Chapter 4 Sterile Preparation Formulation Mark G. Klang INTRODUCTION This chapter will provide insight into the issues of formulation when applied to compounding sterile preparations. The majority of options discussed in this chapter will involve high-risk compounding as defined by USP Chapter <797> Pharmaceutical Compounding—Sterile Preparations.1 Also, sterile compounding that requires specialized formulations may be designated difficult to compound by the newly created U.S. Food and Drug Administration (FDA) Task Force. This group examines specialized formulations and the resources available to pharmacists to safely conduct such procedures. This group then decides which modality or therapy is outside the scope of compounding. The Pharmacy Compounding Advisory Committee has met several times to evaluate what drug products are exempt from compound- ing under both Sections 503A and 503B of the Federal Food, Drug and Cosmetic Act. In June 2015, the FDA advisory group met to consider adding four more drugs to the list: aprotinin, ondansetron, bromocriptine, and acetaminophen. The compounder would be prohibited from any form of compounding that includes one of the banned active ingredients.2 Please refer to Chapter 21 for the stability and incompatibility of drugs, Chapter 15 for labeling compounded preparations, Chapter 16 for documentation, Chapter 17 for sterilization methods, and Chapter 18 for finished preparation release checks and tests. FEDERAL REGULATIONS NEW COMPOUNDING DRUG REGULATIONS The following is an excerpt of an FDA release pertinent to compounding sterile preparations: On November 27, 2013, President Obama signed the Drug Quality and Security Act (DQSA), legislation that contains important provisions relating to the oversight of compounding of human drugs. Note: The author acknowledges E. Clyde Buchanan who authored this chapter in the previous edition. 51 52 Compounding Sterile Preparations Title I of this new law, the Compounding regarded as safe and effective for the intended use.”5 Quality Act, removes certain provisions If the pharmacy fills each prescription as received, from section 503A of the Federal Food, clearance under the “new drug” provisions is not Drug, and Cosmetic Act (FDCA) that required.5 were found to be unconstitutional by the Compounding Phase 1 investigational U.S. Supreme Court in 2002.Section drugs does not require full compliance with 503A describes the conditions under which CGMPs because of the low volume of patients.6 certain compounded human drug products Compounding medications for Phase II and III are exempt from three sections of the FDCA trials requires complete adherence to CGMPs requiring: and products prepared for Phase I cannot be used • Compliance with current good manu- for the subsequent phases if not prepared under facturing practices (CGMPs) (section full CGMPs. 501(a)(2)(B); If a pharmacist compounds finished drugs from • Labeling with adequate directions for use bulk active ingredients that are not obtained from (section 502(f)(1); and an FDA-approved facility or are not compliant with compendial standards (i.e., The United States • FDA approval prior to marketing (sec- Pharmacopeia and The National Formulary [USP– tion 505). NF]), these finished preparations must be covered The new law creates also a new section by a new drug application.7 In other words, bulk 503B in the FDCA. Under section 503B, compounded preparations must conform to USP a compounder can become an outsourcing Chapter <795> Pharmaceutical Compounding— facility. An outsourcing facility will be able Nonsterile Preparations and USP Chapter <797>; to qualify for exemptions from the FDA otherwise, FDA requires that a new drug applica- approval requirements and the requirement tion be filed and accepted for the bulk compounded to label products with adequate directions preparation.1 for use, but not the exemption from CGMP If a pharmacist changes the strength, dosage requirements. Outsourcing facilities: form, or components of a commercially available preparation in a compounded prescription, good • Must comply with CGMP requirements, compounding procedures should be used.7 Pharma- • Will be inspected by FDA according to a cists are responsible for compounding and dispens- risk-based schedule, and ing finished preparations pursuant to prescribed • Must meet certain other conditions, such therapy, and for compounding and preparing those as reporting adverse events and providing preparations in compliance with established boards FDA with certain information about the of pharmacy and other regulatory agencies. These 3 products they compound. requirements vary from state to state. When formulating and compounding sterile prepa- rations, pharmacists must follow both state laws and FDA