Chemistry, Manufacturing and Controls (CMC) is an integral aspect of any drug candidate development and is critical for ensuring protection of the clinical trial subjects. CMC includes information such as the physiochemical or biological properties of a molecule, its manufacturing process, packaging, and details around analytical control testing.

CMC is provided in the Quality part of the Investigational New Drug (IND) application required to initiate the clinical trials in the United States or the Investigational Medicinal Product Dossier (IMPD) expected in the European Union. IND and IMPD both follow Common Technical Document (CTD) format of Module 3.

According to the US Food & Drug Administration (FDA), more than 1,200 IND applications are expected this year, and determining the right strategies and getting guidance on an effective compilation of Quality sections of IND and IMPD submissions takes a committed team.

Assemble a Committed Team for CMC Success

The Quality section of an IND/IMPD submission is complex, comprising multiple highly technical documents to summarize the CMC information for a drug substance, drug product, and often placebo arm, if used in clinical trials.

It can be labour intensive and time consuming to account for all associated source documents, develop an authoring plan based on available sources and determine granularity of the submission, as well as author, QC, and track all quality submission components. Apart from having technical writing training, a chemistry background, and regulatory knowledge, CMC author(s) should also have strong project management skills to successfully lead IND/IMPD submission writing from start to finish.

Sponsors often have a dedicated CMC regulatory team that authors CMC submission documents. In situations where an organization does not have a designated and qualified CMC regulatory personnel, authoring can be assigned to subject matter experts (SMEs) or the QA team. Additionally, CMC writing can be outsourced to a Clinical Research Organization (CRO) to ensure the quality of the submission documents meet high regulatory standards.

Where to Begin in CMC Authoring

Before the CMC authoring starts, the following best practices should be considered:

• CMC writers should have a good understanding of the product development history and background. This requires working closely with the manufacturers, R&D team, and subject matter experts (SMEs).
• Authors should carefully review applicable guidelines and regulations, which can vary based on the type of submission, regional requirements, and/or dosage form, etc. For IND content requirements, refer to FDA guidelines: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well‑Characterized, Therapeutic, Biotechnology-derived Products or INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information. For IMPD submissions, the following guidelines should be referenced: Guideline on the Requirements for the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials, or Guideline on Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials.
• Involve CMC strategists at an early stage to foresee any changes during the drug development process.
• Assign functional leads or SMEs as reviewers.
• Establish clear expectations around data sharing, timelines, and the review process.
• Review source documents, identify gaps and items on the critical path, determine impact on submission target date (common reasons for CMC submission delays are challenges with obtaining final release data for current Good Manufacturing Practice (cGMP) clinical material, insufficient stability data for clinical materials to support the planned clinical trials).
• Develop an IND/IMPD submission authoring plan. CMC sections can be authored in batches when the data is available in the process of the product development or can be initiated after all the data is collectively obtained.
• Written documents must be electronically complied and eCTD submission ready. Use eCTD compliant templates.
• Identify regulatory strategies and align key messaging with functional leads, SMEs, and CMC strategists.

Using a Direct and Lean CMC Authoring Approach

Clear and concise regulatory documentation is critical to the success of any regulatory submission, especially in INDs and IMPDs. Ensure this by using a direct, leaning authoring approach in the following ways:

• For the first IND/IMPD submission, outsource the templates from specialized service providers if the CMC writing is performed in-house.
• Present data in a brief, specific, clear, and structured way.
• Data may be presented within text by briefly outlining the main points, using bullet points, and supported by in-text tables and figures for better data presentation.
• Cite sources and provide references for any data and statements.
• Avoid redundancy and employ a lean authoring approach by providing a cross-reference to relevant information rather than repeating it in multiple sections of Module 3.
• Use consistent nomenclature and abbreviations throughout (e.g., sample names, active ingredient, inactive ingredients, analytical procedures).
• Lastly, Module 3 sections should be checked for accuracy against the source, as well as for consistency, format, style, and grammar.

CMC Content Requirements for IND and IMPD

It is well understood by regulators that the amount and depth of CMC information that would be submitted to global health authorities depends, in large part, on the phase of the investigation. Technical medical writers must develop documents accurately reflecting molecule characterization, production process, and control.

