Compounding nonsterile preparations: USP <795> and <800>

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1 Compounding nonsterile preparations: USP <795> and <800> Abstract Objective: To identify the key components of USP <795> Pharmaceutical Compounding Nonsterile Preparations and USP <800> Hazardous Drugs Handling in Healthcare Settings that are required and recommended when compounding nonsterile preparations, and to prioritize elements that need to be improved to come into compliance. Summary: USP General Chapters numbered under <1000> are enforceable by regulators and accreditation organizations. These include USP <795> Pharmaceutical Compounding Nonsterile Preparations and USP <800> Hazardous Drugs Handling in Healthcare Settings. Many state boards of pharmacy include them in regulations. Pharmacists and pharmacy technicians who compound must be aware of and comply with the USP chapters and related best practices. Compounding hazardous drugs includes requirements in addition to those in <795>. This article identifies the requirements compounders must use to comply with best practices and protect patients from harm. Conclusion: Pharmacists and pharmacy technicians who compound nonsterile preparations need to be aware of the requirements and recommendations of the applicable USP chapters and of best practices promulgated by professional organizations. USP <795> details requirements for nonsterile compounding activities; USP <800> details additional requirements when handling hazardous drugs. Even if facility changes are not required to come into compliance with USP <800> by July 1, 2018, every pharmacy will need to complete an Assessment of Risk to define how hazardous drugs will be safely handled. Pharm Today. 2017;23(10):56 72 Patricia C. Kienle, RPh, MPA, FASHP, Director, Accreditation and Medication Safety, Cardinal Health Innovative Delivery Solutions, Wilkes Barre, PA Correspondence: Patricia C. Kienle, Cardinal Health Innovative Delivery Solutions, 106 Elmwood Dr., Wilkes Barre, PA ; Accreditation Information Provider: APhA Activity type: Knowledge-based Learning level: 1 Target audience: Pharmacists and pharmacy technicians Release date: October 1, 2017 Expiration date: October 1, 2020 ACPE Universal Activity Number: H07-P/T CPE credit: 2 hours (0.2 CEUs) Fee: There is no fee associated with this activity for APhA members. There is a $25 fee for nonmembers. The American Pharmacists Association (APhA) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned to this activity by the accredited provider is H07-P/T. Advisory board: Ryan A. Forrey, PharmD, MS, FASHP, Senior Manager, Hazardous Drug Safety, Becton Dickinson, Franklin Lakes, NJ. Disclosures: Patricia C. Kienle, RPh, MPA, FASHP, declares that she is employed by Cardinal Health. Ryan A. Forrey, PharmD, MS, FASHP, declares that he is employed by Becton Dickinson (BD). APhA s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see Development: This home-study CPE activity was developed by APhA. Learning objectives Upon completion of this activity, pharmacists and pharmacy technicians will be able to Describe how USP standards become part of regulatory requirements, accreditation standards, and best practice recommendations. Differentiate elements of nonsterile compounding, including categories, types of components, expiration vs. beyond-use dates, and documentation. State the scope and controls designed to protect health care personnel from contamination with hazardous drugs. Cite the document that lists drugs that are hazardous to health care personnel. Identify the types of hazardous drugs and dosage forms that may be considered for an Assessment of Risk and the related contamination controls and work practices. 56 PharmacyToday OCTOBER 2017

2 COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> CPE Preassessment questions Before participating in this activity, test your knowledge by answering the following questions. These questions will also be part of the CPE assessment. 1. What is the role of USP? a. Enforce state regulations. b. Enforce federal regulations. c. Set standards. d. Define accreditation standards. 2. USP General Chapters are a. Standards b. Guidelines c. Stretch goals d. Outcomes 3. USP General Chapters numbered under <1000> are a. Advisory b. Enforceable c. Informational d. Guidelines Introduction Compounding is a core competency of pharmacy practice. Federal and state regulations identify the specific requirements of pharmacists and others legally allowed to compound in those jurisdictions. Since 1820, USP has provided guidance for standardizing drug compounding and manufacturing. USP Chapters <795> Pharmaceutical Compounding Nonsterile Preparations 1 and <800> Hazardous Drugs Handling in Healthcare Settings 2 include contemporary requirements and recommendations related to compounding nonsterile preparations. Though USP is not a government entity, it works with regulatory agencies to provide standards of identity, strength, quality, and purity. USP standards are specified in the Federal Food, Drug, and Cosmetic Act, 3,4 in many state regulations, and in standards promulgated by accreditation organizations, such as The Joint Commission (TJC) 5 and the Pharmacy Compounding Accreditation Board (PCAB), a division of the Accreditation Commission for Health Care. 6 USP standards USP standards include three major categories: General Notices provide the basic definitions for applying USP standards. The information in the General Notices applies to any of the more descriptive general chapters and monographs, such as <659> Packaging and Storage Requirements. 7 General Chapters contain more detailed information about a function, such as nonsterile compounding in <795> and hazardous drugs (HDs) in <800>. General Chapters numbered under <1000> are minimum requirements, not guidelines or goals. All elements of the chapter need to be used; partial compliance is not acceptable. USP General Chapters are updated as neces- sary. When new chapters or revisions to current chapters are proposed, they are published in Pharmacopeial Forum and are available for public comment. 