FDA 21 CFR 211.110 Draft Guidance: Strengthening Drug Product Integrity Through In-Process Controls And Advanced Manufacturing

Ensuring drug product integrity, batch uniformity, and consistent quality remains a core expectation under the U.S. FDA’s current good manufacturing practice (CGMP) framework. In line with evolving manufacturing technologies and risk-based quality systems, the FDA has released a draft guidance titled “Considerations for Complying With 21 CFR 211.110”.

This guidance provides critical clarity for pharmaceutical manufacturers on in-process controls, advanced manufacturing approaches, and scientifically sound monitoring strategies all essential for maintaining a validated state of control throughout the product lifecycle.

For companies seeking to future-proof compliance and inspection readiness, understanding this guidance is essential.

Regulatory Context: Understanding 21 CFR 211.110

21 CFR 211.110 establishes FDA’s expectations for in-process controls during drug manufacturing to ensure that finished products consistently meet predefined quality attributes.

Applicability

This regulation applies to:

• Human drug products
• Animal drug products
• Biological drug products

Not applicable to: Active Pharmaceutical Ingredients (APIs)

The regulation reinforces the principle that quality cannot be tested into a product it must be built into the process.

Core FDA Expectations Under 21 CFR 211.110

The draft guidance reiterates and expands on key regulatory requirements, including:

• Written procedures for in-process sampling and testing
• Continuous monitoring of critical quality attributes (CQAs)
• Use of science- and risk-based control strategies
• Maintenance of a validated state of control throughout manufacturing
• Robust data integrity and process understanding

Key Regulatory Requirements Overview

Advanced Manufacturing: FDA’s Forward-Looking Approach

The guidance strongly supports the adoption of advanced manufacturing technologies, recognizing their role in improving process robustness, efficiency, and drug supply resilience.

Examples of Advanced Manufacturing Technologies

• Continuous manufacturing
• Additive manufacturing (3D printing)
• Process Analytical Technology (PAT)
• Real-time release testing (RTRT)
• Automated control systems

These technologies enable real-time quality assurance, shifting the focus from end-product testing to continuous process verification.

Role of Process Models in Modern Manufacturing

Process models statistical, mechanistic, or hybrid are increasingly used to:

• Predict in-process material attributes
• Support real-time decision-making
• Enable continuous manufacturing control

However, the FDA emphasizes that process models alone are not sufficient.

FDA’s Position on Process Models

FDA Recommendation:
Process models must be paired with in-process testing or monitoring systems to ensure continued validity and CGMP compliance.

In-Process Sampling and Testing: Flexibility with Accountability

The guidance provides manufacturers with regulatory flexibility, allowing them to design control strategies based on risk, science, and product knowledge.

FDA-Accepted Sampling Approaches

• At-line testing
• On-line testing
• In-line testing
• Traditional off-line testing

Sampling location, frequency, and methodology should be:

• Scientifically justified
• Based on process understanding
• Capable of detecting variability affecting product quality

This approach supports both batch and continuous manufacturing paradigms.

Maintaining a “State of Control”

A recurring theme in the guidance is maintaining a state of control, defined as a condition in which the process consistently produces output meeting quality specifications.

Key elements include:

• Ongoing process verification
• Trend analysis of CQAs
• Management of planned and unplanned variability
• Change control and lifecycle management

FDA’s Commitment to Manufacturing Innovation

The FDA continues to actively support pharmaceutical innovation through initiatives such as:

Framework for Regulatory Advanced Manufacturing Evaluation (FRAME)

• Encourages adoption of advanced manufacturing
• Supports alternative control strategies
• Promotes early FDA engagement

Manufacturers are encouraged to interact with:

• Emerging Technology Team (ETT)
• Advanced Technologies Team (ATT)

Early dialogue reduces regulatory uncertainty and accelerates technology adoption.

Practical Impact for Pharmaceutical Manufacturers

This guidance has direct implications for:

• Process design and validation
• Control strategy development
• Inspection readiness
• Technology transfer
• Lifecycle management

Compliance Benefits

• Improved batch uniformity
• Reduced deviations and recalls
• Enhanced regulatory confidence
• Stronger inspection outcomes
• Improved supply chain reliability

How Maven Regulatory Solutions Supports FDA 21 CFR 211.110 Compliance

Maven Regulatory Solutions partners with pharmaceutical manufacturers to align operations with FDA’s evolving CGMP expectations by offering:

• In-process control strategy development
• CGMP gap assessments and remediation
• Advanced manufacturing readiness support
• PAT and RTRT regulatory alignment
• FDA inspection preparedness
• Lifecycle process validation strategy

Our approach is science-driven, risk-based, and inspection-focused, supporting sustainable compliance.

FAQs: FDA Draft Guidance on 21 CFR 211.110

Is the guidance legally binding?
No. It represents FDA’s current thinking but reflects inspection expectations.

Does this replace existing CGMP requirements?
No. It clarifies how FDA interprets existing regulations.

Can process models replace testing?
Not entirely. FDA expects models to be supported by monitoring or testing.

Is continuous manufacturing encouraged?
Yes, when supported by appropriate controls and data.

Does this apply to legacy products?
Yes. Lifecycle management and ongoing verification apply to all products.

Conclusion

The FDA’s draft guidance on 21 CFR 211.110 reinforces a modern, science-based approach to drug product integrity, batch uniformity, and CGMP compliance.

By integrating robust in-process controls, advanced manufacturing technologies, and continuous monitoring, pharmaceutical companies can meet regulatory expectations while improving efficiency and quality outcomes.

Maven Regulatory Solutions remains committed to helping sciences organizations navigate FDA regulations with confidence, precision, and future readiness.