Guidance Breakdown: Considerations for Complying With 21 CFR 211.110
A new draft guidance describes how to comply with the requirements in 21 CFR 211.110 to ensure batch uniformity and drug product integrity.
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In January 2025, the FDA released its draft guidance, Considerations for Complying With 21 CFR 211.110, as part of its broader push to modernize pharma manufacturing and quality control. This guidance marks a significant shift in the agency’s approach to process control and batch uniformity requirements specifically.
With the industry embracing advanced manufacturing technologies — such as continuous manufacturing, 3D printing, and process analytical technology (PAT) — this guidance clarifies how manufacturers can integrate these innovations while remaining compliant with longstanding regulations.
At its core, 21 CFR 211.110 requires manufacturers to ensure batch uniformity and drug product integrity through in-process controls, testing, and sampling. This new guidance acknowledges that compliance can be achieved through modern methodologies beyond traditional testing. It recognizes that advanced process understanding and emerging technologies can offer equal or superior assurance of product quality.
It is also a key component of the FDA’s Framework for Regulatory Advanced Manufacturing Evaluation (FRAME), an initiative focused on establishing a regulatory foundation for the adoption of advanced manufacturing technologies.
Let’s break it down.
Scientific- and risk-based process control
The FDA emphasizes that manufacturers must design and control their processes to ensure that in-process materials meet predetermined quality requirements consistently. This means developing comprehensive documentation that demonstrates how process parameters impact product quality and maintaining control throughout the product lifecycle.
To implement this, we suggest manufacturers begin by examining their current process control documentation and monitoring systems. Ask yourself:
Do your controls adequately capture the relationship between process parameters and quality attributes? Consider developing a process control matrix that clearly links critical parameters to quality attributes. Support this with detailed monitoring plans for each parameter.
The guidance particularly emphasizes the importance of maintaining your process in a state of control even as materials, equipment, production environment, personnel, and manufacturing procedures change. This requires monitoring systems that ensure processes remain capable of producing quality products and identify opportunities for continuous improvement.
Defining and managing significant phases
One of the more nuanced aspects of the guidance involves the concept of "significant phases" in manufacturing. Rather than prescribing specific points that constitute significant phases, the FDA provides manufacturers flexibility in making these determinations. However, this flexibility comes with the responsibility to provide robust scientific justification for these decisions.
When defining significant phases, consider:
The nature of your drug product (e.g., dosage form)
The type of manufacturing process used
The potential impact on product quality
The ability to meaningfully evaluate in-process materials
Your quality unit should document these determinations and review them during process changes or when new understanding is gained.
Think of significant phase determination as a strategic process. Consider how different process steps interact and influence each other. Document not just what you've designated as significant phases, but why you've made these determinations. Your justification should include risk assessments and impact analyses that demonstrate your thorough understanding of the process.
In-process controls and testing requirements
The FDA's guidance takes a pretty progressive stance on in-process controls and testing. Physical sampling is no longer the only path forward. When properly validated, manufacturers can now utilize innovative technologies for in-line, at-line, or online measurements. This might include using surrogate measurements, such as monitoring dryer outlet temperature changes, as an indicator of moisture content.
However, this flexibility doesn't diminish the importance of rigorous testing strategies. Whether using traditional or innovative testing methods, your approach must prevent unsuitable materials from continuing in production. The quality unit plays a crucial role here, making science-based decisions about approving or rejecting materials during production.
When implementing modern testing approaches, we suggest focusing on validation. Any alternative testing method must be thoroughly validated, with clear documentation showing its equivalence or superiority to traditional methods. Make sure to establish correlation studies for surrogate measurements and maintain ongoing verification programs to ensure they continue to be reliable over time. (Stale testing methods are a huge problem we find in audits.)
Advanced manufacturing considerations
The guidance provides extensive consideration for advanced manufacturing approaches, particularly continuous manufacturing. These modern methods often require different control strategies than traditional batch manufacturing, especially when dealing with integrated unit operations and real-time release testing.
Consider how continuous manufacturing is changing the game: Instead of easily isolated steps where materials can be tested between each operation, you're dealing with an integrated process where traditional sampling points might not be feasible. The FDA recognizes this challenge and allows for innovative solutions, provided they're scientifically sound and well-documented.
For example, in continuous manufacturing of solid oral dosage forms, you might evaluate blend uniformity at the tablet press feed frame rather than as a discrete step before compression. The key is demonstrating that your chosen approach maintains product quality and process control.
Process model implementation
Process models are a powerful tool in modern pharmaceutical manufacturing, but the FDA is clear about their limitations. Models cannot serve as the sole control strategy; they must be paired with actual testing or monitoring. Think of process models as enhancing your understanding and control rather than replacing traditional quality measures.
When implementing process models, we tend to recommend firms focus on three key aspects:
Validation of any underlying assumptions.
Ongoing verification that these assumptions remain valid.
The ability to detect when assumptions become invalid.
Your model should incorporate process monitoring and in-process testing to maintain a state of control and make sure you can maintain the model over time.
Quality unit oversight
The quality unit is obviously the cornerstone of compliance with 21 CFR 211.110. However, the FDA considers its role to extend beyond traditional approval/rejection decisions to include control strategy review, process monitoring evaluation, and oversight of equipment and process adjustments. Are these in your job description?
Make sure you’ve established clear procedures for quality unit decisions, particularly regarding the approval or rejection of in-process materials. Create well-defined pathways for communication and documentation. Remember that while certain minor adjustments might not need additional quality unit approval, this applies only when they fall within preestablished and scientifically justified limits that the quality unit has already approved!
Maintaining a state of control
Maintaining a state of control requires constant vigilance through robust monitoring systems and effective deviation management. It’s an ongoing process — not a one-time achievement. Regularly assessing your monitoring systems, documentation procedures, and change control processes helps ensure continued compliance.
Focus on developing comprehensive monitoring plans that can detect and respond to process variations before they impact product quality. Document everything — not just the results but the rationale behind decisions and actions. This documentation becomes invaluable for demonstrating compliance and supporting continuous improvement efforts.
A few action items we recommend
Document your process understanding comprehensively. Review and update your documentation of how each process parameter affects product quality. This should include detailed explanations of parameter interactions, critical control points, and the scientific rationale behind your control strategy. Make sure you have data supporting each relationship between process parameters and quality attributes.