The Odd Couple – Part 3: Authoring the Control of Excipients Modules

The Odd Couple – Part 2: Authoring the Manufacture of Drug Substance and Drug Product Modules (S2, P3)
June 23, 2020
The Odd Couple – Part 4: Authoring the Analytical Control and Analysis and Reference Standards Modules
July 14, 2020

The Odd Couple – Part 3: Authoring the Control of Excipients Modules

This full Series follows our initial Primer blogs: Constructing the CTD Quality Module 3, and Quality Overall Summary: Reviewers Guide. For the purposes of this blog series, it will be necessary to produce an admittedly unbalanced summary that shortchanges some sections of the Quality Module but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application. I have therefore focused discussion on selected aspects from a remarkably diverse and technical exercise, which is the production of the CTD Quality Module.

The CTD Module 3

Though the content of these modules is generally well defined, according to the various guidance documents previously referred to, considerable latitude for assimilating, discussing, comparing, and contrasting data is allowed and even encouraged. There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.  

CTD Module 3 is well defined containing both drug substance (active ingredient) and drug product sections, with each containing required presentations of drug technical information, processes and key parameters, and various justification supported by qualification and validation studies.

This data and these reports provide the detailed evidence that a drug’s characteristics are well defined and well controlled, such that one can assure that the next lot produced is essentially the same as the last lot. Drug manufacture control and reproducibility is the essential message that Module 3 must convey if Agency reviewers are to conclude that a new drug application merits approval.

Sponsors have latitude in how data are presented, and how important messages are formatted in the compilation of a CTD application.

Preparation of CTD submissions for various regulatory authorities should be geared toward meeting those unique regulatory standards.

Control of Excipients

P.3.1 Specifications

The acceptance criteria and tests conducted for the excipients should be reviewed relative to the preformulation experimental results. The acceptance criteria for the excipients should consider those qualities critical to the drug product performance and manufacturing operation as described earlier in formulation development.

P.3.2 Description of Analytical Methods

The analytical methods used to test excipients, reagents, and drug product should be reviewed. Sufficient detail should be available in order that the methods could be adequately run in the laboratory.

For example, HPLC methods should provide detail on the type of column used, run time, mobile phase composition, flow rate, and detection means. Adequate validation data should be available to assure the accuracy of the data used to support the physicochemical properties of the drug product.

The ICH text on the validation of analytical procedures provides a good overview of the type of information that should be included in the validation package. Key items include accuracy, linearity, precision (repeatability and intermediate precision), robustness, and specificity.

While all of these aspects of validation may not be complete in early phases of development, some level of detail must be available to assure the accuracy of the information provided.

P.3.4 Excipients of Human or Animal Origin

For excipients of human or animal origin, information should be provided regarding adventitious agents (e.g., sources, specifications, description of the testing performed, viral safety data). (Provide details in Appendix 3.2.A.2). Reference ICH guidances Q5A, Q5D, and Q6B.

P.3.5 Novel Excipients

For excipients used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (nonclinical and/or clinical), should be provided according to the drug substance format.

ICH, EMA: A novel excipient is an excipient which is being used for the first time in a drug product, or by a new route of administration. It may be a new chemical entity or a well-established one which has not yet been used for human administration and /or for a particular human administration pathway. 

FDA: New excipients are any inactive ingredients that are intentionally added to the therapeutic and diagnostic products, but that:

    1. are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g. enhance absorption or control release of the drug substance),
    2. are not fully qualified by the existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration. 

Regulatory Landscape 

Under the current regulatory framework novel excipients are not evaluated independently, but as part of a submitted IND/IMPD in clinical phase development. Therefore, applying guidelines for the EU and US (as described above) should be taken into account early in the development of drug products containing novel excipients. 

Data should be presented in a format similar to the active substance format – meaning a significant amount of detail is expected.

A significant proportion of generated novel excipient data contains commercially sensitive and proprietary details and is therefore the intellectual property of the novel excipient manufacturer. To protect this sensitive data, a Type IV Excipient Drug Master File can be used for the US, but there are no equivalent procedures available in Europe. 

The highly variable approach to a novel excipient strategy should begin with a comprehensive literature search, which should determine all available chemical and toxicological data for the excipient of interest.

Particular attention should be paid to monographs of the major international compendia (Ph. Eur., USP and JP), the international specifications (FAO/WHO/JECFA), FDA Inactive Ingredient Database, Handbook of Pharmaceutical Excipients, historical usage as a food additive or cosmetic product and Food Chemicals Codex.

As a second step, crucial product-specific points, like compatibility and functionality-related attributes should be identified and addressed according to the heterogenous information available from guidelines. Only then the strategy for the development of the novel excipient of interest can be shaped, taking into account the current regulatory framework and aiming at a minimization of required resources while ensuring a high-quality product. 

Common Technical Document SectionRecommendations per Guidance(GMP) Source Documents Electronic Y/N
3.2.P.4 Control of Excipients 

3.2.P.4.1 Specifications 
  • Specifications for excipients should be provided.
  • Reference ICH guidances Q6A and Q6B.
  • Excipient/Specifications Sheet, Monograph
  • Excipient/ Stability Specification
  • Vendor Quality Agreements CoA’s
3.2.P.4.2 Analytical Procedures
  • Analytical procedures used for testing the excipients should be provided
  • Reference ICH guidances Q2A and Q6B.
  • General Analytical (USP)
  • Product Monograph General Monograph
  • Final Products & Intermediates
  • Standard Operating Procedures, Standard Test Methods and Specifications
3.2.P.4.3 Validation of Analytical Procedures 
  • Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients
  • Reference ICH guidances Q2A, Q2B, and Q6B.
Standard Operating Procedures, Standard Test Methods and Specifications
3.2.P.4.4 Justification of Specifications 
  • Justification for the proposed excipient specifications
  • Reference ICH guidances Q3C and Q6B.
CMC (Registration/Filing) Standard Operating Procedures, Standard Test Methods and Specifications
3.2.P.4.5 Excipients of Human or Animal Origin  Reference ICH guidances Q5A, Q5D, and Q6B.
  • Excipient Specifications
  • Excipient Certificates of Analysis
  • Qualification reports (GRAS) status compendial
3.2.P.4.6 Novel Excipients  For excipients used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data 
  • Excipient Specifications
  • Excipient Certificates of Analysis
  • Qualification reports (GRAS) status compendial

Ultimately, the timeliness of an Agency’s review and approval status of a drug’s Quality section is best served by preparation of a well-designed Quality Module. Insights and recommendations from the past fifteen years are provided here to help maximize the potential for a successful outcome.

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