8 Monographs include two types of documents: Documents for bulk drug substances, such as Clonidine, USP, 9 provide standards for the identity, quality, purity, strength, packaging, and labeling of components used in compounds Documents for specific preparations, such as Alprazolam Compounded Oral Suspension, USP, 10 provide detailed information for compounding preparations that are not available during shortages or from FDA-registered manufacturers USP standards are developed through a standardized process (Figure 1). Once a public health need is identified, draft standards are developed by a USP Expert Committee and published for public comments. After a public comment period, the Expert Committee reviews and revises the draft document based on the comments received. Once approved, the standard is published as an official document in the USP National Formulary (NF). Chapter numbering in USP is significant. Chapters numbered under <1000> are enforceable; those numbered over <1000> are informational. Over time, some informational chapters are revised and changed to enforceable chapters. The concepts in General Chapter <795> began with USP <1161> Pharmacy Compounding Practices when the 1997 Food and Drug Administration Modernization Act became law. USP <1161> was retired when <795> was published in USP 24 NF 19 in USP <795> was revised in 2004 and again in 2011, when <1075> Good Compounding Practices was incorporated. A Revision Bulletin posted on November 22, 2013, clarified the distinction between <795> and <797> and became official on January 1, Any pharmacist who compounds needs to have access to the USP standards. The USP Compounding Compendium is available for purchase as an electronic publication. 12 Renewed emphasis on compounding safety The national outbreak of fungal meningitis caused by compounds distributed by the New England Compounding Company that were intended to be sterile 13,14 resulted in increased emphasis on the safety of both nonsterile and sterile compounding. A total of 64 patients died, and more than 753 were affected by fungal meningitis. The public furor over this egregious situation resulted in the 2013 Drug Quality and Security Act (DQSA). 15 The DQSA created a separation in Section 503 of the Federal Food, Drug, and Cosmetic Act, resulting in two parts: 503A, pertaining to compounding pharmacies; and 503B, pertaining to a new entity, registered outsourcing facilities. Though generally focused on sterile preparations, the concepts in this legislation influence all compounding activities. In June 2017, the FDA commissioner issued a statement indicating the importance of DQSA in overseeing compounded drugs 16 and a Human Drug Compounding Progress Report (see Highlights of FDA s Human Drug Compounding Progress Report sidebar) OCTOBER 2017 PharmacyToday 57

3 CPE COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> Figure 1. Development of USP standards Source: Used with permission. USP, Highlights of FDA s Human Drug Compounding Progress Report Explain risks of compounded drugs. Differentiate between 503A compounding pharmacies and 503B outsourcing facilities. Explain FDA oversight of compounding. Describe policy development and stakeholder collaboration. Define the function of PCAB. As a result of this increased emphasis on compounding safety, USP, FDA, states, and accreditation organizations (e.g., PCAB) now require pharmacists and pharmacy technicians who compound to comply with current best practices promulgated in regulations and guidance documents. Drug shortages and prescriber and patient requests for compounds may create an ethical burden to determine if compounding is appropriate. In particular, drugs that are difficult to compound, copies of commercially available products, drugs withdrawn from the U.S. market for safety reasons, and use of manufacturing-scale equipment should be avoided unless extenuating circumstances exist. FDA and 58 PharmacyToday OCTOBER 2017 other organizations regulations and guidance documents may limit the ability to compound such mixtures under any circumstances. Regulations Federal and state agencies issue regulations and require compliance. USP standards are incorporated in many regulations, sometimes by reference to the USP NF, sometimes by citing specific chapters or general notices, and sometimes by placing text from the USP standards into federal or state regulations. The Occupational Safety and Health Administration s (OSHA) 1970 Occupational Safety Act General Duty Clause requires employers to provide a workplace free from recognized hazards that are causing or are likely to cause death or serious physical harm. 18 This issue is significant for pharmacy personnel who handle HDs and other hazards in the workplace. (See Table 1.) For those who work in hospitals and health systems, CMS requires compliance with Conditions of Participation (in hospitals and critical access hospitals) or Conditions for

4 COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> CPE Table 1. Legal considerations and compliance impact Legal considerations 1997 FDA Modernization Act requires compliance with USP monographs Drug Quality and Security Act reaffirmed USP, specifically referencing USP <795> and <797>. USP standards are included in many state laws and regulations. Compliance impact USP <795> and <797> are existing enforceable standards; <800> becomes enforceable on July 1, Compounding requirements are included in the CMS Conditions of Participation. Accreditation organizations include compounding issues in their standards. Coverage (for many other types of health care entities). 19 USP <795>, <797>, and other references to compounding are listed in and of the Hospital Conditions of Participation. 20 FDA has produced a number of final and draft guidance documents and other documents on compounding (see Table 2 for examples of selected documents related to nonsterile compounding). 21 State regulations Compounding regulations vary among states but generally restrict oversight of compounding to a pharmacist. Often, technicians are able to compound under the direction of a pharmacist. Practitioners must be aware of and comply with the regulations of the state in which compounding occurs. If they are providing patient-specific compounds to another state, they must comply with regulations of that state. 22 Accreditation organizations Accreditation organizations are not regulators, but often their standards are used in lieu of or to supplement regulatory inspections. Their standards include medication-related requirements, and many have recently increased their focus on compounding. For example, PCAB offers a compounding pharmacy accreditation, and TJC offers a certification in medication compounding. Best practices Professional organizations, including APhA, the American Society of Health-System Pharmacists (ASHP), the American College of Apothecaries, the International Academy of Compounding Pharmacists, and others, provide guidance documents on compounding. Compounding nonsterile preparations Compounding performed in most pharmacies is limited to preparations for human use and may include ingredients considered hazardous by the National Institute of Occupational Safety and Health (NIOSH). NIOSH-hazardous medications include antineoplastics, hormones, and a number of other commonly compounded medications. Some pharmacies