"Ensuring Drug Safety: Understanding FDA's Role Through GMP Violation Actions and Why the FDA is Important in the Present World"
WHAT IS FDA:
The FDA was founded in 1848 when the Agricultural Division of the Patent Office was established. The 1906 Pure Food and Drug Act, the nation's first significant food and drug safety law, marked the FDA's founding.
In 1930, it was given the designation Food and Drug Administration. The FDA is in charge of ensuring the safety, security, and effectiveness of biological and pharmaceutical drugs, medical equipment, the country's food production, cosmetic, and radiation-emitting products in terms of protecting the health of the public (Food and Drug Administration) (1).
The Office of Regulatory Affairs (ORA) of the U.S. Food and Drug Administration is in charge of all regulatory field operations. The ORA observes the manufacturing of regulated commodities, examines samples of regulated products and evaluates imported goods that are being offered for entry into the US. ORA collaborates with its national, regional, indigenous, territorial, and international colleagues in the accomplishment of its goal (Affairs, 2021) (2).
IN GENERAL, WHAT DOES THE FDA DO:
The FDA also offers the general public precise, fact-based information on health. The FDA is charged with promoting global health by assisting in the acceleration of technological advances that make pharmaceuticals more efficient, safe, and reasonably priced and by assisting the general public in obtaining the precise, scientific information they require to use medical supplies and food products to preserve and enhance their health and well-being.
The FDA is crucial to the nation's ability to combat counterterrorism. The FDA carries out this duty by guaranteeing the safety of the food and nutrient supplies, as well as by encouraging the growth of medical supplies to address both intended and unintended developing public health hazards (Commissioner, 2018) (3).
HOW FDA IMPACTS ONE’S EVERYDAY LIFE:
The FDA has a significant impact on people's lives in several ways on a daily basis:
1. It guarantees the efficacy and safety of our prescription medications.
2. The FDA ensures that all vaccines are secure for usage by the public.
3. It authorizes specific food ingredients before those items can be sold.
4. The FDA ensures that the nutritional information on food labels is correct.
5. The FDA notifies users when any food item or medication presents a new potential danger (Goldberg, 2017) (4).
In simple words, FDA approval denotes that the Food and drug administration has determined that the advantages of the approved product outweigh any potential disadvantages or risks.
WHY IS FDA AUTHORIZATION CRUCIAL?
The FDA's approval is significant because it supports the necessity for research on how medications affect children as well as adults. Additionally, it enables the public to accurately choose the optimum administration route, calculate the dosage amount, and evaluate potential drug interactions.
A company must demonstrate to the FDA that medicine or medical equipment is "effective and safe" in order to receive FDA clearance.
The testing and research must demonstrate that the advantages of the drug or device for a specific illness surpass the harms to patients who use the product, although no medication or medical device is entirely risk-free.
GMP- A KEY SYSTEM OF FDA:
The FDA has created a set of guidelines for creating GXP (which comprises GCP, GLP, and GMP standards) that safeguard both the life sciences sector and the customers it services.
FDA inspections are based in part on GMPs. A manufacturer can show a government license inspector that they have adhered to GMPs by presenting proof of adherence. This inspector will examine the location to determine compliance.
GMP governs the design, oversight, and management of manufacturing facilities and processes and standards are outlined in 21 CFR Parts 210 & 211 for finished medications and 21 CFR Parts 225 & 226 for Type A medicated items and finished feeds respectively (WEBSTER et al., 2005) (5). The FDA's Good Manufacturing Practices (GMP) guidelines provide minimum standards for the quality of the product during the production, handling, packing, labeling, and preservation of food, medicines, cosmetics, and other goods. Following these rules reduces or completely eliminates the possibility of contamination, mix-ups, flaws, and errors that might be dangerous to humans or animals.
HISTORY OF GMP:
There were several historical events that paved the way for GMP's establishment and the FDA's journey toward the GMP:
People have expressed concern about the caliber and security of medicine and food since the start of civilization. The earliest English food regulation, known as the Assize of Bread, was established by England's King John in 1202 and forbade the falsification of bread with items like ground beans and peas.
The death of more than twelve children from a diphtheria antitoxin which was polluted with live tetanus bacilli led to the establishment of the Biological Control Act (1902), which was first implemented in the USA (for monitoring all biological products). This law required product testing for potency and purity as well as surveillance of biological product manufacturers and distributors.
Marketing contaminated (misbranded) foods or meats was prohibited by the first Food and Drug Act, which went into effect in 1906. It also mandated accurate labeling.
Massengill, a reputable pharmaceutical organization, incorporated diethylene glycol, a deadly solvent, into the oral elixir of sulfanilamide after the invention of sulfa medicines in 1935. As a result, 107 individuals died and many of them were children. In reaction to the tragic incident, the Federal Food, Drug, and Cosmetic Act were implemented in the year 1938.
