would be required. there are no test methods provided in the USP that will enable the identification of the presence of this microorganism . Later in the 1980’s there was a series of articles appearing in the literature describing contamination by P. 27]. 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. Likewise. To accomplish this. Again. should be identified” [26. the present chapter does not preclude the detection of Ps. Cepacia – the organism requires subsequent differentiation. it may be acceptable to identify isolates when testing shows high levels. The USP XXII monograph requires no microbial testing for this product. and this prompted increased attention to microbial content of non-sterile drugs. yet. these organisms would not have been identified by testing procedures delineated in the general Microbial Limits section of the Compendia .e. Therefore. 3(1). as the current tests will be disappearing. and 25]. 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.4 Microbiological Quality of Nonsterile Pharmaceutical Products public knowledge. The care must be taken in performing these tests. Why is this concern? To understand this we have to go back to the 1970’s. The chapter does not provide specific methods for this. cepacia (currently Burkholderia cepacia) and its survival in disinfectants. i. Nevertheless.6. The agency classified this as a Class I recall because the product was contaminated with Pseudomonas gladioli/cepacia. inhalants or nasal solutions where there is a major concern for microbiological contamination.Poonam Kushwaha et al. Microbial Limit Tests: The microbial limit Tests are designed to perform the qualitative and quantitative estimations of specific viable microorganisms present in samples. 25]. isolates from plate counts. so that microbial contamination from the outside can be avoided . as well as enrichment testing. to detect all potential pathogens.. / Journal of Pharmacy Research 2010. 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. However. The procedures in USP were designed to detect the presence of specific “index” or “indicator” organisms. They were signed off to Stage 6A at the November. Obviously. we do know that the harmonized tests do not differ greatly from the drafts published in 2003 (USP 2003a. In the late 1960’s several outbreaks of disease were traced back to pathogen contaminated medications.6.
There is a significant controversy in the United States over the intent of this evaluation. But. 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.” This issue is addressed in the final section of this review because the harmonized Chapter ‹1111› deals with “other organisms. 27. the most probable number (MPN) method has several provisions to use. 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 .3.” Tables IIIa–c presents the existing “Microbial Limits—Absence of Specified Microorganisms” tests from the current USP and Pharm Eur. simple design to count the number of colony-forming units (CFUs) in a nonsterile product or raw material.” Thus. / Journal of Pharmacy Research 2010. It should be noted that this harmonized chapter represents a true compromise by all parties.165) relating to the importance of “objectionable microorganisms.124-131 USP harmonized chapters: [11. shall be established and followed. 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. 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. designed to prevent objectionable microorganisms on drug products not required to be sterile.. Though membrane filtration is a good method to test a large volume of liquid. For the US reader. the allowance for twice the specification in observed results is significant. A full description of the MPN method is outside the scope of this article. are not “objectionable”). Pharm Eur. and JP chapters. The “Control of Microbiological Contamination (a)” section of 21 CFR 211. 12. These manufacturing standards (Good Manufacturing Practices or GMPs) are intended to ensure that finished product standards are being attained consistently. of each batch of drug product required to be free of objectionable microorganisms. and may assist in determining whether revalidation of method suitability studies is needed. 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. 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).165 which states in the section “Testing and release for distribution. 21.113 and 21 CFR 211. But.” A test in the “Microbial Limits” chapter demonstrates the absence of P. The method of plating can be pour plate. as well as the harmonized document. aeruginosa.Issue 1. 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.. with (at least in the author’s opinion) significant changes from the current USP. Generally. or material filtration and then placing the membrane filter on an agar plate surface. FDA has been concerned about objectionable organisms. They need not be sterile but it has to 124-131 Journal of Pharmacy Research Vol. Before the introduction of the harmonized Chapter ‹1111›.113 states. industry has had a problem. Although this test may be needed to demonstrate compliance with the monograph requirements laid out in the National Formulary. FDA is bound by the concern expressed in the Code of Federal Regulations (21 CFR 211. as necessary. If the product cannot be put into a solution.January 2010 . there are also microbial standards applying to the conditions under which drug products are allowed to be manufactured. that the product should be protected (usually by its packaging) from additional contamination after release to market. 23. The membrane filtration method should only be used when few CFUs are expected to be found in the material to be tested. USP was only interested in specified organisms.Poonam Kushwaha et al. In addition to standards applying to the products themselves. this is not the major change. 26. 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. The USP monograph for a product (as provided in the current National Formulary [NF]) may require the “Absence of Pseudomonas aeruginosa. This presents two areas of concern relevant to microbial control: first. “Appropriate written procedures. but interested readers can refer to the discussion in the US Food and Drug Administration’s Bacterial Analytical Manual. Non-sterile preparations have less stringent requirements regarding exclusion of microbes. (b) There shall be appropriate laboratory testing. spread plate. it can only count as many as 100 CFUs/membrane. 25. 28 and 29] USP<61>”Microbial Enumeration” The microbial enumeration test is a basic.. 3(1). It is presented as an aid to evaluation. and second.” This is reinforced by 21 CFR 211.e. These organisms are specified in monographs.
