File Name: usp chapter 61 and 62 .zip
This chapter provides tests for the estimation of the number of viable aerobic microorganisms present and for freedom from designated microbial species in pharmaceutical articles of all kinds, from raw materials to the finished forms.
- Instructor: Barry A. Friedman Ph.D.
- Microbial Limits Test
- Regulatory Update: How FDA Assesses Microorganisms in Drug Products
- Microbiological contamination in counterfeit and unapproved drugs
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Instructor: Barry A. Friedman Ph.D.
Growth promotion testing of culture media appears to be a trivial test, but this perception is deceiving. Almost everyone can agree that with the criticality of microbiological tests, it is extremely important that culture media performs properly. Culture media is used in most assays in a microbiology laboratory, and if the media does not properly support growth, false negative results may be obtained.
Likewise, contaminated media may yield false positive results. Opinions on when and how the testing should be performed sometimes vary within the pharmaceutical industry.
This article is written with the pharmaceutical industry in mind. However, the concepts may cross over into other industries that utilize microbial culture media. The article discusses some of the guidance documents and regulatory expectations regarding media growth promotion and provides guidance on establishing a compliant growth promotion test.
Media can be purchased in a ready-to-use format, prepared from dehydrated media, or prepared from raw materials. Regardless of how the media is prepared, it is essential that it functions properly to ensure the assay requiring the media yields accurate results.
If media does not support growth, false negative results may be obtained, and potentially contaminated products may be released to consumers.
Thus, the seemingly simple growth promotion test is a crucial part of any microbiological laboratory. The growth promotion test may also be known as nutritional adequacy testing, fertility testing, media challenge testing, or quality control testing of media. Throughout this article, the term growth promotion test will be used, and it encompasses the associated tests, such as sterility checks, pH checks, inhibitory assays, and indicative assays.
The test samples are incubated for specified time intervals and temperatures. Then, the samples are observed for the expected results. In addition to observing for growth or inhibition of microorganisms, portions of media that are not inoculated with microorganisms are included in the test to verify that the media is not contaminated. The pH of media is also examined and is expected to fall within a specified range. Furthermore, the tests are similar in the European Pharmacopeia and the Japanese Pharmacopeia.
Other compendial chapters may describe how to perform growth promotion testing for that particular compendial assay. Each shipment of media received, or each batch of media prepared in-house i.
Shipping conditions could potentially alter the pH or performance of the media. In addition, improper heating or sterilizing conditions may result in a difference in color change, loss of clarity, altered gel strength, or pH drift from the manufacturer's recommended range.
In my opinion, it is best practice to perform growth promotion testing in-house rather than relying on testing by contract laboratories or media vendors. If contract laboratories must be used, the worst-case scenario of shipment should be utilized. For example, I would recommend receiving a lot of media and then sending a sample of that lot to a contract laboratory for testing.
This would provide opportunities for the media to be exposed to harsh conditions that could occur during shipping. Thus, this scenario would provide further evidence the media is acceptable for use after such treatment. On the other end of the spectrum, some contract laboratories may offer to sell media that has already undergone the growth promotion test. The downside with this convenient offering is that the media must still be shipped to its final destination.
Again, this shipping could impact the ability of the media to properly support microbial growth. In addition, there would not be evidence that the growth properties of the media remained acceptable during the transportation process. This practice could potentially lead to an observation from regulators. When shipments of media arrive in the microbiology laboratory, they should be visually inspected, logged, and quarantined until the growth promotion test has been completed.
Culture media should be inspected for the following: 3. Media should be labeled properly with batch or lot numbers, preparation and expiration dates, and media identification information. Most media vendors will possess shipping validation data demonstrating the media will pass quality controls tests after transportation. Media that is prepared in-house should be processed and handled according to internal standard operating procedures SOPs. In order to establish the proper storage conditions and expiration dates of media prepared in-house, growth promotion stability studies can be developed and executed.
