CTD Module 3 Contents
Q.01
What goes in CTD Module 3?
A.01
CTD Module 3 (Quality) holds the full chemistry, manufacturing and controls (CMC) data for the drug substance and the drug product. ICH M4Q(R1) (Step 4, dated 12 September 2002) sets out its parts: 3.1 Table of Contents, 3.2 Body of Data (3.2.S drug substance, 3.2.P drug product, 3.2.A appendices, 3.2.R regional information) and 3.3 Literature References [1][2][3].
Approach: I used the ICH M4Q(R1) guideline text. The guideline fixes where information goes, not how much data is needed. It says the type and extent of supporting data "may depend upon regional guidance" [4].
3.1 Table of Contents
This is a table of contents for the filed application [5].
3.2.S Drug Substance (name, manufacturer)
If a product contains more than one drug substance, the whole S part is provided for each one [6].
| Section | Contents |
|---|---|
| S.1 General Information | S.1.1 Nomenclature, e.g. INN, USAN/JAN/BAN, CAS number [7][8][9][10]; S.1.2 Structure; S.1.3 General Properties [11] |
| S.2 Manufacture | S.2.1 Manufacturer(s); S.2.2 Description of Manufacturing Process and Process Controls; S.2.3 Control of Materials; S.2.4 Controls of Critical Steps and Intermediates; S.2.5 Process Validation and/or Evaluation [11][12]; S.2.6 Manufacturing Process Development [13] |
| S.3 Characterisation | S.3.1 Elucidation of Structure and other Characteristics [14]; S.3.2 Impurities [15] |
| S.4 Control of Drug Substance | S.4.1 Specification; S.4.2 Analytical Procedures; S.4.3 Validation of Analytical Procedures; S.4.4 Batch Analyses; S.4.5 Justification of Specification [16] |
| S.5 / S.6 | Reference Standards or Materials; Container Closure System [16] |
| S.7 Stability | S.7.1 Stability Summary and Conclusions; S.7.2 Post-approval Stability Protocol and Stability Commitment; S.7.3 Stability Data [17] |
3.2.P Drug Product (name, dosage form)
| Section | Contents |
|---|---|
| P.1 | Description and Composition of the Drug Product [17] |
| P.2 Pharmaceutical Development | P.2.1 Components (drug substance, excipients); P.2.2 Drug Product (formulation development, overages, physicochemical and biological properties); P.2.3 Manufacturing Process Development; P.2.4 Container Closure System; P.2.5 Microbiological Attributes; P.2.6 Compatibility [18]. This section shows that the dosage form, formulation, process, container closure, microbiological attributes and usage instructions suit their purpose, and identifies the critical parameters [19]. It also discusses differences between the pivotal clinical batch process and the commercial process [20] |
| P.3 Manufacture | P.3.1 Manufacturer(s); P.3.2 Batch Formula; P.3.3 Process description and controls; P.3.4 Critical Steps and Intermediates; P.3.5 Process Validation and/or Evaluation [18]. Any proposal to reprocess materials must be justified in P.3.3 [21] |
| P.4 Control of Excipients | P.4.1 Specifications; P.4.2 Analytical Procedures; P.4.3 Validation; P.4.4 Justification of Specifications; P.4.5 Excipients of Human or Animal Origin; P.4.6 Novel Excipients [22] |
| P.5 Control of Drug Product | P.5.1 Specification(s); P.5.2 Analytical Procedures; P.5.3 Validation; P.5.4 Batch Analyses; P.5.5 Characterisation of Impurities; P.5.6 Justification of Specification(s) [22]. Impurity characterisation goes in P.5.5 only if it is not already in S.3.2 [23] |
| P.6 / P.7 | Reference Standards or Materials; Container Closure System [22] |
| P.8 Stability | P.8.1 Summary and Conclusion, covering storage conditions, shelf-life and in-use shelf-life [24]; P.8.2 Post-approval protocol and commitment [25]; P.8.3 Stability Data with the analytical procedures used and their validation [26] |
3.2.A Appendices
- A.1 Facilities and Equipment: a manufacturing flow diagram (raw materials, personnel, waste, intermediates); other products made in the same areas; product-contact equipment and whether it is dedicated or multi-use; and measures against cross-contamination [27][28][29][30]
- A.2 Adventitious Agents Safety Evaluation:
- A.3 Excipients [3]
3.2.R Regional Information
This holds any extra drug substance or drug product information specific to a region, prepared under that region's guidelines [35][36]. One example the guideline gives is the Process Validation Scheme for the Drug Product (EU only). Where validation is not yet complete, a summary of the planned studies goes here [37][38].
