Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Informa Healthcare. <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests. These testing techniques determine if a product meets quality specifications for bioburden testing and microbiology testing. This document is not intended to provide scientific or other advice to be used in a specific fact situation and is intended for general information purposes only. From raw material procurement to the manufacturing process, to the evaluation of the finished product, these standards cover every aspect of the manufacturing supply chain. In the upcoming months, many companies will have to evaluate their non-sterile products to these updated methods. long been recognized as an invaluable instrument to gain an understanding of microbial complex poses a contamination risk in non-sterile, water-based drug products. For years, Sara worked in a hospital, making care possible for others. How are USP 61 product tests performed? The presence of certain microorganisms in nonsterile preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient. the manufacturing process. But it came back in 2019 and just as she was about to start treatment, the pandemic hit. From raw ingredient testing to navigating complex regulations, our dedicated team of researchers, scientists and technicians deliver solutions with accuracy, precision and confidence. 7. A passing result indicates the absence of the tested specified microorganism. Sterilization kills any microorganisms inside the products obtained during manufacturing. Collectively, we offer decades of technical expertise to the pharmaceutical industry, says Timothy Klock, laboratory director of the organizations Wilson, NC, testing facility. in pharmaceutical components or finished product. The bio in bioburden refers to live biological organisms, and the burden in bioburden refers to the concentration of the viable biological organisms. Saudi Pharm J. .a{fill:#4e565b;}.b{clip-path:url(#a);} Report, New Medicines, Novel Insights: Accelerating development of cell and gene therapies, By Chris Learn, Ph.D., PMP, Vice President, Head of the Cell and Gene Center of Excellence, Discussions on Diversity: Gender Identity, .a{fill:#4e565b;}.b{clip-path:url(#a);} Webinar, Adaptive strategies for more efficient, data-rich and patient-friendly trials, By Nate Akers, Senior Vice President, Business Development. The acceptance criteria require the detection of the specified organism. Our experts help you stay at the forefront of the industry - and ahead of change. The procedures and acceptance criteria for effectiveness apply to a product in the original, sealed container in which it was distributed by the manufacturer. By clicking the "Sign up" button below you agree to the terms and conditions of Our Privacy Policy. Our diverse work portfolio includes broad analytical offerings and tested insights across the environmental, foodand life science markets and with 50 years of honing our craft, we offer results you can trust. Want to collaborate with us to offer clinical trials at your site? The end goal for the USP <61> agar methods is to achieve colony forming units or cfu per gram or mL of product. Each organism or organism cluster in a product that is properly diluted and cultured, with appropriate media and temperature conditions, will eventually grow to a colony forming unit that can be visibly counted with the naked eye. Although USP <61> is the legal referee method, this culture test is notoriously inaccurate. A single colony forming unit might actually be several microbes clustered together. And accuracy is further compromised when conducting a series of dilutions. Living systems do not always behave as predicted, and factors such as media age, water content, temperature distribution, and presence of inhibitory compounds may all impact the accuracy of bioburden count. In fact, the USP states that cfu counts which are within 50 200% of one another are considered to be equivalent counts. All Rights Reserved. Registered manufacturers of sterile pharmaceuticals are required to follow Current Good Manufacturing Practices (cGMPs) and adhere to rigorous quality standards to validate the stability, safety, and efficacy of products. Yellow or White Colonies with a Yellow Zone. 10. Results are compared to USP acceptance criteria provided in USP <1111>. Stay in touch with us to get the latest news on microbiology testing and special offers. What are USP 1111 Microbial limits? If you want, you can find out more about it in our Privacy Policy. effective and that the facility is in a state of control. Industry is Growing. International Organization for Standardization. We provide routine and specialty analytical testing to assist a broad range