Assessing the Applicability and Necessity of CGMP to Drug Compounding

To assess the applicability and necessity of CGMP to drug compounding, several definitions provided in section 210.3 Definitions of the FD&C law must be mentioned:

• Drug manufacturing is defined as the “manufacture, processing, packing, or holding of a drug product [that] includes packaging and labeling operations, testing, and quality control of drug products.” The diagram below illustrates the necessary steps required to manufacture several different forms of drug products and a device.

• A drug product “means a finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients.” The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo.

21 CFR section 3.2(e) and (f) define drug as it is applied in combination with a device.

• A combination product includes two key components:

1. A product comprised of two or more regulated components, i.e., drug/ device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity.

2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products.

• A device is defined in section 201(h) of the act as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”

Given these definitions as they apply to drug manufacturing, it’s necessary to ask the core question:

How Does CGMP Apply to Pharmacy Compounding?

The ensuing steps for dispensing, mixing or blending, filtration, compression or filling, container closure system (CCS) filling, coating, polishing, device filling, and packaging of a drug product must occur under a strict CGMP systems of controls:

(1) in a registered and suitable facility on qualified and calibrated equipment,

(2) by a validated production system,

(3) using authorized and recognized materials,

(4) that are processed and tested by trained operators and qualified laboratory analysts and

(5) packaged and labeled,

(6) under a quality management system.

Similarly, the drug compounding steps (shown in the table below) begin with a prescription for traditional pharmacies or anticipatory compounding (preparing compounded medications before the actual receipt of a prescription for outsourcing and hospital pharmacies), followed by gathering together the drug(s) and excipient material(s) being prescribed, weighed, compounded, mixed, sterilized in the case of compounded sterile preparations (CSP and CP for non-sterile compounds), filled and packaged.

The requirements spelled out in the CGMP rules and FDA guidances for drug products are now being enforced for the production of CSP/CP and must also be implemented as directed in the DQSA, 2013 except where exemptions apply, which will not be discussed here. See section 503 of the Compounding Quality Act for a detailed explanation.

Compounding practices have become de facto as originally promulgated by the United States Pharmacopeia (USP) (Section 501(b) of the FD&C), to be recognized by congress as the official drug compendium of the United States and its Territories.

Read Also → Compounding Pharmacies and CGMP: A Primer

The drug compendium creates standards for such characteristics as potency, sterility, endotoxicity, stability, dissolution, weight variation, content uniformity and other product properties that, when taken together, result in a specification for drugs published in a drug substance (DS) or drug product (DP) monograph. A monograph includes the test, method, and acceptance criteria that are the DS and DP specification.

Manufactured Drugs (DS/DP) vs. Compounded Preparations (CSP/CP)

It’s important to note several differences between manufactured drugs (DS/DP) and compounded preparations (CSP/CP):

1. The USP monograph is by definition a public specification for approved drug substances and products. These monographs are mostly intended to be used by pharmaceutical companies that manufacture what are commonly referred to as “generic” DP using an approved DS.
   
   
2. The FDA approves specifications for DS and DP that are private specifications between a branded manufacturer/sponsor of the substance or product. Both generic and branded specifications come under the authority of the FDA and CGMP is strictly enforced when a DS and DP are manufactured.
   
   
3. These approved DS and DP have been approved by a scientific methodical approach that studies the toxicology (safety) and efficacy in animals and humans respectively in designed clinical trials.
   
   
4. Since a compounded preparation is not an approved product (they have not been studied for toxicity or efficacy in animal studies or clinical trials), congress created caveats in DQSA and the FDA has written CGMP guidelines that effectively place safeguards on the extent to which pharmacists can compound a drug.
   
   • A compounded drug cannot be a copy of an approved drug product.
   
   • A compound must consist of only drug substances approved and included in the USP and published by the FDA on approved drug lists. Conversely, compounds cannot consist of drugs that appear on do not use lists published by the FDA.
   
   • DQSA mandates that all compounded preparations meet the minimum standards of CGMP for their identity, strength, purity and quality
   ➡ A violation of any of these caveats by a pharmacy results in an adulterated product under the FD&C Act.

The answer to our core question—how CGMP applies to drug compounding—should now be obvious for the same reason it applies to drug manufacturing:

To prevent an adulterated product from being prescribed to a patient, CGMP creates a state of control for the compounding, processing, packing, or holding of a drug including packaging and labeling operations, testing, and quality control of drug products throughout the life cycle of the drug substance and drug product.”  – Gary E. Ritchie

Now that we’ve connected the CGMP link between drug manufacturing and compounding and described how it applies to the drug compounding process, the next question is, how does a compounding pharmacy comply with CGMP?

Grab our free white paper and learn how compounding pharmacies should take the first steps toward implementing CGMPs throughout their facility. Prefer a presentation? Watch our free recorded webinar here, presented by Gary E. Ritchie.

The Importance of CGMP to the Safety of Compounded Drugs: How CGMPs offer a reliable remedy to poorly compounded drugs

A free white paper from The FDA Group ⤵