1. Non Sterile Pharmaceutical Compounding

2. Chapter Topics Sterile and nonsterile compounding Laws, regulations, and standards Regulations of pharmacy personnel Documentation of nonsterile compounding Equipment for weighing, measuring, and compounding Techniques for mixing compounded drugs Compounding of specific formulations The compounding process Reference sources for the compounding pharmacy

3. Learning Objectives Define the term compounding, describe common situations in which compounding is required, and identify rationale and examples of nonsterile compounding. Discuss the impact of the Food and Drug Administration Modernization Act (FDAMA) of 1997 on the practice of a compounding pharmacy. Understand the distinction between a manufactured product and a compounded nonsterile preparation. Define the regulatory role of the state board of pharmacy. Identify quality standards for nonsterile compounding contained in USP Chapter.

4. Learning Objectives (continued) Review and follow the components of good compounding practices in the pharmacy. Discuss reasons and process for accreditation of specialty compounding pharmacies. Understand the minimum training and attire requirements for pharmacy technicians in a compounding pharmacy. Distinguish the components and purpose of a master control record from a compounding log. Define percentage of error and understand how it relates to accuracy in the compounding pharmacy. Identify and describe the function of the equipment used for the weighing, measuring, and compounding of pharmaceuticals.

5. Learning Objectives (continued) Explain the proper techniques for weighing pharmaceutical ingredients, measuring liquid volumes, and compounding nonsterile preparations. Define the various terms used for comminution and blending. Examine the techniques by which solutions, suspensions, ointments, creams, powders, suppositories, and capsules are prepared. Understand and calculate common mathematical problems that occur in a compounding pharmacy. Identify the steps necessary in the compounding process. Compare the reimbursement procedures of a compounding pharmacy and a retail pharmacy. Identify references with a focus on compounding.

6. Sterile and Nonsterile Compounding Compounding – The process of preparing a medication for an individual patient from bulk ingredients according to a prescription by a licensed prescriber Situation requiring compoundingExample Dose for pediatric patient smaller than commercially available dose Preparing 10 mg capsules from 30 mg tablets Patient cannot swallow solid dosage formPreparing a suspension from tablets Dose for veterinary application that is not commercially available Preparing a thyroid medication for a cat Medication has unpleasant tastePreparing a flavor-masking syrup for a pediatric patient Oral medication causes adverse effectPreparing a gel for a patient who has had ulcers from oral medication

7. Laws, Regulations, and Standards Food and Drug Administration Modernization Act of 1997 – Allows pharmacists to compound nonsterile (and/or sterile medications) for an individual patient if these medications meet established USP standards – Compounding pharmacies overseen by state board of pharmacy

8. Laws, Regulations, and Standards (continued) Food and Drug Administration Modernization Act of 1997 – Compounding a commercially available product is prohibited – Compounding pharmacies not required to follow current good manufacturing practices, adhere to product labeling, or submit drug approval applications – If community pharmacy selling products to healthcare professionals or out-of-state pharmacy, must apply for manufacturing license

9. Laws, Regulations, and Standards (continued) USP Chapter – USP standards developed to enhance patient safety from nonsterile compounded products – Manufactured products Prepared off-site by large-scale drug manufacturer – Compounded preparation A patient-specific medication prepared on-site

10. Laws, Regulations, and Standards (continued) USP Chapter – Sources for bulk ingredients Decision based on cost, quality, purity, reputation of manufacturer Pharmaceutical Compounding Centers of America (PCCA) primary source for many large-volume compounding pharmacies More than one source recommended in case of shortage, back order, or product recall

11. Laws, Regulations, and Standards (continued) USP Chapter – Beyond-use dating The documentation of the date after which a compounded preparation expires and should no longer be used Initiated when product compounded not when dispensed Pharmacy technicians should understand the distinction between a beyond-use date and an expiration date: A beyond-use date is a term that applies to compounded preparations, whereas an expiration date is a term that applies to manufactured products.

