U.S. Pharmacopeia (USP) General Chapter <797> was first published in 2004. The chapter was last revised in USP31–NF26 2nd Supplement, which became official on June 1, 2008. Proposed revisions to USP chapter <797> are expected to be published in late 2021 or early 2022. In many cases, the proposed revisions to USP chapter <797> attempt to clarify areas of the chapter that were previously open for interpretation. Conducting a gap analysis between current operations at your facility and the proposed revisions is necessary to determine the changes needed to become compliant with the revised chapter.
USP. General Chapter <797>. Available at: https://www.usp.org/compounding/general-chapter-797 (Accessed 2021 August 21).
Ultimately compounding of sterile preparations, along with other pharmacy activities, falls under the U.S. Food, Drug, and Cosmetic (FD&C) Act, and CSPs dispensed from a pharmacy must not be adulterated or misbranded in any way. The Drug Quality and Security Act (DQSA) further modified the FD&C Act and established section 503B. CSPs must adhere to different regulations depending on whether they are made in a 503A entity (pharmacy) or a 503B outsourcing facility. Because in most cases the Food & Drug Administration (FDA) enforces the FD&C Act, guidance for industry can be found at the agency website (www.fda.gov). Links to many of the applicable guidance documents on CSPs can also be found in a toolkit on this website.. One of the most notable FDA draft guidance documents that apply to both 503A and 503B entities is the FDA Guidance for Industry titled “Insanitary Conditions at Compounding Facilities.”
USP chapters provide minimum standards that must be met for compounding sterile preparations and are included as provisions for adhering to the FD&C Act. Standards exceeding USP chapters are required for FDA 503B registered outsourcing facilities. States may have additional regulations for compounding sterile preparations. See FAQ on specific state requirements for more information.
U.S. Food & Drug Administration. FD&C Act Chapter V: Drugs and Devices. October 5, 2015. Available at: https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/federalfooddrugandcosmeticactfdcact/fdcactchaptervdrugsanddevices/default.htm (Accessed 2021 August 20).
U.S. Food and Drug Administration. Insanitary Conditions at Compounding Facilities Guidance for Industry. November 2020. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM514666.pdf (Accessed 2021 August 20).
Compounding regulations vary by state and they may be more stringent than the federal requirements and standards of the Food & Drug Administration or U.S. Pharmacopeia. Be sure to have access to the most recent state laws and regulations for your jurisdiction. Most state Boards of Pharmacy have a website that can provide the regulations for their licensees. The National Association of Boards of Pharmacy has a webpage with links to state boards of pharmacy. CriticalPoint, LLC maintains a database with information about state requirements for compliance with USP chapter <797>.
CriticalPoint, LLC, Clinical IQ, LLC. Regulatory Status Levels of States/DC. March 2021. Available at: http://www.criticalpoint.info/Statemap/story.html (Accessed 2021 August 20).
National Association of Boards of Pharmacy. Boards of Pharmacy. Available at: https://nabp.pharmacy/boards-of-pharmacy/ (Accessed 2021 August 20).
In short, a 503A entity is a compounding pharmacy.
The 2013 Drug Quality and Security Act (DQSA) amended section 503A of the Food, Drug, and Cosmetic (FD&C) Act. According to the Food & Drug Administration (FDA) Guidance document entitled Pharmacy Compounding of Human Drug Products Under Section 503A of the Food, Drug, and Cosmetic Act, “Section 503A describes the conditions that must be satisfied for drug products compounded by a licensed pharmacist or licensed physician to be exempt from the following three sections of the FD&C Act: (1) section 501(a)(2)(B) (concerning current good manufacturing practice); (2) section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and (3) section 505 (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)).”
U.S. Food & Drug Administration. Pharmacy Compounding of Human Drug Products Under Section 503A of the Food, Drug, and Cosmetic Act. June 2016. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469119.pdf (Accessed 2021 August 20).
In short, a 503B entity is one that has voluntarily registered with the Food & Drug Administration (FDA) as an outsourcing facility and is subject to requirements for current Good Manufacturing Practices (cGMP) and inspections by FDA.
