"For pharmacies like mine, this means that sterile products...must be prepared in compliance with the new UiSP CAa/;fe;- 7P7 [emphasis added], whether the pharmacy prepares one sterile product per month or 20 per day. The implementation of new procedures and documentation is not easy, but it is necessary [emphasis added]."10

Finally, the following admonition from a prcmicr-in-1949 pharmacy book captures the quintessence of pharmaceutical compounding:

"Compounding is the pharmaceutical task in which all the scientific ^»OIiVe^gf [emphasis added], professional skill [emphasis added] and sense of responsibility [emphasis added] . . . must [emphasis added] find their expression and justification."11

The above statement preceded by 20 years the national emergence of hospital intravenous admixture services using manufactured products, as well as these services increasing the compounding of sterile solutions from nonsterile ingredients for patient-specific treatment.

Where Is Chapter Published and How Can It be Obtained?

Chapter is published in the combined United States Pharmacopeia 27-National Formulatory 22 (IASP-TW) of 2004(5) as either a 2 ½-inch-thick dark red book or a compact disk. In USf 27-NF 22, Chapter was printed in the same format as in-process revisions published in USP's official bimonthly journal, Pharmacopeial Forum (PF). That format includes text of both the new and former content. The "clean" version of , which lacks the deleted former content, is printed in the First Supplement to (JSP 27-NF 22, which was released February 2, 2004.6 Chapter may be purchased by contacting USP Customer Service at 1-800-227-8772 or custsvc@usp.org.

Who Serves on the 2000-2005 Sterile Compounding Committee and Who Is Its USP Staff Liaison?

All USP Council of Experts committee members are unpaid (by USP) volunteers. The seven Sterile Compounding Committee (SCC) members and one FDA ad hoc reviewer are pharmacists whose employers include pharmacies and healthcare facilities, pharmacy and medical schools and the FDA. Preceding 2000, USP oversight of sterile compounding matters was delegated to an ad hoc panel appointed by the USP Convention-elected Water and Parenterals Subcommittee of the USP Committee of Revision. The USP salaried staff liaison for the SCC is pharmacist Claudia C. Okeke, PhD, Associate Director of the General Policies and Requirements Division.

What Is the USP and What Is USP's Relationship with the FDA?

The USP was founded in 1820 by a few physicians.12 The USP revision publication frequency has ranged from 10 years, to 5 years, to annually.12|d The USP is a nonprofit and nongovernmental organization served by hundreds of volunteers as convention delegates and Council of Experts committee members. Volunteers include practitioners and scientists in medicine, pharmacy and other Healthcare professions who represent academia, private practice, industrial manufacturing, national and state professional organizations, healthcare organizations and US government health agencies, as well as consumer organizations.c According to the USP website:

"The USP promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information developed by its volunteers for medicines, other healthcare technologies, and related practices used to maintain and improve health and promote optimal healthcare delivery."13,f

The FDA emerged in 1927 from the Bureau of Chemistry in the US Department of Agriculture, the latter having been created in 1862.14 The 1938 US Food, Drug, and Cosmetic Act assigned the FDA legal authority to enforce standards in the USP and NF. The USP "General Notices and Requirements," drug monographs or articles, and chapters numbered to contain PDA-enforceable standards; whereas chapters numbered and higher contain information considered interpretive.15-16

Do the USP Chapter Standards Provide all There Is to Know About Compounding Sterile Drugs?

In general, USP standards describe the necessary quality requirements for drugs, but they are not intended to be comprehensive sources for drug preparation information. Most USP standards are not accompanied by information describing explicitly how to meet them. Of many standards that could be described, the following are four such examples from USP 27:

1. The cefuroxime axetil tablets monograph gives no information on the names and amounts of excipients, and processing equipment and conditions to make tablets that meet the standard of not less than 60% of labeled cefuroxime axetil content dissolved in 15 minutes.

