The Odd Couple- Part 1: Characterization – He’s Never Developed a Regulatory Submission and She’s Never Submitted One.

The Odd Couple- Part 1: Characterization – He’s Never Developed a Regulatory Submission and She’s Never Submitted One.

The CTD Module 3

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.

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.

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.

Part 1: Authoring the General Information and Characterization of the Drug Substance Modules

General and Characterization Information of Drug Substance

General Information

S.1.1 Nomenclature

The most obvious piece of information, the chemical name of the drug substance should be provided. International Union of Pure and Applied Chemistry (IUPAC) nomenclature should be employed. Laboratory codenames and/or other nonproprietary names should be noted in the application in order to cross reference information from various drug development reports.

S.1.2 Structure

The structural formula, including the relative and absolute stereochemistry, the molecular formula, and the molecular mass should be provided.

Structural elucidation studies may include elemental analysis, mass spectrometry, liquid chromatography/mass spectrometry (LCIMS), NMR spectroscopy, UV-vis spectroscopy, IR spectroscopy, FT-IR spectroscopy, stereochemical analysis, configurational/conformational analysis, X-ray analysis, degradative analysis, and chromatographic analysis.

A careful review of the spectroscopic data used to demonstrate the structure of the drug substance should be applied and a summary available. The complexity of the spectroscopic techniques requires data review by specialists in spectroscopy to assure the accuracy and adequacy of the studies.

Elemental analysis should be used to confirm the theoretical formula. Mass spectrometry studies provide structural information based upon the various fragmentation patterns of the molecule. NMR studies can be performed on the drug substance in the solid state or in solution. Typically, IH and 13C probes are used and give specific spatial information on the chemical structure.

The literature is abounding with references to structure elucidation using NMR techniques including specific references to pharmaceutical compounds. More complex molecules such as synthetic peptides should be characterized by amino acid analysis and peptide sequencing. Mass spectrometry of peptides includes techniques such as fast atom bombardment, electrospray, plasma desorption, or laser desorption which may be used to provide the molecular weight or sequence information.

S.1.3 General Properties

The physical and chemical properties of the drug substance must be understood to develop an adequate formulation. The rationalization of the selection of the salt or free acid/base should be specified and discussed in the application or referenced in a development report regarding the resultant quality of the drug substance and the ability to handle/process the drug product.

Typically, the physicochemical properties of the salts and free acid/base are compared and assessed regarding formulation needs, process chemistry capabilities, and clinical requirements. The ionization constant, pH dependence of the partition coefficient and solubility in aqueous and non-aqueous media of the chosen salt should be well-characterized.

The resultant chemical and physical characteristics of the selected salt should be examined and documentation available regarding ease of processing as well as any potential impact on drug product processing equipment. For example, HCI salts of weak basic drugs can produce corrosion and negatively impact the tableting equipment.

The purity profile for multiple lots should be examined. Reversed phase High Performance Liquid Chromatography (HPLC) is typically employed for the analysis. Is the purity profile reproducible? Are impurities at ICH thresholds appropriately reported, identified, and qualified? This should be discussed.

It is recommended to use complementary detection techniques to verify the purity of the drug substance. Typically, impurities with weak chromophores may not be detected by conventional UV detection techniques. Alternative detection techniques can be employed including LC-MS, LC-NMR, refractive index, and evaporative light scattering. Alternative separation techniques also should be employed and may include normal phase HPLC, Thin Layer Chromatography (TLC) and Capillary Zone Electrophoresis (CZE).

An examination of the solution stability of the drug substance in various solvents also may provide an indication of the propensity for the drug substance to degrade in liquid formulations or during wet processing steps.

Physical properties such as hygroscopicity, polymorphism, hydrate/solvate formation, solid-state stability, and powder characteristics must be documented. The particle size distribution of multiple lots should be examined as an indicator of processing robustness. Special attention should be given to the reproducibility of the particle size distribution since the particle size may impact homogeneity of a tablet formulation.

