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.

• Part 1 covered authoring the General Information and Characterization of the Drug Substance Modules
• Part 2 covered Authoring for the Manufacture of Drug Substance and the Drug Product
• Part 3 covered the Control of Excipients
• Below in Part 4 we will be covering the Control and Analysis of Substance and Product
• Part 5 will cover the Packaging and Labeling submission content
• Parts 6 Stability of Drug Substance and Drug Product
• Part 7 will conclude with the Composition and Pharmaceutical Development Modules

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.

Intimate Connectivity!

The link between product specifications and analytical methods makes intuitive sense. One cannot change without affecting the other.

Process development groups often revise product specifications or apply methods to an application for which it was not originally intended.

A product specification is a list of tests, references to analytical procedures, and associated acceptance criteria consisting of numerical limits, ranges, or other standards for the tests described. Similarly, a critical quality attribute (CQA) is a property either demonstrated through clinical trials or presumed to be related to clinical safety or efficacy.

Each product specification has three key elements: target quality attributes confirmed through some analytical test, analytical test method for a particular attribute, and acceptance criteria.

Justifying product specifications depends on diverse inputs, including a method’s capabilities, regulations, process capabilities (including variation), characterization studies, clinical and nonclinical studies, and literature research.

Perhaps the most consequential specification input is analytical method capability. The attribute of interest must, after all, be assessable. Thus specifications depend on the method’s specificity, sensitivity, variability, and accuracy.

Control of Drug Substance

S.4.1. Specifications

Specifications consist of test methods and their associated acceptance criteria. Each drug substance specification should be presented with a rationale for the limits specified. The following tests and acceptance criteria are applicable to all drug substances.

1. Typically, a qualitative statement or description regarding the appearance of the drug substance is given. The drug substance acceptance criteria entail the observed drug substance meeting the given qualitative criteria.
2. Identification testing should distinguish between the drug substance and closely related compounds. Typically, two identification tests are performed with one test being the HPLC retention time match with a reference standard material. The second test is typically a spectroscopic technique such as IR. It should be noted that UV-Vis absorbance spectra are not generally specific enough to distinguish related compounds.
3. The most common assay procedures for drug substances are titration methods and HPLC methods. If a titration method is employed for assay, an additional specific, stability-indicating method should be employed to control impurities in the drug substance.
4. HPLC methods are commonly used to control impurities in drug substance. The methods should be specific and stability-indicating.

There are additional specifications that may be applicable depending upon the nature of the drug substance and drug product. These specifications include:

1. Particle Size
2. Melting Point
3. Refractive Index (Chiral Molecules)
4. Polymorphic Form
5. Loss on Drying
6. Karl Fischer
7. Volatile organic impurities

For drug substances used in suspensions and solutions, additional physico-chemical characteristics of the drug substance may impact the drug product formulation. These characteristics include:

1. pH of Solution
2. Microbial Limits

S.4.2. Analytical Procedures and Validation

As detailed previously in S.2.3 for the control of starting materials, reagents, and drug substance, enough detail should be provided in order that the methods could be adequately run in the laboratory. Control methods derived from compendial references should clearly detail any requisite sample preparation requirements.

S.4.3. Analytical Validation

A review of the method validation package should ensure that all ICH guidelines are met. Analytical validation information, including experimental data for the analytical procedures used for testing the drug substance, should be provided in the application.

S.4.4. Batch Analyses

Test results for all batches made (including lab scale batches) should be reviewed and discussed where necessary. A comparison of results for those batches used in toxicology studies with those batches made for clinical use should be practiced. The level and type of impurities in the clinical batches typically should not exceed that of the toxicology batches. If the levels of impurities in the clinical, commercial, or registration batches exceed that of the toxicology batches, a full review by the toxicology group should be performed to assure that the level of impurities in batches proposed for the clinic are qualified and this information should be conveyed in the application.

S.4.5. Justification of Specifications

Drug substance specifications provide comprehensive control of identity, purity, quality, and potency. The specifications for the drug substance should be consistent with current process capability and drug safety study results.

Specifications for impurities in early development are controlled primarily by qualification limits determined by toxicology studies. During early stages of development, full justification of specifications is not available as final specifications are determined by the comprehensive development experience.

