1996 and was later renumbered as USP General Chapter <795> Pharmaceutical Compounding- nonsterile Preparations (13). USP General approvals, and restrict further applications. All
FDA actions are subject to appeal. CGMP REQUIREMENTS FOR
MANUFACTURING IN PHARMACIES
The FDA’s cGMP regulations apply to commu- nity or institutional pharmacies engaged in the manufacture, repackaging, or relabeling of drugs and drug products in a supplier function and beyond the usual conduct of professional dispens- ing. Pharmacies that engage in such activities must register with the FDA as a manufacturer or distributor and be subject to FDA inspection at regular intervals. Included are hospital pharma- cies that repackage drug products for their own use and for the use of other hospitals; chain phar- macy operations that repackage and relabel bulk quantities of products for distribution in the chain; and similar repackaging and relabeling by individual pharmacists or pharmacies for distri- bution to other pharmacies or retailers.
Recently, professional and legislative atten- tion has been directed toward differentiating between pharmaceutical manufacturing and compounding as practiced by community phar- macists (12). Pharmaceutical manufacturing is large-scale production of drugs or drug products for distribution and sale, whereas compounding is professional preparation of prescriptions for specifi c patients as a part of the traditional prac- tice of pharmacy.
CURRENT GOOD COMPOUNDING
PRACTICES
In recent years, pharmacists have increased the practice of compounding patient-specifi c medi- cations. An increase in the incidence of pharma- ceutical compounding was noted in the 1970s and continued into the 1980s. By the early to mid 1990s, compounding was making a dramatic comeback in pharmacy practice leading to the development of niche practices. A number of reasons have been presented for the increase in preparing patient-specifi c medications, includ- ing the following:
1. Many patients need drug dosages or
strengths that are not commercially avail- able.
2. Many patients need dosage forms, such as suppositories, oral liquids, or topicals that are not commercially available.
Chap03.indd 75
applicable to a specifi c drug and preparation, the following maximum beyond-use dates are rec- ommended for nonsterile compounded drug preparations that are packaged in tight, light- resistant containers and stored at controlled room temperature unless otherwise indicated” (15).
For nonaqueous liquids and solid formula- tions, (a) where the manufactured drug product is the source of active ingredient, the beyond- use date is not later than 25% of the time remaining until the product’s expiration date or 6 months, whichever is earlier; (b) where a USP or NF substance is the source of active ingredi- ent, the beyond-use date is not later than 6 months.
For water-containing formulations prepared from ingredients in solid form, the beyond-use date is not later than 14 days when stored at cold temperatures.
For all other formulations, the beyond-use date is not later than the intended duration of therapy or 30 days, whichever is earlier.
The chapter goes on to detail that these beyond-use date limits can be exceeded if there is supporting, valid scientifi c stability informa- tion directly applicable to the product being compounded. The product must be the same drug in a similar concentration, pH, excipients, vehicle, water content, and so on.
The section on ingredient selection describes sources for drugs and excipients as follows: 1. A USP- or NF-grade substance is the pre-
ferred source for compounding.
2. A drug of the highest quality, reasonably available, may be used, preferably one listed as ACS (American Chemical Society) or FCC (Food and Chemicals Codex) grade. Material safety data sheets should be maintained on all materials used for compounding in the pharmacy.
3. A manufactured drug product can be used as a source of a drug, excipient, or vehicle. If manufactured drugs are used as the source for the active drugs, then the presence of all excipients must be considered in the overall acceptability of the fi nal product.
Calculations are discussed as they relate to the amount of concentration of drug substances in each unit or dosage portion of a compounded preparation. Special emphasis is placed on calcu- lations involving the purity and potency of drugs, their salt forms, and equivalent potencies. Chapters numbered less than 1,000 are consid-
ered “enforceable,” whereas those chapters num- bered over 1,000 are considered “informational.” The fi rst of the compounding monographs became offi cial in 1998, and there are now approximately 250 compounding monographs. These provide a tested, uniform formulation with valid beyond-use dating.
In 2000, the U.S. Pharmacopeial Convention formed two compounding expert committees; one in nonsterile compounding and one in sterile compounding. The Expert Committee on Sterile Compounding prepared the USP General Chap- ter <797> Pharmaceutical Compounding-sterile Preparations which fi rst became offi cial in 2004 with a revision that became offi cial in 2008. Additional chapters in the USP related to com- pounding include <1075> Good Compounding Practices, <1143> Quality Assurance in Pharma- ceutical Compounding, and <1160> Pharmaceu- tical Calculations in Prescription Compounding. Chapter <795>, “Pharmacy Compounding,” includes the following discussions: (a) compound- ing environment; (b) stability of compounded preparations; (c) ingredient selection and calcula- tions; (d) checklist for acceptable strength, quality, and purity; (e) compounded preparations; (f) com- pounding process; (g) compounding records and documents; (h) quality control; and (i) patient counseling.