also compound medications for animal patients, which requires specialized knowledge of the type of animal (companion, food, or performance) and species-related aspects. Nuclear pharmacies may compound oral radiopharmaceuticals. All need to comply with USP <795> and the other USP General Chapter references in <795>: <659> Packaging and Storage Requirements <1136> Packaging and Repackaging Single-Use Containers <1151> Pharmaceutical Dosage Forms <1160> Pharmaceutical Calculations in Pharmacy Practice <1163> Quality Assurance in Pharmaceutical Compounding <1176> Prescription Balances and Volumetric Apparatus Used in Compounding <1191> Stability Considerations in Dispensing Practice <1231> Water for Pharmaceutical Purposes <1265> Written Prescription Drug Information USP <795> Pharmaceutical Compounding Nonsterile Preparations General Chapter USP <795> presents the standards of care required when nonsterile preparations are compounded. Major elements include Categories of compounds Personnel requirements Facility requirements Component selection Beyond-use dates Documentation requirements Categories of nonsterile compounds USP <795> defines three categories of nonsterile compounding: simple, moderate, and complex. The distinctions are based on the degree of difficulty and the availability of scientifically valid information about the stability of the compound. Simple compounds include those for which clear data are available, such as information from a manufacturer in the FDA-approved labeling or information detailed in most of the USP compounding monographs. For example, the supplier of an 80-mL bottle of amoxicillin oral suspension, USP, instructs compounders to add 59 ml of water to the bottle to create a final concentration of 250 mg/5 ml. Further information provided may include instructions such as Shake well before using. Keep bottle tightly closed. Discard unused portions after 14 days. Refrigeration is preferable but not required. Those specific details have been researched by the manufacturer and are included in the FDA-approved product labeling. OCTOBER 2017 PharmacyToday 59

5 CPE COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> Table 2. Selected documents related to nonsterile compounding Final guidance documents Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act Issued 10/26/2015 Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Issued 6/9/2016 Cosmetic Act: Guidance for Industry Revised 1/13/17 Additions and Modifications to the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness Issued 10/6/2016 Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Issued 12/28/2016 Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities Issued 1/12/2017 Draft guidance documents Hospital and Health System Compounding Under the Federal Food, Drug, and Cosmetic Act Issued 4/15/2016 Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry Issued 7/7/2016 Insanitary Conditions at Compounding Facilities: Guidance for Industry Issued 8/3/2016 Compounding and Repackaging of Radiopharmaceuticals by State-Licensed Nuclear Pharmacies and Federal Facilities Guidance for Industry Issued 12/28/2016 Revised Draft Guidance: Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application Issued 1/12/2017 Other documents Draft Memorandum of Understanding Addressing Certain Distributions of Compounded Human Drug Products Between the State of [insert STATE] and the U.S. Food and Drug Administration Issued 2/13/2015 Request for Nominations: Bulk Drug Substances That Can Be Used To Compound Drug Products in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act Issued 10/26/2015 Proposed Rule: Amendments to the Regulation Regarding the List of Drug Products That Have Been Withdrawn or Removed from the Market for Reasons of Safety or Effectiveness Issued 10/18/2016 Proposed Rule: List of Bulk Drug Substances That Can Be Used to Compound Drug Products Issued 12/15/ PharmacyToday OCTOBER 2017 Two situations present when using an Active Pharmaceutical Ingredient (API) in simple compounding: when using USP monographs and when using commercially available kits containing APIs. USP <795> defines API as any substance or mixture of substances intended to be used in the compounding of a drug preparation, thereby becoming the active ingredient in that preparation and furnishing pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and animals or affecting the structure and function of the body. 1 Several companies supply kits including APIs and other components and supplies needed to provide a patient-specific compound. Mixing of these kits according to instructions backed by valid studies is an example of simple compounding. Most USP monographs also are considered simple compounding because the procedures are straightforward and scientifically valid details have been evaluated. USP 40 contains almost 200 compounding monographs. 23 The monographs include information on formulas, instructions for compounding, beyond-use dates ([BUDs] which often exceed the default dates that would need to be used without this information), packaging and storage information, and other details. They are designed for compounding patient-specific preparations when no suitable conventionally manufactured product is available. Moderate compounding includes either mixing a preparation for which no stability data are available for that particular formulation, or mixing a preparation that requires specialized calculations or procedures that exceed what would be considered simple compounding. A common example of moderate compounding is mixture of two topical ingredients when the stability of the mixture is not known. Some USP monographs, such as Morphine Sulfate Compounded Suppositories, are considered moderate compounding. Complex compounding includes creating a preparation that requires special training, facilities, equipment, or procedures. Examples of complex compounding include making transdermal dosage forms or modified-release preparations. Compounders must be aware of the FDA documents on preparations considered demonstrably difficult to compound and should follow the outcomes of FDA s Pharmacy Compounding Advisory Committee. 24 Requirements, recommendations, and best practices USP General Chapters have a specific wording convention: shall or must means that the statement is a requirement; should means that the statement is a strong recommendation. Some states or accreditation organizations also require compliance with should statements, so knowledge of the jurisdiction s or accreditation organization s standards is key. A summary of shall statements follows each section in this CPE article. The term should used in this text does not necessarily mean that similar wording appears in <795>.