of companies and government agencies with their compliance reporting. United States Pharmacopeial Convention. Approach. Consumer Product Testing Company and CPT are service marks of Consumer Product Testing Company, Inc. USP <61> Microbial Enumeration Tests includes changes in pass/fail criteria and includes longer incubation durations than in previous editions. Operations Technology Cybersecurity Incident Response: Are You Ready? Michael J. Akers. For decades, microbial contamination has been a major problem for pharmaceutical manufacturers, both here and abroad. On a daily basis, we commit ourselves to provide superior service to our valued customers whether they are large, small, or virtual.. USP <1111> providesabsence of specified microorganism criteria based on sample type (raw material or finished drug product) and route of administration. Ethide Labs is an ISO 13485 certified contract testing organization specializing in EO residual and microbiology testing for medical devices. 2021. The new media and solutions recommended are: The Suitability of the Test Method demonstrates that the test specimen to which the testing is applied does not, of itself, inhibit the recovery of the microorganisms that may be present. (USPC <1116>). The Most-Probable-Number (MPN) Methodis generally the least accurate method for microbial counts; how- ever, for certain product groups with very low bioburden, it may bethe most appropriate method. The use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract). of these official methods. Exceptions to this are aerosolized products and transdermal patches. Method Development & Validation Expertise, Preservatives, Antiseptic Products Testing, Microbial Limits / Test Method Suitability, Custom Research Projects / Client Specific Protocols, Skin Irritation and Corrosion Equivalency Assays, Oral and Vaginal Tissue Irritation Equivalency Assays, In-Vitro and In-Chemico Skin Sensitization Assays, Review of Product Claims for the US Market, Determination of Legal Status of Proposed Products for the US Market. Furthermore we understand the connection between the quality of the. If the acceptance criterion is not met, it may be due to the inherent antimicrobial properties of the sample that needs to be neutralized. Rockville, MD, USA. To perform an accurate TAMC test, you should place the TAMC filter on the Tryptone Soya Agar (TSA) media and incubate at 30-35 degrees Celsius for 3-5 days. Culture time and temperature are dependent upon the type of agar plate being incubated. Drugs and the Pharmaceutical Sciences. Important News: Ethide will soon be part of Millstone Testing Services. The higher the concentration of viable organisms on a device or product, the higher the burden is to kill those organisms, whether it is killing the organisms through sterilization procedures or killing the organisms through the effort of the human immune system. Certain microorganisms in nonsterile preparations can reduce or inactivate the therapeutic activity of the product. The presence of disease, wounds, organ damage. Save my name, email, and website in this browser for the next time I comment. When an acceptance criterion for microbiological quality is prescribed, it is interpreted as follows: 10 1 cfu: maximum acceptable count = 20; 10 2 cfu: maximum acceptable count = 200; 10 3 cfu: maximum acceptable count = 2000; and so forth. These incidents prompted the FDA to issue an emergency advisory reminding drug manufacturers to follow a list of specific actions, such as analytical testing of incoming ingredients, to prevent the commercial release of unsafe products.9. The difference between the pour-plate method and surface spread method is that the agar is poured onto the sample dilution for the pour-plate method. Thus, most microbial counts are recommended for the membrane filtration method or the Plate-count Method. There are three primary microbe types that require appropriate sterilization (elimination) before medical product usage: bacteria, fungi (yeast and mold), and viruses. The timing of incubation and temperature of incubation depends upon the agar type. If you disable this cookie, we will not be able to save your preferences. USP 1111 provides bioburden limits (in colony forming units) for different types of therapeutic applications. As mentioned above, antimicrobial properties of the product may inhibit the growth of a microbe in agar to become a visible colony forming unit. Validation or suitability is accomplished by inoculating plated product with low levels (<100 cfu) of test species and demonstrating equivalence to recovery of that organism in the absence of the product. Microbial enumeration methods are considered suitable if product results are 50 200% of control results.
