USP completes <1116> chapter revisions

USP completes <1116> chapter revisions


Rockville, MD — Revisions to the latest chapter of United States Pharmacopeia`s (USP) USP 23 are complete and are expected to become official in November. The final revision describes a de facto standard already in wide use in the pharmaceutical industry and is expected to serve as a benchmark for emerging biotechnology organizations.

Currently under revision is the “General Information” chapter of USP 23 entitled <1116> Microbiological Evaluation of Cleanrooms and Other Controlled Environments. The final revisions, with a targeted publication date of September 15, 1997, will become official by November 15, 1997.

“The industry is very familiar with what`s in this document,” says USP`s Senior Scientist Roger Dabbah. “It has been discussed many times. While many in the industry who have been implementing their own standards will object to our including numbers, others — like the newly emerging companies say, `put it in, we don`t know anything about it; we want some guidelines.` Some of the new biotech companies need to have some type of guideline because they generally start at square one.”

The purpose of the information chapter is to review the various microbiological issues relating to processing pharmaceuticals, bulk drug substances, biological fermentation and purification in cleanrooms and other controlled environments, and in certain cases, medical devices. It also addresses the “establishment, maintenance, and control of the microbiological quality of controlled environments.”

The revisions include changes in frequency of sampling, surface cleanliness guidelines, types of equipment used in quantitating viable airborne microorganisms, media fill, emerging technologies, and a glossary of common terms. Although not a standard, Chapter <1116> is designed to give information to manufacturers and regulators.

Manufacturers of sterile pharmaceutical products have several options to ensure the sterility of their final products. One is to terminally sterilize the final filled-and-closed container using a validated sterilization process. Another option is aseptic processing, which involves the separate sterilization of the product and the package (container and closure) and the combining of the two under aseptic conditions. Aseptic processing is employed where terminal sterilization is not possible.

The current trend toward biotechnology-derived products and products of natural origin that cannot be subjected to terminal sterilization places greater emphasis on aseptic processing, particularly when the products do not contain preservative systems. The guidelines reflect a trend of placing the onus of frequency of sampling and testing on the manufacturer, evaluating data as part of an “overall monitoring program,” rather than closely specifying each level of production.

The United States Pharmacopeia and National Formulary (USP-NF) is the official, nationally recognized compendia of drug standards published by the U.S. Pharmacopeia Convention (USPC). It is a non-governmental organization, but USP-NF standards are enforceable by the FDA under the Federal Food, Drug and Cosmetic Act, which recognizes the standards for strength, quality and purity for drugs contained in the USP-NF as legally enforceable. USP-NF standards and specifications for drugs are also recognized and adopted internationally. Following are the details of the revision:

Sampling frequency. In the Chapter <1116> revisions, requirements for sampling controlled environments for terminally sterilized drug products, devices and enteral products have been eliminated. The section on “Establishment of Sampling Plan and Sites” indicates that environmental monitoring is more critical for products that are aseptically processed than for those that are processed and then terminally sterilized. Therefore, the real concern for these products is determining the type and quantities of microorganisms resistant to the sterilization treatment rather than the microbiological environmental monitoring of the surrounding manufacturing environments.

Air cleanliness guidelines. Surface cleanliness guidelines for equipment and facilities in colony-forming units in a Class 100,000 environment have been eliminated. The guidelines, mentioning that there have been “reports and concerns” about differences in values obtained using different sampling systems, media variability, and incubation temperatures, include the caveat that the values “represent individual test results and are suggested only as guides.”

Types of equipment. “The guidelines indicate that you probably should find out what kind of microorganisms you have and what the source of contamination is,” Dabbah says. While air samplers such as impaction and centrifugal samples are cited as the most commonly used in the pharmaceutical and medical device industries in the United States, a controversial recommendation is the Slit-to-Agar air sampler.

This method is used as a model for data on the various controlled environments in chapter tables. Powered by an attached source of controllable vacuum, air intake is obtained through a standardized slit below, which is placed in a slowly revolving Petri dish containing a nutrient agar. Depending on their mass, particles in the air land on the agar surface, and viable organisms are allowed to grow out. Dabbah comments that other systems — like centrifugal samplers — have an inherent selectivity for larger particles, resulting in a higher count. However, he says, some of the centrifugal systems have been modified to approximate slit-agar results.

Media fill. A media fill is designed to simulate aseptic processing of a specified product, utilizing growth medium in lieu of products to detect the growth of microorganisms. Usually, at least three successful consecutive media fills are run to qualify the microbiological status of the process when an aseptic process is developed and installed. The guidelines state that although 10-3 has been commonly referred to in the industry as a sterility assurance level since the late 1970s, it is only a contamination rate limit and not a sterility assurance level as understood in terminal sterilization, where a 10-6 sterility assurance level can be determined experimentally.

Emerging technologies. Because “human involvement and intervention” introduces the greatest potential source of contamination in aseptic processing, production systems have been developed to remove personnel from critical zones. The use of equipment automation, barriers and isolator systems are and have been in operation for some time. Blow/fill/seal equipment that restricts employee contact with product may be placed in a classified cleanroom, especially if some form of employee intervention is possible during production. Barrier systems will require some form of classified cleanroom, varying according to type and application and the environment surrounding the barrier system. Isolator systems could be operated in unclassified environments when used for sterility testing but for aseptic manufacturing. The choice of outside environment is more complex. Isolators contain sterile air, do not exchange air with the surrounding environment, and are free of human operators. Barriers restrict contact between operators and the aseptic field enclosed within the barrier and use remote sampling systems.

Isolators protect product from contamination from the environment. The sterilization of the interior and all contents are usually validated to a sterility assurance level of 10-6. Isolators are mainstream technology at this time in terms of sterility testing. Of course, isolators should probably be used in manufacturing, and they are — but it`s not widespread yet, Dabbah says.

A question also being raised, which may need to be addressed in the future, is “Does a non-sterile product have to be manufactured under a controlled environment?” asks Dabbah. Information on the sterilization validation of isolator systems used for sterility testing will be found in a new guideline to be proposed by USP in the near future, according to Dabbah, and will be titled Validation of Isolator Systems for Sterility Testing of Compendial Articles (1226).

For more information on USP 23, contact the U.S. Pharmacopeia at (301) 881-0666.


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