3.3 Literature References
Key literature referenced, if applicable [39].
Module 3 is the source for the Quality Overall Summary in Module 2.3. The QOS follows the Module 3 outline and must not add anything that is not already in Module 3 or elsewhere in the CTD [40]. It should normally stay within 40 pages of text, or 80 for biotech and complex products [41].
Q.02
What's the difference between the 3.2.S and 3.2.P sections?
A.02
3.2.S covers the drug substance (the active ingredient) and is identified by its name and manufacturer. 3.2.P covers the finished drug product and is identified by its name and dosage form. Several headings appear in both parts (manufacture, specifications, reference standards, container closure, stability), but each applies them to a different material. 3.2.P also has three areas with no counterpart in 3.2.S: description and composition, pharmaceutical development, and control of excipients [42][17][22].
Approach: I compared the 3.2.S and 3.2.P sections of the ICH M4Q(R1) guideline. Regional authorities may expect more detail than ICH sets out here.
Side-by-side
| Topic | 3.2.S Drug substance | 3.2.P Drug product |
|---|---|---|
| Identity | S.1: nomenclature, structure, general properties [11] | P.1: description and composition. This lists every component with its amount per unit (including any overages), its function and a reference to its quality standard [43][44] |
| Development | S.2.6 Manufacturing Process Development [13] | P.2 Pharmaceutical Development is a full section. It shows that the dosage form, formulation, process, container closure, microbiological attributes and usage instructions are fit for purpose, and it identifies the critical parameters [19] |
| Manufacture: inputs | S.2.3 Control of Materials lists the raw materials, starting materials, solvents, reagents and catalysts, says where each is used, and gives their quality and controls [45] | P.3.2 Batch Formula lists every component with its amount per batch, including overages [46] |
| Process validation | S.2.5: shows the process (including reprocessing) is suitable and justifies the critical process controls, e.g. cell culture and purification steps [47] | P.3.5: validation of critical steps or assays, such as sterilisation or aseptic processing or filling [48] |
| Characterisation and impurities | S.3: structure elucidation and S.3.2 Impurities [15] | P.5.5: impurity characterisation, only if it is not already in S.3.2 [23] |
| Excipients | Not covered | P.4: specifications, analytical procedures, validation, justification, excipients of human or animal origin, and novel excipients [22] |
| Reference standards | S.5: standards used to test the drug substance [49] | P.6: standards used to test the drug product, only if they are not already in S.5 [50] |
| Container closure | S.6: the substance's packaging materials and their specifications [51] | P.7: the same type of description for the product's primary packaging [52]. Its suitability for storage, shipping and use, including dose-delivery performance, is discussed in P.2.4 [53] |
| Stability | S.7.1 to S.7.3 [17] | P.8, which also covers storage conditions, shelf-life and in-use shelf-life [24] |
How the two parts connect
- Number of sections: If a product contains more than one active, you file a complete 3.2.S for each drug substance [6]. There is one 3.2.P for each product and dosage form.
- Substance-product interface: This is covered in 3.2.P, not 3.2.S. P.2.1.1 discusses whether the drug substance is compatible with the excipients. It also covers the substance properties that can affect how the product performs, such as water content, solubility, particle size and polymorphic form [54]. For combination products, P.2.6 discusses whether the actives are compatible with each other [55].
- No duplication: 3.2.P cross-refers to 3.2.S rather than repeating it, as shown for impurities and reference standards in the table above.
Q.03
What's in the M4Q guideline Q&A?
