Compounding Overview: Primary Considerations for the Workplace

Pharmaceutical compounding comprises activities associated with preparation of dosage forms that are not commercially available from major pharma industry. Compounded dosage forms have traditionally been prepared in response to individual patient needs in community settings; they are also prepared in larger quantities for future patients in the physician’s office. The scope of compounding considerations is extensive—patient therapeutics, dosage forms, preparation processes, regulations, personnel, and so on. Compounded preparations include both sterile and non-sterile dosage forms—injections, ophthalmics, capsules, liquids, topicals, and many others. Compounded drug dosage amounts range from neonates to seniors. Compounding occurs in many settings—community pharmacies, hospitals, outsourcing facilities, pharma industry, nursing homes, outpatient care, and others. Regulations governing compounding include federal, state, and local requirements. Personnel involved in compounding have varied expertise and skills—pharmacists, physicians, nurses, scientists, chemists, engineers, technicians, and so on. Compounding also includes the preparation of equivalent commercial products when drug shortages occur; notable examples include certain beta-lactam products and ibuprofen (1–4).

Definitions

FDA has defined human drug compounding and acknowledged its role in modern healthcare. FDA further commented on patient risk in using compounded preparations and described efforts to safeguard public health against poor quality compounding.

“Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient. Although compounded drugs can serve an important medical need for certain patients, they also present a risk to patients” (5).

“FDA’s compounding program aims to protect patients from unsafe, ineffective, and poor-quality compounded drugs, while preserving access to lawfully-marketed compounded drugs for patients who have a medical need for them” (5).

“Compounding is also a practice that is under scrutiny by the Food and Drug Administration (FDA) because of instances in which medications, primarily injectable medications that are intended to be sterile, have endangered public health” (6).

Related terminology. Compounding involves changes to materials or products to prepare new medicinal formulations. Changes to commercial products following directions provided by the manufacturer (reconstitution of multidose containers; dissolving lyophilized products) are not compounding (7). Product transfer to a different container is repackaging; preparing individual syringes from a larger container of drug product is repackaging (8,9). When a dose of medication is drawn for administration at the patient bedside, this is preparation for immediate use (7). The United States Pharmacopeia (USP) definition of compounding differs from the FDA definition and encompasses almost any manipulation of a commercial product (7,10,11).

Compounded preparations have traditionally been designed to address the therapeutic needs of individual patients; traditional compounding identifies a specific patient; traditional compounding occurs in a compounding pharmacy. Compounded preparations prepared on a larger scale for future use (“office stock”) have expanded the definition of compounding; this is non-traditional compounding. Specific patients are not identified in non-traditional compounding. Facilities engaged in non-traditional compounding may or may not be licensed pharmacies and are termed outsourcing facilities.

Discussion topics

This discussion provides a general overview of US human drug compounding—primary considerations that characterize pharmaceutical compounding. Selected themes describe technical topics, FDA regulations, and personnel responsibilities in a workplace environment. Topics include the following:

Pharmaceutics. Scientific and technical aspects of compounding such as formulation design, preparation, and calculations.

Regulatory. Regulations governing compounding include federal, state, and local regulations. Good manufacturing practice (GMP) is required for certain compounding.

Personnel. Compounding staff designs and prepares dosage forms; management monitors performance and provides a suitable workplace environment.

This discussion has been developed considering academic teaching, experiences in multiple settings, and published reports of adverse events. Compounding education typically includes theory and techniques using placebo formulations. Compounding in the workplace is different reality—potent drugs, sick patients, emergency circumstances, imperfect facilities, time pressures, insufficient information, electronic systems, and problematic logistics with interruptions, interferences, and other distractions. Additional discussion on these topics may be found on PharmTech.com (12).

Pharmaceutics

Technical pharmaceutics principles are fundamental in dosage form design and preparation. Technical concepts especially relevant to compounding include solubility, dissolution, compatibility, and chemical and physical stability. Formulation materials, preparatory processes, associated calculations, and actual compounding techniques are of obvious importance. Multiple personnel may be involved in compounding, including technical experts who integrate available technical information, specialists who prepare the designed formulation, and pharmacists who advise patients/clients on drug administration.

Formulation. Formulation design is fundamental in compounding. Formulation ingredients (API and inactive excipients) and the primary container comprise the compounded dosage form. All formulation components must be sourced from approved suppliers, meet quality standards, be stable, and not contaminated (chemical, microbial). Ingredients must be properly stored and be within expiration dating. Inactive formulation ingredients are very relevant in compounded dosage form design. Inactive ingredients may replace problem ingredients in commercial products (e.g., no lactose in lactose-intolerant patients; no dyes and or peanut oil in allergic patients). Liquid formulations are prepared for children or seniors who cannot swallow solids.