USP <62> is critical to ensure dosage forms do not contain specific microorganisms of concern. When an acceptance criterion for microbiological quality is prescribed, it is interpreted as follows: 101 cfu: maximum acceptable count = 20; 102 cfu: maximum acceptable count = 200; 103 cfu: maximum acceptable count = 2000; and so forth. monograph USP <61>, <62> and <60> are dedicated to testing When routine testing results fall out of specification, an investigation is initiated to discover root cause and to establish corrective and preventative actions. Retrieved from https://www.nosco.com/blog/the-pharmaceutical-industry-is-growing, 4. Retrieved from www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile. The tests for specified microorganisms are included in USP <62>, the modifications change many microbiological medias utilized in testing for specific pathogens. All Rights Reserved. Plates showing the highest number of colonies of microorganisms following incubation that is less than 250 for total aerobic microbial count (TAMC) and 50 for total combined yeasts and molds count (TYMC), will be assessed for their colony-forming units (CFUs) per gram or per milliliter of the product tested.
Thats just one of the reasons why companies are choosing Microbac. Contact us to learn more about our pharmaceutical industry services. United States Pharmacopeial Convention. Bioburden is measured in colony-forming units (CFU). As its designation denotes, sterile pharmaceuticals are produced under aseptic conditions, ideally rendering them free of microorganisms. It is important pharmacists ensure non-sterile drug products meet quality specifications before releasing compounded preparations. These are major impact changes for microbial limits testing. AMLS adds strength to this adherence by building and qualifying a well controlled sampling environment, thus eliminating the environment as a root cause of the out of specification result. The updated list now includes: The original microorganisms in the first-half of the list include more stringent requirements for testing, incubation, and growth measurement to determine a pass/fail. The intended recipient: risk may differ for neonates, infants, the debilitated. The article was edited by Ms. Elaine Cung, Head Microbiologist at Microbiology Research Associates, Inc. https://www.facebook.com/pages/Pharmaceutical-Manufacturing/140261116014887, http://www.linkedin.com/groups?gid=1813799, Significant changes include more clarity on enumberation and specified organisms, Water Activity is an essential quality parameter for pharmaceutical products, 8 tips for time-saving software validation. The performance of the Suitability Test ensures that any antimicrobial activity inherent in the sample to be tested does not adversely affect the reliability of the test and that the test procedure to be routinely utilized is otherwise suitable for use with the sample. Your email address will not be published. Thus, manufacturers must ensure that final products contain low (negligible) bioburden. A Buffered Sodium ChloridePeptone Solution pH 7.0 or Phosphate Buffer Solution pH 7.2 is used to create test suspensions. To receive service updates and information on new regulations and technology, please sign up here. The microorganism list in Table 1 isnt exhaustive. USP 1111 microbial limits and sterilization bioburden testing will be covered in the following article. USP <62> Tests for Specified Organisms Colonies of bacteria detected are counted as part of TYMC. (USPC <1115>). For raw materials, the assessment takes account of the processing to which the product is subjected, the current technology of testing, and the availability of materials of the desired quality. The effective date is now May 1, 2009. There are many methods for determining the microbial bioburden of a drug product or drug substance. Rapid methods include monitoring culture impedance, direct cell count with a viability dye, lumen production from microbial ATP interacting with luciferase enzymes, etc. However, the broth and agar culture methods outlined in USP <61> are the compendial methods considered legally acceptable for testing general microbial contamination of pharmaceutical products. In fact the method is now also harmonized with European Pharmacopeia and Japanese Pharmacopeia. Any other rapid or conventional method must be compared to USP <61> and shown to be equivalent or better to be considered valid.. If there is growth, then incubate for another 1-2 days. info@FOCUS-lab.com
