As clinical development of an investigational product proceeds, Sponsors often conduct global clinical trials which require preparation of content to support dossiers in multiple geographies, meeting the regulatory requirements of each region. The major markets follow ICH guidelines, which affords harmonization of a significant portion of the chemistry, manufacturing, and controls (CMC) content. There remains, however, key differences in regulatory requirements from both a content and format perspective. Below, we review three main geographies as part of a global clinical development program – US, EU, and Canada (highlighted in Table 1 below)– with summary information provided on additional regions.

US IND

Clinical studies conducted in the US are carried out under an investigational new drug (IND) application. In terms of application format, the eCTD headings and hierarchy for Module 3 are used for an IND, as outlined in ICH M4Q. The Quality Overall Summary (QOS) section 2.3, however, is not strictly required for Module 2. An IND application may be submitted and cleared without a QOS.

Drug substance content in Module 3.2.S may be incorporated via cross-reference to a US Drug Master File (DMF). It should be noted that the content requirements are the same whether the information is included directly within the dossier or included via cross-reference to a DMF. Process validation and/or evaluation is not applicable for investigational drug substance and drug product. Likewise, a post-approval stability protocol and stability commitment is not applicable to materials for clinical trials. Phase-appropriate information and data to support CMC content, such as impurity characterization, drug substance and drug product analytical method validation and stability studies, should be developed as clinical development progresses.

EU CTA (Q-IMPD)

Clinical studies in the European Union are conducted under a Clinical Trial Application (CTA), which includes a Quality Investigational Medicinal Product Dossier (Q-IMPD) as part of the common scientific documents. While section titles in the Q-IMPD are similar to eCTD headings and hierarchy used for IND, section numbering (e.g., 2.1.S, 2.1.P) is per the specific IMPD guidance. Additionally, the Q-IMPD is nongranular (i.e., it is a single document for submission).

Active substance content in the Q-IMPD may refer to an Active Substance Master File (ASMF) or a Certificate of Suitability (CEP) of the European Directorate for the Quality of Medicines (EDQM). Additionally, reference to either the European Pharmacopoeia (Ph. Eur.), the Pharmacopoeia of an EU Member State, the United States Pharmacopoeia (USP) or the Japanese Pharmacopoeia (JP) is also accepted, though additional information on the drug substance will be required. Similar to the US IND, process validation and/or evaluation is not applicable to investigational material for clinical trials – with the exception of nonstandard sterilization processes not described in the Ph. Eur., USP or JP. In such cases, the critical manufacturing steps, the validation of the manufacturing process as well as the applied in-process controls should be described in the Q-IMPD.

Validation of the analytical procedures and justification of specifications specific to excipients are not applicable for investigational medicinal product and are not required. Likewise, a post-approval stability protocol and stability commitment is not applicable to material for clinical trials. However, for a Q-IMPD, a shelf-life extension plan for the investigational active substance and medicinal product is required to be included to allow for future extensions of the retest or shelf-life period for the active substance and medicinal product, respectively, without a substantial modification submission. Phase-appropriate information and data to support CMC content, such as specifications, analytical methods, analytical method validation, pharmaceutical development, and stability, should be developed as clinical development progresses.

HC CTA (QOS)

Clinical studies in Canada are conducted under a CTA, which includes a phase-specific Quality Overall Summary – Chemical Entities (QOS-CE) for CMC information. Health Canada provides templates for each phase-specific QOS-CE, outlining the format and required CMC content. Specific eCTD-formatted Module 3 sections, such as 3.2.P.8.3 Stability Data, may be included as attachments to the QOS-CE. Of note, the Q-IMPD format submitted in support of EU CTA dossiers is also accepted by Health Canada (HC).

Drug substance content may be incorporated via cross-reference to a Canadian DMF. Analytical methods, validation of the analytical procedures and justification of specifications specific to excipients are not applicable for investigational drug product. As with the US IND, process validation and/or evaluation is not applicable for investigational drug substance and drug product.

Information on reference standards and materials are not required for the QOS. For the post-approval stability protocol and stability commitment section for clinical trials, a summary of the stability protocol and a commitment that the stability of the clinical trial samples or representative batches will be monitored throughout the duration of the clinical trial or proposed shelf life should be included. Phase-appropriate information and data to support CMC content, such as impurity specifications, analytical methods, analytical method validation, pharmaceutical development, and stability, should be developed as clinical development progresses.

