Manufacturing and Compounding of Medications

Transcription

1 Manufacturing and Compounding of Medications Version September 2010 Page 1 of 3

2 Manufacturing and Compounding of Medications Version 1.1 Drug Sector Saudi Food & Drug Authority Kingdom of Saudi Arabia Please visit SFDA s website at for the latest update 1 September 2010 Page 2 of 3

3 Section I- Good Compounding Practices Section II- Pharmaceutical Compounding-Nonsterile Preparations Section III- Pharmaceutical Compounding-Sterile Preparations 1 September 2010 Page 3 of 3

4 Good Compounding Practices Version September 2010 Page 1 of 14

5 TABLE OF CONTENTS : 1. PURPOSE APPLICABLE DEFINITIONS RESPONSIBILITIES OF THE COMPOUNDER TRAINING PROCEDURES AND DOCUMENTATION DRUG COMPOUNDING FACILITIES DRUG COMPOUNDING EQUIPMENT COMPONENT SELECTION PACKAGING AND DRUG PRODUCT CONTAINERS COMPOUNDING CONTROLS LABELING RECORDS AND REPORTS COMPOUNDING VETERINARIAN PRODUCTS COMPOUNDING FOR A PRESCRIBER'S OFFICE USE COMPOUNDING PHARMACY GENERATED PRODUCTS September 2010 Page 2 of 14

6 1 PURPOSE The purpose of this chapter is to provide compounders with guidance on applying good compounding practices for the preparation of compounded formulations for dispensing and/or administration to humans or animals. It is expected that pharmacists or compounders engaged in the compounding of drugs will compound in conformance with applicable compounding laws, regulations, or guidelines. 2 APPLICABLE DEFINITIONS Compounding (see Pharmaceutical Compounding Nonsterile Preparations) Compounding involves the preparation, mixing, assembling, packaging, and labeling of a drug or device in accordance with a licensed practitioner's prescription under an initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice. Compounding includes the following: a. Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns. b. Reconstitution of commercial products that may require the addition of two or more ingredients as a result of a licensed practitioner's prescription drug order. c. Manipulation of commercial products that may require the addition of one or more ingredients as a result of a licensed practitioner's prescription drug order. d. Preparation of drugs or devices for the purposes of, or as an incident to, research, teaching, or chemical analysis. Levels of Compounding Level 1 Nonsterile (topical) Mixing of one or two creams Mixing of creams with alcohol, water, etc. (as per manufacturer's labeling instruction) Level 2 Nonsterile (topical) Preparation of nonsterile topical ointment, cream Preparations with no dosage limitation Level 3 Nonsterile (reconstituting or flavoring) Reconstitution according to manufacturer's 1 September 2010 Page 3 of 14

7 labeling instruction Addition of flavoring Level 4 Sterile (simple injections, e.g., reconstituted for immediate administration) Preparation of injections for immediate administration Level 5 Nonsterile (dosage forms) Preparation of solid oral dosage forms (tablets, capsules) Preparation of liquid oral dosage forms (emulsion, solutions, suspensions, etc.) Preparation of suppositories, lozenges Level 6 Sterile (ophthalmics/otics) Preparation of ophthalmic and otic suspensions, solutions Level 7 Sterile (complex injections) Preparation of injections for many patients Preparation of injection not for immediate administration Preparation of total parenteral nutritions (TPNs) Preparation of multi-component injection Level 8 Other sterile injections and patches Preparation of chemotherapeutic injections or implants Preparation of transdermal medications Level 9 Sterile (radiopharmaceuticals) Preparation of radiopharmaceuticals Manufacturing Manufacturing involves the production, propagation, conversion, or processing of a drug or device, either directly or indirectly, by extraction of the drug from substances of natural origin or by means of chemical or biological synthesis. Manufacturing also includes (1) any packaging or repackaging of the substance(s) or labeling or relabeling of containers for the promotion and marketing of such drugs or devices; (2) any preparation of a drug or device that is given or sold for resale by pharmacies, practitioners, or other persons; (3) the distribution of inordinate amounts of compounded preparations or the copying of commercially available drug products; and (4) the preparation of any quantity of a drug product without a licensed prescriber/patient/licensed pharmacist/compounder relationship. 1 September 2010 Page 4 of 14

8 Component A component is any ingredient used in the compounding of a drug product, including any that are used in its preparation, but may not appear on the labeling of such a product. (for additional definitions See Pharmaceutical Compounding Nonsterile Preparations.) Pharmacy Generated Product (PGP) A pharmacy generated product (PGP) is a product that is prepared, packaged, and labeled in a pharmacy and can be sold by the pharmacy without a prescription. Compounder A compounder is a pharmacist or a physician who is engaged in the act of compounding pursuant to a prescription order by a licensed prescriber. 3 RESPONSIBILITIES OF THE COMPOUNDER a. Compounders who are engaged in drug compounding or nutriceutical compounding shall be proficient in compounding and should continually expand their compounding knowledge by participating in seminars and/or studying appropriate literature. b. A compounder shall be familiar with all of the details of Pharmaceutical Compounding Nonsterile Preparations, Pharmaceutical Compounding Sterile Preparations, and other applicable compounding guidelines or laws. In addition, the compounder shall be responsible for the following: Certifying all prescription orders; Approving or rejecting all components, drug product containers, closures, inprocess materials, and labeling; Preparing and reviewing all compounding records to assure that errors have not occurred in the compounding process; Assuring the proper maintenance, cleanliness, and use of all equipment used in a prescription compounding practice; Assuring that only personnel authorized by the compounding supervisor shall be in the immediate vicinity of the drug compounding operations; Assuring that the drug product and components of drug products are not on the list of drug products that have been withdrawn or removed from the market for public health reasons. 1 September 2010 Page 5 of 14

