FDA Warning Letter Analysis: Diamond Chemical Co., Inc.

On September 6, 2024, the U.S. Food and Drug Administration (FDA) issued a Warning Letter to Diamond Chemical Co., Inc., following an inspection conducted from May 6 to May 16, 2024. 

The inspection identified significant violations of Current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals under 21 CFR parts 210 and 211, leading to the adulteration of Diamond Chemical’s drug products. These violations contravene section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).

Despite the company’s response to the initial FDA 483 Form on May 30, 2024, the FDA deemed the response inadequate.

Key Non-Conformances Identified

Some of the non-conformances identified during this FDA inspection include: 

1. Failure to Test Each Component for Identity, Purity, and Quality

Diamond Chemical did not test components such as ethanol for identity, nor did it validate the reliability of its suppliers’ Certificates of Analysis (CoAs) at appropriate intervals. Without the required identity testing, the company could not confirm the acceptability of its raw materials, risking the use of components that may not meet safety or purity standards.

SEE MORE: Supplier Qualification in GMP

2. Inadequate Batch Release Testing for Identity and Strength of Active Ingredients

The company failed to perform sufficient testing to verify the identity and strength of ethanol in finished drug products before their release. Instead, Diamond Chemical relied on outdated test data from 2020 and used insufficient testing methods that could not determine ethanol strength accurately.

3. Lack of Written Procedures for Production and Process Control

The company failed to validate the manufacturing process for its hand sanitizers, compromising the control of product quality. Additionally, Diamond Chemical did not perform adequate cleaning validation for non-dedicated equipment used for manufacturing both drug and non-drug products.

4. Inadequate Stability Testing Program

Diamond Chemical lacked a comprehensive stability testing program to demonstrate that its hand sanitizer products would maintain their identity, strength, quality, and purity throughout their shelf life. The company failed to provide data supporting the long-term stability of these products.

Recommended CAPA Plan

To address these critical deficiencies, Diamond Chemical Co., Inc. must implement a comprehensive Corrective and Preventive Action (CAPA) plan. Below are the recommended actions for each non-conformance:

1. Failure to Test Components for Identity, Purity, and Quality

Root Cause Analysis: 

The failure to perform component identity testing and validate suppliers’ CoAs likely stems from over-reliance on supplier-provided data without adequate internal oversight. Diamond Chemical did not establish rigorous testing protocols for verifying the integrity of raw materials. 

Corrective Measures:

• Implement the United States Pharmacopeia (USP) identity tests for critical components like ethanol to detect hazardous impurities such as methanol. 
• Establish a routine validation process for supplier-provided COAs, ensuring that all incoming materials meet identity, purity, and quality specifications through in-house testing. 
• Each shipment of raw materials, particularly high-risk components like ethanol, should undergo full identity testing to ensure compliance with established standards.

Preventive Actions:

• Create a supplier qualification program to regularly assess the reliability of component suppliers and ensure ongoing conformity with quality standards. 
• Implement periodic audits of suppliers, focusing on their testing methods and adherence to regulatory standards. 
• Ensure that all Quality Control (QC) personnel are trained in proper component testing protocols and the use of validated testing equipment, with scheduled maintenance and calibration of all analytical instruments.

2. Inadequate Testing for Identity and Strength of Active Ingredients

Root Cause Analysis:

The failure to perform batch-specific identity and strength testing for ethanol in finished products likely results from a combination of outdated practices and a poor understanding of cGMP requirements. 

Diamond Chemical relied on past test data and inadequate testing methods, such as density tables and hydrometers, which are incapable of verifying ethanol strength accurately.

Corrective Measures:

• Develop and implement a rigorous testing protocol that includes both identity and strength testing for ethanol in every batch of drug products manufactured. 
• Full-release testing must be conducted before any product is distributed to the market, ensuring the ethanol content conforms to the required specifications. 
• Implement validated methods, such as gas chromatography, to accurately assess ethanol concentration in hand sanitizers and other formulations.