The Drug Quality and Security Act (DQSA), signed into law on November 27, 2013, created a new section 503B of the Food, Drug, and Cosmetic Act. Section 503B(d)(4) defines an outsourcing facility as “A facility at one geographic location or address that— (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Section 503B(d)(4) further states that an outsourcing facility is not required to be a licensed pharmacy and may or may not obtain prescriptions for identified individual patients. Section 503B(d)(5) defines sterile drug as a “drug that is intended for parenteral administration, an ophthalmic or oral inhalation drug in aqueous format, or a drug that is required to be sterile under Federal or State law.”
It is critical to confirm that any entity you are considering as a vendor is registered as a 503B outsourcing facility if they are providing services outside of what is allowed in a 503A compounding pharmacy. Even if an entity is registered as an FDA 503B outsourcing facility, they may not have been inspected. Registration with FDA as an outsourcing facility is voluntary, and organizations can register or deregister at any time. The FDA’s Registered Outsourcing Facilities website provides a list of entities registered as outsourcing facilities and the inspection status.
U.S. Food & Drug Administration. Guidance for Entities Considering Whether to Register as Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act. August 2015. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434171.pdf (Accessed 2021 August 20).
U.S. Food & Drug Administration. FDA’s Human Drug Compounding Progress Report: Three Years after Enactment of the Drug Quality and Security Act. January 2017. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM536549.pdf (Accessed 2021 August 20).
U.S. Food & Drug Administration. Registered Outsourcing Facilities. Available at: https://www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities (Accessed 2021 August 20).
The Food & Drug Administration (FDA) form 483 is used by the agency to cite “objectionable conditions.” According to the FDA Form 483 Frequently Asked Questions website, “An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts.” The website also explains that “The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection.” Citations range from procedures not being in writing to inadequate batch sizes being tested and personnel not practicing good sanitation and health habits. Many of the observed 483s were insanitary conditions in 503A pharmacies that had been inspected by FDA. Many of these insanitary conditions violate requirements that are found in USP Chapter <797>.
Use of the FDA Form 483 is not limited for 503B registered outsourcing facilities. The Form can be issued to any entity inspected by FDA. The agency may also inspect and issue Forms 483 for compounding pharmacies, producers of sterile drug products, and laboratories that perform sterility and stability testing. For a complete listing of reports and citations issued by the FDA Office of Regulatory Affairs (ORA), visit the ORA Freedom of Information Act (FOIA) Electronic Reading Room. Similarly, inspection results can be searched by vendor name through the FDA Compounding: Inspections, Recalls, and Other Actions site. Perhaps as important as whether or not a 483 was received is what the response to the FDA 483 was by the vendor.
U.S. Food & Drug Administration. FDA Form 483 Frequently Asked Questions. Available at: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fda-form-483-frequently-asked-questions (Accessed 2021 August 20).
U.S. Food & Drug Administration. ORA FOIA Electronic Reading Room. Available at: https://www.fda.gov/about-fda/office-regulatory-affairs/ora-foia-electronic-reading-room (Accessed 2021 August 20).
U.S. Food & Drug Administration. FDA Compounding: Inspections, Recalls, and Other Actions. Available at: https://www.fda.gov/drugs/human-drug-compounding/compounding-inspections-recalls-and-other-actions (Accessed 2021 August 20).
According to FDA, “Guidance documents represent the Agency's current thinking on a particular subject. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.”
Furthermore, “In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.” Despite this information from the Agency, these guidance documents can be used to cite both 503A and 503B entities. The expectation is that compliance with these guidance documents or alternative method must be used to address the activities described in the guidance documents.
Guidance documents are generally published in draft form and a period for public comment is allowed. The Agency reviews comments before publishing final guidance documents. To identify the most up-to-date version of FDA guidance documents for compounding, visit the FDA Regulatory Policy Information website.
U.S. Food & Drug Administration. Guidances (Drugs). Available at: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs (Accessed 2021 August 20).
U.S. Food & Drug Administration. Regulatory Policy Information. Available at: https://www.fda.gov/drugs/human-drug-compounding/regulatory-policy-information (Accessed 2021 August 20).
The repackaged drug needs to meet all applicable laws, regulations, and standards. The FDA Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities Guidance for Industry addresses this topic. As of January 2017, “FDA regards repackaging as the act of taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug. Repackaging also includes the act of placing the contents of multiple containers (e.g., vials) of the same finished drug product into one container, as long as the container does not include other ingredients. If a drug is manipulated in any other way, including if the drug is reconstituted, diluted, mixed, or combined with another ingredient, that act is not considered repackaging.” The FDA document refers to USP chapter <797> for BUD limits.
