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30 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2024 PharmTech.com Compounding mate is reviewed. Does the calculated answer make sense? An intravenous solution containing kilograms of drug, an unusually large number of additive vials, or 0.0005 mL added drug is unlikely. If the calculated value is very small or very large, something is wrong. A correctly completed calculation will also provide direction on the compounding process especially when multiple dilutions are needed (i.e., the equa- tions "talk" to the formulators); technicians need to realize and understand this concept. If the calculated value is significantly different from the calculation estimate or an online calculation, why the difference? Always ask yourself if the final answer makes sense. If the final answer does not make sense, then there is an error and activities must stop. Calculations must be investigated, repeated, and corrected. Documentation. Fina lized ca lculat ions a re re- corded in the Calculations Record, and the Calcula- tions Record is completed. These will be utilized in dosage form compounding. Executed calculations must be clear, concise, and understandable for doc- ument use and for Stage 3 independent review. Stage 2 accountability. Signature/date of person- nel responsible for Stage 2 numeric operations is re- corded in the Calculations Record. Stage 3. Independent verification After equation design and execution, an independent review before calculated values are used for com- pounding is performed. Verification–calculations and documentation. Calculations and supporting documentation are veri- fied by an independent qualified person; a second set of eyes reviewing even the most trivial calculation is effective error prevention (27). Calculations verifica- tion begins with the original medication order. Veri- fication must be rigorous and not superficial (i.e., the reviewer must not approve because the calculations person is a trusted colleague). Verification personnel must not fear correcting a supervisor. Verifiers must be watchful for worker tendences in number transpo- sition and related conditions. The human brain does not read ever y letter in a word (typoglycemia); the same tendency may occur with numbers. Printing calculators are useful to verif y accurate data entry. Calculations verification by an independent individ- ual must be completed before actual compounding or other use of calculated values. Additional verifi- cation of calculations may be required for problem dr ugs (calcium phosphate, intrathecal injections, neonates); a mistake with intrathecal dosage can be fatal. The Calculations Record is the lasting record of the compounded preparation with potential to be accessed many times in the future. The Calculations Record must be a perfect document. Calculations checklist. Review checklists are help- ful to avoid overlooking relevant information. A rep- resentative checklist is illustrated in Figure 4. The site compounding/calculations SOP should contain check- list(s) for use in Stage 3 independent verification (i.e., the checklist must be an approved document). Stage 3 accountability. Signature/date of person- nel responsible for Stage 3 verification is recorded in the Calculations Record. Management responsibilities Ma nagement of a compound i ng orga n izat ion is responsible for daily performance and traditional management activities. Quality systems guidance documents identif y expectations of management, (e.g., leadership, structure, quality system design, policies, objectives, plans, system review, and many others) (28,29). FDA's Quality Management Maturity Program (QMM) (30) addresses management beyond current good manufacturing practice (GMP). FDA goals in QMM are to foster a quality culture mindset, recognize advanced quality management practices, identify areas for growth, performance, and quality improvement; and minimize product availabilit y r isk s. T he Inter nat iona l Counci l for Ha r mon isa- tion's (ICH's) Q9(R1) Quality Risk Management (QRM) describes common methods of hazard assessment applicable to compounding activities (31). ISMP iden- tified communications about medication safety risks occurring internally and outside the organization as best practices for community pharmacy (32) and hos- pital pharmacy (33). The following are primary management responsi- bilities in compounding organizations; note focus on compounding personnel: • Personnel. Hiring capable personnel is the most impor tant f unction of management. Calcula- FIGURE 3. Completed Example Calculations (See Figure 1 Equation Design). Medication Order John Doe, 135 lbs. Drug A 10 mg/kg in 1000 mL saline every 8 hours Calculations Objective Determine mL of Drug A to be added to 1000 mL Normal Saline. Drug A available as 50 mg/mL in 30 mL vials. Equations Patient weight: 135 lbs x kg/2.2 lb = 61.4 kg patient weight Drug A amount needed: 61.4 kg x 10 mg/kg = 614 mg Drug A needed Drug A volume: 614 mg Drug A x mL/50 mg = 12.3 mL Drug A needed