More organisms have been specified in the new USP <62> chapter than in previous USP editions. In the U.S., USP standards are recognized and enforced in various provisions of the Food, Drug, and Cosmetic Act, as well as in-laws, regulations, and policies promulgated by individual states. Microbial examination of nonsterile products is performed according to the methods given in the texts on. The objective of this test is to determine the The number of colonies present on the plates are then counted and the results are calculated. FDA advises drug Clients are being advised to factor these USP methods into their testing schedules.References: Corresponding author Fran McAteer is vice president of quality at Microbiology Research Associates, Inc., 33 Nagog Park, Acton, MA 01720; 1-978-263-2624, fax 1-978-263-2786, an FDA-registered contract microbiology testing laboratory specializing in USP testing for pharmaceuticals, biologics, and medical devices. Parexel International (MA) Corporation. does it have adequate antimicrobial preservation? The objective of this method is to determine the presence or absence of the aerobic microorganisms Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Salmonella, Candida albicans, the anaerobic microorganism Clostridium, or bile tolerant gram-negative bacteria. Fax: (405) 271-1174 2021. USP <62> shows qualitative tests which determines the presence or absence of specified objectionable microorganisms or potential pathogenic microorganisms in non-sterile products. hazard varies according to the route of administration (eye, nose, respiratory tract). We would welcome the opportunity to discuss. many non-sterile manufacturers utilize risk assessment analysis tools to adapt portions online 2014 Dec 8. doi: 10.1016/j.jsps.2014.11.015. Acceptance Criteria include the following: (a) The average plate counts obtained from the test plates, for the total aerobic count and the total yeast and mold count, must be 50% and 200% of those obtained from the positive control inoculum verification plates. Required fields are marked *. Contact us for your next project, 1300 Main Street, West Warwick, RI 02893 (USA), microbial growth, survival, and death kinetics, Sterile Drug Products Formulation, Packaging, Manufacture, and Quality, Any hazard based on the products route of administration, Whether the product would support the growth of the organism if exposed, The intended recipient of the product (risk varies depending on age and preexisting conditions), Likelihood of use of immunosuppressive agents or corticosteroids in the intended patient population, The presence of disease, wounds, or organ damage for intended patients. Please Note: CPT only performs testing for companies. 2021. For more information on USP <61> and USP <62> testing, contact ARL atinfo@arlok.comor (800) 393-1595. All rights reserved. The plates are incubated at a defined temperature and duration. A control is similarly prepared and analyzed. 9. If you want, you can find out more about it in our Privacy Policy. Ethide Labs is an ISO 13485 certified contract testing organization specializing in EO residual and microbiology testing for medical devices. While AM Life Science (AMLS) does not offer services that directly support method validation of biological sample data, many of our personnel have strong QC backgrounds. Retrieved from https://www.statista.com/topics/1764/global-pharmaceutical-industry/, 3. The number of colonies present on the plates are then counted and the results are calculated. The method of application The intended recipient: risk may differ for neonates, infants, the debilitated Use of immunosuppressive agents, corticosteroids The presence of disease, wounds, organ damage USP <61> is critical to ensure non-sterile drug products meet quality control criteria. Generally, it is highly recommended to submit twice the minimum quantity needed for testing. statistics & facts. 8 The presence of yeast and mold accounted During a USP <61> test, a sample is prepared and plated on two types of growth media (Soybean-Casein Digest Agar and Sabouraud Dextrose Agar). Learn more. To recover your password please fill in your email address, Please fill in below form to create an account with us. any information at the genus or species level.8Over the past few years, B. cepacia complex, which poses a contamination risk in non-sterile, water-based drug products, was identified as the cause of a number of highly publicized and costly recalls. Retrieved from https://www.globenewswire.com/news-release/2020/01/17/1972088/0/en/U-S-Pharmaceuticals-Industry-Analysis-and-Trends-2023.html. By Xoli Belgrave, Senior Director, Patient Engagement, .a{fill:#4e565b;}.b{clip-path:url(#a);} Whitepaper, Overview of China's Market Approval Policy Med Insurance Payment System, 2520 Meridian Parkway,Durham, NC 27713+1 919 544 3170. <1111> Microbiological