12. In the Know: True or False A pediatric dose that is smaller than what is commercially available would require compounding. true It is okay to compound a commercially available product. false USP Chapter provides standards for compounding nonsterile products. false Beyond-use dating is the date after which a compounded product can no longer be used. true

13. Laws, Regulations, and Standards (continued) USP Chapter – Estimates for beyond-use date Refrigerated aqueous solution or suspension: 14 to 30 days Solids such as tablets and capsules: 6 months or less – Beyond-use date for prescription with two or more active or inactive ingredients Take 25% of the remaining expiration date or six months, whichever is earlier

14. Laws, Regulations, and Standards (continued)

15. Accreditation – Provides competitive edge in the marketplace – Voluntary accreditation through the Pharmacy Compounding Accreditation Board (PCAB) – Pharmacy must agree to meet all standards for sterile and nonsterile compounding – Includes monthly or quarterly spot check Random product sent to outside lab for analysis Product must be +/-2% of potency Any corrective action must be documented and dated by pharmacist

16. Regulations for Pharmacy Personnel Technician training – Successfully passing a broad national certification exam – Mini-certifications and laboratory training in nonsterile and sterile compounding Nonsterile compounding attire – Clean, protective clothing, hairnet, long lab coat, disposable gloves – If hazardous chemicals to be used, eye goggles, mask, double gowning

17. Documentation of Nonsterile Compounding Master Control RecordCompounding Log Purpose A recipe for a compounded preparation A printout from the master control log used to prepare a compounded prescription Components Drug name Drug strength Drug dosage form Ingredients and quantities Sequencing and mixing instructions Beyond-use dating Storage and labeling information Patient name Date of compounding Rx number Master Control Record number Names of ingredients and their expiration dates Amount needed Quantity made Manufacturer Wholesaler source NDC number Assigned lot number Initials of pharmacist and compounding technician

18. In the Know: True or False USP good compounding practices has standards regarding education of personnel. true Accreditation by the Pharmacy Compounding Accreditation Board is involuntary. false A face mask must be worn when compounding nonsterile products. false A product’s assigned lot number should be included on the compounding log. true

19. Measuring and Compounding Equipment Equipment for weighing – Two-pan balances Class III prescription balance – Capacity of 15 to 120 grams – Should be used to measure no less than 120 mg to maintain acceptable error of less than 5% – Sufficient for infrequent compounding in community pharmacy Counterbalance – Used for weighing larger amounts of materials (up to 5 kg) – Used for measuring bulk products

20. Measuring and Compounding Equipment (continued) Equipment for weighing – Pharmaceutical weights Used on a two-pan balance to offset the ingredient weight Sets contain metric and apothecary weights – Weighing paper Special paper placed on a weighing balance pan to avoid contact between pharmaceutical ingredients and the balance tray Glassine paper used which is coated with paraffin wax

21. Measuring and Compounding Equipment (continued) Equipment for weighing – Class III prescription balance

22. Measuring and Compounding Equipment (continued) Equipment for weighing – Digital electronic analytical balance Uses a single pan, does not need pharmacy weights

23. Measuring and Compounding Equipment (continued) Percentage of error – The acceptable range of variation above and below the target measurement – Based on the least weighable quantity of an ingredient – If sample is too small, margin of error may be unacceptable – Compounded nonsterile preparations must have an error range less than 5% Percentage of error = amount of error X 100 quantity desired Percentage of error = amount of error X 100 quantity desired

24. Measuring and Compounding Equipment (continued) Measuring devices for liquids – Graduated cylinders A glass or polypropylene flask used for measuring liquids Conical and cylindrical shapes, range from 5 mL to more than 1000 mL, calibrated in both metric and apothecary units When measuring liquids with a graduated cylinder, pipette, oral syringe, or dropper, always use the smallest size that can contain the volume to be measured. Doing so minimizes your percentage of error in measurement.