regulations. State pharmacy practice PROFESSIONAL STANDARDS acts and board of pharmacy regulations cover these Formulating, compounding, and sterilizing a activities. The FDA also regulates formulation and pharmaceutical from nonsterile ingredients or in compounding under adulteration, misbranding, nonsterile containers is the most difficult and is and new drug provisions of the FDA.4 considered a high-risk procedure.1 The chemical Since 1980, in their Field Regulatory Guidance, purity and content strength of ingredients must “Hospital Pharmacies Status as Drug Manufacturer,” meet their original or compendial specifications in FDA Guide 7132.06 states that “a physician may unopened or in opened packages of bulk ingredients prescribe an unusual preparation that requires in compliance with the Ingredient Section of USP compounding by a pharmacist from drugs readily Chapter <795>.8 Batch master worksheets should available for other uses and which is not generally include comparisons of actual with anticipated Chapter 4 Sterile Preparation Formulation 53 yields, sterilization methods, and quality control be accompanied by certificates of analysis from and validation of procedures used. Presterilized their suppliers to aid compounding personnel sealed containers should be used when feasible. in judging the identify, quality, and purity in Final containers must be sterile and capable of relation to the intended use in a particular CSP.10 maintaining product integrity through the beyond- Bulk or unformulated drug substances and added use date (BUD). The sterilization method must be substances, or excipients, must be stored in tightly based on the preparation’s properties. Whatever closed containers under temperature, humidity, method of sterilization is used, a sterility test is and lighting conditions, which are either indicated still required to ensure safety of the contents. The by official monographs or approved by suppliers. sterility test must be validated to determine if a Also, the date of receipt in the compounding contamination could be isolated if one were present facility must be clearly and indelibly marked on as well as to determine the sensitivity of the assay each package of ingredient. Careful consideration (USP Chapter <71> Sterility Test). See Table 4-1 for a review of the different types of terminal steril- and evaluation of nonsterile ingredient sources is ization, their advantages, and their disadvantages. especially warranted when the CSP will be admin- See reference 9 for a review of the FDA perspective istered into the vascular, central nervous system, on terminal sterilization.9 and eyes. Upon receipt of each lot of the bulk drug USP Chapter <797> specifies that nonsterile substance or excipient, the individual compound- active ingredients and added substances, or excipi- ing the preparation performs a visual inspection of ents, for compounded sterile preparations (CSPs) the lot for evidence of deterioration, other types of should preferably be officialUSP–NF articles.1 unacceptable quality and mislabeling, as described When unofficial ingredients are used, they must in a written protocol. Table 4-1. Terminal Sterilizationa Sterilization Method Specifications Advantages Disadvantages Dry heat 180 °C for 30 min or Destroys pyrogens Heat sensitivity 170 °C for 1 hr 160 °C for 2 hr Moist eat Pressure: 15 lb/sq inch Uses biological indica- Heat/moisture Temperature: 121 °C tor to verify sufficient sensitivity heat/pressure Autoclave, gravity sterilizer Time: 15 min Filtration 0.2 μm Filter integrity test, Filter must be certified verifies filter did not for volume and filtrate rupture load Numerous fiber/size and load specifica- tions Gamma irradiation ~25 kGy; requires very Containers and pack- Not good for some high radiation to be aging may remain heat sensitive effective intact Ethylene oxide/nitrous Depending on gas Less invasive, good for Requires tight wrap to oxide, hydrogen per- used different satura- heat sensitive but has avoid leaks, contami- oxide fog tion and permeation compatibility issues nates adjacent areas aSee Chapter 17 for a more detailed review. 54 Compounding Sterile Preparations WRITTEN PROCEDURES The pharmacist ensures that the sterile compo- nents under their supervision meet acceptable The compounder of sterile preparations should criteria of stability and sterility by the following14: develop and comply with the following written procedures (Chapters 16, 22, and 31): • Observing expiration dates and dispensing the oldest stock first. The expiration date of a com- • There must be a specifically designated and pounded preparation’s ingredients should exceed adequate area for the orderly placement of equip- the expiration date set for the final product. Not ment and materials