As the Sponsor advances the drug development and clinical phases, a greater level of detail is expected to be included in the submission.

General CMC information expected for the drug substance, drug product, and placebo arm has been outlined below. It should be noted that this is not an exhaustive list, and the level of detail may vary depending on region, the type of submission or product, type of technology used, dosage form, or stage of development, etc.

Drug Substance

• Information on the nomenclature of the drug substance.
• A list of physiochemical or biological characteristics, structure, and identity of the active pharmaceutical ingredient.
• Name, address, and responsibility of manufacturer(s).
• Explanation of the manufacturing process and process controls, as well as a list of the raw materials, starting materials, solvents, reagents, and catalysts used, preferably paired with a flow diagram for an effective representation.
• A concise description of the qualified analytical methods and citation of an official compendium, if applicable, along with the acceptable limits used to confirm the identity, quality, purity, and strength of the drug substance.
• Data related to the quality and control of intermediates isolated during the manufacturing process.
• Information about the quantification of potential impurities which can arise during synthesis, purification, and storage should be presented.
• Test results and analytical data from batch release of representative clinical trial materials should be provided (e.g., batches of drug substance of the actual material to be used in the clinic study should be produced and release data included in the submission).
• Detailed information to support the stability of the drug substance used in human trials throughout the duration of the clinical studies.
• Risk assessment of the safety of biotechnology-derived drugs or drugs extracted from plant, animal, or human sources should be provided.

Drug Product

• List all ingredients of the drug product. This list should include the ingredients which may or may not be included in the manufacturing process.
• An outline of quantitative composition of the investigational new drug product, along with any acceptable discrepancies that could be anticipated during the investigational stage.
• Name, address, and responsibility of manufacturer(s), including laboratories, packaging and labelling facilities, and Qualified Person (QP) required for IMPD.
• Description of the manufacturing process and packaging procedure, including presentation in the form of a flow diagram with in-process tests and parameters identified, as applicable for the product.
• Established specifications for the drug product considered to be used in clinical studies inclusive of endotoxin levels and particulate matter for injectable products, sterility, and pyrogenicity tests, as applicable.
• Description of the qualified analytical methods used to confirm the identity, strength, quality, and purity of the drug product.
• Batches of cGMP drug product of the actual material to be used in the clinical study should be produced and release data presented.
• Degradation products or process-related impurities should be identified, quantified, qualified, and reported as appropriate.
• Description of the container closure system, packaging components with reference compendial standards.
• Data to support the stability of the drug product during the planned clinical studies.

Placebo

While submitting an IND or IMPD with CMC information for clinical supply manufactured under cGMP, it is important to include the placebo arm, if it will be used in clinical trial design.

This quality section should cover a brief general description of the composition, manufacture, stability data, and control of any placebo formulation that would be used in the proposed clinical study. The placebo clinical study material should be tested to demonstrate the absence of the active pharmaceutical ingredient(s).

Moving forward

As detailed, deep CMC regulatory experience and a working technical background are necessary to author an IND and IMPD effectively. Authors should be capable of interpreting scientific data, feel comfortable with navigating through the applicable guidelines and regulations, and efficiently manage CMC teams involved in the development, manufacturing, and regulatory aspects of a drug candidate.

The primary goal of CMC writing is to produce high-quality documents that are scientifically accurate and relevant. The flow of information should be logical, with appropriate content included for the product development stage and type of regulatory submissions.

To explore how MMS can support your CMC writing or strategy needs, please click here and we will connect you with the appropriate expert.

References

• GUIDELINE FOR GOOD CLINICAL PRACTICE (ich.org)
• Current Good Manufacturing Practice for Phase 1 Investigational Drugs. Guidance for Industry. July 2008.
• Food, Drug, and Cosmetics Act 21CFR225.1 Current Good Manufacturing Practice §501(a) (2) (B).
• Thornton R, Hagen A, Sitrin R, et al. Integrating CMC Document Preparation into the Development Process for Vaccine INDs. BioPharm Inter. 1 September 2003; 16(9).

Authored by:

• Frenita Lobo, Medical Writer at MMS Holdings
• Margaret Studzinska, Director of CMC and Nonclinical Writing at MMS Holdings