U.S. Department of Health and Human Services Food & Drug Administration Center for Drug Evaluation and Research. Repackaging of certain human drug products by pharmacies and outsourcing facilities. Guidance for Industry. January 2017. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/repackaging-certain-human-drug-products-pharmacies-and-outsourcing-facilities (Accessed 2021 July 24).
FDA finalized Guidance for Industry entitled Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act in December 2016. In this Guidance document, compounding before receipt of a valid prescription order is described as anticipatory compounding. Section 503A(a)(2) of the Food, Drug, and Cosmetic Act provides for “compounding by a licensed pharmacist or licensed physician in “limited quantities before the receipt of a valid prescription order for such individual patient” if:
- “The compounding is based on a history of the licensed pharmacist or licensed physician receiving valid prescription orders for the compounding of the human drug product; and
- The orders have been generated solely within an established relationship between the licensed pharmacist or licensed physician and either such patient for whom the prescription order will be provided or the physician or other licensed practitioner who will write such prescription order.”
- “The compounder holds for distribution no more than a 30-day supply of a particular compounded drug product (i.e., units of a compounded drug product that the compounder believes it will distribute over a 30-day period) to fill valid prescriptions it has not yet received; and, the amount of the supply of a particular compounded product is based on the number of valid prescriptions that the compounder has received for identified individual patients in a 30-day period over the past year that the compounder selected.”
The Guidance document provides additional limitations and policies applicable to compounding before receipt of a valid prescription order.
U.S. Food & Drug Administration. Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry. December 2016. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/prescription-requirement-under-section-503a-federal-food-drug-and-cosmetic-act-guidance-industry (2021 August 20).
The list of stakeholders for CSP insourcing obviously includes pharmacy personnel, but other departments that need to be included in the planning and implementation of new or expanded services should be considered. These other departments might include risk management, environmental services, infection control, nursing, legal, and hospital administration. Clinicians with high rates of CSP prescribing or clinicians that prescribe high risk CSPs also might be involved.
The Insourcing Sterile Compounding Services Readiness Assessment Tool on this website includes a section on stakeholder relations. This section provides organizations with a way to identify key stakeholders.
The Controlled Environment Testing Association (CETA) provides certifiers with a series of CETA Certification Application Guides (CAGs), including CAG-003 on Sterile Compounding Facilities. Your certifier should use these CAGs and the other resources based on the types of Primary Engineering Controls (PECs) that you use. The report should include findings on key points such as:
- Certification under dynamic (operating) conditions
- Leak testing of the HEPA filters in your PECs and ISO classified rooms
- Particle counts
- Air changes per hour
- Room pressurization
- Smoke tests of your PECs under dynamic operating conditions
- Electronic air sampling for microbial and fungal tests – environmental sampling can be done by the certifier but CAG-003 addresses certification and CAG-009 addresses how to sample.
- Surface sampling of your PECs and room
The CSPInsourcing.org Evaluation Toolkit Quality section provides links to articles and meeting proceedings on this and similar topics.
The certifier should provide a clear report that lists which elements pass, fail, and need attention. Review the report with the certifier to be sure you understand all of the items tested and the results.
The CSPInsourcing.org Evaluation Toolkit Quality section provides links to articles and meeting proceedings on this and similar environmental monitoring topics.
Requirements for pharmacy technicians need to be clearly indicated in the position posting and job description. Not everyone is suited for working in a sterile compounding area. The person needs to have the ability to follow detailed directions, manual dexterity to perform the steps required, and exceptional math skills; be able to recognize deviations from standard practices; and have the disposition to escalate concerns to a supervisor when necessary. It is critical to understand and comply with all state board of pharmacy licensing requirements of pharmacy technicians, if applicable.
The CSPInsourcing.org Implementation Toolkit Personnel section includes a sample job description for personnel working in the sterile compounding area and articles with advice on identifying and training compounding personnel.
If default beyond-use date (BUD) limits of U.S. Pharmacopeia (USP) chapter <797> are not exceeded, or less than 25 units of a high-risk level CSP is not made compounded in a single batch, no sterility or endotoxin testing is required. All CSPs must have BUDs assigned on valid scientific data generated from drug stability-indicating studies. Many of these tests are described in USP Chapters, such as <51> Antimicrobial Effectiveness Testing, <71> Sterility Tests, and <85> Bacterial Endotoxins. Recognize that you need to test the sterility of each batch if you extend the BUDs beyond what is specified in USP chapter <797>.
