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USP Publishes Enforceable Chapter On Sterile Compounding

Cheryl A. Thompson

A new United States Pharmacopeia (USP) chapter that describes appropriate compounding of sterile preparations becomes official on January 1 and can be enforced by state boards of pharmacy and cited during visits by FDA and accreditation personnel, knowledgeable sources said.

The document, known as General Tests and Assays Chapter 797 or "Pharmaceutical Compounding—Sterile Preparations,"1 is the revision of the general information chapter 1206, "Sterile Drug Products for Home Use," said Claudia C. Okeke, a United States Pharmacopeia (USP) associate director who served as the scientific liaison for the expert committee that made the revisions.

By moving the chapter into the General Tests and Assays portion of USP, which has chapter numbers less than 1000, the committee made its revision one of the legal bases by which FDA personnel can determine whether a drug has been adulterated.

"This is all about patient safety," said Joseph H. Deffenbaugh, director of public health and quality for the ASHP Practice Standards and Quality Division. "Let's not forget what the purpose of all this is: to protect patients from microbially contaminated preparations, but also to make sure that those preparations are compounded accurately and appropriately for the conditions for which they're being prescribed."

Why rename and renumber? Okeke said the committee, composed of about 10 academics, pharmacy practitioners, and independent sterile-formulation compounders, decided to revise the general information chapter to reflect FDA's interpretation of the Food and Drug Administration Modernization Act of 1997 (FDAMA).

FDAMA added provisions on pharmacy compounding to the Food, Drug, and Cosmetic Act and left the details to the regulatory agency. One of the details was identifying which drug products should not be compounded because of concerns for patients' safety.

FDA's Jane Axelrad, associate director for policy at the Center for Drug Evaluation and Research, explained: "The law allowed us to prevent the compounding of sterile products that were demonstrably difficult to compound." Axelrad served as cochair of FDA's Pharmacy Compounding Advisory Committee, established in 1998 to help the agency set the compouding-related regulations required by FDAMA.

"This is all about patient safety. Let's not forget what the purpose of all this is."
—Joseph H. Deffenbaugh

In a 2000 "concept paper," FDA proposed factors to consider in making a list of drug products that were demonstrably difficult to compound. One of these factors was the use of procedures other than those described in the most relevant USP chapter, 1206, but that chapter was aimed at the home care setting, Axelrad said.

Members of the advisory committee agreed unanimously at a July 2000 meeting that any sterile formulation not compounded in accordance with USP chapter 1206 should be on the "list of drug products that may not be compounded because they are difficult to compound properly." But in addition to needing a document aimed at all health care settings in which sterile compounding occurs, the committee wanted an "enforceable entity," not something perceived as a guideline.

USP, a year before, had started its revision process for chapter 1206.

For reasons unrelated to FDA's project of identifying drug products too difficult to compound safely, the Supreme Court ruled in April 2002 that FDAMA's compounding provisions were invalid.

The USP expert committee revised its chapter on compounding sterile preparations and published it as chapter 797 with the new name, Okeke said, making it enforceable by state boards of pharmacy.

After the original version of chapter 797 was published, USP received many comments from compounding pharmacists who "felt that no pharmacy could ever meet the requirements of the chapter," she said. The committee, she added, considered every one of the more than 100 comments received and incorporated most of them into the revision.

The meaning of enforceable. Axelrad said FDA does not directly enforce pharmacies' compliance with the USP chapters on compounding.

"Basically what we've been doing is exercising enforcement discretion," she said. FDA can enforce manufacturing standards in places that, in the agency's view, she said, manufacture pharmaceuticals.

"We certainly believe we can go after compounded products that are supposed to be sterile" but are contaminated, misbranded, or adulterated, Axelrad said.

FDA Consumer Safety Officer Fred Richman said that, if USP chapter 797 had been available a year ago, "essentially there wouldn't have been any change in our approach" to stopping a South Carolina pharmacy's distribution of a fungus-contaminated injectable formulation that was responsible for at least one death in North Carolina.

"We did the inspection with the state," he said. "We found practices not conducive with making a sterile product."

Richman said the South Carolina Board of Pharmacy issued a cease-and-desist order to the pharmacy and otherwise took care of everything that needed to be done. Eventually the pharmacy went out of business, he said.

During investigations of compounding pharmacies suspected of improperly preparing sterile formulations, FDA personnel point out certain ASHP guidelines and USP chapters as relevant sources of information, Richman said.

Apparently the Centers for Disease Control and Prevention also considers ASHP guidelines as a source of information on the appropriate preparation of sterile infusions and medications. According to an article in the July 15 issue of AJHP, agency epidemiologists identified a hospital pharmacy's noncompliance with the ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products2 as a factor that may have contributed to an outbreak of bacterial bloodstream infections in pediatric inpatients.3

Efforts to revise FDA's Pharmacy Compounding Compliance Policy Guide, which differentiates manufacturing from compounding, are under way, Axelrad said. Unlike publication of the original guide in June 2002, she said, FDA will probably issue a draft of the document and consider comments from the public before finalizing the guide. She declined to state a time frame for the revision process.

