A description of the drug product and its composition should be provided. The information provided should include, for example:

• Descriptionof the dosage form;
• A batch formula should be provided that includes a list of all components of the product to be used in the manufacturing process, the amounts per unit dose, including overages (if any), and a reference to their quality standards.
• Description of accompanying reconstitution diluent(s); and
• Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable. 

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products – Chemical Substances (Q6A)

Reference ICH Guidelines:

• Pharmaceutical Development (Q8)

The Pharmaceutical Development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. The studies described here are distinguished from routine control tests conducted according to specifications. 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.

 Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products – Chemical Substances (Q6A)

P2.2.1 Drug Substance

The compatibility of the drug substance with excipients listed in P1 should be discussed. Additionally, key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the drug substance that can influence the performance of the drug product should be discussed.

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

P2.2.2 Excipients

The choice of excipients listed in P1, their concentration, their characteristics that can influence the drug product performance should be discussed relative to their respective functions.

 Reference EMA Guideline:

• Guideline On Excipients In The Dossier For Application For Marketing Authorisation of A Medicinal Product

P2.3.1 Formulation Development (name, dosage form)

A brief summary describing the development of the drug product should be provided, taking into consideration the proposed route of administration and usage. The differences between clinical formulations and the formulation (i.e. composition) described in P1 should be discussed. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate.

 P2.3.2 Overages (name, dosage form)

Any overages in the formulation(s) described in P1 should be justified. 

P2.3.3 Physicochemical and Biological Properties (name, dosage form)

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.

The selection and optimisation of the manufacturing process described in P3.2, in particular its critical aspects, should be explained. Where relevant, the method of sterilisation should be explained and justified.

The suitability of the container closure system (described in P7) used for the storage, transportation (shipping) and use of the drug product should be discussed. This discussion should consider, e.g., choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).

Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for nonsterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.

Reference EMA Guideline:

• Guideline on Excipients In The Dossier For Application For Marketing Authorisation of A Medicinal Product

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 to provide appropriate and supportive information for the labeling.

• Active Ingredient Name
• Salt Form
• Strength of Active Ingredient (Quantity unit/ dose)
• Strength Salt-Free
• Source of Active Ingredient (Animal – e.g. Bovine, Porcine, Ovine or Others/ Plant/ Others)
• Remarks (if any)

A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity, where relevant.

Steps in the process should have the appropriate process parameters identified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section P3.3. In certain cases, environmental conditions (e.g., low humidity for an effervescent product) should be stated.

Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section P3.2.

• The full description of manufacturing process must sufficient details to cover the essential points of each stage of manufacture.
• For sterile product the description includes preparation and sterilization of components (i.e. Containers, closures, etc.).

Reference EMA Guideline:

• Guideline on Manufacture of the Finished Dosage Form

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

Critical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in P3.2 of the manufacturing process, to ensure that the process is controlled.

Intermediates: Information on the quality and control of intermediates isolated during the process should be provided.

 Reference ICH Guidelines:

• Validation of Analytical Procedures: Text and Methodology (Q2)
• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A) 

Reference EMA Guideline:

• Guideline on Manufacture of the Finished Dosage Form

Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g., validation of the sterilisation process or aseptic processing or filling).

Options available:

Option 1: The data submission should include a validation report on three consecutive successfully validated production batches.

Option 2: In circumstances where submission of data on 3 consecutive production batches is not feasible at the time of application, the following can be submitted to Health Authority to obtain marketing approval:-

1. Development pharmaceutics report; and
2. Validation data on 1 pilot batch
3. Validation scheme on production scale batches.
4. Commitment letter to undertake that 3 consecutive full production batches are successfully validated before the product is marketed, subject to concurrence by the regulatory authority;

Option 3 (Imported Product):For products that have been approved by a reference agency, the applicant is required to provide a declaration statement to the effect that the same pre-approval dossiers pertaining to process validation that have been submitted to the reference regulatory agency are submitted to regulatory authority for evaluation. Under certain circumstances where validation documents may not form part of the pre-approval dossiers, the regulatory authority may request for Validation Report or Validation Scheme. In addition, the applicant is required to undertake that 3 consecutive full production batches are successfully validated before the product is marketed and to submit the report to regulatory authority upon request.