9 c. The compounder shall ensure that personnel engaged in compounding wear clean clothing appropriate to the type of compounding performed, e.g., coats, gowns, gloves, masks, shoes, aprons, or other items as needed for protection of personnel from chemical exposures and for prevention of drug contamination. d. The compounder shall implement procedures to prevent cross-contamination when compounding with drugs (e.g., penicillins) that require special precaution to prevent crosscontamination. 4 TRAINING All personnel involved in the compounding, evaluation, packaging, and dispensing of compounded preparations shall be properly trained for the type of compounding conducted. All training activities will be covered by appropriate standard operating procedures (SOPs) and documentation. All compounders and all personnel involved in compounding must be well trained and must participate in current, relevant training programs. It is the responsibility of the pharmacist to ensure that a training program has been implemented and that it is ongoing. Standards of pharmacy practice require that all employees be adequately trained in their job functions and that all of the training is properly documented. Steps in the training procedure will include the following: a. All employees involved in pharmaceutical compounding shall read and become familiar with Pharmaceutical Compounding Nonsterile Preparations, Pharmaceutical Compounding Sterile Preparations. b. All employees shall read and become familiar with each of the procedures related to compounding, including those involving the facility, equipment, and personnel, actual compounding, evaluation, packaging, storage, and dispensing. c. The compounder shall meet with employees to review their work and answer any questions the employees may have concerning SOPs. d. The compounder shall demonstrate the procedures for the employee, and will observe and guide the employee throughout the procedure. The employee will then repeat the procedure without any assistance from, but under the supervision of, the pharmacist. e. When the employee has demonstrated to the compounder a verbal and functional knowledge of the procedure, then and only then, will the employee be permitted to perform the procedure without supervision. 1 September 2010 Page 6 of 14

10 f. When the compounder is satisfied with the employee s knowledge and proficiency, the compounder will sign off on the documentation records to show that both the employee and the compounder agree. g. The compounder shall continually monitor the work of the employee and answer any questions the employee may have concerning the SOPs. 5 PROCEDURES AND DOCUMENTATION All significant procedures performed in the compounding area will be covered by SOPs and will be documented. Procedures should be developed for the facility, equipment, personnel, preparation, packaging, and storage of compounded preparations to ensure accountability, accuracy, quality, safety (including access to Material Safety Data Sheets) and uniformity in a compounding practice. More importantly, implementing SOPs establishes procedural consistency and also provides a reference for orientation and training of personnel. Documentation enables a pharmacy, whenever necessary, to systematically trace, evaluate, and replicate the steps included throughout the preparation process of a compounded product. 6 DRUG COMPOUNDING FACILITIES a. Compounding facilities shall have an adequate space that is specifically designated for compounding of prescriptions. This area may include a space for the storage of equipment and materials. b. Sterile compounded preparations shall be compounded in accordance with the provisions in Pharmaceutical Compounding Sterile Preparations and aseptic processes shall be conducted in an area separate and distinct from the area used for the compounding of nonsterile products. c. The areas used for compounding shall be maintained in clean, orderly, and sanitary conditions. d. The areas for drug compounding shall be maintained in a good state of repair. The plumbing system shall be free of defects that could contribute to contamination of any 1 September 2010 Page 7 of 14

11 compounded product. Adequate washing facilities shall be easily accessible to the compounding areas. Such facilities shall include, but not be limited to, hot and cold water, soap or detergent, and an air-drier or single-use towels. e. Potable water shall be supplied under continuous positive pressure. f. The area for compounding shall have adequate lighting and ventilation. g. The area for compounding shall be free of infestation by insects, rodents, and other vermin. Trash shall be held and disposed of in a sanitary and timely manner. h. Sewage and other refuse in the area of compounding shall be disposed of in a safe and sanitary manner. i. Bulk drugs and other chemicals or materials used in the compounding of drugs must be stored as directed by the manufacturer, or according to USP monograph requirements, in a clean, dry area (defined temperature condition), or in a refrigerator or freezer as specified. The bulk chemicals shall be stored in a manner such that they are protected from contamination. All containers shall be properly labeled. j. If parenteral products are compounded, the compounder shall refer to Pharmaceutical Compounding Sterile Preparations for compounding technique applications. 7 DRUG COMPOUNDING EQUIPMENT (See also Pharmaceutical Compounding Nonsterile Preparations.) a. The equipment or utensils used for compounding of a drug product shall be of appropriate design and capacity. The equipment shall be stored in such a manner as to protect it from contamination, and shall be located in such a place as to facilitate operations for its use, maintenance, and cleaning. b. The equipment shall be cleaned and sanitized prior to use to prevent contamination that may affect the safety or quality of compounded preparations. c. The equipment shall be of suitable composition such that the surfaces that contact components are neither reactive, additive, nor absorptive and therefore will not affect or alter the purity of the compounded preparations. d. Automated, mechanical, electronic, and other types of equipment used in compounding shall be routinely inspected, calibrated as necessary, and checked to ensure proper performance. 1 September 2010 Page 8 of 14