USP chapters can be enforced by a state board of pharmacy, but only if that board stipulates so in its regulations, said Carmen A. Catizone, executive director of the National Association of Boards of Pharmacy (NABP). Chapters that become the standard of practice in pharmacy can also be enforced by a state board of pharmacy, he added.

At NABP's annual meeting in April, the Committee on Law Enforcement and Legislation recommended several changes to the "good compounding practices" included in the Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy, also known as the Model Act. One of the changes would add the following sentence: "Compounding Pharmacists and Pharmacies shall practice in accordance with these Good Compounding Practices, the Board's Rules for Sterile Pharmaceuticals, and the current United States Pharmacopeia/National Formulary (USP/NF) chapters on compounding and sterile product preparation." This and other changes will be reviewed by the NABP executive committee.

The Model Act's good compounding practices have been adopted in about 15 states, Catizone said.

Okeke said USP, which wants to ensure that "whoever does any type of sterile compounding has [at least] the minimum expertise to do that job," sent each state board of pharmacy a copy of the finished chapter.

NABP, Catizone said, does not know how many state boards of pharmacy require licensed pharmacies to have a copy of USP.

Accreditation activities. Whether a state decides to include or cite USP chapter 797 in laws or regulations will determine whether surveyors from the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) refer to that document during visits.

Because USP chapter 797 is considered "law and regulation" enforceable by FDA, JCAHO will expect and survey for compliance with these requirements wherever applicable starting in 2004, said Darryl S. Rich, an associate director of surveyor management and development for the accrediting group.

"We have a standard that says that all organizations must be in compliance with all applicable laws and regulations," he said.

JCAHO's new system for conducting accreditation surveys, which is known as Shared Visions–New Pathways and begins January 1, calls for surveyors to concentrate on a health care organization's critical priority focus areas, that is, specific issues that are most relevant to patients' safety and the quality of care.

"Compounding would never arise as a priority," Rich said, because it is not a critical priority focus area. Medication management, however, is a critical priority focus area and, if selected for scrutiny at a health care organization, could draw surveyors' attention to compounding practices, he said. Another critical priority focus area is orientation and training, and surveyors' assessment of an organization could be tied to personnel's knowledge of the orientation and training requirements of USP chapter 797, he said.

"It is our goal to train the surveyors about [USP chapter 797]," Rich said, "and it is our goal to inform organizations that are accredited by us about this particular issue."

He said surveyors will receive "some guidelines as to where specific issues in the chapter would be scored in our standards, but we're specifically telling them that this is not to be the focus of surveyors."

JCAHO will probably publicize the chapter's requirements in an upcoming issue of the monthly Joint Commission Perspectives, Rich said, because hospital administrators and persons responsible for accreditation at organizations may be unaware of the new chapter's requirements.

"We're also concerned that there's probably not very many people out there who actually are in compliance," he said.

Janet Teeters, director of the ASHP Accreditation Services Division, said pharmacy residency program sites surveyed by her personnel are "cited somewhat frequently" for lapses in their sterile compounding practices.

Similar to JCAHO, she said, the ASHP accreditation standards for residencies in pharmacy practice and residencies in specialized pharmacy practice require that a pharmacy "comply with all applicable federal, state, and local laws, codes, statutes, and regulations governing pharmacy practice." In states that have not incorporated USP chapter 797 into laws or regulations, pharmacies found deficient in their sterile compounding practices will be told to improve and use the chapter as a resource, Teeters said. Such sites, when found, have been referred to the ASHP guidelines and will continue to be referred to that document, she said.

Differences from ASHP guidelines. "There's not much difference between the ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products and the USP General Assays and Tests Chapter 797, Pharmaceutical Compounding—Sterile Preparations," said ASHP's Deffenbaugh, except for some differences in terminology and organization.

The two documents use different names for risk levels: 1, 2, and 3 in the ASHP document, and low, medium, and high in the USP document (see the box). ASHP's risk level 1 corresponds to USP's low-risk level, 2 is "very similar" to medium, and 3 matches high, Deffenbaugh said. "Both documents lay out some requirements for defining risk levels and give examples," but both documents, he added, particularly the USP document, note that the examples for each risk level "are neither prescriptive nor exhaustive."

As for the different organization of the documents, he said, the ASHP document starts with risk level 1 and then describes the requirements for policies and procedures; personnel education, training, and evaluation; storage and handling in the pharmacy; and so on through a total of 12 areas of quality assurance (QA). Then the document covers risk level 2, he said, "and usually it will say 'in addition to those requirements for risk level 1, the following requirements are added'" and continue through the various QA requirements in the same order as for the lower risk level. The same pattern follows for risk level 3.

In contrast, Deffenbaugh said, "the USP document emphasizes the compounding conditions, the QA program and practices, outcome monitoring, reports and documents, and so on." Within each section of procedures and requirements lies the information about the three risk levels.

"The one, I think, significant difference between the USP document and the ASHP document is that the USP tends to allow longer storage periods after preparation [but] before complete administration" of the compounded sterile formulation, Deffenbaugh said.

Also notable is the difference in the documents' provision of detail on tests.

