Originally Published MDDI January 2005
Originally Published MDDI January 2005
USP <797>: How It Affects Medical Device Manufacturers
Manufacturers of compounded sterile preparations have been faced with proving the compliance of some of their products with USP's new sterile compounding regulation.
Robert Reich and Hal Patterson
|Products like I-Flow's ON-Q PainBuster postoperative pain relief system are subject to USP <797>.|
On January 1, 2004, United States Pharmacopeia (USP) Chapter <797> “Pharmaceutical Compounding—Sterile Preparations” became effective.1 The regulation has raised many questions for compounding professionals as well as for medical device suppliers. Compounding centers found themselves required to institute and validate certain practices and procedures that were new to them. They also were faced with the requirement for a defined and documented quality system.
Because of these new requirements, medical device suppliers have had to respond to the compounding centers' questions about the suppliers' products complying with <797> requirements.
This article outlines one program a medical device manufacturer can implement to address such questions.
USP <797> was initially published in USP 27/NF 22. Chapter <797> details procedures and requirements for compounded sterile preparations (CSPs) and sets standards that must be followed in any facility that is compounding sterile preparations. CSPs are defined in <797> as
a.) Preparations prepared according to the manufacturer's labeled instructions and other manipulations when manufacturing sterile products that expose the original contents to potential contamination.
b.) Preparations containing nonsterile ingredients or employing nonsterile components and devices that must be sterilized before administration.
c.) Biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals that possess either of the above (a or b) two characteristics, and which include but are not limited to baths and soaks for live organs and tissues, implants, inhalations, injections, powers for injection, irrigations, metered sprays, and ophthalmic and otic preparations.
These new regulations have significant effects on manufacturers that offer sterile, nonpyrogenic, single-use devices to healthcare facilities for use in sterile compounding operations and other types of devices defined in <797>. When these devices are used in a healthcare setting, they are by definition CSPs. Such devices must therefore comply with the requirements of <797>.
In 1938, Congress passed the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FD&C Act recognized USP/NF as the official compendium of drug standards. FDA is responsible for enforcing the FD&C Act.
Each general chapter of the USP/NF is assigned a number, which appears in brackets along with the chapter name. The general chapters <1> to <999> are considered requirements and official monographs standards. Since <797> is a requirement, healthcare facilities that compound sterile preparations may be subject to inspection against it. The inspections may be performed by boards of pharmacy, FDA, and accreditation organizations like the Joint Commission on Accreditation of Healthcare Organizations.
This new regulation is causing problems for compounding professionals because many had never previously considered implementing many of the practices and controls specified in <797>. Now compounding professionals must be concerned with the design and classification of their filling cleanrooms, environmental monitoring, expiration dating, process validations, media-fill qualifications, sterility testing, and preparing a comprehensive quality manual.
However, these issues have been common practice in the medical device manufacturing industry for many years. In <797>, compounding facilities are instructed several times to refer to “manufacturers' labeled instructions” and to “consult the manufacturer of particular products for advice on assigning beyond-use dates on chemical and physical stability.” It is the responsibility of medical device manufacturers that produce the products to provide the compounding centers with this required information. It is a statutory requirement for any medical device manufacturer that claims its products are compatible with <797> to provide this information.
This situation is analogous to medical devices sold into healthcare facilities labeled as sterile but that allow reuse, or for devices sold as nonsterile but intended for resterilization by the consumer before use. In both situations, the device manufacturer must provide the healthcare facility with validated cleaning and sterilization instructions that the facility is capable of executing.2 Because these requirements are new to compounding centers, they are turning more frequently to medical device manufacturers for answers.
Medical Device Manufacturer Responsibilities
There are several sections of USP <797> about which a medical device manufacturer of CSP-application products should be aware. In addition, manufacturers should have validated data available consistent with the pharmacopeia requirements to support the use of their products. The sections include:
• Microbial risk.
• Expiration dating.
• Packaging—chemical stability.
• Product integrity—microbial barrier.
• Validation—media fills.
• Compounding accuracy.
One of the main areas of concern for the compounding professional is the microbial risk assessment required for all CSPs. USP <797> has assigned three potential CSP microbial contamination risk levels (low, medium, and high) that depend upon the compounding environment, contamination risk, and in some cases the nature of production of the CSP (e.g., using automated filling equipment or reservoirs of injection and infusion devices).
An evaluation by the manufacturer is the first step in assisting the compounding center with compliance with <797>. The report should include how the products are used in the compounding center and an assessment of the microbial risk of the device. Medical device manufacturers also should have a documented rationale position that clearly outlines the microbial risk assessment of their devices used in a specific application.
Based on the microbial risk classification, a manufacturer can evaluate “prior to use” and “ beyond use” storage. These terms, used in USP <797>, refer to what medical device manufacturers usually refer to as expiration dating. For example, a CSP designated as a medium-risk preparation can be stored, prior to administration, for no longer than 30 hours at room temperature, 7 days at 2° to 8°C, or no more than 45 days at –20°C.
