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GOOD REGULATORY PRACTICES · 03

Good Regulatory Practices #3: What FDA's Quality Reviewers Are Really Looking For

Explore purity, potency, stability and sterility through the lens of FDA’s quality reviewers.

Dr. Leona Saunders, IRSG · 9 min read

Introduction

When FDA reviews your original IND or prepares for your Pre-IND meeting, their primary concern isn't whether your drug will work. It's whether the people in your trial will be safe.

This sounds obvious, but it has profound implications for how you should prepare your Chemistry, Manufacturing, and Controls (CMC) section. The reviewers assessing your drug product aren't asking "is this good enough to get to market?" They're asking "is this good enough to put into human beings right now?"

A secondary consideration, but still important, is whether your initial development plan makes sense and whether the proposed study fits logically within that plan. FDA wants to understand the path you're on, not just the immediate step.

This edition of Good Regulatory Practices focuses on the CMC elements that FDA's quality reviewers scrutinize most closely: purity, potency, stability, and sterility. These are the foundational attributes that determine whether your drug is safe to administer to clinical trial subjects.

FDA's Review Priorities: Safety First, Strategy Second

Understanding FDA's hierarchy of concerns helps you structure your submission effectively:

Primary Concern: Subject Safety

Before anything else, FDA needs confidence that:

  • The drug substance and drug product are adequately characterized
  • The manufacturing process produces consistent material
  • The product meets appropriate quality standards
  • Subjects won't be exposed to unacceptable impurities, degradation products, or contamination

If FDA has concerns about any of these, your IND will be placed on clinical hold. No amount of promising efficacy data matters if the product itself might harm patients.

Secondary Concern: Development Plan Coherence

Once safety is established, FDA evaluates:

  • Does the proposed study make sense for this stage of development?
  • Is the sponsor's overall plan logical and scientifically sound?
  • Are the right questions being asked in the right order?
  • Does the CMC strategy support the full development program, not just Phase 1?

This is where the "building your IND with the end in mind" principle from our first article comes into play. FDA isn't just checking boxes; they're evaluating whether you're on a path that could lead to an approvable product.

The Four Pillars of Product Quality

FDA's chemistry reviewers (also called product quality reviewers) and microbiology review staff focus on four fundamental attributes. Each must be adequate to support your proposed development phase.

1. Purity

What FDA is assessing: Is the drug substance free from unacceptable levels of impurities? Are those impurities identified and controlled?

Key considerations:

  • Process-related impurities: Residual solvents, reagents, catalysts, and other materials from synthesis or purification
  • Product-related impurities: Degradation products, aggregates (for biologics), variants
  • Elemental impurities: Heavy metals and other elements from equipment, containers, or raw materials
  • Microbial contamination: Bioburden, endotoxins (for parenterals)

What reviewers want to see:

  • Identification of actual and potential impurities
  • Justified specifications with acceptance criteria
  • Validated analytical methods to detect and quantify impurities
  • Evidence that impurity levels are controlled and consistent

Common pitfalls:

  • Unknown impurity peaks dismissed as "not significant"
  • Specifications set based solely on batch history rather than safety considerations
  • Inadequate characterization of degradation pathways
  • Missing or poorly validated analytical methods

Your move: Identify and characterize impurities early. Set specifications based on safety data (ICH Q3A/Q3B guidelines), not just what your process happens to produce. If you have unknown impurities above identification thresholds, address them before filing.

2. Potency

What FDA is assessing: Does the drug have the biological or therapeutic activity it's supposed to have? Can you measure it reliably?

Key considerations:

  • Drug substance potency: Is the active ingredient actually active?
  • Drug product potency: Does the formulated product retain activity?
  • Dose accuracy: Will patients receive the intended dose?
  • Assay precision: Can you measure potency consistently?