"The ASHP document tends to reference USP chapters dealing with sterility testing and so on and the other primary literature," he said. "The USP document provides more detail on a variety of tests and also references its own chapters and several other chapters that are related to compounding and packaging. And you have to remember that the USP document is a General Tests and Assays chapter, so I think it's reasonable that it's more specific in providing requirements for testing."

Pharmacies already adhering to the ASHP guidelines "will have little difficulty being able to comply with USP chapter 797," Deffenbaugh said.

Room for improvement in practice. "The profession must make improvements or [it] risks losing the ability or the prerogative to consider compounding sterile preparations in the pharmacy as a best practice," said Craig A. Pedersen, who surveyed hospital pharmacy directors a year ago about their departments' sterile compounding practices, with 9 of the 12 QA sections in the ASHP guidelines as the basis for the questions.

Pedersen, an associate professor at the Ohio State University (OSU) College of Pharmacy, said about 30% of the 600 directors who received the survey provided usable responses. The research team weighted the responses on the basis of each hospital's number of staffed beds and the number of hospitals of that size in the nation.

"It appeared from the results of this survey that the garb requirements are at the lowest level of compliance," Pedersen said. At facilities in which pharmacy personnel used only manufacturer- supplied sterile products and made relatively few manipulations when compounding, the research team estimated that 5.2% of hospitals were compliant with the ASHP guidelines. Compliance decreased as risk level increased, with about 2% of hospital pharmacy departments that prepare some sterile formulations from nonsterile ingredients complying with the garb requirements whenever personnel compound sterile pharmaceuticals, he said.

Whereas an estimated 77% of hospital pharmacies complied with the ASHP guidelines' restrictions on jewelry that may be worn when personnel compound sterile preparations, Pedersen said the next-best level of compliance with the garb requirements was 21%, for donning low-shed garments or gowns.

Compliance with the garb requirements was low, Pedersen speculated, "because the requirements are so specific and most hospitals don't have policies and procedures in place that actually require all of those things. And quite frankly, it's expensive to supply all of these things to the personnel." He said poor compliance could also be the result of personnel not understanding the importance of apparel in the protection of the pharmaceutical and the preparer.

Hospital pharmacies seem to be doing an excellent job at complying with at least one QA requirement in the ASHP guidelines: assigning a date beyond which a compounded sterile preparation may not be used.

"We're estimating that about 90% of hospitals do a very good job of determining beyond-use dates or expiration dates," Pedersen said.

The survey project was funded by the ASHP Research and Education Foundation, he said, and results were first presented at the ASHP Midyear Clinical Meeting in December 2002.

Efforts at ASHP. Revision of ASHP's book on sterile pharmaceutical compounding, by Philip J. Schneider and E. Clyde Buchanan, recently got under way and will proceed at a quick pace, said Schneider, director of the Latiolais Leadership Program at OSU and a member of Pedersen's research team. The book will bear the title Compounding Sterile Preparations, Second Edition, he said, to conform to FDA's view of "products" being the result of a manufacturing process and hence subject to regulations covering the manufacture of drug and biological products. This edition will update Principles of Sterile Product Preparation Revised 1st Edition and explain USP chapter 797, he said.

ASHP's Kasey K. Thompson, secretary for the Council on Professional Affairs, said the ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products will be considered for "priority revision" when the council meets in mid-September to discuss pharmacy practice standards and other issues.

Charles E. Myers, ASHP group vice president of Professional Development and Member Services, attended a July 7 meeting organized by USP, NABP, and the American Pharmacists Association to consider what might be done to establish standards for the quality of compounded drug preparations, compounding facilities, and compounding processes and the qualifications of persons who compound. Myers indicated that the discussion among the 21 attendees was exploratory and that no firm decision on the issue of standards was made.

  1. Pharmaceutical compounding—sterile preparations (fourth interim revision announcement). Pharm Forum. 2003; 29:940-65.           
  2. American Society of Health-System Pharmacists. ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products. Am J Health-Syst Pharm. 2000; 57:1150-69.           
  3. Selenic D, Dodson DR, Jensen B et al. Enterobacter cloacae bloodstream infections in pediatric patients traced to a hospital pharmacy. Am J Health-Syst Pharm. 2003; 60:1440-6.

USP Microbial Contamination Risk Levels for Compounded Sterile Pharmaceuticals

Low Risk Medium Risk High Risk
  • Compounded from commercially available sterile drug products      
  • Made via prompt execution of a relatively few basic, aseptic manipulations      
  • Prepared by using closed-system transfers under ISO class 5 conditionsa
  • Compounded from commercially available sterile drug products      
  • Made via complex or numerous aseptic manipulations over a relatively long time      
  • Prepared by using closed-system transfers under ISO class 5 conditions and by combining doses of sterile drug products for administration to one patient on multiple occasions or to multiple patients      
  • Intended for administration over multiple days without a broad-spectrum bacteriostatic agent
  • Compounded from a nonsterile ingredient or with a nonsterile device      
  • Made via procedure that involves exposure of sterile ingredients, components, devices, or mixtures to air quality inferior to ISO class 5 conditions

aEquivalent to class 100 conditions in former Federal Standard 209E. ISO = International Organization of Standardization.