Hospira

This section provides important, practical information geared toward today’s busy pharmacy professional—information that can help institutions with their compliance programs. It includes an overview of the purpose of USP <797>, the events leading up to this historic chapter that is changing the way pharmacy is practiced, as well as USP <797> compliance information.

USP Chapter <797>: An Idea Whose Time Has Come
     Voluntary Standards
     Compounding and Compliance Surveys
     Arrival of USP <797> — and Enforceability
     Compounding Risk Levels
     Beyond-Use Dating
     Conclusion
     Additional USP <797> Resources

USP Chapter <797>: An Idea Whose Time Has Come

Voluntary Standards

During the 1960s and 1970s, a new emphasis began to be placed on patient safety when it became apparent that patients were being injured—with some even dying—as a result of medication delivery and sterile compounding problems.¹

While the American Society of Health-System Pharmacists (ASHP) and other organizations developed compounding standards in an effort to curtail the problem, these standards remained voluntary, were not adopted by the majority of pharmacies, and did not appear to significantly impact compounding practices overall.²

Since 1990, the Food and Drug Administration (FDA) has been alerted to more than 55 serious problems relating to the quality of compounded sterile preparations, and many of these cases resulted in product recalls.³

Compounding and Compliance Surveys

In 2001, the FDA conducted a limited survey of compounding occurring in a group of community pharmacies throughout the United States. The goal was to assess the quality of compounded products in the marketplace.

The results of the FDA survey confirmed that compounding problems indeed existed:³

Of 29 sampled products, 34% failed at least 1 standard test of quality

Many of the failures were due to inadequate potency.³ In this small survey, no sterility failures were observed. However, the FDA survey report concluded in part that “These findings also highlight the importance of carefully and properly compounding drug products to minimize risks to consumers.”

In 2003, Morris et al⁴ conducted a national mail survey of 600 hospital pharmacy directors, to study their compliance with the voluntary ASHP Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products. The survey confirmed that voluntary guidelines do not appear to produce significant changes in compounding practice. For example:

5.2% of pharmacies that compounded risk-level-1 preparations were found to be compliant with garb requirements

The authors of this survey concluded that, although some improvements in compliance had taken place compared with a 1995 survey, many pharmacies were still not fully compliant with the voluntary ASHP guidelines.⁴

Arrival of USP <797>—and Enforceability

In January 2004, USP Chapter <797>, Pharmaceutical Compounding—Sterile Preparations, became the first official, enforceable requirement for the compounding of sterile preparations. The goal, as stated in the chapter, is:

“…to prevent harm and fatality to patients that could result from microbial contamination (nonsterility), excessive bacterial endotoxins, large content errors in strength or correct ingredients, and incorrect ingredients in CSPs [compounded sterile preparations].”⁵

The enforceability of USP <797> means that pharmacies may be inspected for compliance with the required standards by state boards of pharmacy, the FDA, and accreditation organizations such as the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), Accreditation Commission for Health Care, and the Community Health Accreditation Program. According to Kastango and Bradshaw:

“FDA exercises enforcement discretion during routine inspections but will intervene when patient injuries or deaths associated with CSPs have occurred.”¹

Compounding Risk Levels

Although the information may be subject to change, the United States Pharmacopeia (USP) has delineated the compounding conditions that are classified as low, medium, and high risk.⁵ Although it is up to the individual pharmacist to determine the acceptable compounding risk for a particular pharmacy need, the following information from USP <797> states how various types of compounding will be considered:

Compounding Conditions and Associated Risk Levels, From USP Chapter <797>⁵

Low-Risk Level	Compounded entirely under ISO Class 5 (Class 100) conditions Compounding involves only transfer, measuring, and mixing manipulations with closed or sealed packaging systems; performed promptly and attentively Manipulations limited to aseptically opening ampuls, penetrating sterile stoppers on vials with sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile administration devices and packages of other sterile products
Medium-Risk Level	All conditions listed under low-risk level, but: Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient on multiple occasions Compounding process includes complex aseptic manipulations other than the single-volume transfer Compounding process requires unusually long duration The sterile CSPs do not contain broad-spectrum bacteriostatic substances, and are administered over several days
High-Risk Level	Nonsterile ingredients are incorporated or a nonsterile device is employed before terminal sterilization Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to ISO Class 5 (Class 100) Nonsterile preparations are exposed for at least 6 hours before being sterilized It is assumed that the chemical purity and content strength of ingredients meet their original and compendial specifications in unopened packages of bulk ingredients

Beyond-Use Dating

While a complete overview of USP <797> is beyond the scope of this Web site, USP classification of beyond-use dating for products of different risk levels may also be particularly pertinent to this discussion of compounding safety. As specified in the chapter, these beyond-use dating periods are as follows. Note that this information applies only to aseptically prepared products that have not undergone sterility testing:

Beyond-Use Dating Based on Risk Level and Temperature, From USP Chapter <797>^5,6

	Low Risk	Medium Risk	High Risk
Controlled room temperature	48 hrs	30 hrs	24 hrs
Cold temperature (refrigeration, 2-8˚C)	14 days	7 days*	3 days
Solid frozen state (≤ -20˚C)	45 days	45 days	45 days

* Proposed extension to 9 days.⁶

Conclusion

Why an enforceable standard for sterile compounding now? Simply put, because voluntary standards have not been sufficiently effective in reducing the number of compounding errors—or protecting patients from the potential consequences of these errors.

Additional USP Chapter <797> Resources

Pharmacists are invited to compare their timelines for completing various sections of USP <797> with that of the experts at JCAHO, visit:
www.ashp.org/news/ShowArticle.cfm?id=8114
For a detailed explanation of proposed changes to USP <797>, visit:
www.usp.org/standards/proposed797Revisions.html
For a selected USP <797> Bibliography, visit:
www.ashp.org/SterileCpd/other-bibliography.cfm
The answers to some common questions can be found, visit:
www.ashp.org/SterileCpd/faq.cfm
To read the results of an FDA compounding survey that influenced the development of USP <797>, visit:
www.fda.gov/cder/pharmcomp/survey.htm
For more information on ASHP Policy and Guidance on USP <797>, ASHP products, and much more, visit:
www.ashp.org/SterileCpd

References:

1. Kastango ES, Bradshaw BD. USP chapter 797: establishing a practice standard for compounding sterile preparations in pharmacy. Am J Health Syst Pharm. 2004;61:1928-1938.

2. Newton DW, Trissel LA. A primer on USP Chapter <797> “Pharmaceutical Compounding—Sterile Preparations,” and USP process for drug and practice standards. Int J Pharmaceutical Compounding. 2004;8:251-263.

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Report: limited FDA survey of compounded drug products. Available at: http://www.fda.gov/cder/pharmcomp/survey.htm. Accessed January 2005.

4. Morris AM, Schneider PJ, Pedersen CA et al. National survey of quality assurance activities for pharmacy-compounded sterile preparations. Am J Health Syst Pharm. 2003;60:2567-2576.

5. USP General Chapter <797>. The current United States Pharmacopeia, 27th rev, and the National Formulary, 22nd ed, and Supplements. Rockville, Md: The United States Pharmacopeial Convention, 2004.

6. The United States Pharmacopeial Convention. Proposed Revisions to USP Chapter <797>. Pharmaceutical Compounding—Sterile Preparations. Available at: http://www.usp.org/standards/proposed797Revisions.html. Accessed January 2005.