Parenteral Drug Association (PDA) Technical Report #13. Scott. 2002.pdf) 22. Applied microbiology. Nigel.2006. 12. 2503–2508. August 2003).microbiol.swissmedic.E. 28.2006. & Knapp. Joseph. Source of support: Nil.2148– 2150 23. page ceutical Products. Judy. Roger.) 14. pharmaceutical chemistry (inorganics).htm) 20. the difference between ‘’ absence of objectionable microorganism and absence of specified microorganism. (http://www. http://www. 29 (5). technical interpretation.ffcr. 1753-1764. (US Pharmacopeial Convention. US food & drug administration. S & Gupta. Vishweshwar. vol. 3. “Guidance for Industry. pharmaceutical technology.html) 25. Understanding control of contamination for process validation. 2002.Corrective actions. (www. Gronostajski.org/docs/sutton. “Revised fundamentals of an environmental monitoring program. Quality control issues related to biological products: microbiological contamination.” (FDA. Scott.pharmpedia. “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests.) 11.com/ Stability_Of_Drugs:Microbiological_Stability 6. 2001 pp.Sci. Pharmaceutical technology. 2006. Mould & Bacteria Reviews. 5. Goingtomeet_com Microbial Contamination . 2006.pdf. 1733–1735. MD. Troubleshooting microbial contamination in an industrial environment.).” USP 29–NF 24 (US Pharmacopeial Convention. Microbial contamination of sterile and nonsterile articles.2001. Monitoring your production envirnment .pharm.pdf) 16. 28-71.org/PMF News 12.nsf/ 7bd44c20b0dc562649256502001b65e9/146fd852c d5e269049 256f 32001a133e/$FILE/B26. Scott. Rockville. Rockville. Joseph. Preventive Actions. 97-98. 18. Pharma Times. 2006. pp. no. viva pharmaceutical.org/docs/ sutton. Envirnmental conditions for the microbiological examination of nonsterile products. Lee. GR. Scott. 2004). March16. 1968. Nov 23. 13.Poonam Kushwaha et al.microbiol.or sub-potency of the active drug substance. Grill. them.pdf. Preventive actions. Chapter ‹61›.”J. 16. (http://www.pharm.” Pharm Forum. 55 (5. “Microbiological Quality of Nonsterile PharmaCONCLUSION: Unwanted and potentially dangerous microbiological contaminants in pharmaceutical manufacturing have long been an area of concern. page no. Pharm.01_01. vol.M impurities and pharmaceutical substances and their limit test. REFERENCES: 1. Sutton.4.technol. Harmonization of the microbial limit tests. USP. the FDA. 3(1). Sutton. 2006.3. pharmaceutical technology.Issue 1.ch/files/ pdf/SMI. requires manufacturers to employ a number of technical and scientific techniques in the manufacturing cycle. 1714–1722.microbial%20%imp/ controlled%20envirnment%20%20understanding%20contamination. 24.0604. Scott. FDA. “Antimicrobial effectiveness testing.gov/ora/inspect/ _ref/igs/micro. north carolina biotech centres. they may be toxic. “guide to inspection of microbiological pharmaceutical quality control laboratories. Process risk assessment to ensure microbial contamination control. Chapter ‹61›. Technol.H. Microbial analysis. Microbial control of pharmaceuticals. 9. 2005. 4. PMF Newsletter. Dabbah.) 19.R. 66-73. 1. Compendia also provide harmonized microbial limit tests which helps in their control.Nov 24.microbiol. Anthony. Microbial limit tests. Clontz.) 15. Sutton. 19191923. Sutton.jp/zaidan/FFCRHOME.technol. Microbial limit test. Activities of the USP microbiology subcommitte of revision during the 1995-2000 rivision cycle.org/docs/ sutton. 2003.” USP 27–NF 22.2007. page no. Chapter ‹1111›. Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice. 2. and Arora . 34. the microbiology network. Worse. old e –ept.quality control.( http://www.microbiol. Knapp. A. Because of the potentially dangerous implications of these contaminants on patient safety.(http:// www. These techniques share a common goal: to provide a high level of assurance that finished drug products meet their intended and defined specifications.pdf. D. USP. FAQ on impurity profile for the bulk drugs. FDA. Rockville. 7. MD.2006. Microbial contamination. draft guidance. Fowler. Scott. pp.Look mart find articles. Xaver. (http://www. The role of USP in the assessment of microbiological Quality of Pharmaceuticals five-year retrospective leading to the future. These contaminants can lead to unpredictable pharmacological effects or super.124-131 be shown that some specifically named organisms are not present in no. drug information journal.pdf) 26. 29 (5).pharm.pdf ) 29.M.2001. march 2003. November. 2002. Harmonization of US and EUROPEAN Microbial limit tests. MD. (http://www.” Pharm Forum. ( http://www. The harmonization of the microbial limit test – Enumeration. page no. 21. vol. Lucia. 8. 17. Conflict of interest: None Declared Journal of Pharmacy Research Vol. Himalaya publishing house.1. vol. / Journal of Pharmacy Research 2010. 2006 . (http:// www. Microbiology forum. (http:// www. page no.org/docs/sutton. “Microbial Limits Tests. Sutton. Chatwal.January 2010 124-131 .2. Microbiological attributes of nonsterile pharmaceutical products. 27. through its Current Good Manufacturing Practices (cGMP) regulations. & Sutton. Issue: #11.pda. King.technol. General Chapter 51. Buhlmann. 10. Scott. And Leyla. Stability of drugs: microbiological stability.TI.or.Corrective Actions. Toksoy. Method for microbiological testing of nonsterile pharmaceuticals. 2003. Sutton. Suppl. 33.
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