2. The fosphenytoin sodium injection monograph gives no information on the identity and amounts of added substances to achieve the pH range of 8.3 to 9.3.

3. Chapter does not specify methods and conditions or frequency of verification of sterilization methods for particular preparations. Compounders are responsible for determining methods and verifying their efficacy to achieve sterility and maintain strength of ingredients in each compounded preparation.

4. The gentamicin injection monograph does not specify methods for sterilization, practices to satisfy the bacterial endotoxins limit, or amounts and names of substances used to buffer pH, preserve sterility, sequester divalent cations, and adjust tonicity.

Neither the practice standards in Chapter 3'6 nor the ASHP Guidelines" will instruct explicitly how to compound particular preparations that will be sterile, pyrogen-free, physically stable and uniform, and chemically pure and stable. Both documents caution persons who compound sterile preparations to have acquired adequate education, training and experience before attempting to satisfy the practice standards therein. In addition to appropriate collegiate education and extracollegiate training, thorough study and proven competence regarding "hands-on" skills for aseptic manipulations and principles of sterile formulation, packaging and processing, such as those explained and illustrated in relevant ASHP publications and videos, are strongly recommended.

As a young PhD, Richard Feynman worked on the Manhattan Project. After World War II some of his colleagues suffered guilt over the destruction and death caused by the atomic bomb. In his 1955 address "The Value of Science" to the National Academy of Sciences, 10 years before his Nobel Prize in physics, Dr. Feynman reflected as follows:

"Scientific knowledge is an enabling power to do either good or bad-but it does not carry instructions on how to use it. Such power has evident value-even though the power may be negated by what one does with it."ls

Analogously, USP standards for drugs, dietary supplements and compounding practices are an enabling power, but only to do good for public health, and they do carry instructions for use, albeit not always complete or explicit ones. Before Chapter , voluntary sterile compounding practice standards from ASHP and USP had evident or inherent healthcare value, but some compounders negated it by their ignorance and negligence that hurt and killed patients.

What Were the First US Sterile Compounding Practice Standards?

The first detailed US information sources specifically for compounding sterile pharmaceutical preparations were the American Society of Hospital Pharmacists' 1992 Draft Technical Assistance Bulletin19'*=' and Chapter "Sterile Products for Home Use" in USP 23 in 1995.

The stimulus to create what became Chapter was resolution 5 to the 1985 USP Convention, urging USP to develop standards for compounded parenterals for home use. That resolution resulted initially in the appointment of the USP Home Health Care Subcommittee (of the Committee of Revision). The first official proposal was Chapter "Dispensing Practices for Sterile Drug Product Intended for Home Use," published in the March-April, 1992 issue of USP's journal, PF.20

Those ASHP and USP documents were prompted by:

1. Increasing early hospital discharges during the 1980s of patients receiving intravenous therapy.'1

2. A coincidence of national injuries and deaths to patients during the late 1980s and early 1990s from pharmacycompounded injections, ophthalmic solutions and organ transplant baths.

As a result of those tragic and publicized instances of alleged pharmacy compounding negligence, some FDA officials suggested banning some types of pharmacy compounding under FDA discretionary authority to regulate compounded preparations as unapproved new drugs under the adulteration and misbranding provisions of the FDC Act.7'21 The following summarizes the FDA perspective:

"Generally, FDA will defer to state authorities regarding less significant violations of the Act related to pharmacy compounding of human drugs. However, when the scope and nature ot a pharmacy's activities raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the new drug, adulteration, or misbranding provisions of the Act, FDA has determined that it should seriously consider enforcement action."21

For several decades before publication of those pioneer ASHP and USP sources for sterile compounding practice, patient-dedicated, risk-taking hospital pharmacists had compounded, especially sterile intravenous solutions, for their critical care patients. The importance of sterile compounding is illustrated by phenytoin,22 nitroglycerin2' and concentrated morphine injections,24'1 which were initially compounded as high-risk preparations by current ASHP17 and USP5'6 designations and later became commercially manufactured drug products.

