CTD Format---FDF registration requirement in China

3.2.P    DRUG PRODUCT

3                              3.2.P.1 Description and Composition of the Drug Product (name, dosage form)

(1) Description of the dosage form

Describe the dosage form, list the composition, i.e., all components of the dosage form, and their amount on a per-unit basis (including overages, if any) the function of the components, and a reference to their quality standards (e.g., compendial monographs or manufacturer’s specifications).

List the solvents used during manufacturing but finally removed.

Table X: Formulation

(2) List the formulation as per the table below of accompanying reconstitution diluents, if applicable.

(3) Provide the type of container and closure system used for the dosage form, if applicable.

 

3.2.P.2 Pharmaceutical Development

Development target and information of marketing of innovator product should be provided.

The Pharmaceutical Development section should contain information on the development studies conducted and references to establish that the dosage form, the formulation, manufacturing process and container closure system, including the general description of the quality of drug substance.

Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and drug product quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical Development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the application.

3.2.P.2.1 Components of the Drug Product

3.2.P.2.1.1Drug Substance

The compatibility of the drug substance with excipients should be discussed. Additionally, key physicochemical characteristics (e.g., BCS classification, polymorphic or solid state form, solubility, particle size distribution, water content) of the drug substance that can influence the manufacturing and performance of the drug product should be discussed.

For combination products, the compatibility of drug substances with each other should be discussed.

3.2.P.2.1.2 Excipients

Discussion on the suitability of all excipients to the proposed administration route should be provided.

Characteristics of excipient that can influence the drug product performance should be discussed relative to their respective functions. Related studies information or references should be provided.

3.2.P.2.2 Drug Product

3.2.P.2.2.1 Formulation Development

Discussion on the development of the drug product should be provided, taking into consideration the references (e.g. formulation information of reference products), studies information (including design, selection, optimization and confirmation of formulation), choice of excipient types and amounts, quality comparative results between self-developed samples and innovator products (with specified source of innovator product, batch and expire date, self-develop sample batches, comparison items, analytical method, etc). Information of main changes during formulation development, their reasons and supportive studies should be provided.

The necessity and rationality of overages in the formulation, if applicable, should be justified with supportive studies.

3.2.P.2.2.2 Properties

Parameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.

Comparison of chemical-physical properties and quality feature (e.g. related substances) between self-develop samples with innovator products should be provided.

For oral solid dosage, comparison of dissolution curves obtained from different dissolution condition between self-develop samples with innovator products should be provided. F2 method is recommended.

For drug substance with chiral centre, control of optical purity and structure configuration stability should be provided.  

3.2.P.2.3 Manufacturing Process Development

Detail manufacturing study (including experimental data and chromatograms) should be provided to justify the choice and optimization of process condition and scale-up of manufacturing process. These studies adequately guarantee that the scale, material control, process operation and equipment of submitted manufacturing process are suitable for commercial production, and that batches already produced and their qualities reflect the consistency and repeatability of the submitted manufacturing process.

Changes (e.g. batch size, equipment, process parameter and process route) made to manufacturing process during development and supportive studies should be adequately submitted.

Tabulate as below the data of process development batches (including but not limited to clinical trial batches, scale-up batches, production onsite inspection batches and process validation batches) with respect to batch NO., manufacturing date and site, manufacturing process, batch size, usage (for stability test, BE test, etc) and analytical results (of related substances, dissolution and other test items):

Table X: Process study summary

* Specify the usage of the sample, like process validation, stability, method validation, structure elucidation, etc;

** If the manufacturing process is different from that under 3.2.S.2.2, provide this process. 

3.2.P.2.4 Container Closure System

(1) Type, source and related certificate of container closure system

Table X: Type, source and related certificate of container closure system

Note¹: The composition and size of packing material should be provided for each packing material.

For example, composition of aluminum plastic blister packaging is PVC/aluminum, PVC/PE/PVDC/aluminum, PVC/PVDC/aluminum.

Note²: All the packing accessories in immediate contact with drug should be provided.

Provide the COA for all packing material (from its manufacturer or supplier).

(2) Choice of container closure system

Information of inner packaging material for innovator product should be provided. 

Sufficient studies and reference basis should be provided if different inner packaging material is used from that of innovator product.
(3) Supportive studies for the choice of container closure system

Compatibility studies of the materials of construction with the packing material should be provided, including the test content, test design, test items, analytical method and validation, sample preparation way, test results and analysis.