What reviewers want to see:

  • Potency assay that reflects mechanism of action (especially for biologics)
  • Demonstrated correlation between potency assay and clinical effect (when possible)
  • Appropriate precision and accuracy for the assay
  • Specifications that ensure therapeutic consistency

Common pitfalls:

  • Using a simple content assay when a bioassay is needed (biologics)
  • Potency specifications too wide to ensure clinical consistency
  • Poorly characterized reference standards
  • Assays not validated for the matrix (drug product formulation)

Your move: Develop your potency assay early and invest in its validation. For biologics, ensure your assay reflects the mechanism of action. Establish a well-characterized reference standard and maintain it carefully; everything is measured against it.

3. Stability

What FDA is assessing: Will the drug remain safe and effective throughout its intended shelf life? What happens as it degrades?

Key considerations:

  • Real-time stability: Data at intended storage conditions
  • Accelerated stability: Predictions of long-term behavior
  • Stress testing: Forced degradation to understand degradation pathways
  • In-use stability: Once opened or reconstituted, how long is it good?

What reviewers want to see:

  • Stability data supporting the proposed clinical use period
  • Identification of degradation products and pathways
  • Appropriate storage conditions and container closure
  • Stability-indicating analytical methods

Common pitfalls:

  • Insufficient stability data at time of IND filing
  • Degradation products not identified or qualified
  • Methods not demonstrated to be stability-indicating
  • Inappropriate container closure system for the formulation

Your move: Start stability studies as early as possible, you can't accelerate real-time data. Conduct stress studies to understand degradation pathways and ensure your analytical methods can detect degradation products. Have at least 1-3 months of real-time data at filing, with a commitment to provide ongoing data.

4. Sterility (When Applicable)

What FDA is assessing: For parenteral products, is the drug free from microbial contamination? Is the sterilization process reliable?

Key considerations:

  • Sterilization method: Terminal sterilization vs. aseptic processing
  • Container closure integrity: Will it stay sterile?
  • Endotoxin control: Especially critical for parenterals
  • Environmental monitoring: Is the manufacturing environment controlled?

What reviewers want to see:

  • Validated sterilization process (or aseptic processing validation)
  • Appropriate in-process and release testing
  • Container closure integrity data
  • Endotoxin limits appropriate for the route of administration

Common pitfalls:

  • Aseptic processing without adequate facility qualification
  • Media fill failures or gaps in environmental monitoring
  • Inadequate container closure integrity testing
  • Endotoxin limits are not appropriate for dose and route

Your move: If you're producing a parenteral product, sterility assurance is non-negotiable. FDA has seen contamination cause serious patient harm. Invest in robust sterilization validation, environmental monitoring, and container closure integrity studies. This is an area where cutting corners can lead to clinical holds.

Who Reviews What: Understanding FDA's Quality Review Team

Knowing who evaluates which aspects of your CMC section helps you anticipate questions and structure your submission:

Chemistry Reviewers / Product Quality Reviewers

Focus areas:

  • Drug substance characterization and manufacturing
  • Drug product formulation and manufacturing
  • Specifications and analytical methods
  • Stability
  • Container closure systems

What they're checking: Can you consistently manufacture a product that meets quality standards? Are your methods valid? Are your specifications scientifically justified?

Microbiology Review Staff

Focus areas:

  • Sterility and sterilization validation
  • Antimicrobial preservative effectiveness
  • Microbial limits and bioburden control
  • Endotoxin/pyrogen testing
  • Environmental monitoring

What they're checking: Is the product free from harmful microorganisms? Will it stay that way? Is the manufacturing environment adequately controlled?

How They Work Together

These reviewers don't operate in isolation. For a sterile injectable product, for example, the chemistry reviewer evaluates the overall manufacturing process while the microbiology reviewer focuses on sterility assurance. Both assess container closure integrity from their respective perspectives.

Complex products may involve additional reviewers like biologists for cell-based products, virologists for products with viral safety concerns, and so on.

Pre-IND Meetings: Discussing CMC Strategy

Pre-IND meetings are valuable opportunities to align with FDA on your CMC strategy before you commit resources. Key topics to consider discussing:

Product Characterization

  • What level of characterization is appropriate for this stage?
  • Are there specific impurities or quality attributes FDA wants addressed?
  • What analytical methods does FDA expect?