The introduction to the chapter discusses the difference between manufacturing and com- pounding. Generally speaking, compounding differs from manufacturing in the specifi c practi- tioner–patient–pharmacist relationships, the quantity of medication prepared in anticipation of receiving a prescription or a prescription order, and the conditions of sale, which are lim- ited to specifi c prescription orders.
The compounding environment section dis- cusses the design and maintenance of the facili- ties to be used and the equipment selected for compounding. It refers to other specifi c chap- ters in the USP, namely “Weights and Balances and the Prescription Balances” and “Volumetric Apparatus.” Any equipment used for compound- ing must be of appropriate design and size for compounding and suitable for the intended use.
The discussion of stability includes packaging, sterility, and stability criteria and guidelines for assigning beyond-use dates for compounded preparations; the latter are detailed as follows: “In the absence of stability information that is
Chap03.indd 76
quality in compounded sterile preparations. The defi nitions section is designed to establish uniform meanings to different terms used in the chapter.
The microbial contamination risk levels sec- tion describes various activities involved in ster- ile compounding as they relate to low-risk, medium-risk and high-risk compounding. Low- and medium-risk compounding involves sterile products and equipment being used and differs in the number of components used in com- pounding a specifi c preparation. High-risk com- pounding involves any nonsterile ingredient or equipment or package in the compounding pro- cess. Personnel training and evaluation discusses the intense training requirements and evalua- tion processes and testing that must be success- fully completed prior to compounding a sterile preparation.
Specifi c cases are discussed including proce- dures for handling hazardous drugs, radiophar- maceuticals, and allergen extracts. Verifi cation of sterilization and accuracy topics are pre- sented with a detailed discussion of methods of sterilization, including steam, dry heat, and fi l- tration. The major portion of this chapter involves environmental quality and control with detailed presentations on primary engineering controls and design of the facility to achieve and maintain proper air quality and associated air quality testing. Personnel training and compe- tency testing, aseptic work practices, and clean- ing and disinfection procedures are included in this section.
A number of standard operating procedures are provided along with elements of quality control standards for ingredients, devices, and equipment that must be met. Any automated compounding device must be verifi ed for accu- racy and precision as described in this chapter. Finished preparation release checks and testing programs for sterility, endotoxin testing and identity and strength verifi cation are presented. Beyond-use dating differs from nonsterile com- pounding because of the potential for contami- nation and microbial growth. Consequently, the beyond-use dates are quite short; there are different dates if a sterility testing program is in place versus when there is no program of testing in place. If no sterility testing program is in place, the following apply. For low-risk preparations at room temperature, beyond-use dates are not more than 48 hours and for refrig- erated temperatures, not more than 14 days. The chapter also details a checklist that can
be used to consider the advisability of preparing a compounded dosage form. It then details many dosage forms and some quality control charac- teristics that can be checked in the fi nal com- pounded products. Following is a discussion of the steps in a compounding process that can be used as a template for compounding prescrip- tions. Record-keeping requirements of various states, generally, include a formulation record and a compounding record.
Quality control and the responsibility of the pharmacist in reviewing each procedure and observing the fi nished preparation are discussed. The chapter ends with the importance of patient counseling in the proper use, storage, and obser- vation for instability of the dispensed product. The overall emphasis of the chapter is to support the pharmacist in the compounding of products of acceptable strength, quality, and purity.
USP Chapter <797> is organized into sections, including (1) Introduction, (2) Organization of this Chapter, (3) Defi nitions, (4) Responsibility of Compounding Personnel, (5) CSP Microbial Contamination Risk Levels, (6) Personnel Train- ing and Evaluation in Aseptic Manipulation Skills, (7) Immediate-Use CSPs, (8) Single-Dose and Multiple-Dose Containers, (9) Hazardous Drugs as CSPs, (10) Radiopharmaceuticals as CSPs, (11) Allergen Extracts as CSPs, (12) Veri- fi cation of Compounding Accuracy and Sterility, (13) Environmental Quality and Control, (14) Suggested Standard Operating Procedures (SOPs), (15) Elements of Quality Control, (16) Verifi cation of Automated Compounding Devices (ACDs) for Parenteral Nutrition Com- pounding, (17) Finished Preparation Release Checks and Tests, (18) Storage and Beyond-Use Dating, (19) Maintaining Sterility, Purity, and Stability of Dispensed and Distributed CSPs, (20) Patient or Caregiver Training, (21) Patient Monitoring and Adverse Events Reporting, (22) Quality Assurance (QA) Program, and a number of appendices.
