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

31 1 INTRODUCTION This section is written to be a reference for the Compounding of Sterile Products (CSPs) to facilitate practitioners understanding of the fundamental accuracy and quality practices of CSPs. The content of this section applies to all facilities in which CSPs are prepared, stored, and dispensed including public hospitals and private sectors in the Kingdom of Saudi Arabia. The Saudi Food and Drug Authority is responsible to implement these regulations. 2 OBJECTIVE To standardize the CSPs to avoid all harms resulting from microbial contamination, excessive bacterial endotoxins, mixing errors of correct ingredients and errors of mixing incorrect ingredients. Also, to understand the CSPs requirements for cleaner facilities, specific personnel training on principles and practices of aseptic manipulations, air quality evaluation and maintenance, knowledge of sterilization tests and solution stability principles and practices. 3 DEFINITION CSPs include: a. Preparations prepared according to the manufacturer s labeled instructions and other manipulations when manufacturing sterile products that expose the original contents to potential contamination. b. Preparations containing nonsterile ingredients or employing nonsterile components and devices that must be sterilized before administration. c. Biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals that possess either of the above two characteristics, and which include, but are not limited to, baths and soaks for live organs and tissues, implants, inhalations, injections, powders for injection, irrigations, metered sprays, and ophthalmic and otic preparations. 4 CONTAMINATION RISK LEVELS This section provides a foundation for the development and implementation of essential procedures for the safe preparation of CSP s in the three risk levels (low, medium, or high), which are classified according to the potential for microbial (microbial organisms, spores, and endotoxins); and chemical, and physical contamination (foreign chemicals and physical matter) 1 September 2010 Page 3 of 26

32 4.1 SOURCES OF CONTAMINATION: Potential sources of contamination include, but are not limited to: a. Solid and liquid matter from compounding personnel and objects. b. Nonsterile components employed and incorporated before terminal sterilization. c. Inappropriate conditions within the restricted compounding environment. d. Prolonged presterilization procedures with aqueous preparations. e. Nonsterile dosage forms used to compound CSPs. The characteristics described below for low-risk, medium-risk, and high-risk CSPs are intended as a guide to the breadth and depth of care necessary in compounding, but they are neither exhaustive nor prescriptive. The licensed health care professionals who supervise compounding are responsible for determining the procedural and environmental quality practices and attributes that are necessary for the risk level they assign to specific CSPs. These risk levels apply to the quality of CSPs immediately after the final aseptic mixing or filling or immediately after the final sterilization, unless precluded by the specific characteristics of the preparation, such as lipid-based emulsions where administration must be completed within 12 hours of preparation. Upon subsequent storage and shipping of freshly finished CSPs, an increase in the risks of chemical degradation of ingredients, contamination from physical damage to packaging, and permeability of plastic and elastomeric packaging is expected. In such cases, compounding personnel consider the potential additional risks to the integrity of CSPs when assigning beyonduse dates. The pre-administration exposure duration and temperature limits specified in the following lowrisk, medium-risk, and high-risk level sections apply in the absence of direct testing results or appropriate information sources that justify different limits for specific CSPs. (For a summary of the criteria according to risk levels, please see the Appendix) 4.2 LOW-RISK LEVEL CSPS CSPs compounded under all of the following conditions are at a low risk of contamination: a. The CSPs are compounded with aseptic manipulations entirely within ISO Class 5 or better air quality using only sterile ingredients, products, components, and devices. b. The compounding involves only transfer, measuring, and mixing manipulations with closed or sealed packaging systems that are performed promptly and attentively. c. Manipulations are limited to aseptically opening ampuls, penetrating sterile stoppers on vials with sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile administration devices and packages of other sterile products. d. For a low-risk preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 48 hours at controlled room temperature for not more than 14 days at a cold temperature, and for 45 days in solid frozen state at 20º or colder. 1 September 2010 Page 4 of 26

33 Examples of Low-Risk Compounding: a. Single transfers of sterile dosage forms from ampuls, bottles, bags, and vials using sterile syringes with sterile needles, other administration devices, and other sterile containers. The contents of ampuls require sterile filtration to remove any glass particles. b. Manually measuring and mixing no more than three manufactured products to compound drug admixtures and nutritional solutions. 4.3 MEDIUM-RISK LEVEL CSPS When CSPs are compounded aseptically under Low-Risk Conditions, and one or more of the following conditions exists, such CSPs are at a medium risk of contamination: a. Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient on multiple occasions. b. The compounding process includes complex aseptic manipulations other than the singlevolume transfer. c. The compounding process requires unusually long duration, such as that required to complete dissolution or homogeneous mixing. d. The sterile CSPs do not contain broad-spectrum bacteriostatic substances, and they are administered over several days (e.g., an externally worn or implanted infusion device). e. For a medium-risk preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 30 hours at controlled room temperature, for not more than 7 days at a cold temperature, and for 45 days in solid frozen state at 20º or colder. Examples of Medium-Risk Compounding: a. Compounding of total parenteral nutrition fluids using manual or automated devices during which there are multiple injections, detachments, and attachments of nutrient source products to the device or machine to deliver all nutritional components to a final sterile container. b. Filling of reservoirs of injection and infusion devices with multiple sterile drug products and evacuation of air from those reservoirs before the filled device is dispensed. c. Filling of reservoirs of injection and infusion devices with volumes of sterile drug solutions that will be administered over several days at ambient temperatures between 25º and 40º d. Transfer of volumes from multiple ampoules or vials into a single, final sterile container or product. 1 September 2010 Page 5 of 26