Manufacturing

  • Is the proposed manufacturing process acceptable for the development phase?
  • What process validation expectations apply?
  • Are there concerns about scale-up or technology transfer?

Specifications

  • Are proposed specifications appropriate?
  • What safety qualification data is needed for impurities?
  • How should specifications evolve through development?

Stability

  • Is the proposed stability program adequate?
  • What data is needed to support the clinical use period?
  • Are there specific stability concerns for this product type?

Your move: Don't use Pre-IND meetings to ask questions you could answer yourself with guidance documents. Use them for genuinely ambiguous situations, novel products, or areas where FDA precedent is unclear. Come with specific proposals, not open-ended questions.

Calibrating to Development Phase

FDA's expectations are scaled with development stage. What's acceptable for a Phase 1 IND may be inadequate for a Phase 3 study:

Phase 1

  • Preliminary specifications based on limited batch history
  • Partial validation of analytical methods
  • Limited stability data (with commitment for ongoing studies)
  • Manufacturing process is still being optimized
  • Impurity qualification may be based on literature or default thresholds

Phase 2

  • Tightening specifications based on accumulated data
  • Full validation of critical analytical methods
  • Extended stability data supporting proposed storage conditions
  • Manufacturing process becoming more defined
  • Impurity qualification with actual toxicology data

Phase 3 / Pre-NDA

  • Final specifications representative of commercial process
  • Fully validated methods for all quality attributes
  • Full shelf-life stability data (or data supporting extrapolation)
  • Validated manufacturing process at commercial scale
  • Complete impurity qualification

Your move: Understand what's expected at each phase and build toward it. Don't over-invest in Phase 1 (you need flexibility to optimize), but don't under-invest either (you can't fix a fundamentally flawed process later). Each phase should build logically on the previous one.

Warning Signs You Need Expert CMC Support

Consider engaging experienced CMC regulatory support when:

  • Novel modality: Gene therapy, cell therapy, mRNA, complex biologics with limited regulatory precedent
  • Complex formulation: Liposomes, nanoparticles, long-acting injectables, combination products
  • Manufacturing challenges: Technology transfer issues, scale-up problems, process consistency concerns
  • Analytical gaps: Difficulty developing stability-indicating methods, potency assays that don't correlate with activity
  • Sterility concerns: Aseptic processing validation issues, container closure integrity questions
  • FDA feedback: Information requests, refuse-to-file, or clinical hold related to CMC
  • Accelerated timeline: Breakthrough therapy or other expedited pathway with compressed CMC development

CMC is the most common reason for FDA Complete Response Letters. An experienced CMC regulatory consultant can help you anticipate issues, structure your submission effectively, and navigate FDA's quality review expectations.

The Bottom Line

When FDA reviews your IND, their first question is "will this product be safe for clinical trial subjects?" The answer depends on purity, potency, stability, and sterility.

These aren't bureaucratic checkboxes. They're fundamental quality attributes that determine whether your product might harm patients. FDA's chemistry reviewers and microbiology staff are experts at identifying gaps and risks, and they've seen what happens when products don't meet standards.

Approach your CMC section with the same rigor you bring to your clinical program. Characterize your product thoroughly, control your impurities, validate your methods, and ensure your manufacturing process produces consistent material. Address potential concerns proactively rather than waiting for FDA to find them.

The sponsors who move fastest through development aren't the ones who submit the minimum acceptable CMC package. They're the ones who submit a clear, well-organized package that demonstrates they understand their product and can manufacture it reliably.

About This Series

Good Regulatory Practices is an educational series designed to share practical regulatory knowledge that helps sponsors navigate drug development more effectively. Topics are drawn from real-world experience and address the strategic questions that make the difference between efficient development and costly delays.

Dr. Saunders is the Founder and CEO of Innovative Regulatory Science Group (IRSG), a regulatory consulting firm with over 25 years of FDA regulatory experience. She also serves as senior adjunct faculty at Northeastern University, teaching several courses including regulatory strategy for product development.

Educational planning content, not regulatory advice. Program-specific decisions require qualified quality, manufacturing and regulatory review.