Note:

If the product contains API Premix, it is mandatory to submit the Process Validation of API Premix (Refer to ASEAN Guidelines on Process Validation - Question and Answers)

 Reference ASEAN Guidelines:

• ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration
• ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration (Q&A)

 Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)

 Reference EMA Guidelines:

• Guideline on Manufacture of the Finished Dosage Form

The specifications for excipients should be provided.

Compendial requirements or appropriate information from the manufacturer.

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products – Chemical Substances(Q6A)

Reference EMA Guidelines:

• Guideline On Excipients In The Dossier For Application For Marketing Authorisation of A Medicinal Product

The analytical procedures used for testing the excipients should be provided, where appropriate.

Compendial requirements or appropriate information from the manufacturer. 

Reference ICH Guidelines:

• Validation of Analytical Procedures: Text and Methodology (Q2)
• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A) 

Reference EMA Guidelines:

• Guideline on Excipients In The Dossier For Application For Marketing Authorisation of A Medicinal Product

Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.

Reference ICH Guidelines:

• Validation of Analytical Procedures: Text and Methodology (Q2)

Justification for the proposed excipient specifications should be provided, where appropriate.

Compendial requirements or appropriate information from the manufacturer.

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)

Reference EMA Guideline:

• Guideline on Excipients In The Dossier For Application For Marketing Authorisation of A Medicinal Product

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).

Detailed information should be provided on the avoidance and control of non-viral adventitious agents (e.g., transmissible spongiform encephalopathy agents, bacteria, mycoplasma, fungi). This information can include, for example, certification and/or testing of raw materials and excipients, and control of the production process, as appropriate for the material, process and agent. 

Reference EMA Guideline:

• Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products
• Guideline on Excipients In The Dossier For Application For Marketing Authorisation of A Medicinal Product

Not applicable to generic products

The specification(s) for the drug product should be provided.Qualitative and/or quantitative characteristics with test procedures and acceptance limits, with which a given product must comply.

Compendial requirements or appropriate information from the manufacturer.

Note on Release Limit - Specifications of the Finished Product (At Release)

Monograph defining qualitative and quantitative characteristics with test procedures and their acceptance limits, with which the finished product must comply at the time of the manufacture (at its release).

Note on Shelf life Limit - Specifications of the Finished Product (Up to the End of Shelf life)

Monograph defining qualitative and quantitative characteristics with test procedures and their acceptance limits, with which a medicinal product (on the market) must comply throughout its valid shelf life.

Note on Periodic or skip testing (ICH Q6A)

Periodic or skip testing is the performance of specified tests at release on pre-selected batches and / or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product. This represents a less than full schedule of testing and should therefore be justified and presented to and approved by the regulatory authority prior to implementation. This concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms.

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)
• Impurities in New Drug Products (Q3B)

Please refer to Section E12

Please refer to Section E13

Batch Analysis

P5.4.1 Certificate of Analysis (COA)

• Batch 1
• Batch 2

A description of batches and results of batch analyses should be provided. Minimum 2 production batches. 

* Certificate of Analysis of Finished Product for locally manufactured product is all. Minimum 1 batch. 

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)
• Impurities in New Drug Products (Q3B)

• Batch 1
• Batch 2

A description of batches and results of batch analyses should be provided. Minimum 2 production batches. 

* Certificate of Analysis of Finished Product for locally manufactured product is all. Minimum 1 batch. 

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)
• Impurities in New Drug Products (Q3B)

Information on the characterisation of impurities should be provided.
Compendial requirements or appropriate information from the manufacturer. 

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)
• Impurities in New Drug Products (Q3B)

Justification for the proposed drug product specification(s) should be provided.
Compendial requirements or appropriate information from the manufacturer. 

Reference ICH Guidelines:

• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)
• Impurities in New Drug Products (Q3B)

Information on the reference standards or reference materials used for testing of the drug product should be provided.

Compendial requirements or appropriate information from the manufacturer.

A description of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification.

The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included where appropriate.

For non-functional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.

Suitability information should be located in P2. 

Specification and control of primary and secondary packaging material, type of packaging and the package size, details of packaging inclusion (e.g. desiccant, etc.) 

Reference EMA Guideline:

• Guideline on Plastic Immediate Packaging Materials

Evidence is required to demonstrate that product is stable, meets the finished product specifications throughout its proposed shelf-life, that toxic decomposition products are not produced in significant amount during this period, and that potency, efficacy of preservative etc. are maintained. 

