Paul L. Pluta

Pharmaceutical research and development in laboratory, with focus on medicine preparation, powder substances, and glass vials for drug formulation and testing | Image Credit: © felix_brönnimann - stock.adobe.com

Compounded pharmaceutical dosage forms may be generally described as preparations that are not commercially available from major pharma corporations. These preparations have traditionally been prepared in 503A pharmacies for identified patients; larger quantities of compounded preparations are also prepared by 503B outsourcing facilities for commercial distribution (1). Numerous dosage forms are compounded, including investigational drugs, parenteral nutrition, oncology preparations, radiopharmaceuticals, veterinary medications, and replacement commercial products during drug shortages (2-3). Individual compounded dosage forms may be prepared by pharmacists in community or hospital settings; greater scale compounding may include formulation scientists, engineers, and QA personnel in multi-facility corporations. Compounding may be completely manual or automated and may utilize electronic systems (e.g., automated compounding [ExactaMix], programmable robots [Equashield Pro], or pharmacy management [DoseEdge]). Aside from patients and clients, compounders may have relationships with other compounding organizations; (e.g., 503A hospitals may purchase compounded preparations from 503B facilities, and 503B organizations may provide clinical supplies to pharma industry.

This discussion describes an ordered process for compounding pharmaceutical dosage forms in workplace environments. The process comprises six stages generally applicable to all compounding 

.The first four stages directly address dosage form preparation, evaluation, packaging, and medical information. Stage 5 evaluates and verifies previous completed stages; stage 6 comprises dispensing/shipping to patients or clients. Individual activities within stages will vary depending on the type of compounded dosage form (e.g., sterile vs. non-sterile). Activities in stages may be done by multiple people (e.g., pharmacists, technicians, engineers, etc.).

The compounding process was developed considering academic teaching of compounding theory and practice, problem experiences in multiple workplaces, published regulatory observations, and medication error incidents. Academic compounding typically focuses on placebo formulations and techniques in a classroom or laboratory. Compounding in the workplace is much different—active drugs with specific and sometimes incompatible physicochemical properties, actual patients, emergency circumstances, imperfect facilities, incomplete information, inadequate staffing, excessive workloads, and logistics with interruptions, interferences, and other distractions. Basic activities in respective compounding stages are described; potential problems are identified; technical science, compliance, documentation, and personal responsibility are emphasized. The process builds on pharmaceutical and regulatory concepts, including Quality by Design (QbD) (4-6), Quality Risk Management (QRM) (7), and Pharmaceutical Quality Systems (8,9). Concepts described by professional pharma organizations are included (10-13). The technical responsibilities of management supporting compounding are also addressed.

This discussion assumes organization compliance with USP, federal, state, local, other regulatory, and professional certifications; 503B outsourcing facilities must also comply with pharmaceutical Good Manufacturing Practices (GMP). It also assumes availability of approved policies and standard operating procedures (SOPs) at the site. Non-technical considerations, such as drugs and supplies inventory, third-party reimbursement, personnel development, performance metrics, and other business responsibilities, are not addressed.

Table I. Pharmaceutical Compounding Process

Stage 1 comprises identification of all activities required to completely prepare the compounded dosage form and its associated final package. This includes formulation ingredients, preparation, testing, and other post-compounding activities for dispensing to patients or shipping to clients. Relevant information is integrated in stage 1. When stage 1 is completed, all activities for future performance will have been documented to guide the compounding process. Actions to minimize potential hazards (i.e., what might go wrong) are incorporated in the process. Stage 1 design provides technical and compliance consistency throughout all compounding activities. Stage 1 design activities are executed in stages 2, 3, and 4.

Dosage form identification and characterization. 

The first significant activity in the compounding process comprises evaluation of the medication order for the compounded dosage form. This includes determining the availability of commercial product fulfilling the medication order and making compounding unnecessary; using a commercial product is preferable to extemporaneous compounding. Compounded dosage forms may not be reimbursed by a third party if similar products are commercially available. If a suitable commercial product does not exist, the compounded dosage form is identified. Objectives analogous to QbD for commercial products, such as Critical Quality Attributes (CQA) and Critical Process Parameters (CPP), are noted. These are straightforward for an IV solution with a single additive; other compounding (e.g., parenteral nutrition, non-sterile formulations, etc.) are much more complex. Clear directions for the dosage form to be compounded are essential.

Concurrent with dosage form identification is verification of information relevant to compounding. Questionable, inconsistent, or otherwise problematic information must be corrected or confirmed. Technical information may be applicable throughout the compounding process (e.g., a light-sensitive drug must be correctly handled during preparation, post-compounding, packaging, shipping, and administration to the patient). Using an investigative approach can be helpful when presented with new compounding—what is known, what is not known and must be determined, and what is the desired outcome? In other words, where do you want to go and what do you need to know and do to get there? This approach will provide guidance and direction for the compounding effort. Missing information has been described as a major cause of medication events (14).

Patient information, such as patient age, weight, medical diagnosis, hepatic function, kidney function, concurrent drug therapy, and other patient factors affecting formulation and dosage, must be reviewed. Is the medication order consistent with diagnosis (e.g., methotrexate dosage for cancer vs. rheumatoid arthritis)?

Drug, excipients, primary package, and dosage

. Textbooks with example formulations provide the basis for pharmaceutical compounding (15-17)

Drugs and excipients to be used in compounding must be reviewed. FDA published a list of bulk drug substances that can be compounded (18,19); these must comply with USP/NF standards (20-24). Compounding must not include drugs withdrawn for reasons of safety or efficacy (25). Relevant physicochemical properties, solubility, stability, compatibility with excipients, and other factors related to formulation design are reviewed. Commercial products must be clearly identified (e.g., which heparin dosage strength will be used for dilutions [26]). Inactive formulation ingredients may be problematic in certain patients (e.g., lactose intolerance, dye allergy). The primary package for the compounded dosage form may be a polymeric IV bag, plastic syringe, glass bottle, or other container, some of which may be incompatible or require extra precautions (e.g., IV nitroglycerin requires a non-PVC administration set). Difficult-to-compound dosage forms identified by FDA should not be compounded (27). Biologic drugs are not compounded (28).