Calculations. There are numerous types of calculations potentially used in compounding. Formulation calculations such as percent calculations, API conversions, ratio strength, and many others are necessary for preparation of dosage forms. Drugs are dosed based on the active drug; chemical forms of active drugs may be available in salt or other forms. Formulation dosage considerations including pharmacokinetic factors, drug half-life, renal clearance, and liver function must be calculated. Final product testing (potency, moisture) may require calculations. Stability data calculations justify expiry dating.

Compounding procedure. Procedures for preparation of compounded dosage forms are likewise critical. Skilled personnel must be trained; aseptic techniques are especially important. A well-designed compounded preparation will fail if execution by the compounding technician is substandard (mixing order, particle size reduction, levigation). Basic aseptic techniques, cleanroom equipment, and controlled air-particulate facilities are critical for sterile preparations. Allen (13,14), Institute for Safe Medication Practices (ISMP) (15,16), Gudeman et al. (17), and Watson et al. (18) have addressed errors associated with sterile and non-sterile compounded preparations.

Post-compounding. Related technical activities executed after completion of compounding must also consider pharmaceutics principles. Dosage form testing (e.g., visual, USP, or other reference), labeling, medical information, packaging, supply chain shipping, and communication with patients/clients (light protection, temperature control, administration methods) have technical considerations.

Regulations

FDA expressed concern for medication safety with use of compounded pharmaceuticals. Compounded preparations are not approved by FDA via the new drug application/abbreviated new drug application (NDA/ANDA) drug approval process. The New England Compounding Center (NECC) incident in 2012 (19) heightened public awareness of problems with compounding and prompted regulations that significantly changed compounding practices. FDA categorized pharmaceutical compounding facilities as 503A compounding pharmacies and 503B outsourcing facilities in the Drug Quality and Security Act (DQSA) of 2013 (20). This amendment strengthened compounding requirements in the existing Food, Drug, and Cosmetic (FD&C) Act regulating compounded drugs and is the current legal basis for pharmaceutical compounding.

503A pharmacies. 503A pharmacies exemplify traditional compounding—individual patient, prescribing physician, and registered pharmacist in a licensed pharmacy. 503A pharmacies are exempt from federal regulations concerning GMP compliance, labeling requirements, and drug approval via NDA/ANDA processes.

503A guidance documents. Section 503A of the FD&C Act (21) addresses applications, conditions, provisions, requirements, and enforcement of 503A regulations. 503A compounding must be compliant with applicable USP requirements. Drug and excipient quality requirements are specified. Compounding must not involve preparations that are copies of commercial products or be identified by FDA as difficult to compound. Compounded preparations must not exceed 5% of total dispensed products of the pharmacy. FDA enforcement conditions addressing adulterated, unapproved, and misbranded drugs will follow risk-based concepts. 503A hospital and health system compounding practices are also addressed (22); some 503A pharmacies have distribution practices that extend beyond their individual facility, i.e., compounded preparations may be transferred to other hospitals, clinics, or infusion centers within their corporate system. 503A pharmacies are regulated primarily by state agencies.

503B outsourcing facilities. FD&C Section 503B addresses organizations that prepare dosage units for sale to various healthcare providers in advance of specific patient identification (i.e., non-traditional compounding for “office stock”). Outsourcing facilities providing these preparations are not required to be a licensed pharmacy but must be supervised by a licensed pharmacist. Section 503B exempts these facilities from NDA/ANDA approval processes, certain product labeling regulations, and drug security requirements. However, Section 503B requires outsourcing facilities to be compliant with GMP (23). Facilities that manufacture 503B sterile products must also register with FDA and pay an annual registration fee.

503B guidance documents. Section 503B (24) addresses requirements including GMP compliance. Specific sections discuss quality assurance and quality control, facility design, control systems and procedures for maintaining suitable facilities; environmental and personnel monitoring, equipment, containers and closures, components, production and process controls, release testing, laboratory controls, stability/expiration dating, packaging and labels, and complaint handling (25).

These documents reflect FDA’s intent to recognize differences between outsourcing facilities and pharma industry manufacturers while maintaining minimum safety standards for public health. Risk levels associated with compounding various dosage forms is acknowledged. Sections in the guidance specify considerations for sterile drug products. GMP-violative conditions in which FDA generally does not intend to take regulatory action are also described; appendices further address GMP release testing and stability testing. 503B facilities are audited by FDA.

503A and 503B characteristics summary. Primary differences characterizing 503A and 503B preparations and associated facilities are summarized in Table I. Items 1–3 list basic characteristics and specific exemptions from FD&C requirements; items 4–16 are requirements for compounded preparations; item 17 lists GMP requirements. Exceptions to described characteristics are possible (e.g., a facility may have both 503A licensed pharmacy and 503B outsourcing operations). Item 18 addresses usual inspections. The FDA website provides FDA-483 observations, Warning Letters, and associated correspondences involving compounding facilities (26,27).

