FDA Draft Guidance: Considerations for Complying with 21 CFR 211.110

In January 2025, the FDA released a draft guidance titled “Considerations for Complying with 21 CFR 211.110.” This document outlines measures for manufacturers to ensure batch uniformity and drug product integrity as required by the Current Good Manufacturing Practice (CGMP) regulations. It reflects the agency’s ongoing commitment to modernizing pharmaceutical manufacturing by integrating advanced technologies and enhanced quality control measures.

The draft guidance applies to the manufacture of human and veterinary drug products, including biologics, while excluding active pharmaceutical ingredients (APIs) and products regulated under separate CGMP frameworks, such as positron emission tomography (PET) drugs.

Key Highlights

Some critical aspects of the FDA draft guidance include its scope, applicability, and primary focus areas for improving manufacturing and quality control practices.

Scope and Applicability

• Drug Products Covered: Includes human and veterinary drug products across traditional and advanced manufacturing contexts.
• Exclusions: APIs and certain specialized drugs, such as PET drugs, which follow separate regulatory standards.

Focus Areas

1. Batch Uniformity and Drug Product Integrity:
   • Outlines regulatory expectations under 21 CFR 211.110 to ensure that in-process materials consistently meet predetermined quality standards.
2. Advanced Manufacturing:
   • Encourages the adoption of innovative technologies like continuous manufacturing and process models to enhance manufacturing efficiency and product quality.
3. Scientific and Risk-Based Approaches:
   • Recommends applying robust product and process understanding to maintain a state of control throughout the manufacturing lifecycle.

General Considerations for In-Process Sampling and Testing

To comply with CGMP regulations, manufacturers must adopt scientifically sound approaches for sampling and testing during the manufacturing process to ensure consistent quality and integrity of drug products.

Critical Quality Attributes (CQAs)

• Manufacturers must identify critical quality attributes (CQAs) and in-process material attributes to ensure product quality.
• The guidance emphasizes tailoring sampling and testing strategies based on the nature of the product and its manufacturing process.

Significant Manufacturing Phases

• The FDA allows flexibility in defining “significant phases” in manufacturing based on scientific rationale.
• As 21 CFR 211.110 (c) mandates, manufacturers must determine and justify when and where in-process testing occurs.

Innovative Testing and Sampling

• Encourages using time-based or surrogate testing methods, such as monitoring dryer outlet temperatures as a proxy for moisture content.
• Supports integrating in-line, at-line, and online measurements to reduce reliance on physical sampling.

Regulatory Flexibility

• Allows manufacturers to implement scientifically justified innovative strategies, provided they ensure product quality and meet regulatory requirements.

Advanced Manufacturing and Process Models

This section of the draft guidance focuses on integrating advanced technologies like continuous manufacturing. It discusses the role of process models in improving control strategies and overcoming challenges in pharmaceutical production.

Benefits of Advanced Manufacturing

• Advanced manufacturing technologies, including 3D printing and continuous manufacturing, improve process robustness, supply chain reliability, and patient access to medicines.
• These technologies enable real-time monitoring and control, offering a more integrated approach to quality assurance.

Use of Process Models

• Process models can mathematically represent manufacturing processes, enabling better understanding and control.
• However, the FDA cautions against relying solely on process models without additional in-process testing to ensure model assumptions remain valid during routine operations.

Challenges and Requirements

• Sole reliance on process models may fail to detect unplanned disturbances, potentially compromising product quality.
• The guidance recommends pairing process models with robust in-process material testing or process monitoring to maintain compliance with 21 CFR 211.110.

Continuous Manufacturing

• The draft guidance addresses specific considerations for continuous manufacturing, where integrated processes require alternative approaches to testing.
• Manufacturers must demonstrate how their control strategies ensure product quality across significant manufacturing process phases.

Industry Collaboration and Submission of Comments

The FDA strongly encourages early engagement with its Emerging Technology Team, Advanced Technologies Team, or Center for Veterinary Medicine to discuss innovative approaches. These interactions can facilitate the adoption of novel technologies and inform future regulatory policies.

Stakeholders are invited to submit comments and suggestions within 90 days of the draft guidance’s publication. 

The draft guidance has several implications for manufacturers:

• Enhanced Quality Control: Emphasis on scientifically sound, risk-based approaches to process monitoring and control.
• Integration of Advanced Technologies: Encourages leveraging innovative manufacturing techniques while maintaining CGMP compliance.
• Regulatory Preparedness: Highlights the importance of robust process understanding to navigate FDA inspections and application reviews.

SEE MORE: How to Prepare for a GMP Inspection

Conclusion

The draft guidance, “Considerations for Complying with 21 CFR 211.110,” reflects the FDA’s dual focus on fostering innovation and ensuring high product quality. The agency is trying to achieve a more robust and efficient pharmaceutical manufacturing ecosystem by providing a flexible framework for integrating advanced manufacturing technologies. Stakeholders are encouraged to engage actively during the comment period to refine and finalize this forward-looking guidance.