12 e. Immediately prior to initiation of compounding operations, the equipment shall be inspected by the compounder to determine its suitability for use. f. The equipment shall be cleaned appropriately using special instructions when crosscontaminating products or products requiring special precaution, e.g., antibiotics, cytotoxins, cancer drugs, and other hazardous materials, are used with the equipment. If possible, special equipment may be dedicated for such use or if the same equipment is being used for all drug products, appropriate procedures must be in place to allow meticulous cleaning of equipment prior to use with other drugs. 8 COMPONENT SELECTION REQUIREMENTS a. The compounder shall first attempt to use USP NF drug substances manufactured in a Ministry of health (MOH)-registered facility. b. The compounder shall also first attempt to use inactive components manufactured in an MOH-registered facility. c. If components are not obtainable from an FDA-registered facility or if the FDA and/or the providing company cannot document FDA registration, compounders shall use their professional judgment in first receiving, storing, or using the components that meet official compendial requirements or are provided by another high quality source. d. If components of compendial quality are not obtainable, components of high quality such as those that are chemically pure, analytical reagent grade, American Chemical Societycertified, or Food Chemical Codex grade may be used. e. When a component is not obtained from an official compendial source or is not obtainable from the sources mentioned above, the component may be obtained from a source deemed acceptable and reliable in the professional judgment of the compounder. f. When a component is derived from ruminant animals (e.g., bovine, caprine, ovine) the supplier shall provide written assurance that these animals were born, raised, or slaughtered in countries where bovine spongiform encephalopathy (BSE) and scrapie are known not to exist. g. The compounder shall not use components that are listed by FDA to be withdrawn from the market for public health reasons. 1 September 2010 Page 9 of 14

13 h. Components shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first. 9 PACKAGING AND DRUG PRODUCT CONTAINERS a. The compounder shall ensure that the containers and container closures used in packaging the compounded preparations meet the international requirements. b. The compounder shall obtain written records from the supplier to show that the containers meet USP requirements. c. Containers and container closures intended for compounding of sterile preparations and nonsterile preparations must be handled, sterilized (if appropriate), and stored as described in Pharmaceutical Compounding Sterile Preparations and Pharmaceutical Compounding Nonsterile Preparations. The use of commercially available presterilized containers may be considered. d. The containers and closures shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest approved stock is used first. e. The containers and container closures shall be stored in such a way as to permit inspection and cleaning of the work area. f. The containers and container closures shall be made of clean materials that are neither reactive, additive, nor absorptive. g. The containers and closures shall be of suitable material so as not to alter the quality, strength, or purity of the compounded drug. h. The compounder shall ensure that the containers and container closures selected to dispense the finished compounded prescription, whether sterile or nonsterile or radiopharmaceutical, meet the criteria in sections (a) (f) above. 10 COMPOUNDING CONTROLS a. The compounder shall ensure that there are written procedures for the compounding of drug products to assure that the finished products have the identity, strength, quality, and purity that they purport to have. 1 September 2010 Page 10 of 14

14 b. The compounder shall establish procedures for listing components, their amounts (weight or volume), the order of component mixing, and a description of the compounding process. c. The compounder shall list all equipment, utensils, and container closure systems relevant to the sterility, stability, and intended use of a drug. d. The written procedures described above shall be followed in execution of the compounding process. e. The compounder shall accurately weigh, measure, and subdivide as appropriate. f. The compounder shall check and recheck each procedure at each stage of the process to ensure that each weight or measure is correct as stated in the written compounding procedures. g. If a component is transferred from the original container to another container (e.g., a powder is taken from the original container, weighed, placed in a container, and stored in that other container), the new container shall be identified with the component name, weight or measure, the lot or control number, the expiration or beyond-use date, and the transfer date. h. The compounder shall have drug compounding procedures available in either written form or electronically stored with printable documentation. i. The procedures shall include a description of (1) the components, their amounts, the order of component additives, and the compounding process; (2) the required equipment and utensils; and (3) the drug product container and closure system. j. The compounder shall have established written procedures that will describe the tests or examinations to be conducted on the product compounded (e.g., the degree of weight variation among capsules) to assure uniformity and integrity of compounded drug products. k. Appropriate control procedures shall be established to monitor the output and to validate the performance of those compounding processes that may be responsible for causing variability in the final compounded preparations. Factors that may cause variability include (1) capsule weight variation; (2) adequacy of mixing to assure uniformity and homogeneity; and (3) clarity, completeness, or ph of solutions. l. Appropriate written procedures shall be designed to prevent microbiological contamination of compounded drug products purporting to be sterile, and these procedures shall be 1 September 2010 Page 11 of 14

