The regulatory rules covering conventional commercial pharmaceuticals and compounded drugs are complicated, and they reach into manufacturing, labeling, marketing, and distribution. States have historically concentrated on pharmacy licensure and protocols, while federal guidance on making and handling compounded substances has been changing quickly.[7]
What is Compounding: Why it’s Done?
Compounding combines drugs with other drugs or substances to meet the needs of an individual patient or a healthcare facility. It may be necessary where someone cannot take a mainstream formulation because of an allergy or an intolerance. Particular dyes or preparations are not always well tolerated by children or elderly patients either. It is also used when an FDA approved drug is not appropriate for that patient.[2]
Compounding involves combining ingredients to help support or treat a number of medical conditions.
Types of compounding include
- Combining an FDA approved drug with another agent Diluting an FDA approved drug
Combining a bulk substance considered an API, or active pharmaceutical ingredient with excipients, or inactive ingredients that together produce a final compounded product.[11]
Compounding can be sterile or non-sterile. Sterile compounding uses aseptic technique and covers injectable, implant, and ophthalmic preparations. Non-sterile compounding happens in a clean environment without aseptic technique, and covers oral and topical formulations such as suspensions, capsules, solutions, ointments, creams, and suppositories. Both have to be prepared with safety, purity, and cleanliness controlled throughout.
Who Dispenses Compounded Drugs?
Hospitals, medical doctors in private practice, clinics, and other healthcare facilities sometimes treat patients with specially formulated compounded medications.[2]
Concerns with Compounding-False or Misleading Claims As demand for compounded drugs has grown, so have concerns about patient safety. Some compounders claim that preparations using particular ingredients are FDA approved when they are not. That misleads patients about the risk they are taking and undermines the approval process itself.
Does the FDA approve compounded drugs?
The Food and Drug Administration does not approve compounded medications, or the way they are prepared, in the manner it reviews mainstream pharmaceuticals.
Consumers generally expect the FDA to keep harmful substances away from them, and to confirm that products work and have not been misrepresented. Compounded drugs sit outside the usual premarket and postmarket regulatory steps that apply during manufacturing.
Are compounded drugs risky for patients?
Compounded drugs do serve patients who would otherwise go without treatment for a specific condition. They are not checked for safety and efficacy the way FDA approved drugs are. Contamination and poor compounding practice both affect quality, and a compounded preparation can carry too much or too little active ingredient, which is harmful either way.
Compounding usually happens in a pharmacy licensed by the state, or in a federal facility. The pharmacist or physician doing it must be licensed in the state where they work. In an outsourcing facility it has to be done under the direct supervision of a licensed pharmacist.
Quality Standards for Compounded Pharmaceuticals-CGMP Requirements
Requirements differ by setting. Drugs compounded in outsourcing facilities fall under Current Good Manufacturing Practice, which among other things forbids handling or packing any drug under unsanitary conditions.
Under the Food, Drug & Cosmetic Act a compounded drug counts as a new drug. Pharmacists do not need FDA approval for one. Given how much compounded formulations vary, evaluating each one individually would be close to impossible for the agency.[12]
FDA Guidance for Current Good Manufacturing Practice
The FDA publishes guidance on human drug compounding under Current Good Manufacturing Practices. The draft covers outsourcing facilities registered under 503B of the Federal Food and Drug Cosmetic Act, and it is revised periodically, including on how it applies to the size and scope of a given facility's operation.[5]
The agency's compounding program provides resources for prospective compounding manufacturers, consumers, physicians, hospitals, and clinics. These include Quality Center of Excellence material and webinars covering education, instruction, and guidelines for people working in the industry.[6]
Current Good Manufacturing Practices and Results
Human pharmaceuticals are held to a uniformed standard based on both safety and efficacy. These involve drug quality, strength, identity, and purity.
Medication manufacturers comply with CGMP by
- Establishing strong quality management systems
- Using only quality raw materials in formulations
- Creating and following strong operating procedures
- Discovering deviations in product quality
- Creating and maintaining reliable testing labs
Following CGMP’s helps reduce the risk for contamination, mix-ups, deviations, failures, and mistakes.[4]
Bulk drugs are the base substances used in manufacturing, processing, or packaging a product. They include the active ingredients that become part of a final compounded formulation. The FDA periodically asks for nominations of bulk drug products for the 503B bulks list.
Under section 503B of the Federal Food, Drug, and Cosmetic Act, an outsourcing facility may not compound with a bulk drug unless that substance appears on the approved 503B bulks list or on the FDA's drug shortage list. It must also be made by a company registered with the FDA under section 510 of the Act.[1]
The FDA meets periodically to decide on proposed bulk ingredients needed to meet demand for compounded medications. Before it finalizes a decision it takes comment from the public on the likely impact and on whether the substance is genuinely needed.