34 4.4 HIGH-RISK LEVEL CSPS CSPs compounded under any of the following conditions are either contaminated or at a high risk to become contaminated with infectious microorganisms: a. Nonsterile ingredients, including manufactured products for routes of administration other than those listed under C in the definition are incorporated or a nonsterile device is employed before terminal sterilization. b. Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to ISO Class 5. This includes storage in environments inferior to ISO Class 5 of opened or partially used packages of manufactured sterile products that lack antimicrobial preservatives. c. Nonsterile preparations are exposed for at least 6 hours before being sterilized. d. It is assumed, and not verified by examination of labeling and documentation from suppliers or by direct determination, that the chemical purity and content strength of ingredients meet their original or compendial specifications in unopened or in opened packages of bulk ingredients 1. e. For a high-risk preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 24 hours at controlled room temperature, for not more than 3 days at a cold temperature, and for 45 days in solid frozen state at 20º or colder. All nonsterile measuring, mixing, and purifying devices are rinsed thoroughly with sterile, pyrogen-free water, and then thoroughly drained or dried immediately before use for high-risk compounding. All highrisk CSP solutions subjected to terminal steam sterilization are passed through a filter with a nominal porosity not larger than 1.2 µm preceding or during filling into their final containers. Sterilization of highrisk level CSPs by filtration (see sterilization process) is conducted entirely with an ISO Class 5 or superior air quality environment. Examples of High-Risk Compounding: a. Dissolving nonsterile bulk drug and nutrient powders to make solutions, which will be terminally sterilized. b. Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to ISO Class 5. This includes storage in environments inferior to ISO Class 5 of opened or partially used packages of manufactured sterile products that lack antimicrobial preservatives. c. Measuring and mixing sterile ingredients in nonsterile devices before sterilization is performed. d. Assuming, without appropriate evidence or direct determination, that packages of bulk ingredients contain at least 95% by weight of their active chemical moiety and have not been contaminated or adulterated between uses. 1 September 2010 Page 6 of 26

35 5 STERILIZATION PROCESS: The licensed health care professionals who supervise compounding are responsible for determining that the selected sterilization method both sterilizes and maintains the strength, purity, quality, and packaging integrity of CSPs. The selected sterilization process is expected from experience and appropriate information sources and, preferably, verified wherever possible to achieve sterility in the particular CSPs. General guidelines for matching CSPs and components to appropriate sterilization methods include the following: a. CSPs have been ascertained to remain physically and chemically stable when subjected to the selected sterilization method. b. Glass and metal devices may be covered tightly with aluminum foil, then exposed to dry heat in an oven at a mean temperature of 250º for 2 hours to achieve sterility and dehyrogenation. Such items are either used immediately or stored until use in an environment suitable for compounding low- and medium-risk CSPs. c. Personnel ascertain from appropriate information sources that the sterile microporous membrane filter used to sterilize CSP solutions, either during compounding or administration, is chemically and physically compatible with the CSP. 5.1 STERILIZATION BY FILTRATION Commercially available sterile filters must be approved for human-use applications in sterilizing pharmaceutical fluids. Both filters that must be sterilized before processing CSPs and those filters that are commercially available, disposable, sterile, and pyrogen-free have a nominal porosity of 0.2 µm, which includes µm porosity. They should be certified by the manufacturer to retain at least 107 microorganisms of a strain of Brevundimonas (Pseudomonas) diminuta on each cm2 of upstream filter surface under conditions similar to those in which the CSPs will be sterilized. In emergency situations when sterile 0.2-µm porosity membranes are not available, filters of the same composition and 0.45-µm nominal porosity may be used. Sterilizing filters with 0.2-µm and 0.45-µm nominal porosities will not remove bacterial endotoxins and viruses by physical retention The supervising health care professional must ensure, directly or from appropriate documentation, that the filters are chemically and physically stable at the pressure and temperature conditions to be used, and that the filters will achieve sterility and maintain prefiltration pharmaceutical quality of the specific CSP. The filter dimensions and material must permit the sterilization process to be completed rapidly without the replacement of the filter during the process. When CSPs are known to contain excessive particulate matter, a prefilter or larger porosity membrane is placed upstream from the sterilizing filter to remove gross particulate contaminants in order to maximize the efficiency of the sterilizing filter When filter devices are assembled from separate nonsterile components by compounding personnel, such devices shall be identified to be sterile and ascertained to be effective under relevant conditions before they are used to sterilize CSPs. For example, sterility can be identified using biological indicators. Filter units used to sterilize CSPs can also be subjected to the manufacturer's recommended integrity test, such as the bubble point test. 1 September 2010 Page 7 of 26