15 followed. Such procedures shall include validation of sterilization processes (see Pharmaceutical Compounding Sterile Preparations). m. The compounder shall establish appropriate beyond-use dates determined either from available USP NF monographs, appropriate testing, or from peer-reviewed literature. n. The compounder shall adopt appropriate storage requirements as provided in Preservation, Packaging, Storage, and Labeling under General Notices and Requirements. 11 LABELING 1. Products prepared in anticipation of a prescription prior to receiving a valid prescription should not be prepared in an inordinate amount. A regularly used amount should be prepared on the basis of a history of prescriptions filled by the pharmacy. These products shall be labeled or documentation referenced with the following: a. A complete list of ingredients or preparation name and reference or established name or distinct common name b. Dosage form c. Strength d. Preparation date e. Name and address of compounder f. Inactive ingredients g. Batch or lot number h. Assigned beyond-use date, based on published data, or appropriate testing, or USP NF standards. Storage conditions for these products shall be dictated by their composition and sterility, e.g., stored in a clean, dry place (defined temperature condition), in a refrigerator, or at controlled room temperature. 2. The compounder shall examine the product for correct labeling after completion of the compounding process. 1 September 2010 Page 12 of 14

16 3. The compounder's prescription label shall contain the following: a. Patient's name b. Prescriber's name c. Name and address of compounder d. Prescription number e. Established name or distinct common name (cannot use trademarked name of a manufactured product) f. Strength g. Statement of quantity h. Directions for use i. Date filled j. Beyond-use date/storage, etc. k. An appropriate designation that this is a compounded prescription 4. The compounder shall label any excess compounded products so as to reference them to the formula used, the assigned control number, and beyond-use date based on the compounder's appropriate testing, published data, or USP NF standards. 12 RECORDS AND REPORTS a. The compounder shall maintain records, including but not limited to, the hard copy of the prescription to indicate that the prescription is compounded. b. The compounder shall keep adequate records of controlled drug substances (scheduled drugs) used in compounding. c. All records of all compounded products shall be kept for a period of time as set forth in the MOH laws or regulations. Such records shall be readily available for authorized inspection. 13 COMPOUNDING FOR A PRESCRIBER'S OFFICE USE a. Compounders may prepare compounded drug products for a prescriber's office use pursuant to MOH requirements. b. An order by the prescriber indicating the formula and quantity ordered may be filled in the compounder's facility. 1 September 2010 Page 13 of 14

17 c. The compounder shall compound the product for the purpose of administration by or for the prescriber. d. A record of the compounding process shall be maintained. e. A label may be generated and a number may be assigned. 14 COMPOUNDING VETERINARIAN PRODUCTS a. Compounders shall compound prescriptions for animals on the basis of prescription orders. b. These prescriptions shall be handled and filled as are human prescriptions. 15 COMPOUNDING PHARMACY GENERATED PRODUCTS a. Compounders may prepare compounded drug products that can be sold without a prescription. b. Pharmacy generated products (PGP) shall be compounded using the same procedures as those for prescription drug products detailed in this chapter. 1 September 2010 Page 14 of 14

18 Pharmaceutical Compounding Nonsterile Preparations Version 1.1

19 Table of Contents 1 PURPOSE BACKGROUND DEFINITIONS POLICY AND PROCEDURE PERSONNEL (QUALIFICATION & EVALUATION) SPACE & STORE EQUIPMENTS & FACILITY INGREDIENTS SELECTION SOURCES COMPOUNDING NONDRUG REQUIREMENTS CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY, AND PURITY COMPOUNDED PREPARATIONS CAPSULES, POWDERS, LOZENGES, AND TABLETS EMULSIONS, SOLUTIONS, AND SUSPENSIONS SUPPOSITORIES CREAMS, TOPICAL GELS, OINTMENTS, AND PASTES COMPOUNDING PROCESS COMPOUNDING RECORDS AND DOCUMENTS FORMULATION RECORD COMPOUNDING RECORD MSDS FILE QUALITY CONTROL VERIFICATION PATIENT COUNSELING PACKAGING STERILITY STABILITY OF COMPOUNDED PREPARATIONS STABILITY CRITERIA AND BEYOND-USE DATING September 2010 Page 2 of 11