How and Why Was Chapter Transformed to Chapter ?

The impetus to transform USP to a chapter numbered less than 1000, ie, from informational status to required standards (enforceable status), began with the june 2000 establishment of the new USP Patenterai Products-Compounding and Preparation Committee, now the S(IC, followed by the july 13 and 14, 2000 meeting of the FDA Pharmacy Compounding Advisory Committee.* That meeting resulted in FDA's August 2001 Concept Paper pertaining to section 127 in the 1997 FDA Modernization Act (FDAMA), from which the following is excerpted:

"FDAMA section 127 amended the {1938} Federal Food, Drug, and Cosmetic Act (the act) by adding section 503A (21 U.S.C. 353a), which governs the application of Federal law to pharmacy compounding. Under section S03A(a) of the act, a compounded drug product is a drug product made in response to, or in anticipation of, receipt of a valid prescription order or a notation on a valid prescription order from a licensed practitioner that states the compounded product is necessary for the identified patient. Compounded drug products are exempt... from three key provisions of the act...

1. Adulteration provision of section 501(a)(2)(21 U.S.C. 351(a)(2)(B)) (current good manufacturing practice [CGMP] requirements);

2. misbranding provision of section 502(f)(1) (21 U.S.C. 352(f)(1)) (labeling ot drugs with adequate directions for use); and

3. new drug provision of section 505 (21 U.S.C. 355) (...use of drugs under...INDs...NDAs...ANDAs).

...drug products that 'present demonstrable difficulties for compounding that reasonably demonstrate adverse effect on the safety or effectiveness of that drug product' (section 503A(b)(3) of the Act) {include}...All sterile products that are compounded under procedures other than those described in Chapter 1206 ['Sterile Drug Products for Home Use'] of the United States Pharmacopeia (USP)."25

Note: The excerpt above is shown verbatim with the exception of those words shown in {}, which were added by the authors of this article. Also, for emphasis, italics were added to certain words of this excerpt by the authors of this article.

On April 29, 2002, the US Supreme Court declared section 503 A of FDAMA invalid in its entirety because it "contained unconstitutional restrictions on commercial speech (ie, prohibitions on soliciting prescriptions for and advertising specific compounded drugs)."21

Consequently, in May 2002 the FDA reissued its March 16, 1992 Compliance Policy Guide on Pharmacy Compounding.19 The USP had originally planned to renumber Chapter to lower than after FDA proposed at its july 2000 Pharmacy Compounding Advisory Committee that shall be followed for sterile compounding. After section 503A was invalidated in April 2002, USP continued to assign numbers less than to its nonsterile and sterile compounding chapters, hoping to reduce or preclude patient harm from compounded preparations via FDA enforcement.

The FDA proposal, stemming from now-defunct FDAMA section 503A, to require former USP informational Chapter for sterile compounding practice indicates PDA's growing concern over the quality of compounded preparations. Some FDA officials have also suggested the possibility of requiring a label, such as the following, on all compounded preparations:1= "This preparation compounded by your pharmacy has not been evaluated for safety and effectiveness by the Food and Drug Administration."26 To reiterate Mr. Talley's statement,2 voluntary sterile compounding standards have not adequately prevented harm to patients from therapies that are supposed to save their lives and lessen their suffering. It should be noted that the quality requirements of Chapter apply to all healthcare practitioners in all locations where sterile preparations are compounded because all patients deserve to be protected. There should be no exemptions from patient safety, according to practitioners or places of sterile compounding.

What Were the Main Events Leading Chapter ?

The formidable challenge to transform Chapter to current Chapter began at the first meeting of the new SCC held in October 2000. The initial task was to review the most recent draft revision of Chapter published on pages 812-832 of the May-June 2000 issue of PF, which remained official until January 2004. The progress of the revision process of Chapter to Chapter is represented by publications in the following three PF issues:

1. PF 2002; 28(2) [Mar.-Apr.]:498-534. In response to this version, many comments were received during May through july 2002,7>1 especially from the following contributors:

* Mr. Trissel submitted 40 detailed specific comments.