6 COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> CPE Personnel requirements Any person who compounds nonsterile preparations needs to be competent to do so and should demonstrate proficiency to a skilled compounder. To standardize procedures among all who compound, the pharmacy needs to establish and regularly review policies and procedures to guide safe compounding (see Example list of policies and procedures sidebar). The list is not exhaustive, and each pharmacy needs to ensure that all key functions are described in their documents. Example list of policies and procedures Scope of compounding State board of pharmacy regulations Training of personnel Acknowledgment of handling of HDs Compounding supervisor Responsibilities of compounding personnel Facilities Equipment Supplies Storage parameters Master Formulation Records Compounding Records Equipment initial and preventive maintenance Daily documentation requirements Cleaning Recalls Patient complaint procedures A person who oversees compounding activities should be assigned. In <800>, this individual is called a designated person. The designated person needs to be highly skilled in compounding, have the ability to oversee personnel activities, and understand the complexity of the compounding performed at the pharmacy. The individual does not necessarily need to be a pharmacist (unless required by the state or accreditation organization) or in a supervisory-level position. The individual may have responsibilities for more than one site if permitted in the organization s policy. The scope of compounding will dictate the appropriate qualifications of the individual, but external training by experts should be considered for pharmacies that provide extensive or complex compounding services. (See Shall statements in <795> concerning personnel sidebar.) Day-to-day oversight is often delegated to other qualified staff. Pharmacists and pharmacy technicians who compound must ensure that the preparations they mix Are appropriate for the patient Have the acceptable strength, quality, and purity Are prepared in accordance with the prescription or medication order Comply with requirements or restrictions in federal or state laws or regulations Follow the Master Formulation Record for those compounds that require it Are packaged and labeled to conform with policies and safe practices The designated person should develop a training program for employees new to that particular pharmacy s compounding needs. Resources can be developed or purchased to target needs of each compounder, but all individuals in the pharmacy need to demonstrate compliance with the requirements, even those who have compounded at other organizations and those who may not compound but are responsible for checking preparations. 25,26 On an annual basis, the designated person should assess the skills of all who compound and document the observations in the compounder s personnel record. Any needed remediation also needs to be documented. Resources can be developed or purchased that provide standardized elements that each compounder should demonstrate. 27 As new compounds, equipment, procedures, or other changes that could affect compounding are incorporated, the designated person or a designee needs to provide in-service training to staff and ensure competency is documented. New equipment should only be used once it has been checked to ensure it is operating as intended, personnel are trained, and personnel competency is documented. Work practices such as hand hygiene, proper garbing, meticulous technique, and the ability to perform the required procedures are essential to monitor. To protect the processes established and to keep patients safe, compounding personnel should also identify situations that need to be brought to the pharmacist in charge or designated person. Compounding HDs requires additional training and monitoring. See the section on Hazardous Drugs for additional requirements when handling HDs. Shall statements in <795> concerning personnel The compounding supervisor shall Meet with employees to review their work, and answer any questions the employees may have concerning compounding procedures. Demonstrate the procedures for the employee. Observe and guide the employee throughout the training process. Be physically present and approve all ingredients and their quantities and the final preparation. Constantly monitor the work of the employee, and ensure that the employee s calculations and work are accurate and adequately performed. All compounders shall Acquire and maintain knowledge and skills for which they compound. Adhere to the general principles listed in <795>. Be proficient and continually expand compounding knowledge. Be properly trained. Document all training activities. Read and become familiar with <795>, associated chapters and all applicable laws, regulations, guidelines, and standards. Read and become familiar with each of the procedures related to compounding. Facility requirements The current USP <795> does not provide much direction in the requirements for facilities (see Shall statements <795> OCTOBER 2017 PharmacyToday 61

7 CPE COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> concerning facilities sidebar). State regulations may provide more detail and often are specific as to location and square footage required for compounding functions. USP <795> describes minimum requirements, including Adequate space specifically designated for compounding Clean, orderly, sanitary, and in good state of repair Orderly placement of equipment and materials Designed, arranged, and used to prevent cross-contamination Well lighted Appropriate heating, ventilating, and air conditioning Hand- and equipment-washing facilities Plumbing system free of defects USP <800> Hazardous Drugs Handling in Healthcare Settings provides details about the separate storage and compounding facility requirements when handling HDs. HDs are not limited to those used for oncology; they include hormones and some antibiotics, antipsychotics, diuretics, anticoagulants, and a variety of other common medications. See the Hazardous Drugs section in this article for more information. Shall statements in <795> concerning facilities Design adequate space that is specific for compounding of prescriptions that is separate and distinct from sterile compounding areas. Place equipment and materials in an orderly