Testing APIs and OTCs to Meet 21 CFR 210 & 211 (cGMP) Regulations
By: Marielle Weintraub, Ph.D.
21 CFR Parts 210 & 211
The Food and Drug Administration (FDA) monitors drug manufacturers' compliance with its current Good Manufacturing Practice (cGMP) regulations in order to ensure the quality of drug products. cGMP regulations for pharmaceutical products, for both prescription and over-the-counter products, contain minimum requirements for methods, facilities, and controls used during manufacturing, processing, and packaging of these products. These regulations are designed to assure products are safe for use and contain the ingredients, strengths, and efficacies of claims made by the product.
- 21 CFR Part 210: Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs
- 21 CFR Part 211. Current Good Manufacturing Practice for Finished Pharmaceuticals.
Regulations in Part 211 cover a large scope of subjects, from personnel, facilities, and equipment, to production processes, laboratory requirements, stability testing, and labeling. The responsibility to adhere to cGMPs is placed firmly on the manufacturer in order to prove adherence to these regulations.
Background
To better understand the evolution of the regulations, looking into their history is imperative. In June of 1906, President Theodore Roosevelt signed the Food and Drug Act1 into law, which prohibited the interstate transport of food that had been “adulterated”, which referred to the addition of fillers, reduced quality, reduced strength, concealment of damage or inferiority, formulation with additives known to be harmful to health, or the use of "filthy, decomposed, or putrid" substances.
Following public outcry to substandard products that caused serious injury, illness, and death (which managed to skirt the 1906 Food and Drug Act), President Roosevelt signed the Food, Drug, and Cosmetic Act (FD&C) into law in 19382. The FD&C increased federal regulatory authority over drugs with increased requirements for review, safety data, and labeling. Enforcement abilities were also expanded with new food standards and inspection allowances, and they continue to expand. In 1978, good manufacturing practices for drugs were expanded to include medical devices (21 CFR 820), and these regulations were finalized.
Drug Monographs
In addition to FDA, the U.S. Pharmacopeia (USP), established in the early 1800s, set standards for identity, strength, quality, and purity, concepts still used for ingredient and product testing today3. This necessitates the extensive development of validation methods and product-specific procedures.
Monographs are written documents that clearly define the quality expectations for a drug compound, active pharmaceuticals, and excipients. These expectations include information on identity, strength, purity, and performance. An active pharmaceutical ingredient (API) is a biologically active drug substance that provides treatment for an indicated disease or condition. An excipient is an inactive ingredient that is combined with an API to form a “drug product”. Monographs also describe the tests to validate that a compound/ingredients meet their criterion.
21 CFR 211 (Subpart I- Laboratory Controls)
Subpart I, cGMP requirements for laboratory controls, lists requirements for specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms. In addition, there are requirements for testing products that will be released for distribution, written specifications for products, tests of each active ingredient, and data to demonstrate products are free from contamination (referred to as “objectionable microorganisms” in the chapter). Requirements for stability testing and storage conditions, as well as reserve sample requirements, are also noted.
Method Validation and Verification with Eurofins
The purpose of method validation and verification is to ensure that the performance characteristics of a method meet those of the intended analytical application. These methods can be developed “in-house,” such as at the Eurofins laboratory located in Madison, WI, or validated methods can be transferred from a company or other laboratories. Regardless of whether the method is being validated or verified, “reliable, meaningful, and specific test methods”4 are required for samples tested to 21 CFR Parts 210 and 211 standards.
Method Validation
The United States Pharmacopeia (USP) defines method validation as “a process by which it is established, through laboratory studies, that the performance characteristics of a method meet the requirements for its intended analytical applications.”4
Method validation typically evaluates the following analytical characteristics of a method: accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. Depending upon the type of method and its application, not all the analytical characteristics indicated above will be required for validation. Specific details regarding method validation may be found in USP <1225> “Validation of Compendial Procedures”.