* The ASHP, via Mr. Joseph Deffenbaugh, submitted four pages of general comments and referred to the above 40 comments from Mr. Trissel.

* Baxter Healthcare Corporation (Deerfield, Illinois) submitted 16 relatively general comments.

* McGuff Compounding Pharmacy Services, Inc. (Santa Ana, California) submitted 48 detailed, specific comments.

* The International Academy of Compounding Pharmacists (IACP) (Sugar Land, Texas), via Mr. L.D. King, submitted 58 detailed specific comments. Approximately 50 comments from Mr. Trissel, McGuff and IACP were substantively similar, and they served as the major basis of the revision. In addition the model of three microbial contamination risk levels and assignment of beyond-use dates based on nonsterility risk"' were adapted from the ASHP Guidelines.17

2. PF 2003; 29(3) [May-June]-.150-809. This draft included content in the then official Chapter and that proposed to become Chapter . This draft resulted from two separate two-day full SCC attendance meetings in Rockville, Maryland in the fall of 2002 (one during the local sniper shootings in October). It was the product of grueling analysis and discussion of the major comments USP received during May-July 2002 in response to the draft on pages 498-534 in the March-April 2002 PF.

3. PF 2003; 29(4) [July-Aug.]:940-965. This draft became official in January 2004.

Is Chapter Too Lenient or Too Strict?

Depending on viewpoints, the requirements of Chapter are neither too lenient nor are they too strict, but no answer will satisfy every person and organization affected by . There are, and will continue to be, persons who categorically disagree with any compounding of sterile preparations at any time for any reason, and persons who object to legal standards of any kind for compounding anything from emollient ointments to critical care injections. In establishing the Chapter standards, the SCC did not use the "lowest common denominator" but instead used high-quality compounding practices as models. all of the requirements of Chapter are within the current practices of these higher-quality compounding practices. In addition, everything cited in the chapter was believed by the SCC to be necessary to adequately protect patients from improperly compounded sterile preparations. The requirements in Chapter are all within the realm of "best practices" for compounding sterile preparations.

A more interesting question to consider may be the following: "What if section 503 A of FDAMA still existed or a similar relevant new federal law was passed, and the old Chapter from a previous USP had been renumbered and made official in USP 27 with the only modification being to change every 'should' in to 'must' or 'shall' in ?"

To explore that possibility, Table 1 compares selected conditions in the current Chapter with those that would have occurred if Chapter in USP 26 had simply been numbered in USP 27. It should be apparent that the more rigorous standards in Chapter would be more difficult to satisfy, whether by a hospital pharmacy or specialty compounding pharmacy that has been compounding more than 100 preparations daily, or a community pharmacy that compounds only one preparation monthly.

Did the USP Consider Practitioners' Cost and Convenience in Chapter ?

The paramount concern of the SCC was the protection of patients from inadequate and unsafe compounding practices. Patient safety was the primary consideration. However, the SCC did consider the practicality of the specific Chapter requirements because this too serves patient safety. All of the requirements in Chapter were considered by the SCC to be reasonable and achievable within current compounding practice settings to help ensure patient safety. The quality assurance requirements of Chapter are already in place voluntarily in high-quality sterile compounding practices.

How Were Chapter Storage and Stability Limits Decided?