20 1 PURPOSE For the purposes of this chapter, the pharmacist or other licensed health care professional responsible for preparing the compounded preparations is referred to as compounder. Compounding is an integral part of pharmacy practice and is essential to the provision of health care. The purpose of this chapter and applicable monographs on formulation is to help define what constitutes good compounding practices and to provide general information to enhance the compounder s ability in the compounding facility to extemporaneously compound preparations that are of acceptable strength, quality, and purity. Compounding is different from manufacturing, which is guided by GMPs. Some of the characteristics or criteria that differentiate compounding from manufacturing include the existence of specific practitioner patient compounder relationships; the quantity of medication prepared in anticipation of receiving a prescription or a prescription order; and the conditions of sale, which are limited to specific prescription orders. The pharmacist s responsibilities in compounding drug preparations are to dispense the finished preparation in accordance with a prescription or a transcriber s order or intent and to dispense those preparations in compliance with the requirements established by Saudi health regulations. Compounders must be familiar with regulations that govern compounding. The compounder is responsible for compounding preparations of acceptable strength, quality, and purity with appropriate packaging and labeling in accordance with good compounding practices (see Good Compounding Practices), official standards, and relevant scientific data and information. Compounders engaging in compounding should have to continually expand their compounding knowledge by participating in seminars, studying appropriate literature, and consulting colleagues. 2 BACKGROUND This chapter provides procedures and requirements for compounding none sterile preparations 3 DEFINITIONS For purposes of this chapter, the following terms shall have these meanings. PREPARATION is a drug dosage form, a dietary supplement, or a finished device. It is the finished or partially finished preparation of one or more substances formulated for use on or for the patient or consumer (see General Notices and Requirements). OFFICIAL SUBSTANCE includes an active drug entity, a dietary supplement, or a pharmaceutical ingredient or a component of a finished device. ACTIVE INGREDIENT usually refers to chemicals, substances, or other components of articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in humans or other animals or for use as dietary supplements. ADDED SUBSTANCES are ingredients that are necessary to prepare the preparation but are not intended or expected to cause a human pharmacologic response if administered alone in the amount or concentration contained in a single dose of the compounded preparation. The term added substances is 1 September 2010 Page 3 of 11

21 usually used synonymously with the terms inactive ingredients, excipients, and pharmaceutical ingredients. 4 POLICY AND PROCEDURE Adequate procedures and records must exist for investigating and correcting failures or problems in compounding, testing, or in the preparation itself. 5 PERSONNEL (QUALIFICATION & EVALUATION) The compounder is responsible for ensuring that the quality is built into the compounded preparations of products, with key factors including at least the following general principles. (See also Good Compounding Practices ) 1. Personnel are capable and qualified to perform their assigned duties. 2. Ingredients used in compounding have their expected identity, quality, and purity. 3. Compounded preparations are of acceptable strength, quality, and purity, with appropriate packaging and labeling, and prepared in accordance with good compounding practices, official standards, and relevant scientific data and information. 4. Critical processes are validated to ensure that procedures, when used, will consistently result in the expected qualities in the finished preparation. 5. The compounding environment is suitable for its intended purpose. 6. Appropriate stability evaluation is performed or determined from the literature for establishing reliable beyond-use dating to ensure that the finished preparations have their expected potency, purity, quality, and characteristics, at least until the labeled beyond-use date. 7. There is assurance that processes are always carried out as intended or specified and are under control. 8. Compounding conditions and procedures are adequate for preventing errors. 6 SPACE & STORE Areas designated for compounding have adequate space for the orderly placement of equipment and materials to prevent mixups between ingredients, containers, labels, in-process materials, and finished preparations. The compounding area is also to be designed, arranged, used, and maintained to prevent adventitious cross-contamination. Areas used for sterile preparations are to be separated and distinct from the nonsterile compounding area Pharmaceutical Compounding Sterile Preparations). The entire compounding area is to be well-lighted. Heating, ventilation, and air conditioning systems are to be controlled to avoid decomposition of chemicals. Storage areas provide an environment suitably controlled to ensure quality and stability of bulk chemicals and finished preparations. Potable water is to be supplied for hand and equipment washing. Purified Water must be used for compounding nonsterile drug preparations when formulations indicate the inclusion of water. Purified Water must also be used for rinsing equipment and utensils. In those cases when a water is used to prepare a sterile preparation, Water for Injection, Sterile Water for Injection, or Bacteriostatic Water for Injection must be used (see Pharmaceutical Compounding Sterile Preparations). 1 September 2010 Page 4 of 11