manner. Maintain the compounding area in clean, orderly, and sanitary conditions and in a good state of repair. Ensure that plumbing system is free from defects. Provide potable water for hand and equipment washing. Provide adequate hand and equipment washing facilities accessible to the compounding area that include (but are not limited to) hot and cold running water, soap or detergent, and an air dryer or single-use towels. Control heating, ventilation, and air conditioning systems to avoid decomposition and containment of chemicals. Hold and dispose of waste in a sanitary and timely manner in accordance with federal, state, and local guidelines. Component selection Three types of components are described in <795>: API, added substances, and vehicles (see Shall statements in <795> concerning component selection sidebar). API is the active ingredient that provides the pharmacological activity. Added substances include inactive ingredients, excipients, and other additives used to complete the compound. The vehicle is the carrier or diluent in which the API and added substances are dissolved or suspended. The best option for obtaining ingredients is to select those that are manufactured in an FDA-registered facility and have the USP, NF, or Food Chemicals Codex (FCC) designation. This provides the assurance that the components have been manufactured under the conditions described in the USP NF compendium. Unless otherwise required, if USP, NF, or FCC components are used, the compounder does not need to obtain a Certificate of Analysis, as the compendial requirements have been met and documented by the manufacturing firm. 62 PharmacyToday OCTOBER 2017 Shall statements in <795> concerning component selection Attempt to use components manufactured in FDA-registered facilities. Use professional judgement in selecting an acceptable and reliable source when components cannot be obtained from an FDA-registered facility, and establish purity and safety by reasonable means. Use purified water for compounding nonsterile preparations when water is included in the formulation. Store components off the floor to prevent contamination and permit inspection and cleaning. If components must be obtained from a source that is not FDA registered, the compounder must use professional judgment to ensure the component is appropriate and must obtain a Certificate of Analysis. Caution must be paramount when using components that are not of compendial quality. Even though substances may be pure (such as those meeting American Chemical Society requirements), they may present safety concerns because the chemicals have not been tested for use in patients. Additional caution must be used with components derived from ruminant animals (including cattle, goats, and sheep). The supplier must provide written assurance that the component complies with federal laws governing processing, use, and importation. Dietary and nutritional supplements used in compounds must comply with any applicable federal and state regulations. Even though supplements are not drugs, they are evaluated for inclusion in FDA s bulk component list. As this is an evolving list and regulation, be sure to stay current with related information. A Certificate of Analysis must be issued for each batch of a component. The certificate should list the component, batch number, date testing was performed, and how each test complies with the compendial requirement (if available), and it should be dated and signed by an authorized individual from the manufacturer. When a firm different from the manufacturer completes the testing or repackages the component, both the manufacturer and the repackager information should be listed on the Certificate of Analysis. 28 When a conventionally manufactured FDA-approved drug product is used as a component in a compound, the compounder must evaluate all the components in the product, as they could affect the therapeutic appropriateness and/ or stability of the final compounded preparation. Expiration dates listed on APIs, added substances, and vehicles can be used through the date listed, provided care is taken to avoid decomposition. If the component is transferred to a different container, the expiration date can still be used as long as the container and closure s integrity is at least as good as that of the original container. If the component does not have an expiration date, the compounder must label the container with the date of receipt and assign a conservative expiry date that is no longer than 3 years from the date of receipt of the component. Water used in nonsterile compounding must meet the

8 COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> CPE standard of Purified Water, USP. Generally, this is water that complies with U.S. Environmental Protection Agency National Primary Drinking Water regulations and contains no other substances. 28 Various methods of purification are acceptable, including the most common method of distillation. Equipment and supplies may be washed with potable water, but consider rinsing them with purified water. Storage of components must meet the requirements of the manufacturer and any compendial requirements of USP, NF, or FCC, including temperature and humidity. If controlled room temperature is required or recommended, the components can be stored between 20 and 25 C (68 to 77 F) with excursions allowed as detailed in <659>. 30 Unless otherwise required by the manufacturer, refrigerated storage temperature is between 2 and 8 C (36 to 46 F). Other common storage requirements include appropriate labeling, storage off the floor, handling and storage to prevent contamination, and rotation so the oldest stock is used first. Compounding practices Compounding practices encompass all of the functions necessary to create a nonsterile compound, including selecting, storing, compounding, dispensing the mixture, and monitoring the patient. Equipment used in compounding needs to be appropriate for use, of sufficient size, and maintained as directed by the manufacturer. Surfaces that come in contact with components must not react with the ingredients. Information about balances, beakers, graduates, and similar devices can be found in USP <1176> Prescription Balances and Volumetric Apparatus. When possible, equipment used for antibiotics should be dedicated to that function. Where HDs are compounded, equipment (such as mortars and pestles, graduates, and similar items) must be dedicated for use with the HDs. Large equipment (such as mixers) used for both non-hds and HDs needs to be evaluated to ensure that cross-contamination between compounds is avoided. Any reusable equipment used for HDs must be decontaminated after use. Filters need to be appropriate for the compound and of sufficient size. Labeling needs to meet federal and state regulations. Labels are key to appropriate patient use, so they need to be carefully designed to promote readability and encourage compliance with medication regimens. In addition to relying on information in the USP General Notices and <17> Prescription Container Labeling, compounders can refer to the Institute for Safe Medication Practices s (ISMP) document Principles of Designing a Medication Label for Community and Mail Order Pharmacy Prescription Packages. 