36 5.1.4 When commercially available sterile disposable filter devices are used, the compounding personnel may accept the written certification from suppliers that the filters retain at least 107 cfu, of Brevundimonas (Pseudomonas) diminuta on each cm2 of filter surface. Compounding personnel must ascertain that selected filters will achieve sterilization of the particular CSPs being sterilized. Large deviations from usual or expected chemical and physical properties of CSPs may cause undetectable damage to filter integrity and shrinkage of microorganisms to sizes smaller than filter porosity Sterile, commercially available sterilizing filter devices for use on handheld syringes may be checked by feeling for greater resistance on the plunger when filtering air after an aqueous fluid has been filtered. 5.2 STEAM STERILIZATION The process of thermal sterilization employing saturated steam under pressure, or autoclaving, is the preferred method to terminally sterilize aqueous preparations that have been verified to maintain their full chemical and physical stability under the conditions employed. To achieve sterility, it is necessary that all materials be exposed to steam at 121º, under a pressure of about one atmosphere or 15 psi, for the duration verified by testing to achieve sterility of the items, which is usually 20 to 60 minutes for CSPs. An allowance must be made for the time required for the material to reach 121º before the sterilization exposure duration is aimed Items that are not directly exposed to pressurized steam may result in survival of microbial organisms and spores. Before their sterilization, plastic, glass, and metal devices are tightly wrapped in low particle shedding paper or fabrics, or sealed in envelopes that prevent poststerilization microbial penetration. Immediately before filling ampuls and vials that will be steam sterilized, solutions are passed through a filter having a porosity not larger than 1.2 µm for removal of particulate matter. Sealed containers must be able to generate steam internally; thus, stoppered and crimped empty vials must contain a small amount of moisture to generate steam The effectiveness of steam sterilization is verified using appropriate biological indicators or other confirmation methods. 6 POLICY & PROCEDURS Written Policy and Procedures are essential for generally ensuring product quality, especially sterility assurance. All compounding facilities are required to keep a written manual Establishing, maintaining, and assuring compliance with comprehensive policies and procedures encompassing all responsibilities in CSPs. These written procedures and instructions should be in line with this regulations and its updates in order to guarantee the highest levels of safety and quality. 1 September 2010 Page 8 of 26

37 These written instructions should include- but not limited to -the following items: a. Description of the general basis used to assign the beyond-use date and storage conditions for all CSPs. b. Description of the processes and techniques involved with transport, handling and placement into storage. c. Description of specific instructions for receiving, acknowledging, and dating receipts; and for recording, or filing, and evaluating reports of adverse events and of the quality of preparation claimed to be associated with CSPs. d. Specifically describe appropriate packing containers and insulating and stuffing materials, based on information from product specifications, vendors, and experience of compounding personnel. e. Description of a detailed Quality Assurance program to provide a mechanism for monitoring, evaluation, correction, and improving the activities and processes described in all sections. In addition to the appropriate follow-up program to make certain that effective corrective actions were performed. (see Quality Assurance Section). f. Also, Additional procedures may be essential for certain products, devices, or techniques. Examples where such special procedures are needed include in-line filtration, the operation of automated infusion control devices, and the replenishment of drug products into the reservoirs of implantable or portable infusion pumps. 7 PERSONNEL 7.1 PERSONNEL TRAINING REQUIREMENTS Compounding personnel are adequately skilled, educated, instructed, and trained to be responsible for ensuring that CSPs are accurately identified, measured, diluted, and mixed; and are correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed, and distributed. These performance responsibilities include maintaining appropriate cleanliness conditions and providing labeling and supplementary instructions for the proper clinical administration of CSPs The compounding facility must design, implement, and maintain a formal education, training, and competency assessment program that encompasses all the functions and tasks addressed in the foregoing sections and all personnel to whom such functions and tasks are assigned. This program includes the assessment and documentation of procedural breaches, administration mishaps, side effects, allergic reactions, and complications associated with dosage or administration, such as extravasation. This program should be coordinated with the institution's adverse-event and incident reporting programs. 7.2 PERSONNEL RESPONSIBILITIES Qualified licensed health care professionals who supervise compounding and dispensing of CSPs shall ensure that the following compounding responsibilities are achieved: Compounding personnel are performing and documenting the following activities in their sterile compounding duties: Perform antiseptic hand cleansing and disinfection of nonsterile compounding surfaces. 1 September 2010 Page 9 of 26

38 Select and appropriately don protective gloves, goggles, gowns, masks, and hair and shoe covers Use laminar flow clean-air hoods, barrier isolators, and other contamination control devices that are appropriate for the risk level Identify, weigh, and measure ingredients Manipulate sterile products aseptically, sterilize high-risk level CSPs, and label and quality inspect CSPs Ingredients have their correct identity, quality, and purity Opened or partially used packages of ingredients for subsequent use in CSPs are properly stored under restricted access conditions in the compounding facility. Such packages cannot be used when visual inspection detects unauthorized breaks in the container, closure, and seal; when the contents do not possess the expected appearance, aroma, and texture; when the contents do not pass identification tests specified by the compounding facility; and when either the beyond-use or expiration date has been exceeded To minimize the generation of bacterial endotoxins, water-containing CSPs that are nonsterile during any phase of the compounding procedure are sterilized within 6 hours after completing the preparation Sterilization methods achieve sterility of CSPs while maintaining the labeled strength of active ingredients and the physical integrity of packaging Measuring, mixing, sterilizing, and purifying devices are clean, appropriately accurate, and effective for their intended uses Potential harm from added substances and differences in rate and extent of bioavailability of active ingredients for other than oral route of administration are carefully evaluated before such CSPs are dispensed and administered While being used, the compounding environment maintains the sterility or the presterilization purity, whichever is appropriate, of the CSP Labels on CSPs list the names and amounts or concentrations of all ingredients. Before being dispensed, and or administered, the clarity of solutions are visually confirmed; also the identity and amounts of ingredients, procedures to prepare and sterilize CSPs, and specific release criteria are reviewed to assure their accuracy and completeness When time and personnel availability so permit, compounding manipulations and procedures are separated from postcompounding quality inspection and review before CSPs are dispensed and administered. 8 STANDARD OPERATION PROCEDURE 8.1 COMPOUNDING PROCESS The prescription orders, written compounding procedure, preparation records, and expended materials used to make CSPs in all contamination risk levels are inspected for accuracy of correct identities and amounts of ingredients, aseptic mixing and sterilization, packaging, labeling, and expected physical appearance before they are administered or dispensed. 1 September 2010 Page 10 of 26