In Phase III of development, draft final specifications should be justified regarding the historical experience with the process at the current scale and synthetic route. At Phase III, the drug substance process should be well-defined and not open to any significant changes since Phase III stability batches and pivotal clinical studies will use drug substance from the current process.

Since specifications are chosen to confirm the quality rather than to characterize the product the sponsor should provide the rationale and justification for including and/or excluding testing for specific quality attributes. Consider answering How:

1. Specifications are linked to a manufacturing process
2. Specifications should account for the stability of drug substance
3. Specifications are linked to preclinical and clinical studies
4. Specifications are linked to analytical procedures

2.P.5. CONTROL AND ANALYSIS OF DRUG PRODUCT

P.5.1 Specifications

Specifications consist of test methods and their associated acceptance criteria. Each specification should be presented with a rationale for the limits specified. The following tests and acceptance criteria are applicable to all drug products.

1. Description—a qualitative statement regarding the appearance of the drug product should be given. The drug product acceptance criteria entail the observed drug product meeting the given qualitative criteria.
2. Identification testing should distinguish between the drug substance in the drug product and closely related compounds. Typically, two identification tests are performed with one test being the HPLC retention time match with a reference standard material. The second test typically is a spectroscopic technique such as IR. It should be noted that ultraviolet-visible absorbance spectra generally are not specific enough to distinguish related compounds.
3. Assay—The most common assay procedures for drug products are titration methods and HPLC methods. If a titration method is used for assay, an additional specific, stability indicating method should be used to control impurities in the drug product.
4. Impurities—HPLC methods commonly are used to control impurities in drug product. The methods should be specific and stability-indicating.

There are additional specifications that may be applicable, depending upon the nature of the drug product. These specifications include:

1. Disintegration.
2. Dissolution.
3. Stereoisomeric purity.
4. Moisture (water).
5. Residual solvents.
6. Microbial limits.

For drug product suspensions and solutions, additional physicochemical characteristics of the drug product may impact the drug product performance. These characteristics provided should include:

1. pH of solution.
2. Particle size of suspended drug.
3. Clarity of solution (turbidity).
4. Color of solution.
5. Viscosity.
6. Volume of fill.
7. Preservative testing.

P.5.2. Analytical Procedures

As detailed previously for the control of excipients, reagents, and drug products, sufficient detail should be provided in order that the methods could be adequately run in the laboratory. Control methods derived from compendial references should detail any requisite sample preparation requirements and any other details, such as the column used in the HPLC method. A review of the method validation package should ensure that all ICH guidelines are met.

P.5.3. Analytical Validation

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P.5.4. Batch Analyses

Test results for all batches made (including small-scale batches) should be reviewed. A comparison of results for those batches used in phase I safety studies with those batches made for later clinical studies should be pursued. The level and type of impurities in the later-phase clinical batches should not exceed that of the phase I safety batches.

P.5.5. Characterization of Impurities

Information on the characterization of impurities should be provided, if not previously provided in 3.2.S.3.2 Impurities.

P.5.6. Justification of Specifications

Drug product specifications should provide comprehensive control of identity, purity, quality, and potency. The specifications for the drug product should be consistent with current process capability and drug safety study results.

Specifications for impurities in early development are controlled primarily by qualification limits determined by toxicology studies. During early stages of development, full justification of specifications is not available as final specifications are determined by the comprehensive development experience.

In Phase III of development, draft final specifications should be justified regarding the historical experience with the process at the current scale and synthetic route. At Phase III, the drug substance process should be well-defined and not open to any significant changes since Phase III stability batches and pivotal clinical studies will use drug substance from the current process.

Since specifications are chosen to confirm the quality rather than to characterize the product the sponsor should provide the rationale and justification for including and/or excluding testing for specific quality attributes. Consider answering How:

1. Specifications are linked to a manufacturing process
2. Specifications should account for the stability of drug substance
3. Specifications are linked to preclinical and clinical studies
4. Specifications are linked to analytical procedures

S.5 and P.6 Reference Standards or Materials

The validity of the analytical results provided is, in part, reliant upon the use of appropriate reference standards. Reference standards used in the analysis of drug substance, starting materials, and intermediates must have additional testing to verify the identity and purity of the reference standard.

Typically, the reference standard is fully characterized including structural elucidation data as well as extended testing for impurities. Once the reference standard is fully characterized, a secondary reference standard may be tested against the primary standard and used for routine testing.

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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