The USP Compounding Compendium is available for purchase from USP. This reference provides the USP chapters, general notices, and other documents required for compounding sterile preparations.
USP chapter <797> proposed revisions were posted July 27, 2018 to the USP website. An intended publication date for the updated standard is June 1, 2019, with an anticipated official date of December 1, 2019.
U.S. Pharmacopeial Convention. Pharmaceutical Compounding – Sterile Preparations. USP31–NF26 2nd Supplement, 2008. Updates on this chapter are available at: https://www.usp.org/compounding/general-chapter-797 (Accessed 2021 August 20).
Technically, yes, but most hospital laboratories are not set up for this testing activity. Consider the reasons why end-product testing is being done in the first place. Both stability and sterility tests are needed if end-product testing is done to extend beyond-use dates (BUDs). Any extension of BUDs must conform with the applicable USP chapters as well as USP chapter <797>, such as chapter <51> Antimicrobial Effectiveness Testing, <71> Sterility Tests, and <85> Bacterial Endotoxins. Additional information on strength and stability testing for compounded preparations is available on the USP website.
The decision to have a hospital laboratory perform end-product testing should be made only after obtaining input from pharmacy, laboratory, infection control, hospital administration, and other stakeholders, depending on the goals of the program.
The CSPInsourcing.org Implementation Toolkit End-Product Testing section provides links to articles on this and similar topics. Links to articles on end-product tests and what the tests are used for also are available on the site.
U.S. Pharmacopeial Convention. Strength and Stability Testing for Compounded Preparations. Available at: https://www.usp.org/sites/default/files/usp/document/FAQs/strength-stability-testing-compounded-preparations.pdf (Accessed 2021 August 20).
Any laboratory that performs end-product testing needs to be registered with the Food & Drug Administration (FDA). Ideally, the laboratory should also be accredited by a third-party vendor, such as the American Association for Laboratory Accreditation (A2LA) or International Organization for Standardization (ISO).
It is critical that staff at any laboratory vendor utilized for end-product testing have extensive knowledge about U.S. Pharmacopeia standards for testing, sample size, and method suitability for sterility testing. Similarly, anyone utilizing a laboratory for end-product testing should have a solid understanding of applicable regulations and standards. For additional information on the types of certifications and laboratory services that should be available, visit the CSPInsourcing.org Implementation Toolkit End-Product Testing section.
When assessing an end-product testing laboratory vendor, review any inspection reports by the Food & Drug Administration. Use the same approach to evaluate the laboratory vendor that you would for an outsourcing facility.
As with any expansion of services within the pharmacy, there are a number of factors to be considered when estimating the need for additional space. Several general questions must be answered prior to evaluating specific square footage needs:
- What is the capacity of the current sterile compounding space?
- Will the quantity or type of CSPs increase or change in a significant way (e.g., will hazardous drugs, parenteral nutrition, or compounding of non-sterile to sterile preparations be added?)?
- What is the total volume of CSPs expected to be insourced?
- What additional product lines will be added, and will there be any special circumstances to consider with those product lines (e.g., need for space for a parenteral nutrition automated compounder)?
Once some of these overarching questions are answered, the Insourcing Sterile Compounding Services Readiness Assessment Tool should be used. It has a section that breaks down specific square footage needs and assists with assigning costs to the space needs. Do not forget to consider any additional facility or equipment needs (e.g., refrigerators, freezers, primary engineering controls, robots, IV workflow devices) in the space evaluations. Much of the cost of sterile compounding service expansion comes from air handling needs; be sure to include this cost when budgeting for any expansion or remodeling.
Hospitals generally have a local or regional architecture firm plan their new buildings and renovations. Few of these firms have experience building sterile compounding areas. The best approach is to identify the amount of initial space allocated, then work with consultants who plan and evaluate sterile compounding facilities to design the space. Space, intended processes, workflow, and current and anticipated changes in USP chapters pertaining to sterile compounding need to be addressed.
The CSPInsourcing.org Implementation Toolkit Cleanroom Design section has links to several articles on cleanroom design from design experts with extensive knowledge of USP chapter <797>. This section also includes an interactive cleanroom design that shows a real world cleanroom scenario with key considerations highlighted throughout the design.