Only the sections in USP <797> that signifi - cantly differ from the standards in USP <795> will be discussed here. The introduction describes the objective of this chapter to describe conditions and practices to prevent harm, including death, to patients that could result from microbial contami- nation, excessive endotoxins, variability in intended strength, unintended chemical and physical contaminants, and ingredients of inappropriate
Chap03.indd 77
The national pharmacy organizations united to protect the rights of pharmacists to compound. The National Association of Boards of Pharmacy promulgated the Good Compounding Practices, which have been either adopted or modifi ed and adopted by many states. The U.S. Pharmacope- ial Convention renewed its commitment to com- pounding by the preparation of chapters for the USP–NF and in establishing monographs for the compendia. In 1997, the efforts of many organi- zations, politicians, and pharmacists resulted in a section of the Food and Drug Administration Modernization Act of 1997 (12) being aimed at supporting pharmacists’ right to compound, with some guidelines.
FOOD AND DRUG MODERNIZATION ACT OF 1997
The purpose of Section 127 of Public Law 105–115 was to ensure patients’ access to indi- vidualized drug therapy and prevent unnecessary FDA regulation of health professional practice. This legislation exempted pharmacy compound- ing from several regulatory requirements but did not exempt drug manufacturing. The legislation also set forth conditions that must be met to qual- ify for exemption from the act’s requirements.
The act states that a compounded product is exempt if the drug product is compounded for an individual patient based on the unsolicited receipt of a valid prescription order or a nota- tion, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identifi ed patient, if the product meets certain requirements outlined in the act. In April 2002, however, the U.S. Supreme Court found unconstitutional one of the provisions of the Act related to the advertis- ing restrictions on compounding. This section was ruled not to be separable from the rest of the pharmacy compounding provisions, so the entire section was thrown out. New legislation may be forthcoming.
The Food and Drug Modernization Act of 1997 removed any doubt that compounding is legal under the FDC Act, and Congress has clearly recognized the importance of compounding.
In addition, a second court action called the Midland Decision (Medical Center v. Gonzales, 451 F.Supp2d 854 (2006), made it clear that the FDA has no authority in the practice of phar- macy provided the pharmacy is adhering to the For medium-risk preparations at room
temperature, the beyond-use dates are not
more than 30 hours and for refrigerated temperatures, not more than 9 days. For high- risk preparations at room temperature, the beyond-use dates are not more than 24 hours and for refrigerated temperatures, not more than 3 days. In all three instances, if stored at −25°C to −10°C, the beyond-use dates are 45 days in the solid state.
If a sterility testing program is in place, the beyond-use dates for nonsterile preparations apply, as previously discussed. The main differ- ence between nonsterile compounding and ster- ile compounding is the requirement for sterility. Physical and chemical properties should be the same or quite similar. By “program of sterility testing,” it is meant that there is a systematic method of periodically testing compounded preparations. Not every preparation must be tested; just a program of testing.
The chapter concludes in discussing standards and procedures for maintaining the integrity of the compounded preparation in packaging, handling, transporting, and even redispensing. Patient or caregiver training and discussion of a quality assurance program com- plete the chapter.
FOOD AND DRUG ADMINISTRATION
During the early-to-mid 1990s, the FDA district offi ces began investigating a number of pharma- cies that were compounding very large quantities of drug products and shipping them throughout the United States. It was the opinion of the FDA that these pharmacies were actually involved in manufacturing, not compounding.
At the American Pharmaceutical Association meeting in 1993, FDA Commissioner Kesler stated that it was not the purpose of the FDA to stop the compounding activities of pharmacists but to stop the practice of manufacturing under the guise of compounding. However, over the next few years, the activities of the FDA inspectors and district personnel increased, and some pharmacists were threatened with arrest and legal proceedings. The FDA was determined to require that all com- pounded medications meet the requirements set forth as a new drug, or else they could not be dis- pensed to patients. Obviously, this was impossible and seriously threatened pharmaceutical com- pounding.
Chap03.indd 78
operation for its intended use and for its cleaning and maintenance. If mechanical or electronic equipment is used, controls must be in place to ensure proper performance.
Subpart (E), Control of Components and Drug Product Containers and Closures, describes the packaging requirements for compounded prod- ucts.
Subpart (F), Drug Compounding Controls, discusses the written procedures to ensure that the fi nished products are of the proper identity, strength, quality, and purity, as labeled.
Subpart (G), Labeling Control of Excess Prod- ucts and Records and Reports, describes the various records and reports that are required under these guidelines.
Many individual states have used this model and implemented their own version. All pharma- cists and pharmacy students should become familiar with the individual state requirements in the state in which they practice.
It will be important as compounding phar- macy increases to ensure reasonable agreement between the national and state agencies so phar- macists will have a set of guidelines within which they can work to provide their patients the needed individualized medications.