Originally Published MDDI January
2005
Sterile Compounding
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>
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.
Microbial Risk
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.
Expiration Dating
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.
Compounding Accuracy
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.
Conclusion
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.
References
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).
Copyright ©2005 Medical Device & Diagnostic Industry