 Information relevant to labeling, patient instructions, secondary packaging, supply chain shipping (e.g., refrigeration, non-freezing, light protection), and related considerations is assembled. Dosage form labeling is prepared. Medication information for distribution to the patient or to 503B clients is compiled. Assembled information must consider the entire compounding process, including patient use.

The compounded dosage form to be prepared is defined based on the medication order and assembled information. Formulation ingredients, process steps, primary package, and relevant information that includes details must be clearly stated in compounding documentation. Exact formulation amounts and process steps that include potential causes of failure are critical. Each medication order should be viewed as a new order and not copied from previous documents; prior calculations must not be assumed to be correct. A specific calculations process has been described (29); calculations may also be incorporated within comprehensive compounding documentation. Calculations must be carefully executed and include written units of measure; omitting descriptive units when calculating is a common cause of error. Problematic notations (e.g., mcg, µg, µ) must be clarified. Calculations should be reviewed by a second person; verification must not be cursory (i.e., the originator is a boss or someone who “never” makes mistakes). Calculations logic, execution, and supporting information must be critically reviewed and include being watchful for number transpositions.

The compounding record, work order, batch record, etc. is the permanent record of the compounded preparation retained at the compounding site. Each compounded preparation requires some form of compounding record; a compounded IV solution with a single IV additive prepared according to an SOP will require much less detail than an oral capsule formulation with multiple ingredients and a multi-step compounding procedure. Hospital IV solutions may be recorded within a pharmacy management system or other electronic record (e.g., Epic, DoseEdge). A site SOP should provide documentation templates; a standardized template will increase process uniformity and prevent omissions and errors. The compounding record will be utilized throughout all stages of the compounding process. SOP references are noted for standardized activities; planned deviations are noted in the compounding record. Documentation may contain descriptive information, rationale, ingredients, sources, lot numbers, equipment, process information, references, labeling, patient counseling, and other content; its level of detail must be sufficient to enable an exact repeat preparation of the compounded dosage form. Document clarity is essential; multiple personnel will utilize the compounding record throughout the process. Documentation must not contain drug name abbreviations, problematic units of measure, and numeric problems, such as leading and trailing zeros; awareness of look-alike sound-alike (LASA) drug names (e.g., tetracycline HCl and tetracaine HCl) and other sources of confusion should be prospectively highlighted. Evaluation criteria used post-compounding are identified. A listing of representative compounding record topics is presented in 

. Signature/date of individuals associated with respective content throughout the compounding process is recorded in the compounding record. Compounding records are used for material traceability, adverse event investigations, skills training, and other applications. Some organizations develop a library of master formulation records for frequently prepared dosage forms.

 Stage 2 activities are also designed in stage 1. These include compounding planning followed by preparation of the compounded dosage form. Precautions for problematic activities are highlighted. Critical process techniques must be reviewed with technicians prior to compounding (e.g., particle size reduction, geometric mixing, levigation, syringe use, etc.); additional training may be necessary. Certain drugs and excipients (e.g., potent drugs, antineoplastics, hormones, peanut oil, allergens, beta-lactams [penicillins]) must not contaminate subsequent compounding and require dedicated or disposable equipment. Personal protective equipment (PPE) may be required for technician protection. Potent and dangerous drugs may require restricted access barrier systems or controlled pressure facilities. Stage 2 activities should be generally described in approved site SOPs; planned deviations are noted in the compounding record.

 Stage 3 activities are also designed in stage 1. These include physical evaluation of the dosage form (e.g., appearance, solution clarity, suspension dispersibility, topical cream absence of particulates, color, and other visuals). Dosage form evaluation must be rigorous and consistent with design expectations. Testing is specified in the compounding record; 503B preparations are submitted for analytical laboratory testing, sterility testing, endotoxin, and other GMP requirements; validated test methods are required. The label for the final dosage form is prepared; labeling must be accurate (e.g., codeine vs. codeine phosphate) without spelling or typo errors, especially in the patient’s name. The compounded dosage form is quarantined to prevent release pending dosage form approval in stage 5. Equipment and facilities must be properly cleaned per SOP; cleaning must consider physical properties of ingredients (i.e., hydrophilic vs. hydrophobic). Dedicated equipment must be identified and stored to prevent inadvertent use; use of disposables eliminates equipment cleaning issues. Drugs or ingredients requiring specialized waste disposal are identified. These activities should be described in approved SOPs; additional requirements are added to the compounding record.

Stage 4 activities include final requirements for dosage form release to patients, clients, or other recipients. Technical information for patients and clients comprises labeling, dosage, administration, verbal counseling, storage conditions, and other relevant communication. Patient information should be equivalent to that provided by pharma manufacturers for commercial products. The final package provided to the patient/client must ensure correct use of the compounded dosage form. Most activities should be identified in SOPs; deviations are noted in the compounding record. Specialized shipping or storage requirements beyond SOP stipulations are noted.

 provides examples of potential stage 1 hazards, risks, and failure modes (i.e., what might go wrong). Most critical among these are identifying critical dosage form characteristics, assembling and verifying information critical to compounding, calculation errors caused by omitting units of measure in equations, and compounding directions that are too general and non-specific. The point of Table II is to encourage prospective thinking about potential problems; personnel designing the compounded dosage form should anticipate problems and include preventive actions in compounding instructions.

. Signature/date of stage 1 responsible personnel is noted in the compounding record. Personal signature/date affirms responsibility for performance of stage 1 activities.

Figure 1: Example Compounding Record Information

Table II. Potential Compounding Problems in Stage 1

Stage 2 compounding comprises pre-work and actual preparation of the compounded dosage form per stage 1 directions. Personnel involved in actual compounding must also plan their activities for expeditious performance, especially when compounding sterile dosage forms.

 Pre-compounding activities include selecting and organizing drugs, materials, equipment, and supplies for efficient dosage form preparation. Personnel who prepare the compounded formulation must have good understanding of compounding techniques before initiating compounding. Activities involved may be conducted in a non-sterile compounding area, laminar air-flow workstation (LAFW) in a clean room environment, or other suitable controlled conditions. Compounding personnel must be dressed appropriately, including scrubs, sterile gowns, gloves, face masks, and personal protective equipment as required.