39 8.1.2 Procedures for measuring, mixing, dilution, purification, sterilization, packaging, and labeling must be done conform to the correct sequence and quality established for the specified CSP Written procedures for double-checking compounding accuracy must be followed for every CSP during preparation and immediately prior to release. The double check system should meet institutes regulations and include label accuracy and accuracy of the addition of all drug products or ingredients used to prepare the finished product and their volumes or quantities. The used additive containers and, for those additives for which the entire container was not expended, the syringes used to measure the additive, should be quarantined with the final products until the final product check is completed. Compounding personnel must visually confirm that ingredients measured in syringes match the written order being compounded. Preferably, a person other than the compounder can verify that correct volumes of correct ingredients were measured to make each CSP. For example, compounding personnel would pull the syringe plunger back to the volume measured When practical, confirm accuracy of measurements by weighing a volume of the measured fluid, then calculating that volume by dividing the weight by the accurate value of the density, or specific gravity, of the measured fluid. Correct density or specific gravity values programmed in automated compounding devices, which measure by weight using the quotient of the programmed volume divided by the density or specific gravity, must be confirmed to be accurate before and after delivering volumes of the liquids assigned to each channel or port. These volume accuracy checks and the following additional safety and accuracy checks in this section must be included in the standard operating procedures manual of the CSP facility Water-containing CSPs that are nonsterile during any phase of the compounding procedure must be sterilized within 6 hours after completing the preparation, to minimize the generation of bacterial endotoxins, All CSPs that are intended to be solutions must be visually examined for the presence of particulate matter and not administered or dispensed when such matter is observed. 8.2 INSPECTION OF FINISHED CSPS Finished CSPs are individually inspected in accordance with written procedures after compounding. If not distributed promptly, these products are individually inspected just prior to leaving the storage area Each product unit, where possible, should be inspected against lighted white or black background or both for evidence of visible particulates or other foreign matter. Pre-release inspection also includes container closure integrity and any other apparent visual defect When products are not distributed promptly after preparation, a predistribution inspection is conducted to ensure that a CSP with defects, such as precipitation, cloudiness, and leakage, which may develop between the time of release and the time of distribution, is not released. 1 September 2010 Page 11 of 26

40 8.3 LABELING No prepackaged CPS shall be offered without a label Labels of CSPs shall be in English languages. When one language or more is used all information in the other languages shall be the same as the information written in the English language. Information included in the label or attached to the container of the CSPs shall be clear, prominent and readily legible and indelible under normal conditions of handling and use. This information may not be obscured by any other illustrated, written, or printed matter. It shall be presented in a color distinguishable from the background. The name of the CSPs shall be written in letters of a size reasonable related to other information printed on the label. The method of preparation and use of the CSP shall be declared in necessary. In summary, the labels of CSPs bear the following: a. Correct names of (patient, medicals, additives, diluents, ingredients etc.) b. Amounts or concentrations of ingredients c. Total volume d. Beyond-use date e. Appropriate route(s) of administration f. Storage conditions g. Other information for safe use 8.4 STABILITY AND BEYOND USE DATE Beyond-use dates for compounded preparations are usually assigned based on professional experience, which should include careful interpretation of appropriate information sources for the same or similar formulations2. Beyond-use dates for CSPs are rarely based on preparation-specific chemical assay results, which are used with the Arrhenius equation to determine expiration dates for manufactured products. The majority of CSPs are aqueous solutions in which hydrolysis of dissolved ingredients is the most common chemical degradation reaction. The extent of hydrolysis and other heat-catalyzed degradation reactions at any particular time point in the life of a CSP represents the thermodynamic sum of exposure temperatures and durations. Such lifetime stability exposure is represented in the mean kinetic temperature calculation3. Drug hydrolysis rates increase exponentially with arithmetic temperature increase; thus, exposure of a beta-lactam antibiotic solution for one day at controlled room temperature will have an equivalent effect on the extent of hydrolysis of approximately 3 to 5 days in cold temperatures Personnel who prepare, dispense, and administer CSPs must store them strictly in accordance with the conditions stated on the label of ingredient products and finished CSPs When CSPs deviate from conditions in the approved labeling of manufactured products contained in CSPs, compounding personnel may consult the manufacturer of particular products for advice on assigning beyond-use dates based on chemical and physical stability parameters Beyond-use dates for CSPs that are prepared strictly in accordance with manufacturers' product labeling must be those specified in that labeling, or from appropriate literature 1 September 2010 Page 12 of 26

