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ASHP Submits Comments on FDA's 'Concept Paper' on Compounding



14 August 2000 

Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, Maryland 20852 

Re: Docket No. 00N-1357

To Whom It May Concern:

The American Society of Health-System Pharmacists (ASHP) is pleased to respond to the Food and Drug Administration's (FDA) request for comments on the agency's Concept Paper on "Drug Products that Present Demonstrable Difficulties for Compounding Because of Reasons of Safety or Effectiveness." ASHP is the 30,000-member national professional association that represents pharmacists who practice in hospitals, health maintenance organizations, long-term care facilities, home care agencies, and other components of health care systems.


It clearly would not be in the public interest to ban pharmacist compounding of sterile products in organized health care settings, given the decades-long constructive experience of hospital pharmacists serving patients by performing this function well. Hospital pharmacists in the United States have been providing centralized intravenous admixture compounding services since the early 1960s, when the concept was pioneered at the National Institutes of Health Clinical Center and other leading hospitals throughout the United States. Countless lives have been saved through this compounding by pharmacists.

In general, we think the FDA has come up with a good approach in dealing with pharmacist compounding of sterile products by recognizing that (1) there are risks associated with compounding sterile products, and (2) that risk can be managed successfully and effectively if pharmacists follow appropriate practice standards and procedures.

ASHP appreciates the FDA's extensive use in the preparation of its Concept Paper of ASHP practice standards, guidelines, Technical Assistance Bulletins and other research on this subject that has appeared over the years in the American Journal of Health-System Pharmacy. ASHP has demonstrated its serious commitment to keeping all its practice standards and guidelines up-to-date and reflective of current scientific knowledge and professional practice.

We have some concerns, however. Our first concern has to do with the categorization of all sterile products as demonstrably difficult to compound. Because there are differences in complexity of compounding individual drugs within drug categories, ASHP believes that Congress intended that the Department of Health and Human Services develop a list of individual drugs that present demonstrable difficulties in compounding, and not a complete category such as sterile. This is the approach that the FDA took in developing the other lists required by the pharmacy compounding section of the Federal Food, Drug, and Cosmetic Act (FFDCA). The development of requirements or criteria for making decisions on whether the preparation of sterile products reaches some threshold of safety is certainly appropriate, however, and the risk levels that are delineated in ASHP's guidelines and the USP Chapter 1206 serve that end better than categorizing all sterile products as difficult to compound.

Another concern relates to the FDA's intentions regarding section 503A(f) of the Food, Drug, and Cosmetic Act, which states that "the term 'compounding' does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling."

We believe that the FDA's Concept Paper has not clearly differentiated between the actions noted in section 503A(f) of the Act and the commonly accepted professional understanding of compounding of sterile preparations. For example, in discussing the complexity of preparing sterile products, the agency says (page 7 of the Concept Paper): "Each time a pharmacist removes a sterile product from its original container or reconstitutes a sterile product, a risk of compromising the sterility of the product exists" (emphasis added). The use of the word "reconstitutes" in this context implies to us that the FDA intends to regulate reconstitution according to manufacturers' instructions as well as compounding. We believe that a determination that "reconstitution" consistent with product labeling is demonstrably difficult would be contrary to the intent of section 503A(f) of the Act. ASHP requests that the FDA correct this erroneous implication either by using a different term than "reconstitutes" in this context, or completely deleting any reference to reconstitution. We are heartened that an FDA spokesperson at the July 14 meeting of the Pharmacy Compounding Advisory Committee indicated that the agency would make this clarification.

We are pleased that the FDA is advocating that professional practice quality assurance standards must be applied to sterile product compounding. ASHP agrees with that philosophy, as reflected in our long history of developing applicable practice standards and fostering the application of those standards, in various articles published in our peer-reviewed, professional practice journal, and, as well, in educational programming and training featured at our conferences and training seminars.

However, if the FDA is suggesting that only "the standards in Chapter 1206 [of the USP], when applied to the compounding of any sterile drug product, would reasonably ensure the potency, purity, and quality of the drug product" (page 18 of the Concept Paper), we must object. As you know, in June ASHP issued its revised "Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products,"1 which updates a document originally created in 1993.2 ASHP believes that the FDA should strongly encourage state boards of pharmacy to base their oversight of sterile drug compounding on both Chapter 1206 of the USP, currently in the process of revision, and our newly-revised guideline for the compounding of all sterile products, as well as new scientific knowledge that may not have yet found its way into these documents.