 Technician training on preparatory skills and safety considerations is conducted as needed. Technical skills to prepare compounded dosage forms will vary depending on type and complexity. Sterile dosage form compounding is high risk due to potential contamination. Non-sterile compounding requires familiarity with preparatory techniques for specific dosage forms.

 Preparations containing potent or toxic injectable drugs such as anti-neoplastics may require the use of dedicated clean rooms with differential air pressure monitoring.

 Compounding equipment must be carefully examined to ensure cleanliness before use. Certain drugs and excipients may require use of dedicated equipment (e.g., potent drugs, hormones, peanut oil, allergenic materials, beta-lactam [penicillin] drugs, and other ingredients that must not contaminate compounded dosage forms).

 PPE beyond usual garb/equipment may be required for technician safety when working with high-alert, oncology, or other hazardous drugs.

 Drugs, excipients, and required materials to be used in compounding are assembled. Compounding personnel must be watchful for similar drug names (LASA), standardized packaging, small fonts on labels, and other features potentially contributing to erroneous material selection. Assembled drugs, excipients, and required materials must be critically examined for evidence of stability issues, contamination (e.g., black specks), discoloration, insoluble material in solutions, package integrity, mold growth, expired dating, and other problems 

. Pictures of final selected materials for inclusion in permanent documentation are recommended.

 Compounding sterile formulations requires aseptic gowning, sterile needles and syringes, alcohol swabs, and other supplies. 

 illustrates a typical arrangement of sterile compounded formulation components in an LAFW. Properly executing planned activities will ensure expeditious preparation of sterile preparations, minimizing potential contamination. Real-time verification of problematic process steps is critical to ensure correct preparation of sterile dosage forms. Contemporaneous observation of sterile compounding through imbedded workstation cameras is recommended; digital photographs and other technology may also be utilized. The Institute for Safe Medication Practices (ISMP) has long discouraged the “syringe pull back method” to verify sterile product compounding (31). Compounding non-sterile formulations includes selection of ingredients, equipment, and other supplies. Equipment must be qualified, clean, and otherwise suitable for use. 

 illustrates a typical arrangement of non-sterile compounded formulation components. Real-time observation of problematic process steps is especially critical to ensure correct preparation of non-sterile compounded dosage forms; video, digital photographs, or other technology are useful for permanent records.

 The designed dosage form is then prepared. The formula, compounding procedure, and documentation as designed in stage 1 are executed. Sterile preparations require attention to aseptic techniques; non-sterile preparations must utilize technical processes specific to the individual dosage form.

 provides examples of potential hazards occurring in stage 2. The point of Table III is prospective thinking about potential problems. Most critical among these are insufficient planning of compounding activities, overlooking materials used during compounding necessitating retrieval during compounding, substandard compounding skills (especially with less-frequent or unfamiliar techniques), and aseptic technique “shortcuts.”

Signature/date of stage 2 responsible personnel is noted in the compounding record. Signature/date affirms personal responsibility for performance of stage 2 activities.

Figure 2. Intralipid 20% with damaged packaging (note black oxygen sensor), undissolved mannitol crystals, and contaminated lactose (black specks).

Intralipid 20% with damaged packaging (black oxygen sensor), undissolved mannitol crystals, and contaminated (black specks) lactose.


Figure 3. Sterile Product Compounding Planning

Figure 4. Non-Sterile Product Compounding Planning

Table III. Potential Compounding Problems in Stage 2

Stage 3 post-compounding comprises testing, other dosage form-related activities, and ancillary activities executed after completion of compounding.

 Activities directly related to the compounded dosage form described in site SOPs are completed. Deviations to SOPs are identified in the compounding record. Most important among these are the critical evaluation of the compounded preparation, submission of samples for testing, and completion of compounding documentation.

 The compounded preparation is evaluated. Visual examination of appearance, color and clarity of solutions, suspension dispersability, topical cream smoothness, absence of solids, freedom from visible foreign particulate matter, package integrity, signs of instability, and other quality attributes are evaluated; physical observation evaluation must be rigorous. 503B compounding samples are submitted for analytical testing to verify potency, sterility, stability, and other requirements identified in stage 1; testing must use validated test methods.

 Deviations, non-conformances, environmental monitoring, and other data related to the compounded dosage form are reviewed. Acceptable results are required for eventual dispensing to patients and shipping to clients.

 Compounding record documentation is completed. Compounding documentation must ensure full traceability of ingredients, processes, and equipment, and it must provide sufficient detail to enable an identical repeat preparation of the compounded dosage form. Documentation for sterile preparations is completed outside the LAFW.

. The compounded dosage form is labeled and associated technical information assembled per stage 1 directions.

 The compounded dosage form is quarantined until all testing is completed and reviewed.

 Ancillary activities include workspace and equipment cleaning and waste disposal. If dedicated equipment is used for specific ingredients, it must be cleaned, dried, labeled, and appropriately stored to prevent future inadvertent use; misuse of dedicated equipment is a common compounding error. Waste disposal must follow site procedures (i.e., “sharps,” recyclables, HIPAA, biologicals, oncology drugs, and drug waste disposed into appropriate containers). Routine post-compounding activities are completed per SOPs. Deviations from SOPs are noted in the compounding record.

 Examples of possible stage 3 hazards are presented in 

. The point of Table IV is prospective thinking about potential problems. A common stage 3 problem is dosage form evaluation; preparations must strive for excellence and not be just “good enough.” Equipment used in compounding must be scrupulously cleaned after use. Dosage forms must be quarantined to prevent release until final approval (stage 5),

Signature/date of stage 3 responsible personnel is recorded in the compounding record. Signature/date affirms personal responsibility for stage 3 activities.


Table IV. Potential Compounding Problems in Stage 3

Stage 4 final package comprises technical and associated activities that complete dosage form preparation. Supportive information for patients or clients is compiled as specified in stage 1.

Test results are compiled and evaluated. Failing or unexpected test results must be investigated, appropriate action taken, and corrective action implemented. Labeling, medication information, patient counseling, and other communication to be provided to patents and clients is compiled. Commercial product manufacturers provide medication information to patients; comparable information should be developed on patient/client interactions. ISMP Medication Learning Guides for Consumers exemplify drug information provided to patients at dispensing (34). The compounded dosage form must be used correctly by the patient to ensure efficacy.