Major Turning Point for the Compounding Industry
Until 2012 the Food and Drug Administration took a largely hands off approach to the compounding industry. Earlier that year a large New England compounding facility released a product that caused a fungal meningitis outbreak, killing 60 people and injuring more than 700.
That incident put the compounding industry in front of the US government. In 2013 Congress passed the Drug Quality Security Act to extend federal reach over compounded medications and the sector as a whole.[8]
A major change to current compounding legislation allows for traditional pharmacy compounding to continue for specific patients, without federal compliance, CGMP, or labeling requirements.
Additionally, compounders can also voluntarily register as an “outsourcing facility”, following CGMP regulations without FDA approval status.
Outsourcing Facilities
- Do not require licensure as a pharmacy
- Can only compound under direct supervision of a licensed pharmacist or physician
- Can obtain prescriptions that are patient specific
- Must use ingredients from a bulk ingredients list
- Cannot compound formulas that are currently commercially available unless they are in short supply
Must be inspected by the FDA regularly (risk-based schedule) Must submit specific product information every 6 months
Must report adverse reactions from compounded drugs to the FDA
Must pay a $15,000 annual fee to the FDA to cover the costs of inspection.[9]
Outsourcing Facility-Defined by the Food and Drug Administration
An outsourcing facility, by the FDA's definition, is a sterile facility set up specifically to compound drugs for commercial use. Under section 503B it registers with the agency voluntarily as a compounding company and agrees to work to the stated guidelines, including Current Good Manufacturing Practices.[3]
Outsourcing Facilities-Their Role in the U.S. Supply Chain
Outsourcing facilities matter to the US drug supply chain because they give hospitals, physicians, and dental offices sterile compounded formulations that are ready to use. Hospitals often need unit-dosed commercial pharmaceuticals in quantity without holding the sterile in-house capacity to produce them.
How Common is the Use of Outsourcing Facilities?
• One survey by the Office of the Inspector General found that of nearly 600 hospitals asked, close to 90% regularly obtained non-patient-specific compounded drugs from FDA registered outsourcing facilities.
• Outsourcing facilities carry real weight in the US supply chain, and they get used when a specific drug is short because manufacturing has slowed or the product has been discontinued.
• Outsourcing facilities can supply compounded medications to small practices, including dentists, ophthalmologists, and podiatrists. Physicians can then dispense directly to patients at set price points, which saves the patient a separate trip to a pharmacy.[10]
Compounded pharmaceuticals keep taking on more of the treatment load, and that puts the responsibility for patient safety on state and federal lawmakers. Working to Current Good Manufacturing Practices is what lets compounders keep contributing to treatment without repeating 2012.
1Center for Drug Evaluation and Research. (n.d.). Bulk drug substances used in compounding under Section 503B. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503b-fdc-act. 2Center for Drug Evaluation and Research. (n.d.). Compounding and the FDA: Q & A. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers. 3Center for Drug Evaluation and Research. (n.d.). Current good manufacturing practice-guidance for human drug compounding. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-practice-guidance-human-drug-compounding-outsourcing-facilities-under. 4Center for Drug Evaluation and Research. (n.d.). Facts about the current Good Manufacturing Practices (cgmps). U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-manufacturing-practices-cgmps. 5Center for Drug Evaluation and Research. (n.d.). Human Drug Compounding. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding. 6Center for Drug Evaluation and Research. (n.d.). Information for outsourcing facilities. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/drugs/human-drug-compounding/information-outsourcing-facilities. 7Center for Drug Evaluation and Research. (n.d.). Notice to compounders: Changes that affect compounding as of March 23. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/drugs/human-drug-compounding/notice-compounders-changes-affect-compounding-march-23-2020. 8Commissioner, O. of the. (n.d.). FDA provides preliminary assessment on Bulk Drug Substances. U.S. Food and Drug Administration. Retrieved December 14, 2021, from https://www.fda.gov/news-events/fda-brief/fda-brief-fda-provides-preliminary-assessment-five-bulk-drug-substances-use-outsourcing-facilities. 9Gabay, M. (2014, July). The Drug Quality and Security Act. Hospital pharmacy. Retrieved December 14, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252230/. 10Gianturco, S. L., Yoon, S. J., Yuen, M. V., & Mattingly, A. N. (2021). Outsourcing facilities and their place in the U.S. Drug Supply Chain. Journal of the American Pharmacists Association : JAPhA. Retrieved December 14, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453203/. 11Sciences, N. A. of, Engineering, & and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy. (2020, July 1). An overview of compounding. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Retrieved December 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK562881/. 12Sciences, N. A. of, Engineering, & and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy. (2020, July 1). Regulatory framework for compounded preparations. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Retrieved December 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK562888/.