Neither the USP Chapter nor the ASHP guideline is comprehensive, but they are complementary. The standards in both documents, used together, could reach the level of comprehensiveness envisioned by the FDA's Concept Paper. The scope of each is determined by the purpose of each document, and the USP Chapter and ASHP guideline serve different purposes. USP Chapter 1206 concentrates on testing and assaying procedures. It leaves out the practice context of compounding sterile products. ASHP's guideline addresses the place for utilizing USP's testing and assaying procedures in a practice environment and provides expert advice on quality assurance in that environment. ASHP's guideline does not include specific testing and assaying requirements, but incorporates them by referencing the USP document for specific methods, such as environmental monitoring, sterile process validation, and end-product sterility testing. The ASHP guideline provides useful shelf-time and temperature criteria for risk level determination and the use of barrier/isolators and autocompounders.

A 1996 article by Laura Thoma comparing Chapter 1206 of the USP and ASHP's document noted that there is little practical difference in content between the documents: "the ASHP and the USP documents both contain much useful information, [and] each has a unique perspective and contains some information not covered by the other." This was due to the fact that the original USP Chapter was limited to home health care practice settings, while the ASHP document applied to pharmacy services in various and broad practice settings. The author of the comparison concluded: "It is recommended that both documents be read for further information and that professional judgment be used in applying these guidelines to individual practice settings."3

The following year (1997) another comparison noted that "both of these guidelines provide directions for setting quality standards and practices for achieving them. Both were published in draft form for comment before the final version was prepared. Therefore, the final form represents the thinking of not only the select committees that drafted them and the distinguished boards that approved them, but to some degree, of the profession at large."4

ASHP believes it is appropriate for the FDA to suggest to state boards of pharmacy the standards they should apply in the oversight of sterile compounding. This will foster the establishment of a national quality assurance standard for compounding sterile drug products in all pharmacy settings. The use of both the USP Chapter and ASHP's guidelines, as well as the latest scientific knowledge in the literature, would provide the assurance the FDA is seeking for the safety and effectiveness of these products.


The role of enforcing the application of specific quality assurance standards in pharmacy practice is one that is well established in law and in practice for state boards of pharmacy. The FDA recognized this in its December 28, 1998, draft "Memorandum of Understanding on Interstate Distribution of Compounded Drug Products." In that document the agency states that "the standard MOU also reflects FDA's policy to defer to State and local officials for the regulation of the day-to-day practice of pharmacy, to the extent permitted under the FFDCA."

In our oral presentation before the Pharmacy Compounding Advisory Committee meeting on July 14, we strongly recommended that the FDA delegate to state boards of pharmacy the responsibility for overseeing pharmacists' adherence to those standards, rather than assume this responsibility directly. ASHP recognizes, however, that while state boards of pharmacy are far more capable of enforcing compounding standards, the FDA has a role to play in ensuring that state boards fulfill this responsibility through the adoption of uniform standards. Uniform standards of practice should be adopted because many compounded products cross state lines. We believe that the FDA's role is best fulfilled by encouraging that the standards in both Chapter 1206 and ASHP's guidelines are followed.

ASHP appreciates the opportunity to comment on the FDA's Concept Paper. Drug products that are necessary in the provision of significant public health benefits and appropriate patient care should not be considered "demonstrably difficult" to compound. Comments on FDA's Concept Paper that we have received from our members throughout the country testify to the many lives that have been saved thanks to the dedication, skill, and professional judgment of pharmacists who have compounded sterile products that otherwise may not have been available. We are pleased with the assurances that were given by FDA staff during the July 14 Pharmacy Compounding Advisory Committee meeting regarding some of our concerns, and we look forward to the continued opportunity to advise the agency as it develops a proposed rule on this important public health and pharmacy practice issue. Please feel free to contact me at (301) 657-3000, ext. 1316, if you have any questions regarding our comments.


Gary C. Stein, Ph.D.
Director, Federal Regulatory Affairs 


1 Am J Health-Syst Pharm. 2000; 57:1150-69.
2 Am J Hosp Pharm. 1993; 50:2386-98.
3 Thoma LA. A Comparison of Sterile Compounding Guidelines for Pharmacists. Pharmacopeial Forum. 1996; 22:2934-37.
4 Avis KE. Assuring the Quality of Pharmacy-Prepared Sterile Products. Pharmacopeial Forum. 1997, 23:3567-76.