Medical device manufacturers should perform container-closure studies that demonstrate that their devices, when used according to instructions, will maintain sterility. Studies should be performed where the container, filled with growth-supporting media and under medium-risk conditions (ISO Class 5 environment), is demonstrated to be capable of maintaining sterility for at least the periods specified above. Appropriate media controls and bacteriostasis and fungistasis studies should be included in the study design.
Some categories of CSPs, such as infusion devices, contain drugs that may be administered to the patient for several days at room temperature. With these types of devices, the stability of the container poststorage and during administration should also be evaluated and documented. Medical manufacturers should conduct or contract protocol-controlled studies and create comprehensive final reports that clearly support their position and recommendations for expiration data. This information should be available for distribution to the compounding centers as requested or required. If the manufacturer includes a <797> compliance statement on the product label, this information must be available.
Packaging, Chemical Stability, and Product Integrity
The regulation specifically requires that manufacturers ensure that the “packaging selected for CSPs is appropriate to preserve the sterility and strength until the beyond-use date.” The final packaging for a CSP, such as empty evacuated containers, plastic infusion bags, or elastomeric pumps, must maintain the sterility and strength of the CSP. Sterility refers to microbial barrier properties, while strength refers to the CSP's potency. Although it is impossible to assess every chemical entity that may be placed into a package, manufacturers can use bracketing studies to identify basic chemical stability parameters like pH, oxygen transmission, etc.
A series of microbial stability studies and microbial ingress studies should be performed to evaluate the container. The studies should be done for each of the USP <797> microbial risk categories that are appropriate for a particular device. Microbial ingress studies with Brevundimonas diminuta and containers filled with microbial growth media, under the appropriate risk conditions for the device, should also be conducted. Since most compounding centers will not have the technical expertise or facilities to perform these studies, medical device manufacturers should perform these studies under defined protocols. The manufacturers can then generate final reports that document and defend their positions. These reports and protocols also should be made available to the compounding centers.
Validations and Media Fills
USP <797> requires that compounding centers have written and approved procedures for filling a CSP under certain conditions of microbial risk. The sterility assurance of an aseptically filled product is based upon process validations, environmental monitoring, and acceptable media fills. USP <797> outlines different media-fill procedures that compounding professionals can perform at their facilities, depending on the risk category of the CSP. Manufacturers should prepare device-filling instructions for the compounding professionals based on media-fill studies performed under the appropriate risk-condition environment. Such studies can be performed either by the device manufacturer, if the laboratory facilities are available, or at a contract laboratory. Typical studies involve filling multiple containers with a growth-supporting medium under the appropriate risk conditions (e.g., ISO Class 5 environment).
Multiple interventions should be designed into the study to represent the worst-case conditions under which the CSP would be filled. Examples of interventions include multiple transfers of a medium from one container to another before final filling. The device manufacturer should prepare comprehensive instructions from these media-fill studies and provide them to the compounding centers.
USP <797> has borrowed much of its content from the aseptic fill industry. It also has established media-fill qualification procedures to train the individual compounding professionals to perform aseptic transfers. These employee qualifications must be performed on an annual or biannual basis. Medical device manufacturers should prepare specific media-fill protocols for their medical devices. These procedures should be independently validated and made available to the compounding centers. This information can also be used by the manufacturers' sales force to structure in-service training programs to reinforce their device's <797> compliance.
The regulation also has set requirements for compounding accuracies. Automated-filling equipment manufacturers should carefully consider their instructions for use. Clear and concise recommendations for calibrating the instrument and verifying fill volumes should be included. Several filling-equipment manufacturers perform this service and offer good examples of filling and calibration procedures on company Web sites and in published literature. Although not a requirement, some medical device manufacturers offer recommendations on specific filling equipment that has been demonstrated to successfully work for filling their devices. Supporting data should be available in these cases to supply to CSP personnel if requested.
The publication of USP/NF 22 <797> “Pharmaceutical Compounding—Sterile Preparations” in the beginning of 2004 raised many questions for compounding professionals as well as for medical device suppliers. Medical device manufacturers have found that they must be able to answer questions from compounding centers about compatibility with USP <797>. Therefore, medical device manufacturers that supply components to be used in filling, packaging, or storing CSPs must be familiar with the regulation and have information to support the compliance of their devices. This information should include a rationale for the risk classification for their device that is consistent with their directions for use, technical reports, and protocols and procedures to support storage. The information should also include expiration dating and validated recommendations for media fill procedures for personnel qualifications. Although it is the responsibility of the medical manufacturer to generate this information for the <797>-compliant use of a product, beyond that, it is also sound business practice.
1. United States Pharmacopeia 27/National Formulary 22, Chapter <797> “Pharmaceutical Compounding—Sterile Preparations,” The U.S. Pharmacopeial Convention (Rockville, MD, 2003).
2. Association for the Advancement of Medical Instrumentation (AAMI), “Designing, Testing, and Labeling Reusable Medical Devices for Reprocessing in Health Care Facilities: A Guide for Device Manufacturers,” AAMI TIR, no. 12, (Arlington, VA, 1994).
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