41 sources or direct testing. Beyond-use dates for CSPs that lack justification from either appropriate literature sources or by direct testing evidence must be assigned as described in the section Stability Criteria and Beyond-Use Dating in the general test chapter Pharmaceutical Compounding Nonsterile Preparations The pharmacist may refer to applicable publications to obtain relevant stability, compatibility, and degradation information regarding the drug or its congeners. When assigning a beyond-use date, pharmacists should consult and apply drug-specific and general stability documentation and literature where available, and they should consider the nature of drug and its degradation mechanism, the container in which it is packaged, the expected storage conditions, and the intended duration of therapy Stability information must be carefully interpreted in relation to the actual compounded formulation and conditions for storage and use. Predictions based on other evidence, such as publications, charts, tables, and so forth would result in theoretical beyond-use dates. Theoretically predicted beyond-use dating introduces varying degrees of assumptions, and hence a likelihood of error or at least inaccuracy. The degree of error or inaccuracy would be dependent on the extent of differences between the CSP's characteristics (such as composition, concentration of ingredients, fill volume, or container type and material) and the characteristics of the products from which stability data or information are to be extrapolated. The greater the doubt of the accuracy of theoretically predicted beyond-use dating, the greater the need to determine dating periods experimentally. Theoretically predicted beyond-use dating periods should be carefully considered for CSPs prepared from nonsterile bulk active ingredients having therapeutic activity, especially where these CSPs are expected to be compounded routinely When attempting to predict a theoretical beyond-use date, a compounded or an admixed product, it should be considered as a unique system that has physical and chemical properties and stability characteristics that differ from its components. For example, antioxidant, buffering, or antimicrobial properties of a sterile vial for injection (SVI) might be lost upon its dilution, with the potential of seriously compromising the chemical stability of the SVI s active ingredient or the physical or microbiological stability of the SVI formulation in general. Thus, the properties stabilized in the SVI formulation usually cannot be expected to be carried over to the compounded or admixed product. Productspecific, experimentally determined stability data evaluation protocols are preferable to published stability information. Pharmacists should consult the general information chapter under Pharmaceutical Stability for the appropriate stability parameters to be considered when initiating or evaluating a product-specific stability study Compounding personnel who assign beyond-use dates to CSPs when lacking direct chemical assay results must critically interpret and evaluate the most appropriate available information sources to decide a conservative and safe beyond-use date It should be recognized that the truly valid evidence of stability for predicting beyond-use dating can be obtained only through product-specific experimental studies. Semiquantitative procedures, such as thin-layer chromatography (TLC), may be acceptable for many CSPs. However, quantitative stability-indicating assays, such as high performance liquid chromatographic (HPLC) assays, would be more appropriate for certain CSPs. Examples include CSPs with a narrow therapeutic index, where close monitoring or dose titration is required to ensure therapeutic effectiveness and to avoid toxicity; where a theoretically established beyond-use dating period is supported by only marginal evidence; 1 September 2010 Page 13 of 26

42 or where a significant margin of safety cannot be verified for the proposed beyond-use dating period. In short, because beyond-use dating periods established from productspecific data acquired from the appropriate instrumental analyses are clearly more reliable than those predicted theoretically, the former approach is strongly urged to support dating periods exceeding 30 days Expiration dating not specifically referenced in the package insert should not exceed 30 days once the MDV has been opened When CSPs will be distributed to and administered in residential locations other than health care facilities, the effect of potentially uncontrolled and unmonitored temperature conditions must be considered when assigning beyond-use dates. It must be ascertained that CSPs will not be exposed to warm temperatures unless the compounding facility has evidence to justify stability of CSPs during such exposure. 8.5 PACKAGE, HANDLING, AND TRANSPORTATION Procedures essential for generally ensuring product quality, especially sterility assurance, when readying a CSP for its subsequent administration include proper hand-washing, aseptic technique, site care, and change of administration sets. Additional procedures may also be essential for certain products, devices, or techniques. Examples where such special procedures are needed include in-line filtration, the operation of automated infusion control devices, and the replenishment of drug products into the reservoirs of implantable or portable infusion pumps The compounding facility must have the sole authority for determining whether a CSP not administered as originally intended can be used for an alternate patient or under alternate conditions. All CSPs that are not used as originally intended must be returned to the compounding facility for appropriate disposition, which may include redispensing, but only if adequate continuing quality can be fully ensured. The following may provide such assurance: the CSP was maintained under continuous refrigeration and protected from light, if required; no evidence of tampering or any readying for use outside the compounding facility exists; and there is sufficient time remaining until the originally assigned beyond-use time and date will be reached. Thus, initial preparation and thaw times should be documented and reliable measures should have been taken to prevent and detect tampering. Compliance with all procedures associated with maintaining product quality is essential. The CSP must not be redispensed if there is not adequate assurance that product quality and packaging integrity (including the connections of devices, where applicable) were continuously maintained between the time the CSP left and the time that it was returned to the compounding facility. Additionally, CSPs must not be redispensed if redispensing cannot be supported by the originally assigned beyond-use time When CSPs are distributed to locations outside the premises in which they are compounded, packing is selected that simultaneously protects CSPs from damage, leakage, contamination, and degradation; and protects personnel who transport packed CSPs from harm. Written instructions that clearly explain how to safely open containers of packed CSPs are provided to patients and other recipients Packaging selected for CSPs must be appropriate to preserve the sterility and strength until the beyond-use date. 1 September 2010 Page 14 of 26