Absence of compatibility test should be adequately justified with sufficient reference basis.

3.2.P.2.5 Compatibility

The compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed.

 

3.2.P.3 Manufacture

3.2.P.3.1 Manufacturer(s)

The full name, address, phone and fax of manufacturer, address, phone and fax of manufacturing line should be provided. Such information should be consistent with the address and manufacturing line reported in application form, government certificates and manufacturing site inspection report.

3.2.P.3.2 Batch Formula

A batch formula should be provided that includes a list of all components of the dosage form to be used in the typical commercial manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.

Table X: Formulation for typical production batch

3.2.P.3.3 Description of Manufacturing Process and Process Controls

(1) Flow diagram

A flow diagram should be presented, giving the steps of the process and showing where materials enter the process and identifying the critical steps and points at which process controls, intermediate tests or final product controls.

(2) Process description

A narrative description of the manufacturing process at current maximum scale, including packaging, should be provided which represents the sequence of steps undertaken, the process parameters and range. Focus of process description should be addressed

Critical steps and parameters should be described with a great level of detail according to the characteristic of dosage form, examples are as below:

- Pretreatment of drug substance and excipient for infusion;

- Washing, sterilization and depyrogenation of inner packing material with immediate contact with drug;

- Input quantity/ratio of drug substance and excipient;

- Drug solution preparation, speed and duration;

- Drug solution pH at different stages;

- Treatment and quantity of active carbon; concentration, temperature, mixing way for absorption; blending way, speed and duration;

- Filter material and pore size, filtration way, temperature and flow rate of filtrate during primary filtration and refined filtration;

- Test items and limit for control of intermediates

- Duration for drug solution to settle;

- Flow rate of drug substance, stopper pressure during filing;

- Sterilization temperature, duration and target F0 value.

The information of the manufacturing process should describe the manufacturing process and process controls adequately and completely enough so that an expert can repeat this process to obtain a product that meets the predefined specification.

Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section.

(3) Manufacturing equipment

Information of manufacturing equipment should be submitted, including mold NO., material, operation principle, batch size range, manufacturer, production steps , and compatibility with the maximum production scale.

(4) Commercial batch size

Proposal and justification of commercial batch size should be provided.

3.2.P.3.4 Controls of Critical Steps and Intermediates

Critical Steps: 

Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.

Intermediates: 

Information on the quality standards (test items, analytical method & limits, with justification) of intermediates during the process, as well as method validation, if necessary, should be provided. 

3.2.P.3.5 Process Validation and/or Evaluation

Process validation report (code and version NO.) for aseptic processing and sterilization should be included for aseptic drug product. Process should be conducted within the predefined parameter range.

Below information should be included during process validation: batch no., batch size, equipment selection and evaluation, process condition/parameter & acceptance criteria, analytical methods, sampling method and planning, evaluation of process steps, confirmation of critical steps and acceptance criteria, etc.

For non-aseptic processing of aseptic drug substance and non-aseptic drug substance, process validation or alternatively process validation protocol and commitment to preform process validation on first three commercial batches after marketing should be provided.

Blank batch manufacturing record should be provided for all drug products. This BMR should be exactly same with the SOP of routine commercial manufacturing.

Validation protocol, validation report and batch manufacturing record should be assigned with document number and version number, and signed by qualified personal (e.g. QA, QC, quality and manufacturing director).

3.2.P.3.6 Manufacturing information for clinical trial/BE test samples

Batch production records and copies of analytical report for clinical trial and/or BE test samples, as well as the obtained chromatograms, should be provided.

 

3.2.P.4 Control of Drug Substances and Excipients

3.2.P.4.1 Specifications

The source, related certificates and specifications for drug substances and excipients should be provided.

Table XX: Drug substances and excipients

Component	Manufacturer	Approval certificates	Specification

If purification is conducted on drug substance and excipients to need the requirement of drug product manufacturing and quality control or administration route (like purifying to injection grade), information concerning choice of purification process, purification description and validation, quality comparison before and after purification, in-house specification of purified drug substance and excipients and its justification, should be provide.

In-house specifications for drug substance and excipients by their manufacturer/supplier and/or by drug product manufacturer, if applicable, should be provided.

Copies of COAs issued by drug substance and excipients manufacturer/supplier and/or by drug product manufacturer should be provided.

BSE/TES risk declaration should be provided.