The microorganisms used by media vendors for their release testing may differ from those described in the compendial chapters. Media vendors are preparing media for many different types of microbiology laboratories and may risk-assess their challenge panel of microorganisms to satisfy as many industries as possible.
To establish a compliant test, I recommend that the end user growth promote its media using the microorganisms and specifications listed in the compendial chapters and its own standard operating procedures rather than the microorganisms used by the vendor.
Table 1 provides an example of a compliant growth promotion testing scheme for some common culture media types utilized in the pharmaceutical industry. The test organisms may be selected from the appropriate compendial test chapter, based on the manufacturer's recommendation for a particular medium or may include representative environmental isolates. It is important to note that the total number of passages from the original isolate strain used for the assay should not exceed five passages from the original culture.
A regulatory expectation that environmental isolates are incorporated into the growth promotion test is gaining momentum. The rationale for deciding which environmental isolates to include in the assay should be established and documented.
One practice of choosing environmental isolates is to trend the recovered isolates, determine which microorganisms are the most predominant in the facility, and then use scientific rationale to decide which microbial isolates are appropriate to include in the growth promotion assay.
This regulatory expectation is demonstrated in observations issued by the FDA. One warning letter dated Oct. Although regulatory observations are occurring for the use of environmental isolates in the growth promotion assay, not all microbiologists agree with this practice. After the incubation of the samples, it is good practice to confirm that the colony morphology and the Gram stains of the recovered microorganisms are typical of the inoculated microorganisms.
This will provide data that the isolates recovered from the assay were the expected microorganisms to be recovered and not from contamination. In addition to the properties of growth promotion, the compendial chapters may require additional challenges, such as inhibitory or indicative assays.
Furthermore, the sterility of the media must be confirmed. After aseptically withdrawing a sample for testing, it is recommended to use a flat pH probe for agar surfaces or an immersion probe for liquids to measure the pH. After all of the required testing challenges have been completed, the media may be deemed acceptable for use if the following criteria are met.
Nonconforming lots should not be used for testing unless an assignable cause and a corrective resolution can be achieved. A warning letter from the FDA dated Aug.
Our investigators observed that you did not have any microorganisms stored at your facility and did not have the test strains and specified microorganisms for completing microbiological testing. You were not able to provide purchasing records for any reference microorganisms or test strains. Microbiological assays are critical to patient safety, product release, and maintaining the manufacturing environment. Most assays require the use of culture media. For accurate and reliable results, it is essential that culture media performs properly.
This can be challenged with the growth promotion test. Remember that each shipment of media received, or each batch of media prepared in-house, should be tested for growth promotion and the associated tests. When the growth promotion test is compliant with compendial chapters and regulatory expectations and is properly executed according to established SOPs, microbial data obtained from assays that utilized culture media generates more trustworthy results.
Crystal M. Booth, M. During her career, she has developed and validated methods for antibiotics, otic products, topical creams, topical ointments, oral solid dose products, oral liquid dose products, veterinary products, human parenterals, vaccines, biologics, aseptically filled products, and terminally sterilized products.
Those methods include microbial limits testing, bacterial endotoxins testing, particulate testing, sterility testing, pharmaceutical water system validations, environmental monitoring programs, surface recovery validations, disinfectant efficacy studies, minimum inhibitory concentration testing, antimicrobial effectiveness testing, hold time studies, and various equipment validations. Get more pharma manufacturing insight with our FREE newsletter sign me up.
Sign in or Sign-up. Guest Column January 7, By Crystal M. Booth , PSC Biotech Growth promotion testing of culture media appears to be a trivial test, but this perception is deceiving.