31 The document includes information on label format, methods to enhance patient comprehension, use of patient identifiers, and other practices to enhance patient safety. Labeling for compounded preparations should indicate, This is a compounded preparation. (See Shall statements in <795> concerning compounding practices sidebar.) Shall statements in <795> concerning compounding practices Store components and finished preparations off the floor and as directed by the manufacturer or according to USP, NF, or FCC monographs, including for appropriate temperature and humidity. Label preparations appropriately. Handle and store components and finished preparations to prevent contamination. Rotate stock so that the oldest is used first. Store components and finished preparations to permit inspection and cleaning of the compounding and storage area. If a component will be transferred from the original container, provide integrity that is equivalent to or better than the original container. If the component has been transferred from the original container, identify the new container with the component name, original supplier, lot or control number, transfer date, and expiration date. Protect equipment from contamination and locate it to facilitate use, maintenance, and cleaning. Use equipment and utensils of appropriate design and capacity. When the same equipment is used for different types of drug products, implement procedures including meticulous cleaning before re-use. Use only equipment and utensils with surfaces that are not reactive, additive, or sorptive. Routinely inspect, calibrate (as necessary), and check equipment used in compounding or testing of compounding preparations to ensure proper performance. Inspect equipment prior to use to ensure suitability. Clean equipment after use. Label the preparation container according to all applicable federal and state laws, including the BUD and storage and handling information. Label the preparation with the generic name and quality or concentration of each active ingredient, the BUD, storage conditions, and prescription or control number. Counsel the patient or patient s agent about proper use, and instruct them to report any adverse event. Compounding for animals Pharmacists who compound for companion, performance, and food animal patients have additional responsibilities. They must be familiar with the Animal Medicinal Drug Use Clarification Act of 1994 and related FDA regulations. 32 (See Shall statements in <795> concerning animal patients sidebar.) Veterinarians are required by law to give caregivers of food-producing animals an accurate length of time to withhold treated animal tissues (e.g., meat, milk, eggs) from the human food supply. This withdrawal time, or WDT, must be included on the label of every prescription prepared for a food-producing species. Guidance documents from the American Veterinary Medical Association ( the Society of Veterinary Hospital Pharmacists ( and the American Academy of Veterinary Pharmacology and Therapeutics ( provide more information. OCTOBER 2017 PharmacyToday 63

9 CPE COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> Shall statements in <795> concerning animal patients Possess a functional knowledge of drug regulation and disposition for animals. Possess a knowledge about the individual species limitation in physiology and metabolic capacity that can result in toxicity when certain drugs or excipients are used in compounded preparations. Identify the intended use of any prescription for an animal prior to compounding. Conduct a literature search if formulations specifically developed for animals are not available to determine if a component of the formulation is toxic to the target species. Include the withdrawal time on the label of every prescription dispensed for a food-producing species. Compounding investigational drugs Pharmacists who compound investigational agents need to be familiar with the additional requirements related to that specialized function. USP <1168> Compounding for Phase 1 Investigational Studies provides further information. Containers and closures Various factors need to be considered when assessing the stability of nonsterile compounding. In addition to the stability of the drug and final preparation, the container and closure system used will affect the appropriate BUD of the mixture (see Shall statements in <795> concerning containers and closures sidebar). Several USP General Notices and General Chapters can be used to evaluate containers and closures, including <659> Packaging and Storage Requirements <660> Containers Glass <661> Plastic Packaging Systems and Their Materials of Construction <671> Containers Performance Testing <1136> Packaging and Repackaging Single-Use Containers Shall statements in <795> concerning containers and closures Use containers and closure systems that meet USP requirements. When appropriate, obtain verification from the supplier of compliance with USP requirements. Use containers made of clean materials so the quality, strength, and purity of the compound is maintained. Store containers and closures off the floor, and handle them to prevent contamination. Store stock in a way that permits inspection and cleaning of the storage area. Rotate stock so the oldest is used first. Monographs and other peer-reviewed literature may provide additional information, but use of those documents must include the components, containers, and closures supporting use of the stability listed in the literature (see Documentation section). Unless the tests listed in monographs and General Chapters are specifically required, compounders do not need to perform the tests, but they do need to be knowledgeable about their function. 