The only specific storage limit in Chapter in the USPs from 1995 to 2003 was 7 days under refrigeration. The SCC decided to include more comprehensive storage limits in Chapter in recognition of those in the ASHP Guidelines.17 In determining the length of storage limits in Chapter , the SCC considered such things as the likelihood of occasional inadvertent contamination occurring even in the best sterile compounding settings, the exponential growth rate of bacteria with increasing temperature and the grave danger to patients from bacterial contamination of repackaged intravenous fat emulsion.27-28,n Based thereon, the SCC assigned the respective storage limits conservatively for preparations compounded under low-risk, medium-risk and high-risk conditions for microbial contamination. With each Chapter contamination risk level, the phrase "in the absence of passing a sterility test, the storage periods cannot exceed the following time periods" offers compounders the opportunity to store for longer durations based on appropriate testing results.

In addition to the microbiologie beyond-use limitations, the chemical and physical stability of sterile preparations must be considered. Beyond-use dates of compounded sterile preparations based on chemical and physical stability for Chapter are the same as those for compounded nonsterile preparations in Chapter .29 During the 1993-1996 development of what was initially USP Chapter on pharmaceutical compounding practices30 and is now Chapter "Pharmaceutical Compounding-Nonsterile Preparations,"2 " the Advisory Panel on Pharmacy Compounding Practices received comments from interested parties protesting proposed beyond-use dates or durations as too short." A typical assertion was that pharmacists inherently command professional judgment adequate to assign beyond-use dates, a sentiment reiterated by one state board of pharmacy regarding Chapter in a February 2004 communication to USP.

Pharmaceutical stability depends on the purity and concentration of specific ingredients, packaging and environmental exposure and storage (humidity, illumination and temperature), especially for solutions.31-35 Small changes in any of those variables can cause rapid loss of drug strength or much shorter than expected shelf-life. Following are three illustrations of why even the most expert and caring pharmacist's visual, olfactory or other professional judgment, in the absence of scientific testing results, about sterility and stability of compounded pharmaceuticals can be dangerously wrong:

* It takes approximately 1 × 10^sup 7^ bacteria per mL, a level which constitutes gross contamination, to sec turbidity in originally clear fluids. However, invisible bacterial densities up to 1 × 10^sup 6^ per mL (a tenth of the amount that would be visible) can cause serious-to-fatai infections.*''

* Clinical concentrations of five adrenergic catccholaminc injections were observed for up to 19n hours for the earliest visual evidence of their oxidation to inactive products, ie, change from colorless to pink- or amber-colored. When oxidation became visible, the drug strengths by stabilityindicating high-performance liquid chromatography (HPLC) were 0% to 78% in four cases and 92% in one case, compared to their original or zero-time concentrations.37

* A difference of one pH unit from the intended value in solutions of some drugs can decrease stability shelf-life to less than $0% of the beyond-use time assigned on labels of compounded preparations. There can be danger in either assuming correct compounding or expecting a seemingly small formulation change to produce an insignificantly small stability change.35'38

How Do I Determine What the Appropriate Risk Level Is?

The decision as to which risk level (and the associated quality assurance needs) of specific preparations resides with the compounder. USP Chapter gives general descriptions of the types of sterile compounded medication in each of the three categories, low-risk, medium-risk and high-risk, with examples, but a complete delineation of every possibility is impossible. Instead, compounding personnel are responsible for making the judgment on each specific preparation and also for being able to defend their decisions should the need arise. It is important to remember that the risk level refers to the risk to the patient's health and even life from the compounded sterile preparation should inadvertent contamination occur. Higher risk-level preparations require commensurately higher levels of quality assurance and more restricted beyond-use periods.

What Is the SCO's Perspective on Enforceable USP Compounding Practices?

Several SCC members who practice sterile compounding understood their new obligations when contributing to the development of Chapter . all USP compounding chapters and monographs may forestall the need for adoption of more restrictive regulations by the FDA and states over this most historic and profession-symbolizing specialty practice of pharmacy. For example, the New Jersey pharmacy board introduced more stringent compounding practice requirements several years ago. Persons who compound drug and nutrient preparations that are intended and labeled to be sterile when administered clinically must be accountable to utilize appropriate conditions, ingredients and practices to achieve sterility and accuracy in such finished preparations.