A.03
The ICH M4Q Q&As (R1) is a placement guide, not a content guide. It tells you which CTD Quality section a given piece of information belongs in, explains how related data is split across linked sections, and leaves "content questions" to regional guidance [56][57]. The ICH Steering Committee approved it on 12 September 2002 and approved the added questions (R1) on 18 July 2003 [58][59]. The text is "Step 4, version 7, July 17, 2003" [60].
Approach: I read the full text of the ICH M4Q Implementation Working Group Q&A (R1). It should be read alongside the M4Q(R1) guideline covered earlier.
Structure
The document has five working parts: General Issues (section 2), Associated Information Located in Different Sections (section 3), and Location Issues for the Drug Substance (section 4), the Drug Product (section 5) and the Appendices (section 6) [56].
General issues
- Repeating sections: When you repeat a section, add a distinguishing title in parentheses after the heading, e.g. "2.3.S Drug Substance (Name, Manufacturer A)" [61].
- One drug substance, several sites: Process differences between sites usually stay inside the same 3.2.S subsection. If they lead to different specifications, add a separate Drug Substance section [62].
- Several presentations of one product (strengths, containers, aseptic vs terminal sterilisation): Use one 3.2.P. Give common data once, and file the differing data as separate documents under the relevant subsection (e.g. P.7, P.8) [63]. The example given is a PVC blister plus a PE bottle: one set of P.1 to P.8, split by container type within P.7 and P.8 [64].
- Reconstitution diluent: Gets its own section, e.g. "3.2.P (Drug Product)" and "3.2.P (Diluent)" [65].
- Novel and non-compendial excipients: If a lot of data is provided, put it in 3.2.A.3, using the 3.2.S format, with one complete 3.2.A.3 per excipient [66].
- Repeating appendices: 3.2.A.1 is repeated for each manufacturing facility of a biotech drug [67].
- 3.2.R: Not harmonised. Follow the region's document titles and order [68].
- Bioanalytical methods: These do not go in Module 3. Methods and validation for nonclinical studies go in Module 4 (4.2.2.1); those for clinical studies go in Module 5 (5.3.1.4) [69].
- DMFs in CTD format: ICH does not address this because DMF systems differ between regions. Ask the competent authority [70].
- Drug substance supplied as a preparation (e.g. a vitamin trituration): Manufacture goes in S.2.2 and control of the added material(s) in S.2.3 [71].
Information split across sections
- Polymorphism: The form used is listed in S.1.3. The form synthesised is stated in S.2.2. Screening studies and the total number of polymorphs go in S.3.1. Any limit goes in S.4.1, with justification in S.4.5. The effect on the product is covered in P.2.1.1 and P.2.2.3, and any product control in P.5.1 and P.5.6 [72][73][74].
- Particle size: Covered in S.2.2, S.3.1 and S.4.1 to S.4.5. Its effect on dissolution goes in P.2.1.1 and P.2.2.1, with reference to the ICH Q6A decision tree [74].
- Impurities: The discussion and qualification go in S.3.2, with S.4.1 to S.4.5 and P.5.1 to P.5.6. P.5.5 covers only impurities not already discussed under 3.2.S [74].
- Development history and batch traceability: Substance development history goes in S.2.6 and batches in S.4.4. Formulation history goes in P.2.2.1 and product batches (with a summary table) in P.5.4. These can be linked to impurity levels in S.3.2 and P.5.5, and cross-referenced to Modules 4 and 5 [75][76].
- Non-viral adventitious agents: This answer replaces the first sentence of 3.2.A.2 in M4Q. Routine controls for bacteria, mycoplasma and fungi go in 3.2.S and 3.2.P, with more detail if the methods are not pharmacopoeial. TSE agents and prions go in 3.2.A.2 [77][78][79].
