Ensuring Drug Quality: An Overview of 21 CFR Parts 210 & 211
Ensuring the safety, efficacy, and quality of pharmaceutical products is paramount in drug manufacturing. The Current Good Manufacturing Practice (cGMP) regulations, outlined in 21 CFR Parts 210 and 211, provide the framework necessary to uphold rigorous standards in production, testing, and quality control. These regulations are not merely guidelines—they are essential safeguards that protect public health by preventing contamination, inconsistencies, and defects in drug formulations.
21 CFR Parts 210 & 211
The Food and Drug Administration (FDA) monitors drug manufacturers' compliance with its current cGMP regulations to ensure the quality of raw ingredients, drug substances, and finished 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 ensure 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 to prove adherence to these regulations.
History of Regulations
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. Excipient are the inactive ingredients combined with an API to form the “drug product”. Monographs list the required testing to demonstrate that compounds or raw ingredients meet the criteria.
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
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”.5
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, GMP laboratories are 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 different climatic zones:
- 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
The Eurofins Solution
The Eurofins GMP laboratory is purpose-built with cutting-edge materials and equipment, designed to uphold the highest standards of safety, efficiency, and sample integrity across our analytical services. Our team of GMP-qualified scientists specializes in handling complex product formulations and all phases of drug development, including stability studies. In addition to the different climatic zones listed in the ICH guidance, Eurofins also offers Refrigerated storage 5C, Freezer storage –20C, and Photostability chambers.
Method validation and verification are essential in ensuring analytical methods meet their intended application. Whether developed in-house at our Madison, WI laboratory or transferred from external sources, all validated methods adhere to stringent requirements, delivering reliable, meaningful, and precise results in accordance with 21 CFR Parts 210 and 211 standards.
Supported by an ISO 17025-certified Quality Management System (QMS), Eurofins ensures exceptional accuracy and proficiency in every test. Our systems undergo rigorous evaluations through regulatory and client audits, proficiency testing, and internal controls. With a robust QMS and highly trained quality assurance personnel, we continuously exceed GMP compliance standards and are committed to upholding the highest standards ensuring product safety, compliance, and reliability.
As an A2LA GMP-certified third-party laboratory, Eurofins is prepared to support your testing needs for OTC products and APIs as required in 21 CFR 210 & 211. For more information, please reach out to Marielle.Weintraub@ft.eurofinsus.com.
Meet the Author - Dr. Marielle Weintraub
Dr. Marielle Weintraub serves as the Director of Scientific Strategy for OTC and GMP testing. In this capacity, Dr. Weintraub supports customers with the development of analytical testing programs for over-the-counter medications, and personal care products. Additionally, she functions as a key resource and subject matter expert for both clientele and internal stakeholders.
Dr. Weintraub actively participates in trade associations pertinent to the over the counter, dietary supplement, and natural product industries. Notably, she holds positions on AOAC International's Technical Programming Council, the Consumer Healthcare Products Association's (CHPA) Quality and Manufacturing of Dietary Supplements and OTCs Committee and participates in technical working groups for the Association of Food and Drug Officials (AFDO).
Her academic background is distinguished by the attainment of a Ph.D. in Behavioral Neuroscience with a specialization in Psycho-neuro-immunology. Her research endeavors were focused on investigating the intricate relationship between inflammation and the pathogenesis of Alzheimer's disease.
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