The requirements for compounded sterile preparations should not be commensurate with those for manufactured sterile drugs and nutrients produced in large lots.39,p Requiring manufacturing quality-assurance rigor for compounded sterile preparations could (1) deprive urgent, appropriate and humane care to patients whose therapists prescribe specific nonmanufactured drug and nutrition therapy and (2) create marketing advantage for large providers of compounded sterile preparations. To further illustrate this matter, Table 2 presents a simplistic comparison of pharmaceutical compounding and manufacturing according to selected attributes.q

Compounded preparations administered by intravascular and intraspinal injection have the highest risk of causing infection when terminal sterility is not achieved before they are administered to patients.s>6 For example, several patients died in 2001 and 2002 from microbial contamination in intraspinalIy injected corticosteroid suspensions compounded by pharmacies in California and South Carolina.3 Furthermore, the risk of severe fever from bacterial endotoxins is greatest from the intrathecal injection route; thus, the USP endotoxins limit for intrathecal injections is 1/25th that for injections administered by other routes.40

The USP should maintain an expert committee with specific responsibility to create and revise sterile compounding chapter^) and monographs. The committee membership should be predominantly pharmacists who have both extensive practice experience with and strong advocacy for patient safety when compounded sterile preparations are therapeutically necessary.

How Does the Public Participate in Creation and Revision of USP Content?

Creation and revision of USP chapters and other content are assigned to appropriate specialty committees of the Council of Experts,r which are called expert committees. Proposals for new and revised chapters are published in USP's journal, PF. The public may comment on PF proposals and USP content by corresponding with appropriate USP staff persons. The general process of introducing and revising USP content is also summarized in the beginning pages of each bimonthly issue of PF.

Whether it is a proposal in PF or official content in USP, the same public comment process applies. Upon accumulating and reviewing comments, usually for several months following a PF or USP publication, the appropriate expert committee meets to consider the comments. Subsequently, the expert committee further determines whether to revise or leave as is the content based on its decisions regarding the comments. For instance, revisions based on some apparent ambiguities and details in current Chapter 5'6 will likely result from the SCC's analysis of public comments that have been and will be received. just as "the road to success is always under construction," so the USP, at age 184 years in 2004, undergoes continual revision.

What Is tKe "Bottom line" of USP Chapter ?

Voluntary standards for compounding sterile preparations available from AHSP and USP for 12 and 9 years, respectively, have not prevented patients from dying from microbial contamination in drugs and nutrients that should have been sterile. Some compounding pharmacists are not and have not been aware of those pioneer ASHP and USP documents. The opinion quoted early in this primer by the ASHP's Mr. Joseph Deffenbaugh clearly argues the need for enforceable standards to achieve Al Capone's "cooperation" of pharmacists in properly compounding sterile preparations: "This is all about patient safety. Let's not forget what the purpose of all this is."7

Acknowledgment

Before submission to IJPC, the essence of this primer was reviewed and endorsed by the remainder of the members of the SCC. The authors are grateful to their colleagues: Samuel C. Augustine, PharmD, BCNP, FAPhA; Gayle A. Brazeau, PhD, BS; David F. Driscoll, PhD, BS, Sterile Compounding Committee Vice Chairman; Donald J. Filibeck, MBA, PharmD; Kenneth L. Hughes, BS; and James W. Wilson III, BS. The authors appreciate review and comments by Kathleen R. Anderson, PharmD, who is ad hoc representative to the SCC from the FDA Center for Drug Evaluation and Research.