25. Measurement and Compounding Equipment (continued) Measuring devices for liquids

26. Measuring and Compounding Equipment (continued) Measuring devices for liquids

27. Measuring and Compounding Equipment (continued) Measuring devices for liquids – Pipette A long, thin, calibrated hollow tube used for measuring small volumes of liquids Pipette filler or rubber bulb works like a suction device – Oral syringe Used to measure small or large quantities More accurate than graduated cylinders when measuring thick, viscous liquids

28. Measuring and Compounding Equipment (continued) Supplies for mixing and molding ingredients – Mortar and pestle Used for mixing and grinding pharmaceutical ingredients – Beakers and flasks Glassware which store, contain, and mix liquids – Ointment mill Mixes and greatly reduces the particle size of powders used to make ointments or creams – Ointment slab Plate of ground glass used for mixing topical compounds

29. In the Know: Fill in the Blank Measurements of a liquid solution should be taken at the bottom of the _________. meniscus An _____ ________ is more accurate than a graduated cylinder when measuring viscous liquids. oral syringe A _______ and ______ is used for mixing and grinding pharmaceutical ingredients. mortar; pestle

30. Measuring and Compounding Equipment (continued) Supplies for mixing and molding ingredients – Spatula Used for transferring solid pharmaceutical ingredients to and from weighing pans, preparing ointments and creams, transferring the compounded product into its final container – Molds and presses Molds used for making suppositories or troches Presses used to make an implantable urethral pellet of medication

31. Techniques for Mixing Compounded Drugs Comminution and blending – Comminution The act of reducing a substance to fine particles – Blending The act of combining two substances

32. Techniques for Mixing Compounded Drugs (continued) Communition and blending – Techniques include Trituration Levigation Pulverization Spatulation Sifting Tumbling Geometric dilution

33. Techniques for Mixing Compounded Drugs (continued) ProcessDescription of processEquipment used TriturationRubbing, grinding, or pulverizing a substance to create fine particles Mortar and pestle LevigationReducing the particle size of a solid when preparing an ointment by adding a levigating agent Glass mortar or ointment slab PulverizationReducing the particle size by adding a solventMortar and pestle SpatulationCombining and mixing substances with a spatulaSpatula, ointment slab SiftingBlending or combining powders using a sieveMesh sieve, glassine paper TumblingCombining powders by placing them in a bag or container and shaking it Bag, container Geometric dilution method Used for combining several ingredients—successively larger amounts added, equal to the amount in the mortar Mortar and pestle

34. Compounding of Specific Formulations Powders – Powders are combined and mixed by trituration, spatulation, sifting, and tumbling. Tablets and troches – Compression tablets are formed by weighing powders, placing them in a die, then compressing the ingredients. – Rapid-dissolving tablets are formed by mixing powders, placing them in a mold, and then baking them in a convection oven.

35. Compounding of Specific Formulations (continued) Capsules – Capsule filled by “punching” it into a cake of the powder or by using a capsule machine Problem Nystatin powder has an activity of 100,000 units/g. How many milligrams of nystatin would you use in each capsule if the final preparation is supposed to be 1,500,000 units per capsule? Convert 100,000 units/g to units/mg: 100,000 units/g X 1 g/1000 mg = 100 units/mg Determine the amount of milligrams needed in each capsule: X mg = 1 mg 1,500,000 units 100 units x mg = 15,000 mg Problem Nystatin powder has an activity of 100,000 units/g. How many milligrams of nystatin would you use in each capsule if the final preparation is supposed to be 1,500,000 units per capsule? Convert 100,000 units/g to units/mg: 100,000 units/g X 1 g/1000 mg = 100 units/mg Determine the amount of milligrams needed in each capsule: X mg = 1 mg 1,500,000 units 100 units x mg = 15,000 mg

36. Compounding of Specific Formulations (continued) Solutions – Prepared by dissolving the solute in the solvent or diluting existing solutions

37. Compounding of Specific Formulations (continued) Suspensions – Tablets are triturated into a powder, a suspending agent (acacia, carboxymethylcellulose) is added, and then the mixture is dispersed in a liquid vehicle. Regardless of their apparent stability, all suspensions should be dispensed with an auxiliary label stating, “Shake Well.”