A variety of particle size techniques exists including laser light scattering, sieve analysis, and optical microscopy. Additional powder characteristics include density, angle of repose, and compressibility and are important indicators of drug substance behavior. For example, the difference between aerated bulk density and packed bulk density can be used to determine the compressibility of the drug substance.

While highly compressible powders may be likely candidates for a direct compression process, the flow of the drug substance decreases as the powder becomes more compressible and may lead to product flow limitations during the manufacture of the drug product.

Other physical characteristics may be determined by x-ray powder diffraction, thermal analysis – Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA), and hot stage microscopy.

Crystal polymorphism is an essential characteristic needed to be fully understood in the drug development process. Polymorphism entails different arrangements of the molecule in the solid state. Crystalline polymorphs differ in crystal structure (internal structure) but are chemically identical having the same liquid and vapor states. The propensity for the drug substance to form polymorphs should be studied extensively in a variety of crystallization solvents. These studies also may include freeze drying and evaporative studies to induce polymorphic transformations.

Where polymorphs exist, the relative difference in energies (and hence the propensity for conversion) may be studied via solution solubility studies. An examination of the solution solubility data is made to assure that no solvent-mediated transformations occurred during the solubility study thereby affirming the validity of the experiment. It is important to note that the most thermodynamically stable polymorph may not necessarily represent the most chemically stable drug substance crystal form. Selection, therefore, of the polymorph to be developed should not be based solely on thermodynamic considerations and must include an assessment of the kinetic behavior of the solid.

When testing polymorphs, some polymorphs may not show differences in either IR or Raman spectroscopic results and thus complementary techniques are employed including techniques such as two-dimensional solid-state NMR.

Polymorphs may have solid state characteristics which impact the stability and robustness of the ultimate drug product process. ICH Q6A discusses the regulatory aspects of polymorphism control in drug substance and drug products. Multiple techniques are available to study the physical characteristics of polymorphs. These techniques include intrinsic dissolution rate studies which may be indicative of differences in bioavailability among the polymorphs.

Finally, the crystal habit of the drug substance details the various forms in which a solid may appear (a reflection of external structural differences). Crystal habit can influence the flow and compaction properties of a drug substance formulated in the solid state. The influence of crystal habit on suspension formulations can be seen in the stability, sedimentation volume, and re-dispersibility of the drug product. The type of crystal habit produced can be affected by the degree of impurities found in the drug substance again underlining the importance of determining the reproducibility of impurity profiles for multiple lots.


S.3.1 Elucidation of Structure

As discussed above in the General Information section of the Drug Substance description, specific data pertaining to structural elucidation should be presented. Clear interpretation of the data should accompany the spectra. For mass spectrometry, the technique (e.g., electrospray ionization), instrument conditions, and sample preparation should be detailed. Major fragments should be identified and related to the proposed structure. NMR spectroscopy should include the sample solvent, operating conditions, and a narrative detailing the assignment of spectral peaks.

S.3.2 Impurities

Impurities of drug substances may be classified into the following categories: Organic Impurities, Inorganic Impurities such as Heavy Metals (USP<231>) and Residual Solvents

Organic Impurities

Organic impurities can be produced during the manufacturing process and during the storage of the drug substance. Organic impurities include: 1) Starting Materials, 2) By-Products, 3) Intermediates, 4) Degradation Products, 5) Reagents, 6) Ligands, and 7) Catalysts.

The organic impurity profile of the drug substance should include the actual and potential impurities most likely to arise during the synthesis, purification, and storage of the drug substance. The results of all pertinent batches (especially toxicology study batches) should be given. The structure and source of the impurity should be discussed.

For synthetic impurities, the side-reactions leading to the impurities should be detailed and the relevance of any process controls used to minimize the impurities given. Potential organic impurities (degradation products) also may be predicted by degradation studies of the drug substance.

Like studies carried out for the structural elucidation of the active drug substance, studies detailing the structural identity for each impurity should be provided.