Associated activities are identified in an SOP or specified in the compounding record. Deviations to SOPs may include specialized protective packaging, time/temperature limitations with tracking devices, and other shipping requirements. Shipping should be performed by a dedicated delivery service in a controlled manner with location-tracking capability; shipping must include temperature control.

. Compounding record documentation is finalized. This is the final compounding record retained by the organization. After the compounded dosage form is dispensed or shipped, the compounding record is the lasting evidence of compounded dosage form preparation.

 Examples of possible stage 4 hazards are presented in 

. The point of Table V is prospective thinking about potential problems. Most important among these are assembly of communication for patients and clients. The compounded dosage form must be used properly by the patient, administered correctly, and otherwise handled to be efficacious. Completion of documentation is also critical in stage 4. Compounded dosage form quarantine (stage 3) should prevent inadvertent release to patients or clients.

Signature/date of stage 4 responsible personnel is recorded in the compounding record. Signature/date affirms personal responsibility for stage 4 activities.

Table V. Potential Compounding Problems in Stage 4

Stage 5 verification is the final check on the compounded dosage form, packaging, documentation, and related information before dispensing to the patient or shipping to clients.

Review of the completed dosage form and associated elements is a critical step in the compounding process. Ideally, verification is accomplished by an independent observer separate from people involved in the compounding process. Verification addresses the final dosage form, test results, completed documentation, and associated communications to be provided to patients or clients. The compounded dosage form is not dispensed to patients or shipped to clients until the final compounded dosage form and associated information are approved.

Review by a competent, independent observer must be a serious and thorough activity by an impartial observer—not a perfunctory ”rubber stamp” exercise. ISMP has discussed the judicious use of independent double-checks in pharmacy practice (35). Final dosage form and associated information must be reviewed vs. the original medication order. Review must be completed before the compounded dosage form is dispensed or shipped. Checklists are useful to ensure a comprehensive review. Errors, omissions, or insufficient details in compounding documentation are corrected. Documentation will be utilized in future investigations, training, and other applications. Final documentation is retained in prescription files, patient records, manufacturing batch records, or electronic systems. An example checklist with relevant topics is provided in 

When dosage form appearance, test results, documentation, and other reviewed content are acceptable, the compounded dosage form is approved for release by the responsible pharmacist. Approval is documented in the compounding record. The dosage form is removed from quarantine.

Examples of possible stage 5 verification hazards are presented in 

. The point of Table VI is prospective thinking about potential problems. Potential hazards in stage 5 are critical; this is the final check of dosage form quality, test results, patient/client documentation, and compounding record documentation. Compounding record documentation is the lasting record of the compounding process.

Signature/date of stage 5 responsible personnel is recorded in the compounding record. Signature/date affirms personal responsibility for stage 5 activities.

Figure 5. Example Compounding Verification Checklist

Table VI. Potential Compounding Problems in Stage 5

Stage 6 comprises activities in which compounded dosage forms are provided to users.

Dispensing/shipping to patients/clients. 

Stage 6 includes dosage form dispensing to patients, providing drug information, and counseling as needed. Dispensing and counseling are performed according to the clinical situation and patient needs. Stage 6 also includes shipping to patients per secondary package design, including temperature control, light protection, package tracking, and other requirements. Approval to dispense/ship is documented in stage 5; dispensing or shipping must not occur before the responsible pharmacist has provided final dosage form approval. Stage 6 also includes shipping to clients per secondary package design after responsible pharmacist approval.

Numerous examples exist of drug products being dispensed to the wrong patient and conditions under which this may occur. Errors may occur in community settings or in the hospital environment for a variety of reasons. Obvious causes involve patients with identical last names. Hospitalized patients may switch beds without notifying the nursing staff. Electronic order entry may be confused; mis-transcribed telephone orders, dispensing system overrides, and other potential patient mixups may occur. Verification using two patient identifiers is recommended to confirm the intended patient as well as verify correct treatment to the individual. These actions should occur at each step in the medication process (i.e., from original medication order, through multiple transcriptions {physicians, pharmacists, nurses}, and final dosage form administration to the patient). Examples of questions to be asked before drug administration, dispensing, or counseling to verify they are the intended patient typically include the patient’s name, date of birth, last four digits of the US social security number, or other government identification. Only verifying the patient’s name is not sufficient. Patients for whom English is a second language require increased assurance that they are the intended patient.

 Stage 6 also includes shipping to clients per secondary package design. Approval to dispense/ship is documented in Stage 5; again, dispensing or shipping must not occur before the responsible pharmacist has provided final dosage form approval.

Examples of possible stage 6 hazards are presented in 

. The point of Table VII is prospective thinking about potential problems. Most significant among these are dispensing a drug to the wrong patient. This may occur in community and hospital settings; there are numerous opportunities for actions that contribute to dispensing/administration of dosage form to the wrong patient (36-38).

 Signature/date of stage 6 responsible personnel is noted in the compounding record.Signature/date affirms personal accountability for stage 6 activities.


Table VII. Potential Compounding Problems in Stage 6

Management of a compounding organization is responsible for daily compounding performance, as well as related supportive activities. Quality systems guidance documents identify expectations of management (e.g., leadership, structure, quality system design, policies, objectives, plans, system review). FDA issued CDER’s Quality Management Maturity Program (39) addressing expectations beyond current GMP; compounding management must aspire to much more than minimal GMP compliance. Development of a quality culture mindset in which risks to compounded product quality are minimized is led by management (40)and should be forefront in the organization. ICH Q9(R1) QRM addresses “What might go wrong?” and describes common methods of risk assessment; these methods are directly applicable to pharmaceutical compounding.

Primary management responsibilities in compounding organizations include the following:

 Hiring capable personnel is the most important function of management. Compounding personnel must have appropriate technical compounding skills; organizational skills, self-discipline, attention to detail, language skills, legible handwriting, common sense, and realization of personal deficiencies (i.e., knowing what you don’t know) are desirable. Interpersonal skills in a teamwork environment are essential. Sufficient number of personnel must also be hired commensurate with workload.Management is also responsible to assure that each staff member knows and understands their roles and responsibilities, as well as accepts personal responsibility for performance.

