Top 5 CMC Mistakes in IND Submissions That Companies Overlook

Early investment in a sound CMC strategy, aligned with ICH and FDA guidance, accelerates development timelines and reduces regulatory risk.

Chemistry, Manufacturing, and Controls (CMC) content is often underestimated during early development stages of an Investigational New Drug (IND) application.

While FDA recognizes that CMC data will evolve across clinical phases, reviewers expect sufficient information to ensure patient safety, drug substance integrity, and clinical supply reliability. Gaps in CMC can trigger information requests, clinical holds, or delays in first-in-human studies.

Generating lists with online tools is simple, as I’ve done here. Each program faces unique challenges, and we can help you navigate beyond the list below.

1. Insufficient Drug Substance Characterization and Control Strategy

Even in Phase 1, Module 3.2.S (Drug Substance) should demonstrate adequate understanding of the active pharmaceutical ingredient (API). Sponsors frequently omit:

• Synthetic route / manufacturing description (3.2.S.2.2) with identification of key steps and reagents

• Critical impurity assessment, including potential genotoxic impurities (GTIs) in line with ICH M7

• Adequate analytical characterization (identity, assay, purity, solid-state form)

⚠️ Common pitfall: Submitting supplier Certificates of Analysis (CoAs) without justification or orthogonal testing. FDA expects independent verification or scientific rationale for acceptance.

Reference: FDA Guidance for Industry: INDs for Phase 2 and 3 Studies – Chemistry, Manufacturing, and Controls; ICH Q6A; ICH M7.

2. Lack of Justification for Specifications and Interim Acceptance Criteria

Specifications are not “placeholders.” Even for early clinical trials, Module 3.2.S.4.1 and 3.2.P.5.1 should include scientifically justified criteria that protect subjects. FDA expects:

• Interim acceptance criteria based on available data (process capability, toxicology limits)

• Safety-based justification of limits for impurities, residual solvents (ICH Q3C), and elemental impurities (ICH Q3D)

• Alignment between methods, detection limits, and specifications

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⚠️ Common pitfall: Writing “specifications will be finalized later” without linking interim limits to patient safety.

Reference: ICH Q6A, Q3A/B, Q3C, Q3D; FDA M4Q IND guidance.

3. Stability Data and Storage Conditions Are Missing or Inadequate

Regulators expect assurance that drug substance and drug product remain stable under proposed storage and use conditions. At IND stage, stability packages should include:

• Preliminary accelerated and real-time data on representative batches (Module 3.2.S.7 and 3.2.P.8)

• Justified storage conditions and shelf life, even if provisional

• Ongoing commitment to stability protocol execution through Phase 1

⚠️ Common pitfall: Submitting only a proposed protocol without supporting data, leaving reviewers uncertain about trial supply integrity.

Reference: ICH Q1A(R2), FDA IND CMC guidance (2010).

4. Inadequate Control of Excipients and Ancillary Materials

Excipients are often treated as “routine,” yet their safety and quality must be justified in the IND. FDA evaluates:

• Source, grade, and compendial status (USP/NF, Ph. Eur.)

• Novel excipients requiring toxicology justification or prior use evidence

• Adventitious agent safety (e.g., TSE/BSE risk in animal-derived excipients, per EMA Note for Guidance and FDA expectations)

• GMP compliance for critical raw materials

  
  

⚠️ Common pitfall: Relying solely on pharmacopeial monograph status without assessing suitability for route of administration (e.g., parenteral vs. oral).

Reference: ICH Q7, Q9; FDA Guidance on Novel Excipients; EMA Note for Guidance on Minimising TSE Risks.

5. Weak Linkage Between Manufacturing Process, In-Process Controls, and Clinical Supply

IND reviewers look for evidence that manufacturing processes produce consistent clinical trial material (CTM). Sponsors sometimes under-document:

• How batch records and in-process controls (IPCs) ensure reproducibility (Module 3.2.S.2.2 and 3.2.P.3.3)

• Controls for aseptic processing / sterilization validation (critical for injectables)

• Scale-up rationale when moving from lab-scale to GMP Phase 1 batches

  
  

⚠️ Common pitfall: Treating manufacturing details as “internal know-how,” rather than demonstrating a defendable control strategy tied to the CTM used in clinical trials.

Reference: ICH Q8 (Pharmaceutical Development), Q10 (Pharmaceutical Quality System), FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing.

Conclusion

CMC requirements at the IND stage are not exhaustive, but they must be sufficiently robust and risk-based to assure product quality and patient safety.

Addressing these five common oversights—drug substance characterization, justified specifications, stability data, excipient control, and manufacturing-process linkage—helps prevent FDA information requests and clinical holds, while laying a strong foundation for late-phase development.