Personnel: staff and management

Personnel in compounding organizations have significant responsibilities; essentially, all work in compounding requires human judgment and performance. In brief, staff designs and prepares the compounded dosage forms. Management must monitor actual compounding as well as execute support responsibilities (hiring, scheduling, training, facilities, equipment, maintenance, budgets). Management is responsible for policies, procedures, and quality systems supporting compounding—a substantial responsibility for 503B outsourcing facilities requiring GMP. Management must integrate technical compounding performance and daily workplace operations to develop a quality culture. Compounding errors caused by dosage form design omissions, insufficient training, distractions, inexperience, and other issues are caused by staff and attributable to management. Regular management communication to heighten staff awareness of problematic situations is recommended to minimize potential for medication errors (33).

Supporting references and standards. Numerous references supporting 503A and 503B pharmaceutical compounding relevant to technical considerations and regulatory compliance provide the fundamental bases for personnel performance in compounding organizations. USP <795>, <797>, and <800> (34–36) are primary documents that have legal basis cited in FDA-483 observations. USP also contains more than 100 compounding-related chapters (37,38). FDA offers training on various compounding activities through their Compounding Quality Center of Excellence (39). Principles associated with ICH Q9(R1) Quality Risk Management (QRM) and Human Factors Engineering (HFE) are directly applicable to compounding organizations. ICH Q9(R1) describing hazard identification and evaluation (“what might go wrong?”) in pharmaceutical manufacturing (40) is likewise applicable to compounding. HFE (41,42) addresses human performance with technology, processes, device operation, and user interface; electronic systems overridden in compounding activities exemplify HFE issues. Staff and management must collaborate to proactively prevent—as opposed to correct—hazards causing substandard compounding and medication errors (40). Documentation is intrinsic to pharmaceutical compounding and GMP compliance. Most relevant is documentation associated with the preparation of compounded dosage forms (descriptive information, ingredients, lot numbers, preparative procedures) and personnel accountability. Other associated compounding documentation supporting site quality systems and GMP compliance include personnel training records, performance certification, equipment qualification, facility maintenance, cleaning, sanitization, and related activities. The pharma industry adage, “If it isn’t written down, it didn’t happen” must also be practiced in pharmaceutical compounding operations (43).

Summary

This discussion provides a brief overview of pharmaceutical compounding—key topics that characterize compounding. FDA has defined compounding; compounding requires changes to materials and is distinguished from repackaging and drug-readiness for administration. FDA has also cautioned against risks associated with compounded preparations.

Technical pharmaceutics. Assuming correct patient considerations, formulation, calculations, and actual dosage form preparation are primary technical areas relevant to compounded dosage forms. Compounded pharmaceuticals may include sterile and non-sterile preparations.

Regulations. Legislation enacted following the NECC incident in 2012 explicitly categorized pharmaceutical compounding operations. Compounding facilities are either 503A pharmacies (traditional compounding for identified patients) or 503B outsourcing facilities (non-traditional compounding for future patients). GMP requirements in 503B facilities include requirements for release testing, stability and file samples, validation, environmental monitoring, and other requirements. State inspectors audit 503A pharmacies; FDA investigators audit 503B facilities and may issue FDA-483 observations if non-compliant conditions are observed.

Personnel. Compounded preparation quality is dependent on human performance—staff and management—in the workplace environment. Human performance in dosage form design, preparation, documentation, and user communication is critical for success. Workplace interferences may impact medication safety. Compounding personnel must be conversant with key compounding guidances, such as USP <795>, <797>, and <800>. QRM and HFE concepts are directly applicable to pharmaceutical compounding. Documentation is a key requirement in compounding. Staff and management must collaborate to continually improve the quality culture in the compounding organization.

Acknowledgments

Comments from Varanya Chaiyaperm, RPh, PharmD, clinical assistant professor, University of Illinois College of Pharmacy; Jan M. Keresztes, RPh, PharmD, pharmaceutical educator; Alan M. Mancini, RPh, pharmaceutical scientist; Jeanne Moldenhauer, pharmaceutical consultant, Excellent Pharmaceutical Consultants; Richard Poska, RPh, pharmaceutical scientist, Flexo; William R. Porter, PhD, principle scientist, Peak Process Performance Partners; and Nishant B. Thakar, RPh, PharmD, assistant professor clinical sciences, Roosevelt University College of Pharmacy, are greatly appreciated.

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About the author

Paul L. Pluta, PhD, RPh, is a pharmaceutical scientist with pharma industry, academia, journal editorship, community pharmacy, and hospital pharmacy experience.

Article details

Pharmaceutical Technology
Volume 48, No. 2
February 2024
Pages 18–22

Citation

When referring to this article, please cite it as Pluta, P. L.Compounding Overview: Primary Considerations for the Workplace. Pharmaceutical Technology 2024, 48 (2), 18–22.