38. Compounding of Specific Formulations (continued) Ointments, creams, and lotions – When combining ointments or creams, mix them with a mortar and pestle or an ointment slab. – If dry ingredients are used, triturate to a fine powder then add the powder to the ointment base in small amounts. – If mixing three or more ingredients to the base, add them using the geometric dilution method.

39. Compounding of Specific Formulations (continued) Suppositories – Prepared by melting the base material, adding the active ingredients, pouring the resultant liquid into a mold, and then solidifying at room temperature

40. In the Know: Short Answer What is the term for the process of pulverizing a substance to create fine particles? trituration What is the term for the process of combining powders by placing them in a bag? tumbling Suppositories should be solidified at _____ temperature. room

41. The Compounding Process Pharmacist judges the suitability of the prescription. Pharmacist retrieves and reviews the master control record. Pharmacist prints out a compounding record for the technician. Pharmacist performs calculations and identifies necessary equipment. A medication container label is created. Pharmacy technician uses appropriate protective clothing and hand-washing technique. The Compounding Process Steps 1 through 6 The Compounding Process Steps 1 through 6

42. The Compounding Process (continued) Technician gathers all ingredients, prepares and calibrates equipment. Technician weighs and adds ingredients, initials steps, documents it on compounding record. Technician stores product in a suitable container. Technician affixes medication container label. Pharmacist reviews the compounding record and medication container label, checks the product. Pharmacist signs and dates the compounding log, files it in records, and puts product in storage bin for patient pickup. The Compounding Process Steps 7 through 12 The Compounding Process Steps 7 through 12

43. The Compounding Process (continued) Technician cleans equipment, reshelves ingredients, and properly labels and stores excess product. Pharmacist counsels patient at time of pickup. The Compounding Process Steps 13 and 14 The Compounding Process Steps 13 and 14

44. The Compounding Process (continued) Reimbursement – The majority of the cost of a compounded product is based on the work time of pharmacy personnel, not the ingredients. – Insurance does not immediately cover the cost of a compounded prescription. – If a patient pays out-of-pocket, the compounding pharmacy provides the patient with a Universal Claim Form (UCF), which is then submitted to insurance. – UCF includes NDC numbers, cost of each ingredient, time to prepare.

45. Reference Sources for the Compounding Pharmacy Remington: The Science and Practice of Pharmacy – Standard reference source Professional Compounding Centers of America (PCCA) – Membership entitles the compounding pharmacy to the master formulas – Holds educational and certification seminars Pharmacists’ Pharmacopeia – Published by United States Pharmacopeia (USP) – Contains monographs for more than 120 compounded preparations

46. Reference Sources for the Compounding Pharmacy (continued) Secundum Artem: Current & Practical Compounding Information for the Pharmacist International Academy of Compounding Pharmacists (IACP) – Political action group which promotes personalized medication solutions for patients – Also keeps compounding pharmacy personnel aware of legislative challenges that have an impact on their profession

47. Chapter Summary Nonsterile compounding is used to prepare medications not available commercially. Pharmacies must follow good compounding practices as outlined in USP Chapter. Quality of bulk ingredients is important in compounding a high-quality product. Beyond-use dating must meet USP guidelines. Many compounding pharmacies seek national accreditation for marketing and reimbursement. Pharmacy technicians often need additional training and certification to practice in a compounding pharmacy. Minimum proper attire includes a long lab coat, hairnet, and disposable gloves.

48. Chapter Summary (continued) The compounding log documents the patient-specific prescription. There are a variety of instruments used for nonsterile compounding. Proper technique and the use of correct measuring devices are crucial when weighing and measuring ingredients. Geometric dilution is used when mixing potent or toxic ingredients. Compounding is used to prepare many dosage forms. There are several steps in the compounding process. The pharmacist is legally responsible for the final check and for counseling the patient.