Examination Of Nonsterile Products: Acceptance Criteria For Pharmaceutical Preparations And Substances For Pharmaceutical Use. USP <795> states compounders are responsible for ensuring compounded drug products are of acceptable strength, quality, and purity. The higher the concentration of viable organisms on a device or product, the higher the burden is to kill those organisms. The surface-spread method is nearly the same as the pour-plate method. USP <62> results determine if objectionable microorganisms that could cause patient harm based on the route of administration are present in non-sterile drug substances or products. Microbiological quality of The following section provides a brief overview Acceptance criteria for nonsterile pharmaceutical prod-ucts based upon the total aerobic microbial count (TAMC) and the total combined yeasts and molds count (TYMC) are 1111 MICROBIOLOGICAL given in Tables 1 and 2. Thinking about joining a clinical trial? for the detection of B. cepacia not required to be sterile. The FDA defines objectionable microorganisms as microorganisms that can cause A value of 102 CFU means that the maximum acceptable count is 200. The Pharmaceutical Non-sterile medications include solutions, suspensions, ointments, creams, powders, suppositories, capsules, and tablets. USP <1111> provides acceptance limits for microorganisms present based on sample type (raw material or finished drug product) and route of administration. Each of the bacterial or fungal test strains is grown separately, as detailed in Table 1. illness in patients or adversely affect a non-sterile product., Largely left to their own devices, Careers. When an acceptance criterion for microbiological quality is prescribed, it is interpreted as follows: What follows if form USP Table 1: Acceptance Criteria for Microbiological Quality of NonSterile Dosage Forms: Total Aerobic Microbial Count (cfu/g or cfu/mL), Total Combined Yeasts/Molds Count (cfu/g or cfu/mL), Transdermal patches (limits for one patch including adhesive layer and backing), Inhalation use (special requirements apply to liquid preparations for nebulization), 177 N. Commerce Way
USP <60> specifies the We recognize the long incubation periods involved in these tests, so we set samples up almost as soon as they are received. (c) Positive control inoculums must be performed for each organism preparation and have an average value of (NMT) 100 CFU per total inoculated volume for the specified organism. USP <1111> Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use is an informational chapter that offers some guidance on acceptable specifications. Method suitability is performed by inoculating the sample with a quantity of each specified microorganism of interest individually. Fax: 610 866-7287
contamination sources. Rockville, MD, USA. Call us at 610-866-7272 for a free quote. at the same time, we excel in building trusting and collaborative relationships that allow our clients to rest easy at night. INTRODUCTION The tests described hereafter will allow determination of the ab-sence of, or limited occurrence of, specified microorganisms that may be detected under the conditions described. When testing is complete, the results must be within the two-fold specification of the organism tested. The author has expertise and experience in Pharmaceutical microbiology and acts as a consultant for many companies. for 52 recalls of sterile and non-sterile pharma drugs, with only 12% providing It is also recommending that these products be revalidated to conform to the new USP <61> and <62> Suitability Test. The goal is to examine the colonies to determine distinct morphology. Retrieved from https://hpi.georgetown.edu/rxdrugs/#, 2. First, appropriate dilutions of the product sample are prepared. Similarly, the total combined yeasts and molds count (TYMC) is equal to the number of CFU found using Sabouraud Dextrose Agar. A USP <62> test is initiatedsimilar to USP <61> but uses microorganism specific growth media. Adherence to USP 61 and 62 enable Quality Control Microbiologists to accurately report microbiological levels in process samples. 6. The two standards break down as USP 61 for Microbial Enumeration Tests that determine the allowable number of microorganisms in a testing area and USP 62 for Tests for Specified Microorganisms that determine the presence of specific microorganisms. To perform an accurate TYMC test, you should place the TYMC filter on the Sabouraud Dextrose Agar (SDA) media and incubate at 20-25 degrees Celsius for 5-7 days. When interpreting results, the total aerobic microbial count (TAMC) is equal to the number of colony-forming units (CFU), found with soybean-casein digest agar.