22 Compounding areas are to be maintained in a clean and sanitary condition. Adequate washing facilities are to be provided, including hot and cold water, soap or detergent, and air driers or single-service towels. Sewage, trash, and other refuse in the compounding area is to be disposed of in a safe, sanitary, and timely manner. Equipment is to be thoroughly cleaned promptly after use to avoid cross-contamination of ingredients and preparations. Special precautions are to be taken to clean equipment and compounding areas meticulously after compounding preparations that contain allergenic ingredients (e.g., sulfonamides or penicillins). 7 EQUIPMENTS & FACILITY Equipment is to be of appropriate design and size for compounding and suitable for the intended uses. The types and sizes of equipment will depend on the dosage forms and the quantities compounded (see equipment manufacturers instruction manuals). All equipment is to be constructed so that surfaces that contact pharmaceutical components, in-process materials, or finished preparations are not reactive, additive, or adsorptive to avoid altering the safety, identity, strength, quality, or purity of the preparation. The use of micropipets, electronic or analytical balances, or triturations or dilutions shall be considered when needed quantities are too small to accurately measure. Equipment and accessories used in compounding are to be inspected, maintained, cleaned, and validated at appropriate intervals to ensure the accuracy and reliability of their performance. 8 INGREDIENTS SELECTION 8.1 SOURCES Official compounded preparations are prepared from ingredients that meet requirements of the compendial monograph for those individual ingredients for which monographs are provided. A USP or an NF grade substance is the preferred source of ingredients for compounding all other preparations. If that is not available, or when food, cosmetics, or other substances are or must be used, then the use of another high-quality source, such as analytical reagent (AR), certified American Chemical Society (ACS), or Food Chemicals Codex (FCC) grade, is an option for professional judgment. For any substance used in compounding not purchased from a registered drug manufacturer, the compounder must establish purity and safety by reasonable means, which may include lot analysis, manufacturer reputation, or reliability of source. A manufactured drug product may be a source of active ingredient. Only manufactured drugs from containers labeled with a batch control number and a future expiration date are acceptable as a potential source of active ingredients. When compounding with manufactured drug products, the compounder must consider all ingredients present in the drug product relative to the intended use of the compounded preparation. A compounder may not compound a drug preparation that appears on the list of drug products withdrawn or removed from the market for safety reasons. 8.2 COMPOUNDING NONDRUG REQUIREMENTS If the preparation is intended for use as a dietary or nutritional supplement (to supplement the diet) or cosmetic (e.g., to beautify), then the compounder must adhere to Good Compounding Practices and to this chapter, and must comply with any Ministry of health requirements. 1 September 2010 Page 5 of 11

23 9 CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY, AND PURITY The following questions are to be considered carefully before compounding. 1. Have the physical and chemical properties and medicinal, dietary, and pharmaceutical uses of the drug substances been reviewed? 2. Are the quantity and quality of each active ingredient identifiable? 3. Will the active ingredients be effectively absorbed, locally or systemically according to the prescribed purpose, from the preparation and route of administration? 4. Are there added substances (see Definitions), confirmed or potentially present from manufactured products, that may be expected to cause an allergic reaction, irritation, toxicity, or undesirable organoleptic response from the patient? Are there added substances (see Definitions), confirmed or potentially present, that may be unfavorable (e.g., unsuitable ph or inadequate solubility)? 5. Were all calculations and measurements confirmed to ensure that the preparation would be compounded accurately? 10 COMPOUNDED PREPARATIONS The term compounded preparations includes the terms compounded dosage forms, compounded drugs, and compounded formulations, and means finished forms that are prepared by or under the direct supervision of a licensed compounder. When controlled substances are used, check the Ministry of Heath policies. Unless otherwise indicated or appropriate, compounded preparations are to be prepared to ensure that each preparation shall contain not less than 90.0% and not more than 110.0% of the theoretically calculated and labeled quantity of active ingredient per unit weight or volume and not less than 90.0% and not more than 110.0% of the theoretically calculated weight or volume per unit of the preparation. Compounded preparations include, but are not restricted to, the following pharmaceutical dosage forms described under 10.1 CAPSULES, POWDERS, LOZENGES, AND TABLETS When compounding these dosage forms, the compounder is to prepare an amount of the total formulation sufficient to allow the prescribed amount or quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following: Reducing solid ingredients to the smallest reasonable particle size; Implementing appropriate checks to ensure that all ingredients are blended to achieve a homogeneous mixture; Monitoring humidity if moisture might cause hydrolysis, dosage form adhesion to containers, or softening or partial dissolution of capsule shells; Accurately performing weightings to ensure that each unit shall be not less than 90% and not more than 110% of the theoretically calculated weight for each Packaging dosage units according to container specifications for capsules and tablets of the specific active ingredient unless specified otherwise in individual monographs 1 September 2010 Page 6 of 11

