CMC strategy: what needs to be in place before submitting your IND or IMPD
The IND or IMPD submission is the first moment at which the quality of a CMC strategy for IND IMPD submission becomes visible to an external reader. Internal reviews can be adjusted. Pre-IND interactions can be steered. Once the dossier is filed, the package speaks for itself. If it is coherent, the programme moves into the clinic. If it is not, the programme enters a cycle of requests for information, ground for non-acceptance (GNA) points or, in the worst case, a clinical hold.
The regulatory framework on both sides of the Atlantic has been unambiguous on this. In the United States, the FDA may place an IND on clinical hold when the CMC content is not sufficient to support the assessment of risks to trial subjects (21 CFR 312.42(b)(1)(iv)). In the European Union, the EMA guidelines on IMPD quality documentation set out what is expected from Phase 1 through to Phase 3, with explicit escalation of requirements as the programme progresses. In the United Kingdom, the MHRA publishes a regularly updated list of common deficiencies identified during clinical trial applications, which reads as a practical blueprint of what reviewers consistently find missing or inadequate.
Yet a recurring pattern remains. Programmes arrive at the point of submission with a dossier that is technically complete but conceptually thin. The individual sections are populated, but the connections between them are not clear. The reviewer is left to reconstruct the logic of the development programme from fragments of data, and the dialogue that follows absorbs weeks or months of timeline that the sponsor had not planned for.
The purpose of this article is not to reproduce regulatory guidelines, which are freely available. It is to focus on the elements that, in practice, most often determine whether an IND or IMPD submission moves smoothly or triggers a cycle of delays. For sponsors approaching their first clinical entry, these are the areas where investment of time and senior attention pays back most directly.
A Quality Target Product Profile that is more than a document
The QTPP is often prepared late and in isolation, as a companion document to the IND or IMPD. In that form, it rarely adds value. The QTPP only becomes useful when it is developed early and used as a reference against which every subsequent CMC decision is tested.
A useful QTPP translates the clinical intent of the programme into measurable product attributes: patient population, route of administration, dose concept, container-closure, shelf life and acceptable variability for the clinical phase concerned. From those attributes, the critical quality attributes (CQAs) of drug substance and drug product are derived, and from the CQAs, the control strategy follows. As discussed in our article on the Target Product Profile (TPP), this kind of upfront alignment tool makes every subsequent CMC decision easier to defend.
When the QTPP is developed in reverse, after the process and the methods have been fixed, it becomes a retrospective justification rather than a planning tool. Reviewers often detect this. The specifications read as if they were constructed from the data available rather than from what the product needs to be, and the justification of specifications section becomes difficult to defend.
Sponsors who invest in a proper QTPP early typically find that several downstream deliverables become simpler to prepare, because the logic has already been established.
Drug substance: characterisation that a reviewer can interpret
The drug substance section is the first major technical area of Module 3, and it is also one of the most common sources of deficiency points. The MHRA's published common issues list places characterisation data at the top of the list, noting that data are often either missing or presented without sufficient interpretation.
This is worth pausing on. A reviewer does not simply want to see spectra, chromatograms or analytical results. They want to see what those results demonstrate about the structure, the physicochemical properties and, for biologics, the higher-order structure, glycosylation profile, charge variants and post-translational modifications of the active substance. The interpretation is what transforms a collection of measurements into a coherent characterisation package.
For biologics and advanced therapies, characterisation is also the foundation on which the comparability argument will later be built. If the early characterisation package is thin, any subsequent manufacturing change, whether a site change, a scale change or a raw material change, becomes more difficult to defend. The cost of under-characterising the drug substance at IND or IMPD stage is therefore not only immediate; it accumulates through the life of the programme.
Impurities: the single most consequential area
If one area concentrates more late-stage deficiency points than any other, it is impurities. The principles are well established, but their application to a specific programme requires judgement. Three points deserve particular attention at IND or IMPD stage.
Qualification against toxicology material. Every impurity present in clinical material above the relevant threshold should be qualified in the toxicology package. When a new impurity appears in clinical lots that was not present in, or not controlled to the same level as, the toxicology material, the safety bridge is broken. The correction is usually time-consuming: additional toxicology studies, reformulation, or a change in process. It is far cheaper to anticipate this during process development.
Mutagenic impurities (ICH M7) and nitrosamines. Regulatory scrutiny on mutagenic impurities, and on nitrosamine impurities in particular, has continued to intensify. MHRA expects at least a summary nitrosamine risk assessment in the IMPD at all phases of clinical development, covering both drug substance route of synthesis and drug product formulation. The assessment should explicitly consider route of synthesis, starting materials, solvents, reagents, catalysts, intermediates, excipients and packaging. Sponsors who treat this as a late addition to the dossier are routinely asked for clarification.