Does the product support growth? Each of the sample dilutions is transferred to two membrane filters for rapid filtration. The updated USP 61 reference includes stronger testing requirements for the total aerobic microbial count (TAMC) and the total combined yeasts and mold counts (TYMC). Oklahoma City, OK 73104, Toll Free: (800) 393-1595Phone: (405) 271-1144 USP <61> and USP <62> are tests primarily used to evaluate raw materials, non-sterile pharmaceuticals, OTC finished products, personal care/cosmetic products and nutritional supplements. For acceptance criteria, a value of 101 CFU means that the maximum acceptable count = 20. At the conclusion of incubation, a result of "Pass" or "Fail" is generated. This means that every time you visit this website you will need to enable or disable cookies again. At the conclusion of incubation, a result of "Pass" or "Fail" is generated. Now, after being diagnosed with breast cancer, she was the one in need of care. ARL is accredited to the ISO 17025:2017 standard as applicable to our scope of accreditation that outlines general requirements for the competence of testing and calibration laboratories. U.S. Table 1 includes a list of microorganisms for which bioburden acceptance criteria (USP microbial limits) are set. We are one of the largest CROs in the world, speeding life-changing medicine to market by engaging patients With Heart. Taking medications is an everyday part of the lives of many people, ranging from the very old to the very young. No retesting is allowed, whereas the previous USP 61 version allowed for a 25-gram sample to be retested. A rapidly graying American population that is facing illnesses and chronic diseases that come with age; The continued rise in lifestyle diseases, such as heart disease, atherosclerosis, diabetes, and obesity; Greater public access to lower-priced pharma drugs through state and federal health policies, such as the landmark Affordable Care Act (ACA); Concerted efforts by the U.S. Food and Drug Administration (FDA) to facilitate the faster approval of new pharmaceuticals, allowing drug manufacturers to expedite products to the marketplace; and. Three chapters in the organizations that determine the allowable number of microorganisms in a testing area and, USP 62 for Tests for Specified Microorganisms. The microorganisms of concern listed in USP <62> include: A USP <62> test is initiatedsimilar to USP <61> but uses microorganism specific growth media. Nosco. Microbiological testing in the non-sterile manufacturing environment is of paramount importance in preventing product recalls and protecting consumer health. Bioburden is the initial population of a microorganism before a product or item is sterilized. We use cookies to give you the best experience on our website. Prescription The responses of the sample and control are compared for acceptance. Global pharmaceutical industry After incubation, the Soybean-Casein Digest Agar is used to calculate TAMC and the number of CFUs per gram or milliliter of the product. Ethide Labs is a contract testing organization that specializes in Bioburden Testing. Active substances with small batch sizes test up to one percent of the total batch. Sterilization is related to the term sterile, which means a complete absence of viable microorganisms or viruses that have the potential to reproduce. The growth promotion organisms and the methodology had been significantly updated to include more types of organisms and different growth medias. Copyright 2021 Microbac Laboratories, Inc. All rights reserved. Retrieved from https://www.pharmawebinars.com/usp-60-tests-for-burkholderia-cepacia-complex. Learn the drug development process, what its like to participate, how to find a trial, and answers to frequently asked questions. Our industry expertise and analytical strength support your food safety programs for compliance with FSMA regulations. Does it have adequate antimicrobial preservation? Clients must now specify which microorganisms are required to be absent. Learn more here. The two-fold acceptance criterion for microbiological quality breaks down as such: The updated version of the USP 62 reference includes testing for additional microorganisms. Further, disease-causing organisms can cause patient illness if someone is accidentally exposed to them. We specialize in delivering timely and value-added services to our customers . The ability of the test to detect the specified microorganisms in the presence of a product must be established. A passing result indicates the absence of the tested specified microorganism. Fungi colonies are counted as part of the TAMC. Ethide isan ISO 13485 certified facility. The last sterilization process after manufacturing is known as terminal sterilization. Sample prepared in diluent as in Pour Plate or Spread plate but the resulting dilution is passed through a 0.22 micron filter. The filter is removed and placed on the surface of nutrient agar plates, allowing microbes to growth to visible colony forming units. Membrane filtration is recommended with chemical neutralization of antimicrobial agents is not possible, such as with antibiotics. The filtration physically separates the antimicrobial from the contaminant, leaving the microbe on the surface of the filter for further culturing. It is also useful when the limit of detection must be <1 cfu/gm, as the entire dilution will be plated. 10 gm of sample is diluted with a pH balanced, isotonic diluent, usually supplemented with chemical neutralizers for any antimicrobial agents which might be present in the drug product, and further homogenized by shaking, stomaching, vortexing or other means. During a USP <61> test, a sample is prepared and plated on two types of growth media (Soybean-Casein Digest Agar and Sabouraud Dextrose Agar).