 Management is responsible for the standards that define daily workplace activities. Compounding organizations must have written and approved documents; compliance with these documents is mandatory. Inadequate procedures, training, and non-compliant performance are always among the most frequent GMP violations in pharma (41). SOP compliance must be forefront in compounding organization performance. SOPs should be living documents, periodically reviewed for accuracy and relevance and updated when new information is available.

Personnel must be trained and periodically re-trained on SOPs. Training must be documented; if not documented, it didn’t happen. Training must emphasize personal accountability for SOP requirements; personnel must understand that their signature/date in compounding documentation affirms personal responsibility.

 The workplace environment must encourage communication of problems, mistakes, and issues without fear of punishment or embarrassment. Management must develop a collaborative relationship with staff with ongoing focus on quality (i.e., a true quality culture that is evident in personnel performance). ISMP identified communications about medication safety risks occurring within and outside the organization as best practices for community (42) and hospital pharmacy (43). FDA-483 observations and warning letters demonstrating compliance deficiencies in compounding organizations are readily available (44).

Beyond hiring, procedures, and training are the everyday expressions of management commitment to quality. Management focus must expand from traditional management to include anticipation of performance hazards and risks (i.e., what might go wrong). Management daily performance in routine activities must exemplify commitment to quality.

 Management is responsible for administrative functions supportive to compounding (e.g., funding, scheduling, maintenance, calibration, facility cleanliness).

Examples of possible management hazards are presented in 

. Most significant among these are deficiencies in management commitment to responsibilities; organization culture is directly related to management commitment. The actions of individual employees reflect the attitude and commitment of management—what management wants, management gets. Management is also ultimately responsible to address potential hazards identified above in respective stages of the compounding process.

 Signature/date of management on policies, procedures, and other documents affirms management accountability.


Table VIII. Potential Compounding Problems by Management

This discussion describes an ordered process for pharmaceutical compounding based on academic teaching of compounding theory and practice, problem experiences in multiple settings, regulatory observations, and published medication errors. Technical activities occurring in the compounding workplace beyond physical compounding techniques are addressed. The process describes what and why activities, as well as what might go wrong throughout the comprehensive process.

Six stages of compounding activities are identified, each having specific objectives. Stage 1 design activities address considerations to be executed in all subsequent compounding stages; technical consistency throughout the process is forefront. Compounding activities are executed in stages 2, 3, and 4. Stage 2 comprises selection of materials and equipment, compounding planning, and actual dosage form preparation. Stage 3 post-compounding comprises dosage form review, sampling, testing, and related activities. Stage 4 includes final review of test results; medical information and packaging for dispensing to patients or shipping to clients is compiled. Stage 5 verification comprises review of the compounded dosage form, labeling, drug information, and secondary packaging; stage 5 activities require an independent observer. The compounded medication is approved for dispensing in stage 5. Stage 6 dispensing/distribution provides the compounded dosage forms to users, including patient counseling, medical information, and/or appropriate supply chain shipping. Compliance with regulations and site procedures is required throughout the process. Personnel understanding of their responsibilities and affirming accountability by signature/date on documentation is required. Examples of potential hazards are identified throughout; case studies further demonstrate problematic circumstances.

Management has significant technical responsibilities in the compounding process. Management is responsible for the actual compounding, as well as for supportive functions. Management must continually support employee training and awareness of possible problems. As risks are identified and knowledge is gained, SOPs are modified, including corrective and preventive actions for continuous improvement. A workplace environment in which quality is forefront (i.e., a quality culture) must be an ongoing goal of compounding management and staff.

Pluta, P.L. Pharmaceutical Compounding Overview – Technical, Regulatory, and Management in a Workplace Environment. 

Compounding Overview: Primary Considerations for the Workplace (pharmtech.com)

https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm

Articles

An ordered pharmaceutical compounding process for use in 503A pharmacies, 503B outsourcing facilities, pharmaceutical industry, and other applications.

Dosage Form Compounding in the Workplace Environment

Pharmacist weighing chemical | Image Credit: © Kzenon - stock.adobe.com

Performing calculations for the formulation of pharmaceutical dosage forms and related preparations is a key activity in compounding. Calculations provide the amount of drug specified in the medication order needed for compounding; it is the objective of the medication order. Correct drug calculations for compounded preparations are essential; if drug calculations are incorrect, the resulting preparation form will be incorrect, potentially with significant therapeutic and technical consequences.

) addresses numeric calculations for types of bulk drugs. It builds on drug calculations topics previously described (1), including guidance documents (2–5). Textbooks (6–8) have always provided the foundation for mathematical calculations; discussion herein reflects academic teaching and practice in multiple workplace settings and integrates basic principles and problem experiences. Concepts that are often omitted, confused, or otherwise misunderstood that affect the accuracy of calculations are addressed.

Part two discussion describes a simple medication order and demonstrates calculations and labeling for each bulk drug type. The medication order identifies the active moiety. Types of active moieties and their differences must be understood. Calculating the active moiety amount for compounding follows. The active moiety is provided in the medication order by a proprietary or generic name, but not necessarily a precise name. Active moiety calculations determine the drug amount needed to prepare the dosage form quantity. The importance of active moiety calculation must not be underestimated. Interpreting a confusing medication order and verifying its intent is a critical step prior to numeric calculations. After the active moiety amount is calculated, the drug molecule for compounding is selected. Each molecule type is different, has different dosing, and requires different calculations. Notations and drug types in this discussion are as follows.

The active moiety expressed in the medication order is identified as Drug Z. Drug Z represents a common or familiar drug name (e.g., diazepam, Plavix, codeine—proprietary or generic drug name) applicable to all of the drug types to be calculated.

 These drugs comprise molecules with covalent bonds and other non-salt molecule bonds. The active moiety of a covalent drug is usually the entire drug molecule (i.e., active moiety is same as bulk drug). The non-salt drug noted in the following discussion is also identified as Drug Z.

 These drugs comprise molecules with ionic bonds (e.g., sodium drug, potassium drug, drug hydrochloride, drug acetate, etc.). The active moiety is the drug-ion part of the salt molecule. The compounded product dosage strength reflects the amount of drug-ion and not the entire salt molecule amount. The salt drug noted in this discussion is identified as Drug ZA.