Drug substance (3.2.S): main placement answers
| Topic | Where it goes |
|---|---|
| Secondary, tertiary and quaternary protein structure drawings | S.3.1, not S.1.2 [80] |
| General properties | S.1.3 lists them for the form used only. Alternative forms and detailed properties go in S.3.1 [80] |
| Process controls | All are identified in S.2.2. Extra detail on critical controls goes in S.2.4 [80] |
| Starting material justification, material test methods, recombinant reagents | S.2.3. Adventitious-agent testing of biological materials goes in 3.2.A.2 [81] |
| Intermediate batch data, methods and criteria | S.2.4, cross-referenced from S.4.1 and S.4.2 [81] |
| Reprocessing | Described in S.2.2, critical controls in S.2.4, validation in S.2.5 [81][82] |
| BA/BE reports after process or formulation changes | Module 5, cross-referenced from S.2.6, P.2.2.1 or P.2.3 [83] |
| Impurities | Characterisation, qualified levels and observed batch data go in S.3.2, whether or not the impurity is specified. Impurity reference standards go in S.5 and chromatograms in S.4.3 [83][84] |
| Several specifications, alternative methods | All go in S.4.1 [85] |
| Historical methods / stability-only methods / methods shared with the product | S.4.4 / S.7.3 / placed in both 3.2.S and 3.2.P, because sample preparation differs [85] |
| All relevant batches, and results of tests not in the specification | S.4.4 and S.4 [86] |
| Skip-testing justification | S.4.5. Summaries with cross-references are acceptable [86] |
| Stress studies, historical stability methods, supporting stability data | S.7.3 [87] |
Drug product (3.2.P): main placement answers
| Topic | Where it goes |
|---|---|
| All components, including inks and capsule shells; overfill | P.1. The overfill rationale goes in P.2.2.1. Co-packaged diluent gets its own Drug Product section, and its compatibility goes in P.2.6 [88] |
| Substance properties or salt form affecting manufacturability | P.2.1.1. Substance stability data stays in S.7 [89] |
| Excipient incompatibility justification / functional excipients through shelf-life / preservative effectiveness | P.2.1.1 / P.2.1.2 / P.2.5 [89][90] |
| Development formulation tables, IVIVC summary, tablet scoring, controlled-release mechanism | P.2.2.1 [91] |
| Overage justification / dissolution development | P.2.2.2 / P.2.2.3. The dissolution test justification goes in P.5.6 [92] |
| Sterilisation justification; process differences between clinical, stability and commercial batches | P.2.3. Clinical trial formulations go in P.2.2.1 [92] |
| Extractables and leachables, MDI priming and cleaning, light protection | P.2.4. Leachables may also appear in P.5.1 and P.5.5, shelf-life leachables and photostability data in P.8.3 [93] |
| ICH Q6A decision trees 6 and 8 | P.2.5 [93] |
| Diluent compatibility, co-administered drugs, incompatible diluents | P.2.6. In-use dilution data from formal stability studies goes in P.8.3 [94] |
| Overages in the batch formula | P.3.2 [95] |
| Reprocessing, all process controls, overfill, ruminant-material handling statement | P.3.3. Critical controls go in P.3.4 and validation in P.3.5. Cross-contamination risk is covered in 3.2.A.1 and A.2 [95] |
| Critical process control values; in-process tests replacing end-product tests | P.3.4. A replacement test is also listed in P.5.1 as a process test [96] |
| Novel or non-compendial excipient data | 3.2.A.3. Minimal (pharmacopoeial) information goes in P.4.1 and/or P.2.1.2 [96][97] |
| Excipient certificates of analysis / human or animal origin | P.4.4 / P.4.5. Adventitious-agent evaluation goes in 3.2.A.2. TSE/BSE certificate location depends on the region [98] |
| Release and shelf-life specifications | Both in P.5.1 [99] |
| All batches with their descriptions | P.5.4 [100] |
| All observed impurities | Listed in P.5.5. Justification for leaving any out of the specification goes in P.5.6 [100] |
| Reference standards | Those in S.5 can be cross-referenced. All others go in P.6 [101] |
| Shelf-life specification / bracketing and matrixing design | P.8.1 / P.8.3 [101] |
| Stress studies, statistical analysis | P.8.3. The statistical summary or conclusions go in P.8.1 [102] |
Appendices (3.2.A)
Within each appendix, give drug substance information first and then drug product. The title of 3.2.A.3 was changed from "Novel Excipients" to "Excipients" so that it also covers non-compendial, non-novel excipients [103].
Q.04