64 PharmacyToday OCTOBER 2017 Stability and beyond-use dates Manufacturers perform specific tests to determine the expiration date of their products. The products can be used until the date listed on the package, provided they are stored as required in the labeling. This differs from BUDs used by compounders, as the extensive studies are generally not completed. (See Shall statements in <795> concerning beyonduse dates sidebar.) Shall statements in <795> concerning beyond-use dates Review stability factors in <1191> Stability Considerations in Dispensing Practices. Use your compounding education and experience. Consult and apply drug-specific and general stability documentation and literature. Observe the compounded preparation for signs of instability. When the manufacturer s information is available, the information in the package insert can be used. For example, the BUD to use when reconstituting an antibiotic suspension is listed in the product labeling (package insert). Though this is defined as simple compounding by <795>, the manufacturer has completed sufficient study to allow that information to be placed in the FDA-approved labeling. Some compounded preparations such as those in USP compounding monographs or in peer-reviewed literature have undergone testing according to USP standards to support a specific BUD. However, most compounds have not undergone such studies, so depend on the default BUDs established in <795>. (See Table 3.) When determining the BUD for a compound, compounders must consider a variety of elements: Chemical stability of the compounded preparation Drug-specific and general stability documentation and literature to limit the potential of a compound falling outside the required USP strength or potency (generally, ±10% of labeled content) Stability in the container Expected storage conditions Competency of compounding personnel For a more complete reference on strength and stability testing for compounded preparations, see sites/default/files/usp_pdf/en/healthcareprofessionals/ strength-stability-testing-compounded-preparations.pdf. 33 Unless manufacturer, USP compounding monograph, or peerreviewed literature for the specific compound is available and used, the default BUDs listed in <795> must not be exceeded. Documentation Four key types of documents are required for safe and contemporary compounding (see Shall statements in <795> concerning documentation sidebar). Policies and procedures Safety data sheets Master Formulation Records Compounding Records Policies and procedures. Unless otherwise required by laws, regulations, or organizational policy, documentation

10 COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> CPE Table 3. Beyond-use dates Type of formulation Maximum beyond-use date (BUD) The BUD cannot exceed the expiration date of the API or any other component. Nonaqueous formulation 6 months Water-containing topical/dermal and mucosal liquid and semisolid formulation 30 days Water-containing oral formulation 14 days, under refrigeration Source: Adapted from <795>. can be written or electronic as long as it is retrievable. Most state boards of pharmacy, some states, and many organizations have record-retention policies and regulations with which the pharmacy must be compliant. Policies and procedures should be designed to standardize practices. They should be reviewed at least annually and whenever dictated by changes in processes or personnel or addition of new or revised equipment. Standard operating procedures need to be designed and clearly written to ensure accuracy, quality, safety, uniformity in compounding, and accountability. (See Example list of policies and procedures sidebar on page 61.) Safety data sheets. Employers are required to comply with OSHA s Hazard Communication Standard. 34 Safety data sheets (SDSs), previously known as material safety data sheets, are required to be available for pharmaceuticals that the drug manufacturer has determined to be hazardous and that are known to be present in the workplace. 35 As defined in the Federal Food, Drug, and Cosmetic Act, drugs in solid, final form for direct administration to the patient (i.e., tablets, pills, capsules) are exempt. 36 The newer format of SDSs presents the information in a standardized format containing 16 sections. SDSs for required medications and chemicals should be available to staff for reference when needed. Master Formulation Records (MFR). The MFR is designed to standardize formulas. Many often refer to recipe cards, which define the ingredients and mixing instructions for compounds. MFRs contain similar content but are more comprehensive. USP <795> requires the MFR to contain Official or assigned name, strength, and dosage form Ingredients and quantities Calculations and doses Compatibility and stability information and references Equipment needed Mixing instructions Label information Container used Packaging and storage requirements Description of the final preparation Quality control procedures and expected results An MFR is not required when preparing a compound according to the manufacturer s instructions in the labeling. Compounding Records (CRs). CRs are documents that detail the specific compound dispensed to a particular patient. USP <795> requires the CR to contain Official or assigned name, strength, and dosage Reference to the MFR Names and quantities of all components Sources, lot numbers, and expiration dates of components Total quantity compounded Names of personnel who prepared, performed quality control, and approved the preparation Date of preparation Assigned control or prescription number Assigned BUD Copy of label Results of quality control Documentation of any quality control issues and any adverse drug reactions reported by the patient Shall statements in <795> concerning documentation Include all required elements in the MFR. Follow the MFR. Quality control Each compounding pharmacy should have a quality assurance plan containing specific elements to indicate safety and quality of compounds mixed. Personnel training is key to maintaining quality. Trends and variances from expected results are valuable to ensure a quality system. (See Shall statements