. These drugs are also salts that ionize. However, the drug moiety is dosed together—drug-ion with counterion. Policy-exception salts include simple salts (lithium carbonate, iron sulfate, potassium chloride, and other common intravenous additives); salts affecting absorption, distribution, metabolism, and excretion; drugs with clinically significant amounts of cations (sodium, potassium, magnesium, calcium); drugs affecting physiological acid-base balance; and drugs approved before 2013 with established dosages; these exceptions are specified in the 

) salt policy. The policy-exception salt drug noted in this discussion is identified as Drug ZB.

Some active moieties may be available in multiple drug types (e.g., phenytoin and sodium phenytoin; codeine and codeine phosphate). Each drug type may have different pharmacologic effects on patients (9) and different physicochemical properties relevant to compounding (e.g., a sodium salt will be more water-soluble than an acid or base) (10). After the bulk drug is selected, calculations are executed. Values determined in calculations are used in compounding and are reported in labeling. Pharma industry and 503B outsourcing facilities are likely to use bulk drugs for large-scale compounding. 

illustrates the bulk drug compounding process; specific topics addressed in this discussion are highlighted in red.

The following describes a structured sequence of expressions used in these calculations. Examples addressing calculations for three types of drugs (non-salts, salts, and policy-exception salts) are provided. The medication order is identical for each drug category in the following discussion. This enables direct comparison of calculated values and label statements. Drugs in mixtures are another form of drugs for compounding; calculations for drugs in mixtures will be addressed in part three of this series. The following describes four steps to accomplish required calculations.

Drug calculations are based on the medication order.

The active moiety amount needed to prepare the required medication amount order is calculated.

 The bulk drug amount needed to prepare the compounded dosage form is calculated. Molecule calculations and mole calculations are used if needed.

 Labeling is determined from the medication order and calculated drug amounts. Additional molecule calculations and mole calculations may be needed. Labeling for the primary and secondary labels are determined.

Active moiety amount calculations determine the amount of active moiety required to fulfill the medication order; in turn, this value will be used to calculate the drug substance amount. Active moiety calculation values come from the medication order. Values may be expressed in grams, milligrams, micrograms, specific drug units (e.g., heparin units, nystatin units, insulin units, etc.), liters, milliliters, teaspoonfuls, ounces, ratio strength, parts, and numerous other measurement units 

. The number of dosage units may likewise be expressed in multiple ways (e.g., doses per day, doses at hourly intervals, at bedtime, number of capsules, ounces or liters of liquid dosage form, and many others). Units of measure will cancel if an equation is properly designed, leaving the equation amount objective. Expressing the unit of measure is a critical activity in the active moiety calculation; omitting units of measure in calculations (i.e., using a smartphone or other calculator without recording units of measure) is a common cause of calculation errors.

Active moiety calculations. Units of measure may include mL, mg/mL, mg/5 mL, mg/teaspoon, ounce, liter, milliliter, specific drug units, or other units of measure. Number of dosage units may be expressed in mL, 5 mL, teaspoons, ounces, capsules, doses per day, time interval, doses per day, and many others.

Molecule calculations may be needed to determine a drug-ion molecular mass (molecular weight [MW]) if not available in reference literature. Calculating the MW of a drug active moiety or bulk drug requires addition of the individual element atomic masses (AW)—not atomic numbers—of the drug-ion or bulk drug. The drug-ion MW may be significantly different from the drug MW (e.g., clopidogrel [Plavix] MW 321.9, and clopidogrel bisulfate MW 419.9). Some drug molecules contain multiple active moieties (e.g., one divalproex sodium molecule contains two valproic acid moieties). Waters of hydration, solvates, complexes, and other molecular components must be included in drug molecular weights (e.g., ampicillin is commercially available as either anhydrous or trihydrate). 

 illustrates molecular weight calculations of clopidogrel molecules using the general summation equation ∑AW = MW, where AW = atomic weights and MW = molecular weight.

Mole calculations are needed to correlate salt-ion active moieties, salt drugs, and pharmaceutical alternatives. Calculations involving moles are critical for certain drugs. The mole equation includes drug gravimetric weight and molecular weight 

. Recall from general chemistry that chemical reactions are balanced based on moles of reactants and products; pharmacologic action has the same quantitative relationship. Pharmaceutical alternatives (e.g., codeine, codeine sulfate, and codeine phosphate) provide equivalent clinical activity based on equivalent molar amounts—not equivalent gravimetric weights. If pharmaceutical alternatives are used in compounding, mole calculations are utilized to provide equivalent dosages (e.g., metronidazole benzoate gravimetric dosage larger than metronidazole base dosage). Ephedrine, pseudoephedrine, and phenylpropanolamine consumer purchasing restrictions are determined by mole calculations (e.g., 3.6 grams of pseudoephedrine base [daily sale limit] is available in 146 pseudoephedrine hydrochloride 30 mg tablets) (11). The equation shown in 

 demonstrates the general mole equation, while the equation shown in 

 illustrates the active moiety-drug relationship for salt drugs; note 

. Compounded product labels must accurately reflect the content of a compounded dosage form. Labels are described as primary labels on the front of the compounded preparation container and secondary labels on the side panels. Accurate compounded product labeling requires attention to detail (i.e., labeling “codeine” is not the same as labeling “codeine phosphate”). The labeling of non-salt compounded preparations is straightforward; covalent active moieties are same as corresponding bulk drugs; the stated amount of drug must clearly identify the name and drug amount (e.g., Diazepam tablets, 10 mg). Salt dosage form labeling may require additional calculations for compliance with labeling requirements. Molecule and mole calculations as described above may be required for secondary label information. FDA guidance documents illustrate labeling salt drugs and associated active moieties.

Example labels below illustrate compounding labels involving salt drugs—labeling according to their active moiety or according to the bulk drug. 

 illustrates a salt-ion drug label with active moiety as dosage form name; this label represents product in compliance with the drug salt policy. This labeling would likely have been approved for a salt-active moiety after 

’s salt policy was implemented in 2013. Note active moiety on primary label and both active moiety and bulk drug amount on secondary label.

 illustrates a policy-exception salt dosage form label with bulk drug name on the primary label, and bulk drug and active moiety calculation in the side panel—the opposite of 

. This label demonstrates labeling for a pre-2013 approved salt drug product—the entire salt drug weight (Olddrug palmitate) is dosed as the active moiety. This approach is applied to compounded dosage forms involving drugs identified as salt policy-exceptions to the 

salt policy. Note significant labeling differences between salt drug and salt-exception drug dosage forms.