Table 1. Overview for US, EU, and Canada Clinical Applications

Geography	US	EU	Canada
Clinical application	IND	CTA (Q-IMPD)	CTA (QOS-CE or Q-IMPD)
Submission format	eCTD per ICH M4Q guidance	IMPD format per EU guidance	QOS-CE per HC template
			or IMPD format per EU guidance
	Module 3 – required	Nongranular	Nongranular
	Module 2.3 QOS – optional
Module 3.2.S	May cross-reference DMF	May cross-reference ASMF or CEP of EDQM	May cross-reference Canadian DMF

Additional considerations

Looking beyond the above three regions for global clinical development, a few additional considerations regarding CMC dossier content to note are as follows:

• For clinical trial notification (CTN) submissions in Australia, the only CMC information required is included within the Investigator’s Brochure (IB).
• The National Medical Products Administration (NMPA) and the Pharmaceuticals and Medical Devices Agency (PMDA) both follow the CTD format for submissions to China and to Japan, respectively. For China, the long-term storage condition for stability is per ICH Zone IVa (30°C/65% RH); however, if stability data is acquired according to a global study design per ICH Zone IVb (30°C/75% RH), this is also acceptable.
• CTA submissions to the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK accept the EU Q-IMPD format. MHRA also provides example IMP dossiers for modified product types on their website, as well as common mistakes to avoid.
• Similarly, clinical submissions to the Central Drugs Standard Control Organisation (CDSCDO) in India accept the EU Q-IMPD format. Note that for India, stability data per ICH Zone IVb will be required.
• The Dossier de Desenvolvimento Clínico de Medicamento (DDCM), translated Clinical Drug Development Dossier, is submitted to the Brazilian regulatory authority Agência Nacional de Vigilância Sanitária (ANVISA). Stability data per ICH Zone IVb will be required for this region, to be included as part of the Experimental Drug dossier. Again, the EU Q-IMPD may be used here for submission.

Conclusions

Preparation of CMC content to support global dossiers, meeting the regulatory requirements of multiple regions, is increasingly a goal of Sponsors as clinical development of pharmaceuticals is conducted with global clinical trials. While many of the major markets follow ICH guidelines, bringing harmonization to a significant portion of the CMC content, there remains key differences in regulatory requirements from both a content and format perspective in the individual country submissions that should be taken into consideration during the planning and preparation of such dossiers.

CMC experts at Premier Consulting are experienced in multi-country submissions and can provide guidance and support to Sponsors for submissions across different regulatory regions. If you have any questions or want to learn more, contact us today.

References:

1. Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products, November 1995:
   https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-and-format-investigational-new-drug-applications-inds-phase-1-studies-drugs-including-well
2. INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information, May 2003: https://www.fda.gov/media/70822/download
3. ICH M4Q (R1), 12 September 2002:
   https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdf
4. Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials:
   https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-and-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-revision-2_en.pdf
5. Guideline on Active Substance Master File Procedure – CHMP/QWP/227/02 Rev 4/Corr:
   https://www.ema.europa.eu/en/documents/report/final-guideline-active-substance-master-file-procedure-revision-4_en.pdf
6. Guideline on Summary of Requirements for Active Substances in the Quality Part of the Dossier – CHMP/QWP/297/97 Rev 1:
   https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-summary-requirements-active-substances-quality-part-dossier-revision-1_en.pdf
7. Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals:
   https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qual_cta_dec-eng.pdf
8. Quality Overall Summary – Chemical Entities Clinical Trial Application – Phase I (QOS-CE (CTA – Phase I)):
   https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qoscecta_sgqecdec_ph_i-eng.pdf
9. Quality Overall Summary – Chemical Entities Clinical Trial Application – Phase II (QOS-CE (CTA – Phase II)):
   https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qoscecta_sgqecdec_ph_ii-eng.pdf
10. Quality Overall Summary – Chemical Entities Clinical Trial Application – Phase III (QOS-CE (CTA – Phase III)):
    https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qoscecta_sgqecdec_ph_iii-eng.pdf
11. Australian clinical trial handbook, Version 2.4, August 2021: https://www.tga.gov.au/sites/default/files/australian-clinical-trial-handbook.pdf
12. Pharmaceutical Regulations in Japan: Drug Development: https://www.jpma.or.jp/english/about/parj/eki4g6000000784o-att/2020e_ch03.pdf
13. https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk
14. https://clinregs.niaid.nih.gov/
15. Stability conditions for WHO Member States by Region, March 2021: https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/regulatory-standards/trs953-annex2-appendix1-stability-conditions-table-2018.pdf?sfvrsn=74032aec_12&download=true