in <795> concerning quality control sidebar.) USP <1163> Quality Assurance in Pharmaceutical Compounding provides a framework for the elements to include in a quality assurance plan. Clear policies, robust personnel training, and testing and verification of finished preparations should all be included in a pharmacy s plan. Shall statements in <795> concerning quality control Follow the MFR and complete the CR when executing the compounding process. Review each procedure in the compounding process. Check and recheck each procedure at each stage of the process. Establish written procedures that describe the tests or examination conducted on the compounded preparation to ensure uniformity and integrity. Observe the finished preparation to ensure it appears as expected. Take appropriate corrective action when any discrepancies are found. Establish control procedures to monitor the output and to verify the performance of compounding processes and equipment that may be responsible for causing variability in the final compounded preparation. Investigate and document any reported problems with a compounded preparation, and take corrective action. OCTOBER 2017 PharmacyToday 65

11 CPE COMPOUNDING NONSTERILE PREPARATIONS: USP <795> AND <800> Handling hazardous drugs USP <800> Hazardous Drugs Handling in Healthcare Settings was published in February 2016 and had one errata published in May <800> becomes official on July 1, By that date, compliance with all containment requirements and work practices must be completed. Major elements of <800> include identification of the HDs handled in the workplace, use of the appropriate facilities in which to store and compound HD nonsterile preparations, and use of robust work practices to protect personnel from contamination with HDs. The concepts in <800> are not new; they date from pharmacy guidance documents from the 1980s. 37 USP <795> includes requirements for HDs, but much more extensive information and requirements are listed in <800>. (See Shall statements in <795> concerning hazardous drugs sidebar.) USP <800> is designed to protect health care personnel in addition to protecting patients and the environment. It addresses but is not limited to containment and protection for receipt, storage, compounding, dispensing, administration, and disposal of HDs. Just like <795>, it applies to all health care personnel and all health care entities, but its scope is wider: from receipt of HDs in the pharmacy through dispensing, administration, and proper waste disposal occurring in a health care setting. Several NIOSH documents provided structure and significant content to the development of <800>. Use of Tables 1, 2, and 3 in NIOSH s List of Antineoplastics and Other Hazardous Drugs in Health Care Settings, 2016, is required by <800>. 38 These are drugs that meet the definition of an HD: Carcinogenicity Teratogenicity or other developmental toxicity Reproductive toxicity Organ toxicity at low dose in humans or animals Genotoxicity New drugs that mimic existing HDs in structure or toxicity NIOSH s list sorts the HDs into three tables: antineoplastics, non antineoplastics, and those that are reproductiveonly hazards. Note that not all dosage forms create the same risk; agents in final form that are not further manipulated may not create the same level of hazard as those that are further manipulated or those that are APIs. Entities may add additional agents to their list of HDs, but there is no requirement to do so. Any items added need to comply with the elements in <800>. NIOSH s Hierarchy of Controls (Figure 2) was used to design the controls that support safety when handling HDs. The two most effective risk-limiting steps elimination and substitution are generally not practical when considering compounding because the patient needs the preparation. Protection of health care personnel then falls to use of the three other controls: engineering controls, administrative controls, and personal protective equipment. These three controls have been incorporated into <800> to help contain HDs and minimize their risk to health care personnel. Figure 2. Hierarchy of controls Most effective Shall statements in <795> concerning hazardous drugs Store, prepare, and handle HDs by appropriately trained personnel under conditions that protect the health care workers and other personnel. Before preparing or handling HDs, train all personnel who compound in the storage, handling, and disposal of HDs. Train all personnel who perform routine custodial waste removal and cleaning activities in storage and preparation areas. Comply with all applicable federal and state regulations for disposal of HD waste. See additional requirements in <800>. Least effective Elimination Substitution Engineering Controls Administrative Controls PPE Physically remove the hazard Replace the hazard Isolate people from the hazard Change the way people work Protect the worker with Personal Protective Equipment 66 PharmacyToday OCTOBER 2017 Source: Graphic courtesy of National Institute of Occupational Safety and Health. Identifying the hazardous drugs handled USP <800> has a wider scope than <795>, as it is intended to protect all health care personnel in all health care sites. To ensure safety, each pharmacy must identify the HDs it handles. The HDs on the NIOSH list are those that are hazardous to personnel. These HDs are different from pharmaceutical waste, which must be handled in compliance with Environmental Protection Agency (EPA) requirements. 39 EPA waste of which pharmaceuticals are only a part includes substances that are detrimental to the environment. Both personnel and environmental safety are important, but <800> and the NIOSH list are limited to those drugs that affect the health of health care personnel. Each entity, such as a pharmacy, must review the NIOSH list and determine the drugs on the list that are handled at its site, as well as the dosage forms of those drugs. USP <800> allows two options for handling: Handle all the drugs and dosage forms on the list with all of the containment strategies and work practices listed in <800>. Perform an Assessment of Risk for those drugs allowed for entity exemption, and establish and implement alternative containment strategies and work practices for those agents. Some drugs on the list contain ingredients that may not be entity exempt and must be handled with all of the contain-