Section P New Chemical Entity

• Description
• Dosage form and characteristic
• Describe accompanying reconstitution diluents (if any)
• Type of container and closure used for dosage form and reconstitution diluents (if applicable)
• Composition
• Name, quantity stated in metric weight or measures (overages, if any), function and quality standard reference  (pharmacopoeia/manufacturer’s) of all materials used

*Not applicable for generics

• Data on the development of studies to establish that the dosage form, formulation, manufacturing process. Container closure system microbiological attribute and usage instruction are appropriate.
• Should identify and describe the formulation and process attributes (clinical parameters) that may influence batch reproducibility, product performance and drug product quality.
• Supportive data and result from specific studies or published literature may be included within or attached to this section. Additional supportive data may be referenced to the relevant non-clinical sections of the application

 *Not applicable for generics

• Active ingredient
• Justification of the compatibility of the active ingredient with excipients listed in P1
• In case of combination products, justification of the compatibility of active ingredients with each other
• Key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the drug substance, which may influence the performance of the drug product should be included
• Literature data
• Excipients
• Justification of the choice of excipients listed in P1, which may influence the drug product performance

• Formula development
• A brief summary describing the development of the finished product, taking into consideration the proposed route of administration and usage
• Overages if any should be justified.
• Physiochemical & biological properties
• Parameter relevant to the performance of the finished product e.g. pH, dissolution.

*Not applicable for generics

• Selection and optimization of the manufacturing process (in particular its critical aspects should be explained
• Method of sterilization should be explained and justified
• Differences between the manufacturing process used to produce pivotal clinical batches and the process described in P3.2, if applicable, should be stated.

Suitability for storage, transportation and use of the drug product 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 contraction, and performance such as reproducibility of the dose delivery form the device when present as part the drug product.

• Microbiological  attributes of the dosage form (where appropriate) including   rationale for not performing MLT for non sterile products
• Selection and effectiveness of preservative systems in products containing anti-microbial preservatives.
• For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.

*Not applicable for generics

Literature data acceptable for the compatibility of the drug product or reconstitution diluents(s) or dosage devices, e.g. precipitation of drug substance in solution, sorption on injection vessels and stability should be addressed to provide appropriate and supportive information for the labeling.

• Essential points of each stage of manufacture should be covered
• Description of manufacturing process & process control
• Description of assembling of the product in final containers
• If the product is  repacked/assembled by  another manufacturer, details of repacking/assembly and quality control must be supplied.
• The full description of manufacturing process must sufficient details to cover the essential point of each stage of manufacture.
• For sterile product the description includes preparation and sterilization of components (i.e. containers, closures, etc.)

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 P3.3 of the manufacturing process to ensure that the process is controlled.
• Intermediates:  Information of the quality and control of intermediates isolated during the process should be provided.
• Summary of:
• Test performed
• Stages at which test is done
• Frequency of sampling & no. of samples taken each time
• Acceptance criteria
• Tests and acceptance criteria

- Specifications for quality assurance of the product should be supplied

• Description, documentation, and result of the validation studies should be provided from critical steps or critical assays used in the manufacturing process (e.g. Validation of the sterilization process or aseptic processing or filling).

• Specifications for all excipients
• Reference for specifications (Compendial/Manufacturer)
• Source (manufacturer and country of origin)

• Analytical procedures used for testing excipients where appropriate
• Compendial requirements or appropriate information from the manufacturer

• Only required for non-compendial method

*Not applicable for generics

• Justification for the proposed excipient specifications should be provided, where appropriate.
• Compendial requirements or appropriate information from the manufacturer.

• Information regarding sources and/or adventitious agents
• Compendial reference requirements or appropriate information from the manufacturer

*Not applicable for generics

• For excipient(s) used for the first time in a finished product  or by a new route of administration, full details of manufacture, characterization and controls, with cross reference to supporting safety data (non-clinical or clinical)

Give details of quality control specifications including a list of tests (for both release and expiry/check specifications, if they are different) and state the limits of acceptance

• Specification(s) for the finished product
• List of test and specification 
• State the limits or criteria of acceptance
• Reference used

• Analytical procedures used for testing the finished product

Please refer:

• Section C: Quality Control, REGOVP
• Appendix 10: Guidelines for the Submission of Protocol of Analysis and Analytical Method Validation Documents, REGOVP

• Information including experimental data for the analytical procedure used for testing the finished product
• Non-compendial method
• Verification of compendial method applicability – precision & accuracy

• Description and test results of all relevant batches used to establish specification and evaluate consistency in manufacturing.
• A tabulated summary of the batch analysis, with graphical representation where appropriate should be provided.

• Batch 1
• Batch 2

Current batch of Certificate of Analysis (COA) should be attached

*Not applicable for generics

• Information on the characterization of impurities
• Compendial or appropriate information from manufacturer

*Not applicable for generics

• Justification of the proposed finished product specification
• Compendial requirements or appropriate information from the manufacturer

• Information on the reference standards or reference materials used for testing of the finished product
• Compendial requirements or appropriate info from manufacturer

• Identity of materials of construction of each primary packaging component & it’s specification
• The specification include :
• Description and identification (and critical dimensions with drawings where appropriate)
• Control of primary and secondary packaging material
• Package size
• Details of packaging inclusion e.g.  desiccant, etc.

• 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. 3 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.

1. 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