Overview Of The Growth Promotion Assay Media can be purchased in a ready-to-use format, prepared from dehydrated media, or prepared from raw materials. Receiving Shipments And Handling Media When shipments of media arrive in the microbiology laboratory, they should be visually inspected, logged, and quarantined until the growth promotion test has been completed. Culture media should be inspected for the following: 3 Cracked containers or lids 3 Unequal filling of containers 3 Dehydration resulting in cracks or dimpled surfaces on solid medium 3 Hemolysis 3 Excessive darkening or color change 3 Crystal formation from possible freezing 3 Excessive number of bubbles 3 Microbial contamination 3 Status of redox indicators if appropriate 3 Lot number and expiry date 3 Sterility of the media 3 Fluid thioglycollate medium FTM with indicator resazurin should be inspected to ensure that no more than the upper one-third of the bottle is pink.
The pink color indicates oxygen in the media. Selection Of Microorganisms The microorganisms used by media vendors for their release testing may differ from those described in the compendial chapters.
Additional Testing Requirements After the incubation of the samples, it is good practice to confirm that the colony morphology and the Gram stains of the recovered microorganisms are typical of the inoculated microorganisms. Visual evidence of growth appears within the time specified on both inoculated samples. The average of the recovered colony forming units if applicable and the average of the titer counts of the challenged inoculums are within 50 percent of one another.
Microbial Limits Test
P harmaceutical products are classified into two groups according to the microbiological point of view: 1 sterile products and 2 non-sterile products. The sterilized term refers to the products that are free of any microorganisms, their production were done under aseptic conditions, but the production of non-sterile products were not under aseptic conditions 1 ; they are not free from microorganisms; for this type of products legal authorities defined microbial limit ranges. The requirements for non-sterile products acceptance depending on the legal authorities of different countries or even different pharmaceutical companies may vary slightly. These microorganisms can grow under certain temperature and nutritional conditions and could affect the quality and safety of the product. Contamination at any stage of the process can represent a serious risk to the final product and must be controlled so to maintain the quality and safety of the product 3.
Regulatory Update: How FDA Assesses Microorganisms in Drug Products
Counterfeit and unapproved medicines are inherently dangerous and can cause patient injury due to ineffectiveness, chemical or biological contamination, or wrong dosage. Growth of the counterfeit medical market in developed countries is mainly attributable to life-style drugs, which are used in the treatment of non-life-threatening and non-painful conditions, such as slimming pills, cosmetic-related pharmaceuticals, and drugs for sexual enhancement. Serious danger may also arise from microbiological contamination. We therefore performed a market surveillance study focused on the microbial burden in counterfeit and unapproved medicines. Counterfeit and unapproved medicines confiscated in Canada and Austria and controls from the legal market were examined for microbial contaminations according to the US and European pharmacopoeia guidelines.
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Growth promotion testing of culture media appears to be a trivial test, but this perception is deceiving. Almost everyone can agree that with the criticality of microbiological tests, it is extremely important that culture media performs properly. Culture media is used in most assays in a microbiology laboratory, and if the media does not properly support growth, false negative results may be obtained. Likewise, contaminated media may yield false positive results.
Microbiological contamination in counterfeit and unapproved drugs
Scott Sutton, Ph. It appears here with permission. However, the signed-off versions have yet to be published.
Friedman Ph. These Chapters present information that relate to both non-sterile and aseptic processing. Several of these chapters have been recently updated and all have been updated since Each of these Chapters has relevance to each other and provides a significant knowledge base of microbiological requirements. Several of these have also been harmonized and permit one to not only follow the USP, but simultaneously meet the requirements of both the European and Japanese Pharmacopeia. Friedman, ensuring that trainees will be provided with the most up to date and practical information on the topic. This multi-part live training program is instructed by Dr.
Clients must now specify which microorganisms are required to be absent. This requirement is based on the unique characteristics of the product based on formulation process, raw materials, etc. 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. 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. The new USP methods are now more inclusive for more organisms.
11/21/ 34(6) Sixth Interim Revision Announcement: 61 MICROBIOLOGICAL (Entire Chapter and revisions marked for IRA—Official May 1, ).
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