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Microbial Tests for Non-Sterile Products

Container Closure Testing

Sample Submission Form

Quality Compounding Summit

USP <795> states that pharmacists performing non-sterile compounding must ensure that the finished preparation has its accepted potency, purity, quality, and characteristics.  This article discusses the tests described in USP <61> and USP <62> that are used to determine if non-sterile products meet quality requirements.  These tests can also be used by sterile compounders for qualifying raw materials and performing in-process quality control testing. 

Testing Conditions

The general considerations for testing non-sterile products are much like USP <71> Sterility testing.  Growth promotion is required to demonstrate that every lot of media will grow the microorganisms required for each test.  Method suitability is also performed prior to product testing to establish the ability of the test to detect microorganisms in the presence of the specific formulation to be tested.  All testing must be completed under aseptic conditions to avoid extrinsic microbial contamination of the product tested and must include proper positive and negative controls.  

USP<61> Microbial Enumeration Tests

USP <61> is often called “Bioburden” or “Microbial Limits” because the test determines how many microorganisms are present in the sample.  To perform the test, the sample is plated onto two types of growth media (Soybean-Casein Digest Agar and Sabouraud Dextrose Agar).  The plates are incubated at a defined temperature and duration.  At the conclusion of the test, the number of colonies present on the plates are counted and the results calculated.   The results can then be compared to the acceptance criteria.  USP <1111> can be referenced for acceptable amounts of microorganisms present based on whether the sample is a raw material or finished drug product.  If the sample is a finished drug product, the acceptance criteria depends on the route of administration. 

USP<62> Tests for Specified Organisms

USP <62> provides instructions on how to perform tests that demonstrate particular microorganisms are not present in non-sterile substances and products.  These tests are performed similarly to USP <61> tests, but with microorganism specific growth media.  At the conclusion of incubation, a result of “Pass” or “Fail” is generated.  A passing result indicates the absence of the tested specified microorganism.  USP monographs and <1111> define which organisms to test based on the route of administration of the raw material or finished drug product.  For example, USP <1111> recommends that cutaneous (topical) products be tested for the absence of both Pseudomonas aeruginosa and Staphylococcus aureus,  versus an oral preparation where the recommendation is to test for the presence of Escherichia coli.

Please contact ARL (800) 393-1595 or info@arlok.com with questions.

Andrew Taylor, Microbiology Supervisor

Reference Documents:
United States Pharmacopeia <61>

United States Pharmacopeia <62>

United States Pharmacopeia <1111>

Extending Beyond Use Date

Q&A with Dr. Kupiec

Quality Compounding Summit

Extending Beyond Use Dates for Compounded Preparations
Dr. Qiang Liu, Research and Development Laboratory Supervisor

A beyond use date (BUD) is the date after which a compounded preparation shall not be used. The BUD is determined from the date the preparation is compounded. This date should be based on drug-specific, scientifically valid studies when possible. Things to consider when assigning BUD include: 

• The drug and its degradation mechanism
• The dosage form and its components
• The potential for microbial proliferation
• The container in which the preparation is packaged
• The expected storage conditions
• The intended duration of therapy

USP <797> describes four methods for assigning a beyond use date:

• Product labeling
• Commercial product manufacturer consultation
• Appropriate literature
• Direct testing

Beyond use dating must be carefully interpreted with respect to the actual compounded formulation and conditions for storage and use. Predictions based on literature are considered theoretical beyond-use dates as the published data introduces varying degrees of assumptions with a likelihood of error or inaccuracy. Pharmacists using literature to assign a beyond use date must look for the exact drug formula, storage conditions, and container/closure to reduce the likelihood of errors. State and federal regulations also require pharmacists to have written justification for a beyond use date assignment.

The only truly valid beyond use date is obtained through product-specific studies supported by scientific data. These direct testing studies use stability indicating methods (SIM) to ensure therapeutic effectiveness of compounded drug products.  

A SIM is a reliable, meaningful, and specific analytical procedure that accurately and precisely measures active pharmaceutical ingredients (API) by separating the API from its degradation products and excipients.  A SIM must be validated for the exact formulation being tested.  High performance liquid chromatograph (HPLC) is one of the most commonly used techniques for examining the chemical stability of compounded product, but not all HPLC tests are stability indicating. A forced degradation study must be performed on the compounded drug product and not inferred from testing on only the API.

Testing the concentration of the drug is just one component of a stability study. Testing should include evaluation of the physical, chemical, and microbiological properties of the product. Common tests in a stability study include:

• Assay (Stability Indicating Method)
• Sterility – USP <71> (sterile preparations)
• Endotoxin – USP <85> (sterile preparations)
• pH – USP <791>
• Visual Inspection   (Appearance)
• Particulate Matter – USP <788> / <789> (all sterile solutions for IV injection or ophthalmic)
• Preservative Effectiveness – USP <51> (preparations containing an antimicrobial preservative)
• Preservative Quantification – (preparations containing an antimicrobial preservative)
• Microbial Limits – USP <61> (nonsterile preparations)
• Absence of Specified Organisms – USP <62> (nonsterile preparations)

Additional tests for biological products BUD include:

• Protein content – USP <1057>
• Potency or activity – such ELISA assay
• Product related impurity including protein aggregates, size and charge variants

Please contact ARL (800) 393-1595 or info@arlok.com with questions.

·         Potency  Testing

·         Q&A with Dr. Kupiec

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Potency testing measures the concentration of the active pharmaceutical ingredient (API). This essential test ensures the API concentration matches its intended amount and provides value-added benefits to pharmacies including:

The practice of assigning beyond-use dates for compounded sterile preparations (CSPs) is complicated and often misunderstood. A CSP's beyond-use date identifies the time by which the preparation – once mixed – must be used before it is at risk for chemical degradation, contamination, and packaging permeability.

Pyrogens are a group of fever causing substances.  The most widely known pyrogen is bacterial endotoxins.