Explanatory Kotes

a At the start of the 2000-2005 USP quinquennium, the USP Council of Experts Committee responsible for monographs (articles) and chapter(s) on sterile pharmaceutical compounding was officially titled the Parenteral ProductsCompounding and Preparation Committee. By unanimous vote of the USP General Policies and Requirements Division Executive Committee on November 17, 2003, that committee was renamed the Sterile Compounding Committee.

b E-mail message from Mr. Frank Barletta, a USP staff pharmacist, to Dr. Newton on March 15, 2004. Mr. Barletta stated that Chapter represents the USP contribution to resolving conflict between the FDA and compounders regarding whether Positron Emission Tomography (PET) is manufacturing or compounding.

c E-mail message from Darryl S. Rich of the JACHO to USP marketing communications department on January 27, 2004. The message was forwarded from USP to Dr. Newton.

d The USPwas revised every 10 years after 1820 until USP 77 in 1936. After the US Food, Drug and Cosmetic Act in 1938, USP 72(in 1942) began the five-year cycle, followed by USP 13('m 1947) and then every half-decade quinquennia with USP 74 (in 1950). In 2002 USP25became the first annual revision.

e As delegates to the convention and members of the Council of Experts Committees, USP volunteers do not promote particular healthcare professions, professional organizations and businesses; do not pay membership dues; and do not derive member services and benefits.

f USP standards are public as contrasted to those in PDA-approved new drug applications (NDAs), which are the private property of NDA sponsors.

g Refere nee 18 by ASHP also includes recommendations for pharmacist-prepared nonsterile and ophthalmic products on pages 1452-1463. The three AS HP compounding documents in Reference 18 were followed by several updated versions. Dr. Newton was an invited prepublication reviewer for the AS HP Technical Assistance Bulletin on Compounding Nonsterile Products in Pharmacies. Am J Hosp Pharm 1994; 51: 1441-1448; and the ASHP Technical Assistance Bulletin on Quality Assurance for Pharmacy- P re p a red Sterile Products. Am J Hosp Pharm 1993; 50: 2386-2398. Mr. Trissel of the 2000-2005 SCC was a contributor to all drafts of ASHP's Technical Assistance Bulletin and eventual Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products (Reference 17).

h In particular, the emergence of intravenous drug and nutrition therapy administered to patients in their homes resulted from the (then) new US governmental prospective payment lim its for treating diseases and medical conditions, which were termed diagnosis related groups(DRGs).

i Although reference 24 was published in 1995, its authors reported having compounded 50-mg/mL morphine sulfate injection "at this hospital for nearly 20 years..."

j Dr. Loyd V. Alien, Jr., who chairs the 2000-2005 USP Compounding Pharmacy Committee (for nonsterile preparations), and Mr. Trissel are members of the FDA Pharmacy Compounding Advisory Committee.

k Dr. Newton personally heard such comments in 2001 and 2002 in meetings of FDA and USP representatives who have responsibility for pharmaceutical compounding.

i This explanatory note refers to a statement in reference 7 by Dr. Claudia Okeke of USP.

mThe beyond-use dates pertain to potential risks of clinically hazardous microbial contamination. Assignment of beyond-use dates in relation to physical and chemical stability of preparations requires additional relevant documentation or directtesting evidence.

n The authors of references 27 and 28 are 2000-2005 SCC members.

0 Dr. Newton and Dr. Loyd V. Alien, Jr., the founding editor of IJPCana chairman of the 2000-2005 USP Compounding Pharmacy Committee (for nonsterile preparations), served on the panel from its june 1993 inception until it became the Compounding Pharmacy Committee of the USP Council of Experts in june 2000.

p "The agency [FDA] recognized in its brief...in 2002 Supreme Court case...that applying FDCA's [Food, Drug and Cosmetic Act] new drug approval requirements to drugs compounded on a small scale is unrealistic-that is, not... feasible to re qui re dru g compounding pharmacies to undergo testing for new drug approval process for drugs compounded to meet the unique needs of individual patients."39

q The USPreiers to compounded drugs, nutrients and other therapies as preparations because the term products is generally construed to represent items resulting from industrial manufacturing.