24 10.2 EMULSIONS, SOLUTIONS, AND SUSPENSIONS When compounding these dosage forms, the compounder is to prepare a 2% to 3% excess amount of the total formulation to allow the prescribed amount to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following. For single-unit containers, the weight of each filled container, corrected for tare weight, shall be the equivalent of not less than 100% and not more than 110% of the labeled volume. Aqueous suspensions are prepared by levitating the powder mixture to a smooth paste with an appropriate wetting agent. This paste is converted to a free-flowing fluid by adding adequate vehicle. Successive portions of the vehicle are used to wash the mortar, or other vessel, to transfer the suspension quantitatively to a calibrated dispensing bottle or graduate. The preparation may be homogenized to ensure a uniform final dispersion. Reducing solid ingredients to the smallest reasonable particle size. Solutions shall contain no visible undissolved matter when dispensed. [NOTE An exception may occur with supersaturated solutions such as Potassium Iodide Oral Solution.] Emulsions and suspensions are labeled, Shake well before using SUPPOSITORIES When compounding suppositories, the compounder is to prepare an excess amount of total formulation to allow the prescribed quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following: Not using ingredients that are caustic or irritating, and thoroughly comminute solids that are abrasive to the mucous membranes; Selecting a base that allows active ingredients to provide the intended local or systemic therapeutic effect; Reducing solid ingredients to the smallest reasonable particle size; and Weighing a representative number of suppositories to ensure that each is not less than 90% and not more than 110% of the average weight of all suppositories in the batch CREAMS, TOPICAL GELS, OINTMENTS, AND PASTES When compounding semisolid dosage forms, the compounder is to prepare an excess amount of total formulation to allow the prescribed quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following: Not using ingredients that are caustic, irritating, or allergenic to the skin or other application sites unless they are necessary for a treatment; Selecting a base or vehicle that allows active ingredients to provide the intended local or systemic therapeutic effect; Reducing solid ingredients to the smallest reasonable particle size; Geometrically incorporating the active ingredients with the added substances to achieve a uniform liquid or solid dispersion in the dosage form; and observing the uniformity of the dispersion by spreading a thin film of finished formulation on a flat transparent surface. 1 September 2010 Page 7 of 11

25 11 COMPOUNDING PROCESS The compounders are to consider using the following steps to minimize error and maximize the prescriber s intent. 1. Judge the suitability of the prescription to be compounded in terms of its safety and intended use. Determine what legal limitations, if any, are applicable. 2. Perform necessary calculations to establish the amounts of ingredients needed 3. Identify equipment needed. 4. put-on the proper attire and wash hands. 5. Clean the compounding area and needed equipment. 6. Only one prescription should be compounded at one time in a specified compounding area. 7. Assemble all necessary materials to compound the prescription. 8. Compound the preparation following the formulation record or prescription (see Compounding Records and Documents below), according to the art and science of pharmacy. 9. Assess weight variation, adequacy of mixing, clarity, odor, color, consistency, and ph as appropriate. 10. Annotate the compounding log, and describe the appearance of the formulation. 11. Label the prescription containers to include the following items: a) the name of the preparation; b) the internal identification number; c) the beyond-use date (see Beyond-Use Labeling); d) the initials of the compounder who prepared the label; e) any storage requirements; 12. Sign and date the prescription affirming that all procedures were carried out to ensure uniformity, identity, strength, quantity, and purity. 13. Thoroughly and promptly clean all equipment, and store properly. 12 COMPOUNDING RECORDS AND DOCUMENTS All compounders who dispense prescriptions must comply with the the applicable record keeping requirements. If the compounder compounds a preparation according to the manufacturer s labeling instructions, then further documentation is not required. All other compounded preparations require further documentation. Such compounding documents are to list the ingredients and the quantity of each in the order of the compounding process. The objective of the documentation is to allow another compounder to reproduce the identical prescription at a future date. The formulation record provides a consistent source document for preparing the preparation (recipe), and the compounding record documents the actual ingredients in the preparation and the person responsible for the compounding activity. These records are to be retained for the same period of time that is required for any prescription under MOH laws. The record may be a copy of the prescription in written or machine readable form that includes a formulation record, a compounding record, and a Material Safety Data Sheets (MSDS) file FORMULATION RECORD The formulation record is a file of individually compounded preparations. This record must list the name, strength, and dosage form of the preparation compounded, all ingredients and their quantities, equipment needed to prepare the preparation, when appropriate, and mixing instructions. Mixing instructions should include the order of mixing, mixing temperatures or other environmental controls, such as the duration of mixing, and other factors pertinent to the replication of the preparation as compounded. The formulation 1 September 2010 Page 8 of 11

26 record must include an assigned beyond-use date; the container used in dispensing, the storage requirements, and any quality control procedures COMPOUNDING RECORD The compounding record contains documentation of the name and strength of the compounded preparation, the formulation record reference for the preparation, and the sources and lot numbers of ingredients. The compounding record also includes information on the total number of dosage units compounded, the name of the person who prepared the preparation and the name of the compounder who approved the preparation, the date of preparation, the assigned internal identification number or the prescription number and an assigned beyond-use date, and the prescription number. For all compounded preparations, results of quality control procedures are to be recorded (e.g., weight range of filled capsules) MSDS FILE MSDS are to be readily accessible to all employees working with drug substances or bulk chemicals located on the compounding facility premises. Employees are to be instructed on how to retrieve and interpret needed information. 13 QUALITY CONTROL The safety, quality, and performance of compounded preparations depend on correct ingredients and calculations, accurate and precise measurements, appropriate formulation conditions and procedures, and prudent pharmaceutical judgment. As a final check, the compounder is to review each procedure in the compounding process. To ensure accuracy and completeness, the compounder is to observe the finished preparation to ensure that it appears as expected and is to investigate any discrepancies and take appropriate corrective action before the prescription is dispensed to the patient (see the Checklist for Acceptable Strength, Quality, and Purity, the appropriate pharmaceutical dosage form under Compounded Preparations, and the steps under Compounding Process). 14 VERIFICATION Compounding procedures that are routinely performed, including batch compounding, shall be completed and verified according to written procedures. The act of verification of a compounding procedure involves checking to ensure that calculation, weighing and measuring, order of mixing, and compounding techniques were appropriate and accurately performed. 15 PATIENT COUNSELING The patient or the patient's agent should be counseled about proper use, storage, and evidence of instability in the compounded preparation at the time of dispensing 1 September 2010 Page 9 of 11