Approximately 300 individuals died suddenly after consuming phenobarbital contaminated sulfathiazole tablets, which were produced by a New York company named Winthrop Chemical Company.
The above incident caused the FDA to update production and standards of quality across the sector. This strategy served as the foundation for production planning and control standards for all medicines and eventually gave rise to what is now known as GMP.
Several experts worked on the World Health Organization's (WHO) initial version of GMP at the request of the 20th World Health Assembly in 1967.
A WHO expert panel later reprinted the text with slight changes in 1968, and the second version of the International Pharmacopoeia was published in 1971 (Arayne et al., 2008) (6).
FDA ACTIONS FOR NON-COMPLIANCE IN CGMP:
When any violation of GMP regulations is found during the inspections, FDA has the authority to act. The FDA typically sends warning letters, but there are times when it will also order product recalls drug seizures, and license suspensions.
In this article, two such cases where the companies failed to adhere to GMP rules are described.
7.1 CASE 1 – Warning letter issuance for two national drug manufacturers by FDA:
The US Food and Drug Administration (FDA) recently issued warning letters to two local drug companies for failing to follow good manufacturing practices (GMPs).
In the warning letter, one was instructed to improve contamination regulations and retain drugs made by other manufacturers apart from those produced on-site, while the other faced opposition for maintaining the facility in poor repair.
1st Warning letter:
The first warning letter was sent to 'X' company, a drug manufacturer based in West Columbia, South Carolina. The complaint specified that the company had other microorganism contamination-related problems and also had failed to prevent the contamination and mixing of products manufactured at the company's facility with those that were outsourced.
Following an inspection, they found that many drug products waiting for approval contained the drug bupivacaine, which was made at one of its outsourcing facilities.
A combination of the design of final sterilizing procedures and the susceptibility of the container closure system (CCS) utilized to generate the drug items was claimed to be the primary contributor to the issue. As a result of the significant differences between the applicable standards in some areas, the FDA responded that the company needed not to start introducing risks through the crossover of the outsourcing and traditional manufacturing operational processes by sharing equipment, infrastructures, methods, or employees.
According to the FDA, gram-negative microorganisms found in a medium fill or an aseptic manufacturing cleanroom setting are exceedingly unusual. It was also stated that by attempting to combine these processes and adhere to two distinct standards, complexity and product dangers are increased.
After the FDA notified them, the company withdrew its lot of injection ketorolac tromethamine and products manufactured by four other contracting facilities were also recalled.
2nd Warning letter:
The second warning letter was issued to 'X' company in Chatsworth, CA. Investigators highlighted the inadequate building conditions in the issued
Warning letter.
Investigators discovered rusted, debris-covered pipelines just above uncovered combining tanks, and foreign materials lying in a mixer directly beneath one of the pipes. In the letter, they stated that the products in the tanks were exposed to filth and debris due to the several aluminum sheet plates on the top that were partially covering uncovered mixing tanks and were either damaged, dropping, or had voids. They also mentioned that there were numerous insect zappers close to packaging and failure lines as well.
FDA highlighted that the company's quality control unit (QCU) controls were also insufficient. As a result, the FDA advised the company that the company could not verify the reliability of the manufacturing process and the alleged identity, potency, quality, and pureness of drug supplies delivered to the market without proper quality controls and supervision. Additionally, the company was cited for producing lidocaine lotion for unauthorized indication.
The FDA has given the organization 15 days to reply to the notice and stated that failing to do so may result in regulatory action, such as seizures or an injunction (Eglovitch, 2022) (7).
7.2 CASE 2 – Warning letter issuance to 'X' company over GMP by FDA:
The US Food and Drug Administration (FDA) released a warning to Indian generic pharmaceutical manufacturer for various good manufacturing practice (GMP) infractions discovered during an audit of its Goa, India factory in last May. The warning notice, issued on November 22, 2022, listed four breaches involving failed medication batch investigations, written manufacturing and operational control procedures, lab controls, and inadequate documentation.
As a result of the problems specified and according to section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, the FDA informed the company that its drug supplies were adulterated.
According to FDA, Desmopressin acetate tablets in strengths of 0.1 mg & 0.2 mg were rejected by the manufacturer 15 times due to out-of-specified (OOS) content consistency testing results. FDA claimed that the company has failed to examine other samples of drug products that employed the same (redacted) method and compressing equipment, despite the company attributing the problem to one batch's lack of established compression settings. After the audit, the company admitted that it didn’t adhere to the corrective measures for the compression parameters for its 0.2mg strength tablets. In June, the company started a product recall of several 0.2mg dosage pills after identifying a lot with a failed stratified sample assay report.