43 8.5.5 Compounding facilities that ship CSPs to locations outside their own premises must select modes of transport that are expected to deliver properly packed CSPs in undamaged, sterile, and stable condition to recipients Compounding personnel should ascertain that temperatures of CSPs during transit by the selected mode will not exceed the warmest temperature specified on the storage temperature range on CSPs labels. It is recommended that compounding personnel communicate directly with the couriers to learn shipping durations and exposure conditions that CSPs may encounter Compounding personnel must include specific handling and exposure instructions on the exteriors of containers packed with CSPs to be transported and obtain reasonable assurance of compliance therewith from transporters. Compounding personnel must periodically review the delivery performance of couriers to ascertain that CSPs are being efficiently and properly transported Compounding facilities that ship CSPs to patients and other recipients outside their own premises must ascertain or provide, whichever is the appropriate case, the following assurances: Labels and accessory labeling for CSPs include clearly readable beyond-use dates, storage instructions, and disposal instructions for out-of-date units Each patient or other recipient is able to store the CSPs properly, including the use of a properly functioning refrigerator and freezer if CSPs are labeled for such storage Compounding facilities must clinically monitor patients treated with CSPs according to the regulations and guidelines of accepted standards of practice. Compounding facilities must provide patients and other recipients of CSPs with a way to address their questions and report any concerns that they may have with CSPs and their administration devices Reports of adverse events with CSPs must be reviewed promptly and thoroughly by compounding supervisors to correct and prevent future occurrences. Compounding personnel are encouraged to participate in adverse event reporting and product defects programs Techniques should be specified to prevent the depression of syringe plungers or dislodging of syringe tips during handling and transport Disconnection of system components (for example, where CSPs are dispensed with administration sets attached to them) must be prevented throughout the life cycle of the product Foam padding or inserts are particularly useful where CSPs are transported by pneumatic tube systems Inappropriate transport and handling can adversely affect the quality of certain CSPs having unique stability concerns. For example, the physical shaking that might occur during pneumatic tube transport, or undue exposure to heat or light, have to be addressed on a product-specific basis. Alternate transport modes or special packaging measures might be needed for the proper assurance of quality of these CSPs The use of tamper-proof closures and seals on CSP ports can add an additional measure of security to ensure product integrity regardless of transport method used Chemotoxic and other hazardous CSPs require safeguards to maintain the integrity of the CSP and to minimize the exposure potential of these products to the environment and to personnel who may come in contact with them. Special requirements associated with the packaging, transport, and handling of these agents include the prevention of accidental 1 September 2010 Page 15 of 26

44 exposures or spills and the training of personnel in the event of an exposure or spill. Examples of special requirements of these agents also include exposure-reducing strategies such as the use of Luer lock syringes and connections, syringe caps, the capping of container ports, sealed plastic bags, impact-resistant containers, and cautionary labeling. Appropriate cushioning for pneumatic tube transport should be selected and evaluated to ensure that the products so conveyed can withstand the stresses induced by the system. Pneumatic transport of nonevaluated packaging alternatives should be avoided. Additional references should be consulted as necessary for further information on handling chemotoxic and other hazardous drugs Delivery and patient-care-setting personnel must be properly trained to deliver the CSP to the appropriate storage location. Outdated and unused CSPs must be returned to the compounding facility for disposal or possible reuse. 8.6 STORAGE Those products that are not immediately distributed are stored in an appropriate location as described in the written procedures To inhibit microbial growth from undetected contamination, finished CSPs that will not be immediately dispensed and administered must be refrigerated at 2º to 8º, unless their chemical and physical stability are known to be adversely affected by cold temperatures. When CSPs are filled into patient-worn infusion devices that are likely to attain temperatures exceeding 30º for more than 24 hours, the chemical and physical stability at such temperatures and durations must be confirmed from either appropriate literature sources or direct testing If multiple-dose parenteral medication vials (MDVs) are used, refrigerate the MDVs after they are opened unless otherwise specified by the manufacturer. Discard the MDVs when empty, when suspected or visible contamination occurs, or when the manufacturer's stated expiration date is reached, provided the manufacturer s storage conditions have been adhered to To ensure that product potency is retained through the manufacturer's labeled expiration date, pharmacists must monitor the drug storage areas within the compounding facility. Controlled temperature storage areas in the compounding facility (refrigerators, 2º to 8º; freezers, 20º to 10º; and incubators, 30º to 35º; etc.) should be monitored at least once daily and the results documented on a temperature log. Additionally, compounding facility personnel should note the storage temperature when placing the product into or removing the product from the storage unit in order to monitor any temperature aberrations. Suitable temperature recording devices may include a calibrated continuous recording device or an NBS calibrated thermometer that has adequate accuracy and sensitivity for the intended purpose and should be properly calibrated at suitable intervals. If the compounding facility uses a continuous temperature recording device, compounding facility personnel should verify at least once daily that the recording device itself is functioning properly The temperature sensing mechanisms should be suitably placed in the controlled temperature storage space to reflect accurately its true temperature. In addition, the compounding facility should adhere to appropriate procedures of all controlled storage spaces to ensure that such spaces are not subject to significantly prolonged temperature fluctuations as may occur, for example, by leaving a refrigerator door open too long. 1 September 2010 Page 16 of 26