Product-related impurities for biologics. Aggregates, fragments, charge variants, deamidated and oxidised forms, host cell proteins and residual DNA each carry their own analytical and safety considerations. The specifications and analytical methods should be calibrated to the development phase, but the reasoning must be defensible.
Analytical methods: fit for purpose, not fit for the bench
For Phase 1, EMA and MHRA guidance is explicit: a full validation report is not required. What is required is confirmation that the analytical methods used are suitable for their intended purpose, with acceptance limits and validation parameters presented in tabulated form. For Phase 2 and 3, a tabulated summary of validation results becomes mandatory.
This phase-appropriate approach is sometimes misread as permission to be informal at Phase 1. It is not. Fit for purpose at Phase 1 still requires that methods are specific, sensitive, stability-indicating where relevant, and capable of supporting the control strategy described in the specifications. It also requires that the methods can travel; that is, they can be transferred between laboratories, between CDMOs and between development phases without a complete redevelopment each time.
Potency assays deserve particular mention for biologics and advanced therapies. FDA guidance on cellular and gene therapy products recommends initiating potency assay development during preclinical and early clinical investigations, precisely because these assays take time to mature. A surrogate method may be acceptable for the first clinical trial, but the pathway to a relevant, stability-indicating potency method needs to be already visible in the dossier. If it is not, the programme will face that discussion again, under pressure, at the next phase.
Stability: a plan, not a snapshot
Stability is another area where the MHRA common issues list identifies recurring deficiencies: absent or insufficient stability data, or the absence of a clearly proposed retest period or shelf life. The principle is simple, and the execution is where programmes stumble.
Three elements should be in place before submission. Stability data appropriate to the phase — for early clinical trials, a limited number of batches is acceptable, but the data must cover the intended shelf life, with appropriate extrapolation where necessary. Accelerated and stress conditions should be included to support the stability-indicating properties of the analytical methods.
A clearly proposed retest period or shelf life is the second element. This is where programmes are often caught. Sponsors submit stability data without explicitly proposing a retest period (for chemical drug substances) or a shelf life (for biological drug substances and for drug products) justified by those data. The MHRA will then raise a deficiency point asking the sponsor to propose and justify one, which could have been anticipated.
The third element is a stability protocol and a shelf life extension plan. Although not strictly required, including both in the IMPD allows the shelf life to be extended later without a substantial amendment. Over the course of a multi-year programme, this administrative foresight saves considerable time. It signals to the reviewer that the sponsor is planning across the lifecycle, not only for the point of submission.
For biologics, stability planning also anchors the comparability strategy. A well-designed stability protocol is the most natural place to detect process drift and to support post-change comparability assessments.
Justification of specifications: the test of the control strategy
The specifications section is often the clearest test of whether a CMC package holds together. The specifications themselves are usually easy to list. The justification is where the coherence of the control strategy becomes visible.
A defensible justification links each specification to one or more of the following: safety data (including toxicology qualification and clinical experience), process capability, analytical method performance and relevant regulatory guidance. When a specification is set at a given level, the reviewer expects to see why that level, and not another, was chosen.
Two patterns of deficiency are particularly common. The first is the absence of a justification for limits on specific impurities, particularly where those limits appear tighter or looser than would be expected from the toxicology package or process data. The second is the absence of a justification for the absence of control over certain attributes, such as particulate matter, subvisible particles, or aggregate content, where a reviewer would expect such control to be present. Both lead to requests for clarification that could have been avoided.
Batch analysis data: representativeness is what matters
Representative batch analysis data must be provided for each manufacturing site listed in the IMPD or IND. This is not a new requirement, but it is a recurring source of GNA points because of how sponsors interpret "representative".
Batches produced at a different scale or using a modified method may still be acceptable, provided the dossier includes an explicit justification that these batches are representative of the clinical trial material. For biological and biotechnological products, batch analysis data are required for each site of clinical manufacture. For early phase trials with a limited number of batches, relevant non-clinical batches should be included, with clear explanations of how they relate to the material to be used in the trial.
The practical implication is that every manufacturing site in the dossier needs its own supporting batch data, or an explicit justification. Alternative sites that are not used for the proposed trial should be removed from the dossier, not left in as options. Reviewers interpret the list of sites as a list of sites that require documentation.
Comparability: start the argument before you need it
Few programmes complete development without at least one significant manufacturing change. A site transfer, a scale-up, a CDMO change, a raw material change, a container-closure change. For biologics, where minor process changes can affect product structure or function, comparability is particularly sensitive.