Additionally, the regulatory body penalized the company for failing to sufficiently validate its production procedures for an undisclosed gel product. The FDA stated that the process validation of that company did not sufficiently analyze inter and intra-batch variations. The FDA stated that because only one batch was used in a second process performance evaluation study to qualify a critical additive that used control viscosity, this made it challenging to evaluate inter-batch variability.
Furthermore, according to the FDA's examination of chromatographic information processing, the company lacked appropriate methods for merging chromatographic findings. FDA inspectors found one instance where the company manually entered timed integrating occurrences into processing methods and reported acceptable findings without sufficient procedural controls or rationale.
FDA stated that if the automated integrate process had been used on the contaminant results in the same way that it was on the standard as well as other peaks, the results would not have satisfied release specifications. Ultimately, FDA claimed that the drugmaker's lot records were insufficient and there was no batch-specific evidence for compressing machine rejection levels.
Production personnel admitted that they did not calculate the batch-specific rejection limits as specified by the company's policy, but instead used default preset tablet values for rejection in the instructions for the compression process of tablets.
Tablets that did not adhere to the requirements for tablet hardness were discovered in two investigations carried out. In the investigations, since the automated mass control or compacted pressure controls were activated, the impact assessment concluded that there was little chance of discovering tablets that did not match specifications.
FDA mentioned that there was an absence of confirmation to make sure the compression machine was correctly rejecting the tablets which did not comply with specifications. The written notice called on the firm to fix the issues and provided a timeline of 15 business days to respond in written format (Mezher, 2022) (8).
7.3 CASE 3 – FDA warning letters to two organizations with respect to violations in eDRSL:
FDA acted against two firms for failing to provide accurate information about the product to its electronic Drug Registration and Listing System (eDRSL).
1st Warning letter:
In the warning letter to 'X' Company, the FDA stated that a difference between the labeling that was provided and the electronic listing file for the active ingredient was observed. Phenylephrine HCL, a different active component does not present on the label, is added to the computerized listing.
2nd Warning letter:
According to the letter to 'X' Company, the carton label image for the specified product on the eDRLs for lisinopril was wrongly provided. In its warning letters, the FDA informed both companies that "complete, accurate, and current establishment registrations and drug listing documentation is vital to promote and safeguard patient safety. For various important activities, such as drug facility inspections, distribution security, and post-market management, FDA generally relies on information from establishment registration and drug listing databases.
FDA provided a timeline for both organizations to respond to the noncompliance issues that occurred (Eglovitch, 2022) (7).
7.4 CASE 4 – Warning letters to 'X' Pharmaceuticals India Private Limited and 'X' company Hair Limited concerning CGMP violations:
1st Warning Letter:
FDA issued a warning notice to 'X' Pharmaceuticals India Private Limited over major violations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
FDA noted in the warning letter that the production, manufacturing, packaging, or storage facilities, procedures, or controls did not adhere to CGMP and that the API is adulterated in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2) (B). FDA reviewed the response sent by the company on July 22, 2022 in response to Form FDA 483 and stated that the quality unit (QU) of the company did not provide sufficient document control for both paper and electronic documents and there are not enough controls in place for computerized systems.
According to the FDA, the company failed to establish and adhere to written instructions for investigating critical deviations, did not ensure that API batches met specifications, and failed to ensure that all test procedures were scientifically valid and relevant to guarantee that the API complied with defined quality standards and purity.
Furthermore, the FDA stated that the response doesn't include a thorough strategy for guaranteeing future paper and electronic record-keeping and documentation processes adhere to CGMP. The fact that the response does not contain a thorough retrospective risk assessment of the implications and scope of the subpar document control at the firm made it insufficient as well.
The FDA mandated that the company thoroughly evaluate the whole system to look into complaints, out-of-specification (OOS) results, deviations, and failures. The FDA also asked for a comprehensive action plan to fix this system, which should include major advancements in investigative skills, scope definition, root cause analysis, CAPA effectiveness, quality unit supervision, and written procedures. Finally, the FDA ordered the company to explain how it plans to make sure that all aspects of investigations are carried out correctly.
FDA placed the organization on Import Alert 66-40 on November 21, 2022 and provided a timeline of 15 working days to respond in writing within 15 working days (Center for Drug Evaluation and Research, 2022) (9).
2nd Warning letter:
A warning letter outlining significant violations of Current Good Manufacturing Practice (CGMP) standards for finished pharmaceuticals in accordance with Title 21 Code of Federal Regulations (CFR), parts 210 and 211, was issued to the drug manufacturing facility, 'X' Company Hair Limited by the United States Food and Drug Administration (FDA) after an inspection.