45 8.6.6 Written procedures have to exist to ensure that storage conditions in the patient-care setting are suitable for the CSP-specific storage requirements. Procedures include daily monitoring and documentation of drug storage refrigerators to ensure temperatures between 2º and 8º The monthly inspection of all drug storage locations by compounding facility personnel. Inspections must confirm compliance with appropriate storage conditions, separation of drugs and food, proper use of multiple-dose containers, and the avoidance of using singledose products as multiple-dose containers. CSPs, as well as all other drug products, must be stored in the patient-care area in such a way as to secure them from unauthorized personnel, visitors, and patients. 8.7 DESTRUCTION Products with observed defects should be immediately discarded or marked and segregated from acceptable products in a manner that prevents their administration When CSPs are known to have been exposed to temperatures warmer than the warmest labeled limit, but not exceeding 40º for more than 4 hours, such CSPs should be discarded, unless appropriate documentation or direct assay data confirms their continued stability. 9 QUALITY ASSURANCE In developing a specific QA plan, focus is on establishing objective, measurable indicators for monitoring activities and processes that are deemed high-risk, high-volume, or problem-prone. Appropriate evaluation of environmental monitoring might include, for example, the trending of an indicator such as settling plate counts. In general, the selection of indicators and the effectiveness of the overall QA plan (including the following steps) is reassessed on an annual basis: All high-risk level CSPs for administration by injection into the vascular and central nervous systems that are prepared in groups of more than 25 identical individual single-dose packages (such as ampuls, bags, syringes, vials), or in multiple dose vials for administration to multiple patients, or exposed longer than 12 hours at 2º to 8º and longer than 6 hours at warmer than 8º before they are sterilized must be tested to ensure the following: 3 They are sterile before they are dispensed or administered. The Membrane Filtration method is the method of choice where feasible (e.g., components are compatible with the membrane). A method not described in the USP may be used if verification results demonstrate that the alternative is at least as effective and reliable as the USP Membrane Filtration method or the USP Direct Inoculation of the Culture Medium method where the membrane filtration method is not feasible. 4 They do not contain excessive bacterial endotoxins. In the absence of a bacterial endotoxins limit in the official monograph or other CSP formula source, the CSP must not exceed the amount of USP Endotoxin Units (EU per hour per kg of body weight or m2 of body surface area). 5 positive sterility test results should prompt a rapid and systematic investigation of aseptic technique, environmental control, and other sterility assurance controls to identify sources of contamination and correct problems in the methods or processes. 1 September 2010 Page 17 of 26

46 9.1 Characteristics of a QA plan include the following: Written formalization. Consideration of all aspects of the preparation and dispensing of products as described in this section, including environmental testing, validation results, etc. Description of specific monitoring and evaluation activities. Deficiencies in compounding, labeling, packaging, and quality testing and inspection can be rapidly identified and corrected. Specification of how results are to be reported and evaluated. Identification of appropriate follow-up mechanisms when action limits or thresholds are exceeded. Delineation of the individuals responsible for each aspect of the QA program. 9.2 Quality assurance procedures for low-risk level CSPs include, but are not limited to, the following: 1. Routine disinfection and air quality testing of the direct compounding environment to minimize microbial surface contamination and maintain ISO Class 5 air quality. 2. Visual confirmation that compounding personnel are properly donning and wearing appropriate items and types of protective garments and goggles. 3. Review of all orders and packages of ingredients to assure the correct identity and amounts of ingredients were compounded. 4. Visual inspection of CSPs to ensure the absence of particulate matter in solutions, the absence of leakage from vials and bags, and the accuracy and thoroughness of labeling. Example of a Media-Fill Test Procedure This, or an equivalent test, is performed at least annually by each person authorized to compound in a low-risk level under conditions that closely simulate the most challenging or stressful conditions encountered during compounding of low-risk level CSPs. Once begun, this test is completed without interruption. Within an ISO Class 5 air quality environment three sets of four 5-mL aliquots of sterile Soybean Casein Digest Medium are transferred with the same sterile 10-mL syringe and vented needle combination into separate sealed empty sterile 30-mL clear vials (i.e., four 5- ml aliquots into each of three 30-mL vials). Sterile adhesive seals are aseptically affixed to the rubber closures on the three filled vials, then the vials are incubated. 9.3 Quality assurance procedures for medium-risk level CSPs: Include all those for low-risk level CSPs, as well as a more challenging media-fill test passed annually, or more frequently. Example of a Media-Fill Test Procedure This, or an equivalent test, is performed under conditions that closely simulate the most challenging or stressful conditions encountered during compounding. This test is completed without interruption within an ISO Class 5 air quality environment. Six 100-mL aliquots of sterile Soybean Casein Digest Medium are aseptically transferred by gravity through separate tubing sets 1 September 2010 Page 18 of 26

47 into separate evacuated sterile containers. The six containers are then arranged as three pairs, and a sterile 10-mL syringe and 18-gauge needle combination is used to exchange two 5-mL aliquots of medium from one container to the other container in the pair. For example, after a 5-mL aliquot from the first container is added to the second container in the pair, the second container is agitated for 10 seconds, then a 5-mL aliquot is removed and returned to the first container in the pair. The first container is then agitated for 10 seconds, and the next 5-mL aliquot is transferred from it back to the second container in the pair. Following the two 5-mL aliquot exchanges in each pair of containers, a 5-mL aliquot of medium from each container is aseptically injected into a sealed empty sterile 10-mL clear vial using a sterile 10-mL syringe and vented needle. Sterile adhesive seals are aseptically affixed to the rubber closures on the three filled vials, then the vials are incubated. 9.4 Quality assurance procedures for high-risk level CSPs : Include all those for low-risk level CSPs In addition, a media-fill test that represents high-risk level compounding is performed semi-annually by each person authorized to compound high-risk level CSPs. Example of a Media-Fill Test Procedure This, or an equivalent test, is performed under conditions that closely simulate the most challenging or stressful conditions encountered when compounding high-risk level CSPs. This test is completed without interruption in the following sequence: a. Dissolve 3 g of nonsterile commercially available Soybean Casein Digest Medium in 100 ml of nonbacteriostatic water to make a 3% solution. b. Draw 25 ml of the medium into each of three 30-mL sterile syringes. Transfer 5 ml from each syringe into separate sterile 10-mL vials. These vials are the controls, and they generate exponential microbial growth, indicated by visible turbidity upon incubation. c. Under aseptic conditions and using aseptic techniques, affix a sterile 0.2-µm porosity filter unit and a 20-gauge needle to each syringe. Inject the next 10 ml from each syringe into three separate 10-mL sterile vials. Repeat the process into three more vials. Label all vials, affix sterile adhesive seals to the closure of the nine vials, and incubate them at 25º to 35º. Inspect for microbial growth over 14 days. A written quality assurance procedure includes the following in-process checks that are applied, as is appropriate, to specific CSPs: accuracy and precision of measuring and weighing; the requirement for sterility; methods of sterilization and purification; safe limits and ranges for strength of ingredients, bacterial endotoxins, particulate matter, and ph; labeling accuracy and completeness; beyond-use date assignment; and packaging and storage requirements. The dispenser shall, when appropriate and practicable, obtain and evaluate results of testing for identity, strength, purity, and sterility before a CSP is dispensed. 10 LIST OF REFERENCES 1 (Ingredient Selection under Pharmaceutical Compounding Nonsterile Preparations) 2 (Stability Criteria and Beyond-Use Dating in the Pharmaceutical Compounding Nonsterile Preparations) 3 (Pharmaceutical Calculations in Prescription Compounding) 1 September 2010 Page 19 of 26