Method Verification
The United States Pharmacopoeia (USP) defines method verification as “a measure by which a compendial method can be tested for its suitability under actual conditions of use."4 Following 21 CFR 211, Eurofins is required to demonstrate that a previously validated method (either a compendial method or a method that was validated elsewhere) can meet specific performance criteria on the sample in question. This differs from a method being “fit-for-purpose,” as you are not allowed to use expected results, previously seen on other samples, as confirmation of a method’s performance.
ICH Chambers for Real-Time and Accelerated Stability Studies
Stability testing for APIs provides evidence of how quality may be altered due to environmental factors such as temperature, humidity, and light. It also establishes a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions. Stability programs can also help determine if there are product-associated degradation factors, such as product closures and packaging materials, which could alter the quality of the API.
Recognizing the importance and need for global harmonization on topics of safety, quality, and efficacy, the International Conference on Harmonization (ICH) developed the guidance document “Stability Testing of New Drug Substances and Product Q1A(R2)”. This document outlines the required stability testing needed for registration of both APIs and finished pharmaceutical ingredients in the United States of America, Japan, and the European Union.
ICH divides storage conditions into four climatic zones. In order to support the OTC industry, Eurofins offers customers the following ICH conditions:
- Zone I – Temperature 21C/45%RH
- Zone II – Mediterranean/Subtropical 25C/60%RH
- Zone III – Hot, Dry 30C/35%RH
- Zone IVa – Hot Humid/Tropical 30C/65%RH
- Zone IVb – Hot/Higher Humidity 30C/75%RH
- Refrigerated storage 5C
- Freezer storage -20C
- Photostability
Eurofins GMP Processes and Quality Assurance Oversight
The Eurofins GMP laboratory was purpose-built with state-of-the-art materials and equipment. The intentional GMP design plays a critical role in maintaining safety, efficiency, and sample integrity throughout our analytical scope of services. Our staff of experienced GMP-qualified scientists is uniquely positioned to handle difficult product formulations and all phases of drug development including stability. Our ISO 17025 certified Quality Management System includes all aspects of GMP. This robust QMS enables us to maintain high levels of accuracy and proficiency. Eurofins’ systems are vigorously tested via regulator and client audits, proficiency testing, and internal controls on a regular basis. The QMS and highly trained quality assurance personnel ensure we exceed compliance standards for GMP analysis.
As an A2LA GMP-certified third-party laboratory, Eurofins is prepared to support your testing needs for OTC products and APIs as described (and required) in 21 CFR 210 & 211. For more information, please reach out to Marielle.Weintraub@ft.eurofinsus.com.
Meet the Author - Marielle Weintraub, Ph.D.
Dr. Marielle Weintraub is the Director of Scientific Strategy for OTC and Contaminants Testing at Eurofins in Madison, WI. In this role, she is tasked with the development of product quality programs designed to support products required to comply with regulations described in 21 CFR Parts 210 & 211. Dr. Weintraub is very active in many trade associations for the OTC, dietary supplement, and natural product industries. She participates in Expert Review Panels and Working Groups for AOAC International's-Cannabis Analytic Science Programs and is a member of both the Consumer Healthcare Products Association's Quality and Manufacturing of Dietary Supplements and OTCs committee and the American Herbal Products Association-Government Relations committee. Dr. Marielle Weintraub earned her M.S. and Ph.D. in Behavioral Neuroscience focusing her research on Alzheimer’s disease pathology.
1https://www.fda.gov/about-fda/changes-science-law-and-regulatory-authorities/part-i-1906-food-and-drugs-act-and-its-enforcement
2https://www.fda.gov/about-fda/changes-science-law-and-regulatory-authorities/part-ii-1938-food-drug-cosmetic-act
3https://www.usp.org/200-anniversary/history-of-medicine-quality#:~:text=The%20U.S.%20Pharmacopeia%20was%20first,entry%20with%20tools%20to%20identify
4https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.166
5https://www.drugfuture.com/Pharmacopoeia/usp35/PDF/0877-0882%20%5B1225%5D%20VALIDATION%20OF%20COMPENDIAL%20PROCEDURES.pdf