Policy-exception salt drug dosage form label.

The following describes a sequence of numeric operations for compounding calculations. Examples addressing three types of drugs (non-salts, salts, and policy-exception salts) are provided.

Example drugs in this category include diazepam, digoxin, thyroid, and ospemifene (i.e., non-salt drugs). In this example, the drug amount (Drug Z) is identical to the calculated active moiety amount. No additional calculations are required beyond the active moiety amount calculation; molecule and mole calculations are not needed.

 Drug Z, 50 mg. 100 capsules. One capsule four times daily

The medication order is received and evaluated. Existing conditions in patients (e.g., cardiac, immunogenicity, hepatic, diabetes) affecting compounding and drug dosage must be known. The compounded dosage form amount must not exceed 

 Beyond Use Date (BUD) limitations without supporting stability data.

The active moiety amount needed to provide the medication order is calculated.

X = 5,000 milligrams Drug Z active moiety amount needed.

Drug Z active moiety will be provided by Drug Z bulk drug.

Active moiety amount needed: 5,000 mg. Bulk drug amount needed: 5,000 mg.

Drug Z 5,000 mg is combined with other formulation ingredients (i.e., excipients) to prepare 100 Drug Z Capsules, 50 mg.

 Primary label and secondary label are essentially identical for non-salt drugs. No additional calculations are needed.

Secondary label: Each capsule contains Drug Z 50 mg.

Dosage in salt dosage forms is defined as the drug-ion amount. Example drugs in this category include clopidogrel (bisulfate), and other salt drugs dosed according to their drug-ion active moiety. The salt drug (Drug ZA) contains the drug-ion active moiety in the molecule. Drug Z 50 mg dosage is drug-ion active moiety; the non-drug counterion is not part of the calculated active moiety dosage. The bulk drug amount providing 50 mg active moiety is calculated using mole calculations. If the drug-ion active moiety molecule mass is not available in references, it is calculated using molecule calculations described above. For this example, the Drug ZA-ion active moiety MW = 400 and Drug Z salt MW = 550.

The medication order is received and evaluated as described above.

Let X = Drug Z-ion active moiety needed for compounding.

X = 100 capsules × Drug Z 50 mg /capsule = 5000 mg Drug Z-ion needed for compounding.

 Active moiety amount needed = 5000 mg Drug Z-ion. Drug Z-ion active moiety will be provided by bulk drug ZA. The bulk Drug ZA amount as the salt form providing 5000 mg Drug Z-ion must be calculated. In other words, the drug-ion amount to be dosed is known; the bulk Drug ZA amount providing 5000 mg Drug Z-ion is not known and must be calculated. If not otherwise available, the drug-ion molecular mass is calculated as demonstrated above. The drug-ion MW should be available in the 

, drug product information, or other sources.

Drug Z-ion 5000 mg / 400 MW = X milligrams Drug ZA-salt drug mg / 550 MW

Therefore, the amount of bulk Drug ZA-salt needed for compounding = 6875 mg. The 6875 mg of bulk ZA drug will provide 5000 mg Drug Z-ion active moiety. Note that the amount of Drug ZA-salt is larger (i.e., 6857 mg > 5000 mg) than the amount of Drug Z-ion. The extra bulk drug weight is counterion weight. The 6875 mg of Drug ZA-salt will be combined with other formulation ingredients to prepare 100 Drug Z 50 mg drug-ion capsules.

 The primary label will specify the activity moiety (Drug Z-ion) and 50 mg strength consistent with the medication order. The secondary label will specify the Drug ZA-ion amount per capsule and the equivalent Drug Z-salt amount consistent with FDA labeling guidance. Mole calculations are used to calculate Drug ZA salt amount per capsule for the secondary label.

Drug Z-ion 50 mg active moiety / 400 MW = X mg Drug ZA drug / 550 MW

X = Drug ZA-mg bulk drug = 69 mg that provides drug Z-ion 50 mg.

The amount of Drug ZA salt must be larger than the amount of Drug Z drug-ion stated on the label.

Secondary label: Each capsule contains Drug Z 50 mg equivalent to Drug ZA, 69 mg.

Salt-exception drugs (Drug ZB) utilize the entire drug molecule for dosage (i.e., 50 mg dose is Drug ZB salt). Example drugs in this category include morphine sulfate, lithium carbonate, potassium chloride, and other drugs dosed as drug-ion with counterion. Even though the salt drug active moiety is the drug-ion part of the drug molecule, dosage and labeling are based on the entire drug molecule per 

 salt policy. The 50 mg dosage represents drug-ion with counterion per 

 salt policy (e.g., drug dosage is codeine phosphate, morphine sulfate, dexamethasone phosphate, or other drug-ion with counterion). Additional mole calculations are needed only for drug-name labeling per FDA guidance (

 above). Drug ZB MW and drug Z-ion MW calculations are needed for secondary labeling. Active moiety and bulk drug molecular weight assumptions: Drug Z-ion active moiety MW = 400 and Drug ZB salt MW = 550.

. Drug Z, 50 mg. 100 capsules. One capsule four times daily

The medication order is received and evaluated as above.

Let X = Drug Z active moiety needed for compounding.

X = 100 capsules × Drug ZB 50 mg /capsule = Drug ZB 5000 mg

3. Drug amounts for compounding calculations.

 Drug amount needed: 5000 mg = drug dosed as salt (active moiety with counterion).

X = 5000 mg of Drug ZB is combined with excipients to prepare 100 capsules containing Drug ZB, 50 mg.

 The primary label will specify the bulk drug name (Drug ZB) and dosage strength. The secondary label will specify the salt molecule and the active moiety equivalent as specified in the FDA guidance (

 above). Drug Z active moiety is provided by Drug ZB policy-exception salt bulk drug. Calculate the drug-ion molecular weight as demonstrated above. The drug MW should be available in the 

, drug product information, or other sources. This calculation is needed for secondary labeling per FDA guidance.