3.2.P.5 Control of Drug Product

3.2.P.5.1 Specification(s)

The specification for the drug product should be provided according to table below, and compared with existing pharmacopeia. Release specification and shelf specification, if applicable, should be discussed.

Table XX: Comparison of Specification

Test item	Test method	Release specification	Shelf specification	USP	EP	CP	JP
Appearance
Identification
Degradation products
Dissolution
Content uniformity
Residual solvent
Water
Particle size distribution
Sterility
Endotoxin bacterial
…
Assay

 

3.2.P.5.2 Analytical Procedures

The analytical procedures used for testing the drug product should be provided.

Analytical method for key test items (e.g. related substance, dissolution, assay) should be compared with those in other pharmacopeia. Example as below:

Table XX: Comparison of Related Substance Analytical Method

If in-house method is different from any pharmacopeia method, detail method comparison studies, including results and chromatograms, should be provided to prove the rationality and feasibility of the in-house method.

3.2.P.5.3 Validation of Analytical Procedures

Analytical validation information, including experimental data and all obtained chromatograms, for the analytical procedures used for testing the drug product, should be provided.

Validation results can be summarized in table below:

Table XX: Summary of Method Validation

Method validation for related substance should be conducted with impurity working standards/reference standard and sample to be tested, to prove the method detectability with the these impurities.  

3.2.P.5.4 Batch Analyses

A description of at least three consecutive validation batches or production batches, and results of batch analyses should be provided.

COAs of clinical trial/BE test samples should be provided.

3.2.P.5.5 Characterisation of Impurities

All potential impurities should be listed in table below. Information about their formations/route/purge should be provided. Structure of known impurities should be characterized and limits of known impurities, unknown impurities and total impurities should be justified.

Table XX: Impurity profile analysis

Impurity name	Impurity structure	Impurity formation	Control strategy / Whether or not control it in specification	Limit

Studies on degradation mechanism and degradation products should be conducted; results and chromatograms should be provided.

3.2.P.5.6 Justification of Specification

Justification for the proposed drug product specification should be provided with sufficient basis (compliance with the ICH guidelines, requirements of existing pharmacopeia, quality comparison with innovator product).

Conduct quality comparison between three batch self-develop samples with several batches of innovator products to prove the quality consistence. Results and chromatograms should be provided.

Table XX: quality comparison results

Samples/ items	Innovator products			Self-develop products
	Batch 1	Batch 2	Batch 3	Batch 1	Batch 2	Batch 3
Appearance
pH
Related substance
Heavy metal
Dissolution
…
Assay

 

Table XX: related substance comparison results

Samples/ items		Innovator products			Self-develop products
		Batch 1	Batch 2	Batch 3	Batch 1	Batch 2	Batch 3
Known impurities	Imp A
	Imp B
	Imp C
	…
Unknown impurities
Total impurities

 

3.2.P.6 Reference Standards or Materials

Information on the reference standards or reference materials, including drug substance and impurity reference standards/materials, used for studies of the drug product should be provided.

Proof of legal sources, photos of standards, labels and insert for official reference standards should be provided.

Alternatively, information of manufacturing process, structure elucidation, specification and COA for self-developed reference standards should be provided.

 

3.2.P.7 Stability

Minimum 6-month accelerated stability data and 12-month long-term stability data for three scale-up and/or commercial batches should be provided, to draw conclusions with respect to shelf-life and storage conditions.

3.2.P.7.1 Stability Summary and Conclusion

(1) Stability test samples

Table XX: sample information

(2) Stability test details 

Table XX: Common stability testing

Note 1: If the analytical method for stability test is different from that in 3.2.P.5, validation of this method should be provided. 

Note 2: Refer to attachment 1 for test design.

Note 3: Here refers to stability tests conducted according to the features of drug products, like container integrity test for injections.

Table XX: In-use stability testing

(3) Test conclusion

The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.

Generic drug stability should not be inferior to those of innovator products or pharmacopeia.

Table XX: Stability conclusion

 

3.2.P.7.2 Post-approval Stability Protocol and Stability Commitment

The post-approval stability protocol and stability commitment should be provided.

3.2.P.7.3 Stability Data

Below stability test related information should be provided: COA copies of test samples, sample storage location and thermostatic cabinet number, sampling quantity for stability test at each interval, stability test chromatograms.

Results of the stability studies should be presented in an appropriate format, examples as below:

(1)    Affecting factor test (1 batch )

 

(2)    Accelerated stability test (3 batches)

 

(3)    Accelerated stability test (3 batches)