An impurity profile should be available and provided for each drug substance lot used in toxicological evaluation, primary clinical studies, stability evaluations of both drug substance and drug product, validation of the manufacturing process, and the development of the drug product. A comparison of impurity profiles across lots should be provided.

Inorganic Impurities

Inorganic impurities can result from the manufacturing process and include: 1) Reagents, 2) Ligands, and Catalysts, 3) Residual Metals, 4) Salts, 5) Other Materials (e.g., Filter Aids, Charcoal).

An impurity profile should be available regarding the inorganic impurities for each drug substance lot used in toxicological evaluation, primary clinical studies, stability evaluations of both drug substance and drug product, validation of the manufacturing process, and the development of the drug product.

A comparison of impurity profiles of these lots should be performed and where any differences are noted, the implications regarding quality impact on the drug substance should be assessed and discussed.

Residual Solvents

Solvents are used in the preparation of solutions or suspensions during the synthesis of a new drug substance. The maximum levels of residual solvents should be limited by ICH guidance. Information on residual solvents should be available for all of the lots discussed above.

“Three Critical Aspects (or Features) of the Common Technical Document (Location, Location, Location.”

Efforts over the past 20 years by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have resulted in a unified dossier for drug applications, the Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use. Several ICH documents related to the preparation of various Quality Module sections of the CTD were issued since 2002.

The technical information submitted in Module 2.3 and Module3 of the CTD, and the organization of the information, is carefully specified in guidance documents. Although the CTD is now the preferred format for a new drug application within the regions covered by the ICH, including the United States, the CTD does not in any way replace or supersede the regulations described for example in the US Code of Federal Regulations.

The CTD is an agreed-upon format for the presentation of summaries, reports, and data. Indeed, the actual content of the CTD must still conform to requirements and recommendations found in the regulations and in Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents. Likewise, there may be components that are required by other ICH regions.  

Common Technical Document Section

Recommendations per Guidance

(GMP) Source Documents

Electronic Y/N

3.2.S Drug Substance
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
  • Recommended International Nonproprietary Name (INN)
  • Compendial name if relevant
  • Chemical name(s)
  • Company or laboratory code
  • Other nonproprietary name(s) (e.g., United States Adopted Name (USAN))
  • Chemical Abstracts Service (CAS) registry number
  • Identification (e.g. Item number, NDC Number) and brief description of the item
  • Contractor Information
  • Contracts, Tech Transfer Reports
  • Quality Agreements
3.2.S.1.2 Structure
  • Structural formula, including relative and absolute stereochemistry
  • The molecular formula
  • Relative molecular mass
  • Schematic amino acid sequence indicating glycosylation sites or other posttranslational modifications (Biologic)
  • See characterization section
  • Characterization Reports (ie. Solid state)
  • Characterization study data
  • Chemical and Solid-state characterization, polymorph screens, forced degradation work
3.2.S.1.3 General Properties
  • List should be provided of physicochemical and other relevant properties
  • Biological activity
  • Reference ICH guidance’s Q6A and Q6B.


CMC (Registration/Filing)

  • API Formulation, Stability Data Summaries and Stability Study Protocols
3.2.S.3 Characterization
3.2.S.3.1 Elucidation of Structure and other Characteristics
  • confirmation of structure based on, for example, synthetic route and spectral analyses
  • Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.
  • Reference ICH guidance Q6A.
  • For desired product and product-related substances, details should be provided on primary, secondary and higher-order structure; posttranslational forms (e.g., glycoforms); biological activity, purity, and immunochemical properties, when relevant.
  • Reference ICH guidance Q6B.

Characterization Reports

CMC (Registration/Filing)

  • Chemical and Solid-state characterization, polymorph screens, forced degradation work
  • Characterization Reports (ie. Solid state)
  • Characterization study data
3.2.S.3.2 Impurities
  • Information on impurities
  • Reference ICH guidances Q3A, Q3C, Q5C, Q6A, and Q6B.


CMC (Registration/Filing)

  • ID of degradation products
  • Impurity Profile report

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