Compounding, Outsourcing Facilities, Current Good Manufacturing

The regulatory laws that govern both conventional, commercial pharmaceuticals and compounded drugs are complex. These pertain to many areas of manufacturing, labeling, marketing, and distribution. While individual states have focused on pharmacy licensure and protocols in the past, federal guidelines for the creation and handling of compound substances are quickly evolving.[7]

What is Compounding—Why it’s Done?

Compounding includes the process of combining drugs with other drugs or substances to meet the specific needs of individual patients or healthcare facility. Drug compounding may be necessary for those who may not be able to use a more mainstream drug formulation due to an allergy or intolerance. Specific dyes, or preparations may not be well tolerated by children or elderly patients as well. Compounding may also be performed when an already FDA approved drug is not appropriate for the 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]

Both sterile and non-sterile compounding can be performed. Sterile compounding involves aseptic techniques and is used primarily in injectable, implant, and ophthalmic preparations. Non-sterile compounding is prepared in a clean environment, without aseptic techniques. Oral and topical formulations include suspensions, capsules, solutions, ointments, creams, and suppositories. These are considered non-sterile compound formulations. These must each be prepared with optimal safety, purity and cleanliness in mind.

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 the demand for compound drugs increases, concerns over patient safety have arisen as well. Some compounders assert that preparations using specific ingredients are FDA approved when, in fact they are not. These false claims could put patients at serious risk and also undermine the FDA approval process.

Does the FDA approve compounded drugs?

In a general sense, the Food and Drug Administration does not “approve” compounded medications or their preparation in the same way mainstream pharmaceuticals are reviewed.

Many consumers look to the FDA to keep them safe from potentially harmful substances. Many also rely on the agency to ensure products are effective and have not been misrepresented in any way. Drugs that are compounded are not subject to the usual regulatory actions included in the manufacturing process both before and after market.

Are compounded drugs risky for patients?

Compounded drugs serve a purpose for some patients who may not otherwise get treatment for specific medical conditions. They are not checked for safety and efficacy the same way that FDA approved drugs are monitored. Problems with contamination and poor compounding practices can affect quality and safety. Some compounded pharmaceuticals may contain too much or too little of an active ingredient which can be harmful to a patient.

Compounding is usually performed in a pharmacy that must be licensed by the state, or in a federal facility. The pharmacist or physician who performs the compounding must be licensed by the state in which they work. If compounding is done at an “outsourcing facility”, it must be performed under the complete supervision of a licensed pharmacist.

Quality Standards for Compounded Pharmaceuticals—CGMP Requirements

Requirements for compounded drugs differ depending on the setting in which compounding occurs. Drugs compounded in outsourcing facilities are subject to Current Good Manufacturing Practice (CGMP) requirements. Under CGMP, all drugs must not be handled or packed under unsanitary conditions.

Under the FDCA, Food, Drug & Cosmetic Act, a drug that is compounded is viewed as a “new drug”. Further, pharmacists do not need FDA approval for a compounded medication. Due to the variation in compound formulations, it would be nearly impossible for the agency to evaluate each individually.[12]

FDA Guidance for Current Good Manufacturing Practice

The Food and Drug Administration offers guidance for human drug compounding under Current Good Manufacturing Practices. This draft outlines regulations for compounding outsourced facilities registered under 503B of the Federal Food and Drug Cosmetic Act. The guide gets periodically revised to reflect recent changes including how it can be be used to cover the size and scope of a particular outsourcing facility’s operation.[5]

As part of the FDA’s compounding program, the agency provides many resources for potential compounding manufacturers, consumers, physicians, hospitals and medical clinics. These include Quality Center of Excellence links and webinars that help provide education, instruction, and guidelines for individuals and companies involved in the compounding 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 and Compounding

Bulk drugs are base substances used in either the manufacturing, processing, or packaging of a product. These include active ingredients that when compounded, become part of the final formulation. Periodically, the FDA solicits nominations for bulk drug products to be placed on a 503B bulks list.

Under the 503B portion of the Federal Food, Drug, and Cosmetic Act (FD&C Act) an outsourcing facility may not use bulk drugs for compounding unless the bulk drug is part of a list of drugs on an approved 503B bulks list, or the bulk drug substance is on the FDA’s drug shortage list. These must be manufactured by a company registered with the FDA under section 510 of the FD&C Act.[1]

The Food and Drug Administration meets periodically to make decisions about proposed bulk ingredients necessary to help meet the demand for compounded medications. Before making a final decision however, the agency welcomes comments from the public regarding impact and the need for possible new substances.

Major Turning Point for the Compounding Industry

Until 2012, the Food and Drug Administration took a mostly “hands off” approach to oversight in the compounding industry. Previously that year, a large New England drug compounding facility released a compounded product that led to a fungal meningitis outbreak, killing 60 people and injuring over 700 individuals.

After that incident, the U.S. government took notice of the compounding industry. In 2013 Congress passed the Drug Quality Security Act (DQSA) to attempt to extend federal reach over compounded medications and the compounding industry 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, under the FDA definition, is a sterile facility used for the express purpose of compounding drugs for commercial use. Under section 503B of the FDA guidelines, the outsourcing facility must voluntarily register with the agency as a compounding company and agree to operate under the guidelines set forth, including the CGMP, Current Good Manufacturing Practices.[3]

Outsourcing Facilities—Their Role in the U.S. Supply Chain

Outsourcing facilities play a vital role in the U.S. drug supply chain by providing hospitals, physicians, and dental offices with sterile, readily available compounded drug formulations. In many cases, hospitals require vast quantities of unit-dosed commercial pharmaceuticals, but lack the sterile in-house facilities to meet the demand. Outsourcing facilities provide an important resource.

How Common is the Use of Outsourcing Facilities?

• One survey conducted by the Office of the Inspector General found that of the nearly 600 hospitals surveyed, close to 90% said they regularly obtained non, patient-specific compounded drugs from FDA approved outsourcing facilities.

• Outsourcing facilities play a large role in the U.S. supply chain and can be used when there are specific drug shortages due to manufacturing slow down, or discontinuation of a drug.

• Outsourcing facilities can provide compounded medications to small office practices, including dentists, ophthalmologists, and podiatrists. Physicians can dispense medications directly to patients at predetermined price points, offering the convenience of in-house pharmaceuticals with no need to visit the pharmacy.[10]

The role compound pharmaceuticals play in the field of healthcare continues to rapidly expand. With that comes the responsibility of both state and federal lawmakers to ensure patient safety. Through ongoing and Current Good Manufacturing Practices compounders can also continue to make an important contribution to the medical treatment of many individuals.

References

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/.