FDA noted in the warning letter that the production, manufacturing, packaging, or storage facilities, procedures, or controls did not adhere to CGMP and that the drug products were adulterated in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act
(FD&C Act), 21 U.S.C. 351(a)(2) (B).
According to FDA, regardless of whether the batch has already been delivered, the company failed to adequately analyze any inexplicable variation or failure of a batch or any of its components to fulfill any of its standards (21 CFR 211.192). Additionally, in accordance with 21 CFR 211.160(b), the company also failed to set up laboratory controls with valid scientific and appropriate standards, guidelines, sampling plans, and test procedures to make sure that constituents, drug product containers, closures, in-process equipment, labeling, and drug products comply to the required standard of individuality, strength, efficiency, and purity FDA stated that, in accordance with 21 CFR 211.84(d)(1) and 211.84(d)(2), the company also failed to test samples of every component for identification and compliance with all pertinent written standards for purity, strength, and quality.
The FDA asked for the company's chemical and microbiological quality control criteria, as well as information on how each component lot is tested for compliance with the necessary specifications for identity, strength, quality, and purity, before being released for use in production.
In addition, FDA recommended that the company's SOP, which outlines this COA validation program, be included along with a commitment to always perform at a minimum of one identity test for every inbound component lot and an overview of the results from testing all components to assess the validity of the COA from each component manufacturer. On October 28, 2022, FDA placed the firm on Import Alert 66-40 and provided a timeline of 15 working days to respond in writing within 15 working days (Center for Drug Evaluation and Research, 2022) (10).
Conclusion:
Whenever certain occurrences involving non-compliance with rules and regulations occur, the FDA generally acts; the severity of the action depends on the non-compliance that happened, and the response received from the organization that caused the non-compliance.
The FDA typically gives the firms a few days to respond; if the response is acceptable to the FDA and the firm has addressed the issues, the FDA sends a clearance notice; if not, the FDA takes additional steps to address the issues. Thus, this regulatory strategy assures in marketing of safe and effective drugs to patients.
Key Takeaways and Questions:
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References:
1) Food and Drug Administration. USAGov. (n.d.). Retrieved December 8, 2022, from https://www.usa.gov/federal-agencies/food-and-drug-administration
2) Affairs, O. of R. (2021, June 11). Office of Regulatory Affairs. U.S. Food and Drug Administration. Retrieved December 8, 2022, from https://www.fda.gov/about-fda/fdaorganization/office-regulatory-affairs
3) Commissioner, O. of the. (2018, March 28). What we do. U.S. Food and Drug Administration. Retrieved December 8, 2022, from https://www.fda.gov/about-fda/whatwe-do
4) Goldberg, H. (2017, May 12). 5 ways you didn't know the FDA impacts your everyday life. SELF. Retrieved December 8, 2022, from https://www.self.com/story/ways-the-fdaimpacts-your-everyday-life
5) WEBSTER, G., KOTT, L., & MALONEY, T. (2005). Considerations when implementing automated methods into GXP Laboratories. Journal of the Association for Laboratory Automation, 10(3), 182–191. https://doi.org/10.1016/j.jala.2005.03.003
6) Arayne, M. S., Sultana, N., & Zaman, M. K. (2008). Historical incidents leading to the evolution of Good Manufacturing Practice. Accreditation and Quality Assurance, 13(8), 431–432. https://doi.org/10.1007/s00769-008-0363-0
7) Eglovitch, J. S. (2022, October 28). FDA warns us sterile injectable maker on contamination controls, another us maker warned for poor building conditions. Regulatory Affairs Professionals Society (RAPS). Retrieved December 8, 2022, from https://www.raps.org/news-and-articles/news-articles/2022/10/fda-warns-us-sterileinjectable-maker-on-contamina
8) Mezher, M. (2022, December 6). FDA warns Glenmark over GMP, laboratory control issues. Regulatory Affairs Professionals Society (RAPS). Retrieved December 15, 2022, from https://www.raps.org/news-and-articles/news-articles/2022/12/fda-warns-glenmarkover-gmp-laboratory-control-iss
9) Center for Drug Evaluation and Research. (2022, December 13). Centrient Pharmaceuticals India Private Limited - 640196 - 12/07/2022. U.S. Food and Drug Administration. Retrieved December 15, 2022, from
10) Center for Drug Evaluation and Research. (2022, December 6). Ag hair limited - 638646 - 11/28/2022. U.S. Food and Drug Administration. Retrieved December 15, 2022, from https://cacmap.fda.gov/inspections-compliance-enforcement-and-criminalinvestigations/ warning-letters/ag-hair-limited-638646-11282022