r Before the April 2000 USP Quinquennial Convention, the group of volunteers that created and revised USPsnu /VFcontent was titled the Committee of Revision. During the 1995-2000 USP quinquennium, the USP ad hoc Committee on Structure and Processes of the USP Committee of Revision recommended thatthe Committee of Revision be renamed the Council of Experts. In 2000 the Council of Experts and Board of Trustees were modified to adopt the new structure and process. Beginning with the 2000-2005 USP cycle, the chairpersons of the committees of the Council of Experts, or expert committees, were elected by majority vote of the several hundred delegates to the April 2000 USP Convention. Nonchairperson members of USP expert committees were recommended by chairpersons and approved by vote of all committee chairpersons in the particular USP division. For example, the SCC is assigned to the General Policies and Requirements Division, which consists of 12 expert committees, all of which are responsible for PDA-enforceable chapters and monographs.

s The "few" designation assumes the traditional direct patient-prescriber-pharmacist triumvirate relationship for compounded therapies, as is described in LASP Ch apte r .

References

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2. Talley CR. Sterile compounding in hospital pharmacies. Am J Health Syst Pharm 2003; 60(24): 2563.

3. Spencer J, Mathews AW. As druggists mix customized brews, FDA raises alarm. 'Compounders' often meet special needs, but industry falls in regulatory gap. Rare fungus in the steroids. The Wall Street Journal. February 27, 2004: AI, A6.

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9. [No author listed.] Limited FDA survey of compounded drug products. [US Food and Drug Administration Website.J Available at: www.fda.gov/cder/pharmcomp/survey.htm Accessed March 4, 2004.

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12.AndersonL, HigbyGJ. The Spirit of Voluntarism, A Legacy of Commitment and Contribution. United States Pharmacopeia, 1820-1995. Rockville, MD: US Pharmacopeial Convention, Inc.; 1995: 14-29,41-294.

13. [No author listed.] [The United States Pharmacopeial Convention, Inc. Website.] Available at: www.usp.org Accessed January 30, 2004.

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17. [No author listed.] American Society of Health-System Pharmacists. Guidelines on Quality Assurance for Pharmacy-Prepared Sterile Products. Am J Health SystPharm 2000; 57: 1150-1169.

18.Feynman RP. What Do You Care What Other People Think? Further Adventures of a Curious Character. New York, NY: Bantom Books; 1988:241.

19. [No author listed.] American Society of Hospital Pharmacists. Drafttechnical assistance bulletin on quality assurance for pharmacyprepared sterile products. Am J Hosp Pharm 1992; 49:407-417.

20. Okeke C, Barletta FP, Newton DW et al. Evolution of the United States Pharmacopeia Chapter : "Sterile Preparations-Pharmacy Practices." /JPC2001; 5(4): 265-267.

21.[No author listed.] US Food and Drug Administration. [US Food and Drug Administration Website.] Compliance Policy Guides Manual. sec. 460.200 Pharmacy Compounding. Available at: www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg460-200.html Accessed January 30, 2004.

22. Newton DW. Phenytoin injections: From compounding to Cerebyx. IJPC2002; 6(6): 410-413.

23. Weishar DA. Nitroglycerin injection. Am J WospWian77l970;27:883.

24. Grom JA, Bander LC. Compounding of preservative-free high-concentration morphine sulfate injection. Am J Health Syst Pharm 1995; 52(191:2125-2127.

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26. Newton DW. Compounding Paradox: Taught Less and Practiced More. A J PE 2003; 67(1): 12-14.

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36. [No author listed.] Millipore Corporation. Hospital Pharmacy Filtration Guide (Cat. No. MP801). Bedford, MA: Millipore Corporation; 1980:3.

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38. Swenson CF. Importance of following instructions when compounding. Am J Hosp Pharm 1993; 50(2): 261.

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40. US Pharmacopeial Convention, Inc. United States Pharmacopeia 27. Chapter "Bacterial Endotoxins Test." Rockville, MD: US Pharmacopeial Convention, Inc.; 2004: 2169-2173.

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