All criteria under ICH Guidelines are acceptable with the exception of real time storage conditions which should be 30^oC, 75% RH. Provisional of moisture protection of packaging should be taken into consideration. 

Results of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included. 

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.

Note:

For Locally Manufacturer/In-House Product

• Long term (Zone IV B - 30^oC ± 2^oC/75%RH ± 5%RH) stability data (min. 1 batch)
• Minimum 6 months stability data on-going upon submission
• Accelerated (40°C ± 2°C/75%RH ± 5%RH) stability data

(min. 1 batch)

• 6 months stability data upon submission

For Imported Product

• Long term (Zone IV B - 30^oC ± 2^oC/75%RH ± 5%RH) stability data (min. 2 batches)
• Minimum 12 months stability data on-going upon submission
• Accelerated (40°C ± 2°C/75%RH ± 5%RH) stability data

(min. 3 batches)

• 6 months stability data upon submission

Reference ASEAN Guidelines:

• ASEAN Guideline on Stability Study of Drug Product
• ASEAN Guideline on Stability Study of Drug Product (Q&A)
• ASEAN Guideline on Validation of Analytical Procedures
• ASEAN Guidelines for Validation of Analytical Procedures (Q&A)

Reference ICH Guidelines:

• Stability Testing of New Drug Substances and Products (Q1A)
• Stability Testing: Photostability Testing of New Drug Substances and Products (Q1B)
• Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products (Q1D)
• Evaluation of Stability Data (Q1E)
• Stability Data Package for Registration Applications in Climatic Zones III and IV (Q1F)
• Validation of Analytical Procedures: Text and Methodology (Q2)
• Specifications – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products -Chemical Substances (Q6A)
• Impurities in New Drug Products (Q3B)

Reference EMA Guidelines:

• Declaration of storage conditions for medicinal products particulars and active substances
• In-Use stability testing of human medicinal products

Maximum shelf-life for sterile products for human use after first opening or following reconstitution

The type of studies conducted, protocol used and the result of the studies should be presented in the study report.

In Vitro: Comparative dissolution study as required

In Vivo: Bioavailability (BA)/Bioequivalence (BE) study as required

Note: This requirement is applicable to all generics (scheduled poison) in oral solid dosage form (including immediate released, modified released, effervescent, dispersible, orodispersible, sublingual, buccal and chewable oral tablet/capsule) only.

Kindly note that the application will need to conform to current requirements, guideline, circulars and directives which includes BE centre accreditation.

1. For BE Centres that have not been accredited by NPRA or regulatory authorities accepted by NPRA/not listed in the NPRA, Compliance Programme for Bioequivalence Centre, an application for the purpose of BE study centre inspection must be submitted to Centre for Investigational New Product (CINP) before submission of product application for screening. Kindly submit proof of payment (receipt issued by NPRA) along with proof of application to CINP at the point of screening.
2. For BE Centres that have been accredited by regulatory authorities accepted by NPRA, the BE Centre inspection report (study specific) needs to be submitted to Centre for Investigational New Product (CINP), NPRA for evaluation and verification before submission of product application for screening. A verification letter on the accreditation status issued by CINP must be submitted during submission of application to Centre for Product Registration (at the point of screening).
3. Kindly ensure the complete following documents are submitted (attached) in the Quest 3+ system (in E14 if unable to attach the complete report in P9).

• clinical study report
• method validation report
• bioanalytical report ,
• pharmacokinetic (PK) report
• statistical analysis report
• comparative dissolution profiles (conducted as per ASEAN Guideline) between test and reference product used in BE study
• comparative dissolution profiles (conducted as per ASEAN Guideline) between Malaysian Comparator Product (MCP) and reference product used in BE study (* if reference is not MCP)

    4. If BE study of a different strength is used to support a product application and a waiver for additional strength(s) is claimed and applied, the following documents must be submitted and fulfilled:

          i)The pharmaceutical products are manufactured by the same 

          manufacturing process

          ii)The qualitative composition of the different strengths is the same

          iii)The composition of the strengths are quantitatively

          proportional, i.e. the ratio between the amount of each excipient

          to the amount of active substance(s) is the same for all strengths

          iv)Appropriate in vitro dissolution data should confirm the  

          Adequacy of waiving additional in vivo bioequivalence testing

Reference ASEAN Guidelines:

• ASEAN Guideline for the Conduct of Bioequivalence Studies

Reference EMA Guidelines:

• Guideline on the Investigation of Bioequivalence