The CSPInsourcing.org Insourcing Sterile Compounding Services Readiness Assessment Tool has a section on real estate and facility needs and cleanroom design. Working through the Assessment Tool with stakeholders prior to meeting with engineers or architects will provide a systematic way to evaluate your space and configuration needs. Similarly, the Real Estate and Facility Considerations Worksheet found in the Facility section of the CSPInsourcing.org Evaluation Toolkit can be a valuable exercise for stakeholders to complete.
Yes, as long as any and all environmental monitoring requirements listed in U.S. Pharmacopeia (USP) chapter <797> are met, using qualified and trained personnel using the appropriate equipment that has been calibrated. USP chapter <797> requires an independent certification at least once every 6 months. Pharmacies may choose to conduct environmental monitoring, including viable and non-viable sampling, more frequently to identify trends and deviations from acceptable limits. If you conduct sampling more often than the minimum requirements of USP <797>, it may make sense to perform your own testing, with testing by certifiers used as an independent test.
Organizations opting to conduct in-house environmental monitoring programs must have trained pharmacy technicians, pharmacists, or other personnel to conduct the testing and monitor samples.
The CSPInsourcing.org Evaluation Toolkit Quality section includes links to several articles and meeting proceedings on environmental monitoring, including taking on the responsibility of conducting in-house testing. Additionally the Policies and Procedures section links to detailed policies and procedures for conducting viable and non-viable sampling, and root cause analyses worksheets.
Start by identifying the CSPs that you outsource and your organization’s current needs. Some general questions to consider include:
- Are all currently outsourced CSPs still necessary?
- Could some CSPs be standardized with a single concentration, volume, or base solution?
- Are commercially manufactured products available that could be used instead of CSPs?
- Would it be practical to compound small batches of CSPs with beyond-use dates that conform to USP chapter <797> limits?
- What operational and clinical issues do you need to address? For example, could standardization of cardiovascular or oxytocin solutions minimize the workload involved in preparation?
- If you need concentrated solutions for analgesia pumps, do you have the capacity to test these high-risk CSPs?
The Insourcing Sterile Compounding Services Readiness Assessment Tool has a section on CSP product line evaluation. This section of the tool provides a downloadable Excel spreadsheet to assist with critically evaluating currently used CSPs and forecast potential changes. Working through the Assessment Tool with members of the pharmacy sterile compounding services team and other stakeholders will provide a thorough overview of your organizational CSP product line needs. Similarly, the Product Line Evaluation section of the CSPInsourcing.org Implementation Toolkit provides links to articles and presentation proceedings from other organizations outlining strategies that they have used to evaluate product line needs.
The inspection of the vendor facility by the Food & Drug Administration (FDA) will focus on assessing current Good Manufacturing Practices (cGMP). The 503B status and a review of the FDA inspection report provide insight into regulatory and process issues that were identified during an inspection. You would want to discuss any findings from the inspection with a potential vendor. However, you may have additional questions that are more closely related to your operational and product line needs.
American Society of Health-System Pharmacists. ASHP Guidelines on Outsourcing Sterile Compounding Services. 2015. Available at: https://www.ashp.org/outsourcing-compounding-services (Accessed 2021 August 20).
It is critical to confirm that any entity you are considering as a vendor is registered as a 503B outsourcing facility if they are providing services outside of what is allowed in a 503A compounding pharmacy. Technically, to be considered an outsourcing facility, the organization should register with the FDA, but registration is voluntary.
Even if an entity is registered as an FDA 503B outsourcing facility, they may not have been inspected. Registration with FDA as an outsourcing facility is voluntary, and organizations can register or deregister at any time. The FDA’s Registered Outsourcing Facilities website provides a list of entities registered as outsourcing facilities. The website also provides links to inspection reports, FDA Forms 483 that have been issued, additional actions taken by FDA, and information on outsourcing facility plans to use bulk substances.
The FDA’s Human Drug Compounding Progress Report published in January 2017 summarizes outcomes from FDA inspections of registered outsourcing facilities.
U.S. Food & Drug Administration. FDA’s Human Drug Compounding Progress Report: Three Years after Enactment of the Drug Quality and Security Act. January 2017. Available at: https://www.fda.gov/media/102493/download (Accessed 19 January 2017).
U.S. Food & Drug Administration. Registered Outsourcing Facilities. January 6, 2017. Available at: https://www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities (Accessed 19 January 2017).