50 mg Drug ZB salt dosage / 550 MW = X mg Drug Z ion active moiety / 400 MW

The amount of Drug Z must be smaller than the amount of Drug ZB drug stated on the label.

Secondary label: Each capsule contains Drug ZB, 50 mg, equivalent to Drug Z, 36 mg.

There are numerous hazards with potential to cause errors in drug calculations and labeling. The following are most relevant to calculations topics discussed above. Additional problems such as substandard documentation, insufficient or delayed verification, and lack of personal accountability have been previously discussed (1). Prospectively addressing potential problems as part of quality risk management (i.e., what might go wrong) (12) and continuous improvement programs are essential in compounding organizations.

Personnel must clearly identify objectives in compounding calculations—exactly what is to be calculated? Identifying the calculations objective forces prospective thinking about future numeric operations. Correct equations are not possible when the values to be calculated are not clearly understood. Information required for compounding must be complete, correct, and verified if necessary. First determine what is known, and then ascertain what information is needed and unknown. After all relevant information has been compiled but before starting actual calculations, values to be calculated should be estimated; this also forces prospective thinking about calculations. Estimating a value to be calculated requires both self-discipline and time. Both Ansel (6) and Teixeira and Zatz (7) describe estimation as part of the calculations process. Each calculation should be a new effort. Do not copy from previous completed calculations; if mistakes were previously made, mistakes will be continued.

Some active moieties may be available in different molecular structures (e.g., phenobarbital and sodium phenobarbital) 

. Compounding personnel must select the appropriate drug for calculations and eventual use in compounding. While alternate drugs have the same active moiety, they may have different pharmacologic effects affecting patients or different physicochemical properties affecting the dosage form preparation. Selecting of the appropriate pharmaceutical alternative requires technical judgment. Respective alternatives may have different pharmacologic effects on patients. From the Dilantin package insert:

“The free acid form of phenytoin is used in DILANTIN-125 Suspension and DILANTIN Infatabs. DILANTIN extended capsules and parenteral DILANTIN are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.” (9)

Active moieties and pharmaceutical alternatives.

Pharmaceutical alternates may also have different physicochemical effects on the compounded dosage form (e.g., valproic acid is a water-insoluble oil and divalproex sodium is a water-soluble salt). Personnel must evaluate drug options for use in compounding before initiating calculations. Drug alternatives used in commercial product formulations may be helpful to provide rationale for drug selection (e.g., commercial clindamycin topical preparations are formulated with clindamycin phosphate). The same bulk drug for compounding as used in approved commercial products should be the preferred alternative.

 Units of measure must be included with all terms in equations. Writing numeric values without units of measure is the most frequent cause of calculations errors. Without the unit of measure, number identity is lost. Some calculations require a series of numeric operations; units of measure are critical when multiple terms are involved. Smartphones and calculators do not enable unit of measure notation. Numerators and denominators may be transposed when units of measure are not written. Calculations are best executed on paper with units of measure without use of calculators. Calculations should not be done in your head no matter how simple the calculations. Calculators with printouts to verify numeric entries are recommended. Auto-correct or default functions in computer systems may contribute to unit of measure errors.

. When calculations are completed, they should be critically evaluated—do the calculated values make sense? Critical thinking and common sense are key when executing calculations. Evaluation may indicate that calculated values are incorrect or unreasonable. Depending on the scale of preparation, very large or very small calculated values are probably incorrect. Incorrect calculated values may be impossible or illogical (e.g., 7000 mL IV additive, 0.0005 mL drug solution, or 30 × 30 mL vials to be added to an IV). Comparison of the calculated value to the initial estimated value should be done; if the calculated value is significantly different from the estimate, then something is wrong.

This discussion demonstrated numeric calculations for compounded dosage forms using bulk drugs as sources of active moieties. Calculations are described for non-salt, salt, or policy-exception salt drugs. Despite an identical medication order for all examples, the actual drug dosage and drug amount is different for each drug type. The key to understanding these calculations lies with understanding respective active moiety dosages. Non-salt drugs are dosed with the entire molecule; salt drugs are dosed per the drug-ion; policy-exception salts are dosed with the entire salt molecule (drug-ion with counterion). Subsequent calculations reflect respective dosages. Salts will thus require larger bulk drug amounts to compensate for the bulk drug counterion. Policy-exception salts provide smaller drug active moiety amounts for the same labeled drug dosage.

A standardized calculations process is utilized throughout. The calculations process begins with the medication order; the amount of active moiety needed for dosage form preparation is then determined. The applicable type of bulk drug is identified. General equations (active moiety amount, molecule, and mole calculations) are described. After calculations, drug naming on dosage form labels must be consistent with the drug type and active moiety amounts.

Differences between calculations and labeling for non-salt, salt, and salt exception drugs are presented in 

 Calculations for compounded dosage forms with non-salt drugs are straightforward. Non-salt active moieties and drugs are the same molecule; the entire drug molecule is the active moiety. Non-salt drugs are named using their drug name. Primary and secondary labels for non-salt dosage forms are identical.

Non-salt, salt, and policy-exception salt bulk drug calculations comparison. (Medication order: Drug Z, 50 mg, 100 capsules.)

Calculations for salt and salt-exception drugs are much different. Salt drugs identify the drug-ion as the active moiety and amount dosed in the dosage form. Policy-exception salt drugs are dosed using the entire salt molecule including the counterion. Policy-exception salt drugs thus provide less actual drug-ion active moiety than the labeled amount of drug. Regarding labeling, the compounded salt dosage form is named/labeled as the drug ion; the policy-exception salt dosage form is named/labeled as the drug name with counterion. This approach to salt drugs was adopted by 

 and FDA in 2013. Specific policy-exception salt drugs are identified in regulatory references (2–5).

Bulk drug calculations for different types of active moieties and drugs require different calculations and labeling.

Pharmaceutical Compounding Calculations, Part Two–Bulk Drugs

Drug calculations for the formulation of dosage forms and associated preparations are key activities in pharmaceutical compounding. Calculations determine the amount of drug identified in the request for compounding. Correct drug calculations for compounded preparations are essential; if drug calculations are incorrect, resulting preparations will be incorrect—potentially with significant therapeutic and technical consequences.

Calculating the amount of drug needed for compounding requires different considerations for respective drug types and forms.