Preventive Actions:

• Train laboratory personnel in modern analytical techniques suitable for identity and strength testing. 
• Establish a routine internal audit system to evaluate compliance with batch release testing requirements. 
• Ensure that all testing procedures are reviewed periodically and updated to reflect changes in regulatory standards and product formulations. 
• The introduction of automated systems for tracking batch testing and approval can further enhance compliance oversight.

3. Inadequate Process and Cleaning Validation

Root Cause Analysis: 

The absence of process and cleaning validation likely stems from inadequate process oversight and the absence of formalized procedures for validating critical stages of production. 

The use of non-dedicated equipment without proper cleaning validation raises the risk of cross-contamination, especially when manufacturing both drug and non-drug products. 

Corrective Measures:

• Conduct comprehensive process validation studies for the manufacture of hand sanitizers and other drug products, including each significant process stage. These studies should involve intensive monitoring and testing to identify batch variability and confirm that the manufacturing process consistently produces products that meet their intended specifications. 
• Implement cleaning validation for all non-dedicated equipment, ensuring that residual contaminants from non-drug products do not compromise drug product quality.

SEE MORE: Cleaning Validation in Pharma Industry

Preventive Actions:

• Develop written procedures for routine process validation and cleaning validation to ensure the ongoing quality of all drug products. 
• Introduce a risk-based approach to cleaning validation, especially for non-dedicated equipment, with regular testing to detect possible contamination. 
• Train manufacturing staff on the importance of adhering to validated processes and cleaning protocols, and conduct regular inspections of production areas to ensure compliance.

4. Lack of a Comprehensive Stability Testing Program

Root Cause Analysis: The absence of a robust stability testing program is likely due to a lack of understanding regarding the importance of demonstrating that drug products maintain their quality over time. During the pandemic, the company may have deprioritized stability testing in favor of rapid production, leading to an incomplete evaluation of product shelf life.

Corrective Measures:

• Establish a comprehensive stability testing program that includes both chemical and microbiological tests to confirm that drug products retain their identity, strength, quality, and purity throughout their labeled shelf life. 
• Begin stability testing for all currently manufactured products and ensure that future batches undergo stability testing during and after production. This program should be aligned with ICH stability guidelines to assess product performance under various storage conditions.

Preventive Actions:

• Integrate stability testing as a core component of the quality management system (QMS), with dedicated resources for ongoing product evaluation. 
• Ensure that all stability studies are properly documented and updated to reflect any changes in product formulation or manufacturing processes. 
• Conduct training sessions for QC personnel on stability testing protocols and the interpretation of test results. 
• Periodic reviews of stability data should be conducted to assess trends and adjust production processes as needed.

Timeline for Implementation

Our recommendations for Implementation of the CAPA Plan include:

Immediate Actions (0-3 months)

• Initiate identity testing for all ethanol stocks and other critical raw materials.
• Engage a third-party CGMP consultant to conduct an independent audit of the facility and operations, focusing on component testing and batch release processes.

Short-Term Actions (3-6 months)

• Complete process and cleaning validation studies, with results reviewed and incorporated into routine production.
• Develop and launch a comprehensive stability testing program, starting with all currently marketed products.

Long-Term Actions (6-12 months)

• Finalize and validate all corrective measures, including supplier qualification and testing protocols.
• Maintain continuous stability monitoring and implement a long-term quality management strategy for compliance with CGMP regulations.

Conclusion

FDA’s warning letter emphasizes critical cGMP violations at Diamond Chemical Co., Inc., particularly in the areas of component testing, batch release, process validation, and stability testing. Immediate and long-term corrective actions are required to prevent further non-compliance and potential regulatory or legal actions. 

Diamond Chemical must promptly address these issues, improve its quality systems, and ensure that all future manufacturing operations adhere to the highest standards of safety and efficacy.