27 16 PACKAGING Compounded preparations should be packaged in containers meeting USP. The container used depends on the physical and chemical properties of the compounded preparation. Container drug interaction is to be considered with substances such as phenolic compounds and sorptive materials (e.g., polypeptides and proteins). 17 STERILITY Assurance of sterility in a compounded sterile preparation is mandatory. Compounding and packaging of sterile drugs, such as ophthalmic solutions, will require strict adherence to guidelines presented in the Pharmaceutical Compounding Sterile Preparations and in the manufacturers labeling instructions. 18 STABILITY OF COMPOUNDED PREPARATIONS Stability is defined as : the extent to which a preparation retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of compounding. The compounder must avoid formulation ingredients and processing conditions that would result in a potentially toxic or ineffective preparation. The compounder s knowledge of the chemical reactions by which drugs degrade provides a means for establishing conditions under which the rate of degradation is minimized. The factors that influence the stability of compounded preparations are generally the same as those for manufactured drug products. 19 STABILITY CRITERIA AND BEYOND-USE DATING The beyond-use date is the date after which a compounded preparation is not to be used and is determined from the date the preparation is compounded. Because compounded preparations are intended for administration immediately or following short-term storage, their beyond-use dates may be assigned based on criteria different from those applied to assigning expiration dates to manufactured drug products. Compounders are to consult and apply drug-specific and general stability documentation and literature when available, and are to consider the nature of the drug and its degradation mechanism, the container in which it is packaged, the expected storage conditions, and the intended duration of therapy when assigning a beyond-use date. Beyond-use dates are to be assigned conservatively. When using manufactured solid dosage forms to prepare a solution or aqueous suspension, the compounder is also to consider factors such as hydrolysis and the freezethaw property of the final preparation before assigning a beyond-use date. In assigning a beyond-use date for a compounded drug preparation, in addition to using all available stability information, the compounder is also to use his or her pharmaceutical education and experience. 1 September 2010 Page 10 of 11

28 When a manufactured product is used as the source of active ingredient for a nonsterile compounded preparation, the product expiration date cannot be used to extrapolate directly a beyond-use date for the compounded preparation. However, a compounder may refer to the literature or to the manufacturer for stability information. The compounder may also refer to applicable publications to obtain stability, compatibility, and degradation information on ingredients. All stability data must be carefully interpreted in relation to the actual compounded formulation. At all steps in the compounding, dispensing, and storage process, the compounder is to observe the compounded drug preparation for signs of instability. However, excessive chemical degradation and other drug concentration loss due to reactions may be invisible more often than they are visible. In the absence of stability information that is applicable to a specific drug and preparation, the following maximum beyond-use dates are recommended for nonsterile compounded drug preparations that are packaged in tight, light-resistant containers and stored at controlled room temperature unless otherwise indicated. For Nonaqueous Liquids and Solid Formulations o Where the Manufactured Drug Product is the Source of Active Ingredient The beyonduse date is not later than 25% of the time remaining until the product s expiration date or 6 months, whichever is earlier. o Where a USP or NF Substance is the Source of Active Ingredient The beyond-use date is not later than 6 months. o For Water-Containing Formulations (prepared from ingredients in solid form) The beyond-use date is not later than 14 days for liquid preparations when stored at cold temperatures between 2 and 8 C (36 and 46 F). o For All Other Formulations The beyond-use date is not later than the intended duration of therapy or 30 days, whichever is earlier. These beyond-use date limits may be exceeded when there is supporting valid scientific stability information that is directly applicable to the specific preparation (i.e., the same drug concentration range, ph, excipients, vehicle, water content, etc.). 1 September 2010 Page 11 of 11

29 Pharmaceutical Sterile Compounding Version 1.1

30 Table of Contents 1 INTRODUCTION OBJECTIVE DEFINITION CONTAMINATION RISK LEVELS SOURCES OF CONTAMINATION: LOW-RISK LEVEL CSPS MEDIUM-RISK LEVEL CSPS HIGH-RISK LEVEL CSPS STERILIZATION PROCESS: STERILIZATION BY FILTRATION STEAM STERILIZATION POLICY & PROCEDURS PERSONNEL PERSONNEL REQUIREMENTS PERSONNEL RESPONSIBILITIES STANDARD OPERATION PROCEDURE COMPOUNDING PROCESS INSPECTION OF FINISHED CSPS LABELING STABILITY AND BEYOND USE DATE PACKAGE, HANDLING, AND TRANSPORTATION STORAGE DESTRUCTION QUALITY ASSURANCE LIST OF REFERENCES APPENDIX September 2010 Page 2 of 26