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The United States Pharmacopeia: Beyond <797>

The United States Pharmacopeia (USP) Chapter <797> is one that has become very familiar to the certifier. This chapter is revisited often, and many compounding customers rely on their certification company for help in understanding this chapter. Because of this, the certifier must not only be familiar with the content of <797> but also with the chapters and General Notices referenced within the chapter. <797> references the General Notices, ten general chapters and five informational chapters. Familiarizing the certifier with these other chapters will allow for better customer service and meeting customer needs beyond <797>. This article discusses general information about the USP as well as a high level overview of some chapters that would be of value to the certifier.

The General Notices

Before discussing the general chapters, it is essential to review the General Notices. The General Notices section, located at the beginning of the USP, is a vital piece for anyone referencing USP chapters. It provides basic assumptions, definitions and default conditions to be applied to all general chapters and monographs, unless specifically stated otherwise. There are ten (10) segments within the General Notices. Sections six (6) through eight (8) discuss testing procedures, test results and definitions. Although these provide very general information about testing, such as all temperatures use Celsius as the unit, this information is essential in understanding the USP chapters and ensuring that the best possible service is provided to your customers.

General Chapters and General Information

The chapters within the USP are divided into what is termed General Chapters and General Information. Chapter numbers below 1000 are the General Chapters and are enforceable. In the General Chapters, the words “shall” and “should” may be used. “Shall” indicates whatever is referenced must be done, and “should” indicates whatever is referenced is a best practice but not required. Chapter numbers 1000 or higher are considered the General Information chapters. These are strictly meant to be informational and will not include the use of the word “shall” unless directly referencing a General Chapter.

Specified Chapters of Interest

In many instances, the certifier is not only performing cleanroom and PEC certification but also the semi-annual environmental monitoring required by <797>. Just by performing this sampling, many compounders will ask the certifier about other microbiological testing they are expected to perform in order to be in compliance. Basic knowledge about this testing will allow the certifier to help his or her customer find the best option for testing or compliance.

Chapter <51> Antimicrobial Effectiveness Testing

As the title indicates, this chapter provides procedures to demonstrate the effectiveness of added antimicrobial preservatives to a product. Multiple-dose containers of sterile material have antimicrobial preservatives added to inhibit the growth of microorganisms that may be introduced as a result of repeatedly withdrawing individual doses. The test requirements depend on the category (e.g. ophthalmic, parenteral) of the material being tested. To perform this test, the test material is inoculated with 1.0 x 105 to 1.0x 106 of a panel of five microorganisms. The material is stored at 20°C to 25°C, and aliquots are plated at different intervals over the course of 28 days. Each product type has specific log reduction acceptance criteria that must be met. Failure to meet the log reduction indicates that the preservative system is not effective and must be reevaluated.

Chapter <71> Sterility Test

This chapter reviews the test procedure for performing a sterility test on a product or compound that needs to be sterile. It may have been aseptically produced or terminally sterilized. Very specific amounts of material are required for the testing. This is based on the category of the material, the volume per container, and the batch size. Tables 2 and 3 in the chapter provide the test requirements. The test consists of transferring a specific amount of material to soybean casein digest broth (also known as tryptic soy broth) and fluid thioglycollate medium. These are incubated at specific temperatures for 14 days and analyzed for turbidity. The test itself can be performed two different ways, direct inoculation or filtration, with the latter being the preferred method. Method suitability testing must be performed to ensure the chosen test method can recover microorganisms in the presence of the product.

Chapter <85> Bacterial Endotoxins Test

The Bacterial Endotoxins Test (BET) utilizes amoebocyte lysate from the horseshoe crab to detect or quantify endotoxins from Gram-negative bacteria that may be found in pharmaceutical grade water, in a product or on a medical device. It is important to remember that endotoxins are not microorganisms but are pyrogens, which is an agent that causes fever. There are three techniques for this test: the gel-clot technique, which is based on gel formation; the turbidimetric technique, based on the development of turbidity; and the chromogenic technique, based on the development of color. The acceptance criteria for this test may be found in the USP monograph for the product, or it may need to be calculated based on the expected patient dosage of the drug.

Chapter <1072> Disinfectants and Antiseptics

This informational chapter provides definitions of the different terms used for cleaning materials, as well how to select a cleaning material and the disinfectant challenge test. Knowledge of this chapter is essential, as many times the certifier is asked to interpret the environmental monitoring results and provide cleaning recommendations. In many compounding facilities, the chosen cleaning materials have not been specifically tested using the disinfectant challenge test and have not been shown to be effective on the types of surfaces in the facility. These data are valuable to confirm what has been chosen for use is actually meeting the cleaning needs of the compounding facility.

Chapter <1163> Quality Assurance in Pharmaceutical Manufacturing

Just as the General Notices are helpful in describing the general use of the USP, chapter <1163> provides information on how a quality assurance program is necessary to ensure the quality of compounded preparations. SOPs, documentation, verification, analytical and microbiological testing, and responsible quality assurance personnel are discussed. Being familiar with the chapter will allow the certifier to provide comprehensive reports that ensure his or her customer’s documentation needs are met.

The USP contains many chapters used by the compounding world on a daily basis. A basic understanding of a few of the common microbiological tests the compounding customer may require enables the certifier to act as a liaison between the compounder and the microbiology laboratory. In turn, the certifier is able to provide the best possible service and can confidently discuss general aspects of the tests their customer.