48 11 APPENDIX CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL Compounding Conditions QA Program f. Compounded entirely under ISO Class 5 (Class 100) conditions g. Compounding involves only transfer, measuring, and mixing manipulations with closed or sealed packaging systems that are performed promptly and attentively h. Manipulations are limited to aseptically opening ampuls, penetrating sterile stoppers on vials with sterile needles and syringes and transferring sterile liquids in sterile syringes to sterile administration devices and packages of other sterile products Formalized in writing Describes specific monitoring and evaluation activities Reporting and evaluation of All conditions listed under low-risk level Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient on multiple conditions Compounding process includes complex aseptic manipulations other than the single-volume transfer Compounding process requires unusually long duration The sterile CSPs do not contain broad-spectrum bacteriostatic agents, and are administered over several days Nonsterile ingredients are incorporated or a nonsterile device is employed before terminal sterilization Sterile ingredients, components, devices and mixtures are exposed to air quality inferior to ISO Class 5 (Class 100) Nonsterile preparations are exposed for not more than 6 hours before being sterilized Nonsterile preparations are terminally sterilized but are not tested for bacterial endotoxins It is assumed that the chemical purity and content strength of ingredients meet their original or compendial specifications in unopened or in opened packages of bulk ingredients

49 CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL results Identification of follow-up activities when thresholds are exceeded Delineation of individual responsibilities for each aspect of the program QA Practices Routine disinfection and quality testing of direct compounding environment Visual confirmation of personnel processes regarding gowning, etc. Review of orders and packages of ingredients to assure correct identity and amounts of ingredients Visual inspection of CSP Media-fill test procedure performed at least annually for each person Outcome Monitoring Yes Yes Yes Reports/Documents Written policies and procedures Adverse event reporting Complaint procedures Periodic review of quality control documents 1 September 2010 Page 21 of 26

50 CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL Patient and Caregiver Formalized program that Training includes Understanding of the therapy provided Handling and storage of the CSP Appropriate administration techniques Use and maintenance of any infusion device involved Use of printed material Appropriate follow-up Maintaining Product Quality and Control once the CSP leaves the Compounding facility Packaging, handling, and transport Written policies and procedures including the packaging, handling, and transport of chemotoxic/hazardous CSPs Use and storage Written policies and procedures Administration Written polices and procedures dealing with such issues as handwashing, aseptic technique, site care, 1 September 2010 Page 22 of 26

51 CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL etc. Education/Training Written policies and procedures dealing with proper education of patients and caregivers ensuring all of the above Storage and Beyond-Use Dating Specific labeling requirements Specific beyond-use dating policies, procedures, and requirements Policies regarding storage Storage Conditions and Beyond-Use Dating for completed CSP Finished Product-Release Checks and Tests In the absence of sterility testing, storage periods (before administration) shall not exceed the following: Room temperature 2º 8º - 20º 48 hours 14 days 45 days Written policies and procedures that address:- Room temperature 2º 8º - 20º 30 hours 7 days 45 days Room temperature 2º 8º - 20º 24 hours 3 days 45 days Physical inspections Compounding accuracy checks Finished Product-Release Checks and Tests Written policies and procedures that address Sterility testing 1 September 2010 Page 23 of 26

52 CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL Pyrogen testing Potency testing CSP Work Environment Appropriate solid surfaces Limited (but necessary) furniture, fixtures, etc. Anteroom area Buffer zone Equipment Written policies and procedures that address calibration, routine maintenance, personnel training Components Written policies and procedures that address Sterile components Sterile and nonsterile drug components must meet the compendial standards if available Written policies and procedures that address:- Sterile components Nonsterile components Processing: Aseptic Technique Written policies and procedures that address specific training and performance evaluation Critical operations are carried out in a Direct Compounding Common Area (DCCA) 1 September 2010 Page 24 of 26

53 CRITERIA LOW-RISK LEVEL MEDIUM-RISK LEVEL HIGH-RISK LEVEL Environmental Policies and procedures Control that address: Cleaning and sanitizing the workspaces (DCCA) Personnel and gowning Verification Procedures Standard operating procedures Not required Not required Yes, recommended Sterility Testing Verification Procedures Environmental Monitoring Certification of LAFW and barrier isolates every six (6) months Certification of the buffer room/zone and anteroom/zone every six (6) months Bacterial monitoring using an appropriate manner at least monthly Verification Procedures Personnel Training and Education Initially and annually thereafter Didactic review Written testing Media-fill testing 1 September 2010 Page 25 of 26

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