Comparability is rarely a single study. It is a structured argument supported by aligned characterisation, analytical testing, stability data and, where necessary, non-clinical or clinical bridging data. At IND or IMPD stage, it is often too early to present a full comparability package, but it is not too early to start the argument. The characterisation data, the analytical method qualification and the stability protocol should all be designed with the possibility of a later comparability exercise in mind.
Programmes that treat comparability as something to address when a change happens tend to lose time at each change. Programmes that build the underlying data architecture from the start absorb changes with less disruption.
The GMP framework: QP declaration, MIA(IMP), TSE/BSE
For EU and UK trials, the GMP framework around the IMP is a recurring source of avoidable deficiency points. The MHRA common issues list identifies four that appear again and again.
QP declaration for third-country manufacturing sites, signed by a QP named on the manufacturer's authorisation of the importer, trial- and product-specific.
Manufacturer's authorisation (MIA(IMP)) for all EU and UK sites involved in manufacture, packaging, labelling, importation or batch certification.
TSE/BSE documentation for all relevant materials, including reagents, active ingredients and excipients.
Labelling compliant with Annex 13 of the EU GMP guidelines, with explicit justification for any deviation.
None of these are technically complex, but they are frequently either missing or non-specific. The pattern is often the same: the sponsor relies on generic templates, or inherits documentation from another trial, without adapting it to the specific programme. The practical recommendation is to treat the GMP framework as a distinct workstream in the submission preparation, owned by a named person, with explicit completion criteria.
CDMO footprint: what the dossier reveals
The list of sites in the IMPD or IND is a small section, but it has disproportionate implications. Each site triggers its own documentation requirements: batch analysis data, QP declaration where applicable, MIA(IMP) or equivalent, and a clear description of the site's role. When the CDMO footprint has been selected late or opportunistically, this is where the consequences become visible.
Two common mistakes recur. The first is listing alternative manufacturing sites that are not actually used for the trial; this creates unnecessary documentation obligations and raises deficiency points. The second is listing sites whose documentation maturity is not consistent with the phase of development, particularly for specialist steps such as cell banking, viral clearance or aseptic fill-finish. The dossier reveals what the CDMO evaluation process did not. For more on this, see our article on CDMO partnerships.
Sponsors who treat CDMO selection as an extension of the quality system, rather than a purchasing decision, typically arrive at submission with a footprint that is both defensible and execution-ready.
The Pre-IND or scientific advice meeting: ask the right questions
For sponsors in the United States, the Pre-IND meeting is a Type B meeting and is normally granted only once per product and indication. For sponsors in Europe, scientific advice from EMA or national authorities serves a comparable function. In both cases, the meeting is an opportunity to reduce uncertainty before filing, and the value of the meeting is directly proportional to the quality of the questions asked.
Three categories of CMC questions tend to produce the most useful feedback. First, questions that confirm the acceptability of a specific strategy — for example, the proposed control strategy for a particular impurity, the proposed approach to potency measurement, or the proposed comparability plan in the event of a planned manufacturing change. Second, questions that seek alignment on phase-appropriate expectations where the guidance leaves room for interpretation, for example the level of analytical validation considered appropriate for the proposed phase, or the extent of process characterisation expected before the first clinical batch. Third, questions that surface reviewer concerns early, before they become submission issues.
Questions that are too open-ended, or that seek general commentary on the dossier, tend to produce general answers. Questions that are specific, supported by data, and framed around a concrete proposal tend to produce actionable feedback that can be referenced later.
The underlying principle
The elements above are not a checklist to be ticked. They are the visible surface of a development strategy. A reviewer assessing an IND or IMPD is, in effect, reconstructing the reasoning of the sponsor from the documents provided. When the reasoning is coherent, the individual sections hold together and the dossier is persuasive. When the reasoning is fragmented, individual sections can still be technically correct while the overall package fails to convince.
The programmes that move through IND or IMPD review most smoothly are not necessarily those with the largest CMC teams or the longest development history. They are those where the QTPP, the characterisation package, the analytical strategy, the specifications, the stability plan, the GMP framework and the CDMO footprint have been developed as a single integrated strategy, with senior judgement applied early and consistently.
For biotech sponsors approaching their first clinical entry, this is where the difference is made. Not in any single section of Module 3, but in the coherence that runs across all of them.
If your programme is preparing for an IND or IMPD submission, 3Biotech helps sponsors identify gaps in the CMC package and align strategy, documentation and execution before the dossier is filed.
Learn more about how 3Biotech supports biotech companies through our CMC advisory services.
