Part II, Section P: Drug Product (Finished Product)
Section A: Quality Overall Summary (QOS)
To attach the Print Form (Section P – Product Information) once all the documents are completed prior to submission
Section B: Table of Contents
To prepare the Table of Contents based on completed Print Form (Section P – Product Information)
Section C: Body of Data
To attach the Print Form (Section P – Product Information) once all the documents are completed prior to submission
Product description
- Dosage form and characteristics
- Describe accompanying reconstitution diluents (if any)
- Type of container and closure used for dosage form and reconstitution diluents (if applicable)
Product composition
- Name, quantity stated in metric weight or measures (overages, if any), function and quality standard reference (pharmacopoeia/manufacturer’s) of all materials used in the vaccine formulation
- To indicate minimum titer of the vaccine antigen(s) per mL and per dose.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
- Data from the development studies to establish that the dosage form, formulation, manufacturing process, container closure system, microbiological attribute and usage instruction, as appropriate for the purpose specified in the application.
- Should identify and describe the formulation and process quality attributes and clinical parameters that may influence batch reproducibility, vaccine performance and 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
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
- Active ingredient – justification of the compatibility of the active ingredient with the chosen excipients
- Information on the source materials: source materials include any component/ unformulated active substance used in the manufacture of the product (e.g. microorganisms, cells/ cell substrate, immunogen) including their specifications and the tests used to demonstrate compliance with the specifications. For combination vaccines, each active substance, which will be pooled, combined with other antigens and formulated, shall be described.
- Any chemical modification or conjugation of the drug substance shall be described in detail.
- List of inactive substances, which may be present in the drug substance.
- Adjuvant/ Conjugate: The choice of adjuvant or conjugate should be justified and approved.
- Excipients: Justification of the choice of excipients listed, their concentration and characteristics which influence the drug product performance, should be discussed relative to their respective function.
· Formula development
o a brief summary describing the development of the finished product, taking into consideration the proposed route of administration and usage
o The differences between clinical formulations and the formulation (i.e. Composition) described in Item P 1 and P 2 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.
· Overages, if any, should be justified.
· Description of physiochemical & biological properties (including potency and immunological activity)
· Selection and optimization of the manufacturing process
· Differences between the manufacturing process used to produce pivotal clinical batches and the process described in P3.2, if applicable, should be discussed.
Please refer:
ICH Q5E: Comparability of Biotechnological/ Biological Products Subject to Changes in their Manufacturing Process
- Suitability used for the storage, transportation (shipping) and use of the finished 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 contraction, and performance such as reproducibility of the dose delivery from the device when present as part the drug product.
· Microbiological attributes of the dosage form (where appropriate)
· 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.
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.
· Complete formula inclusive of any adjuvants, diluents, preservatives, additives, stabilisers etc. The formula with name and quantities of all ingredients (active and otherwise) including substance(s) which are removed in the course of manufacture should be included:
o The actual quantities (g, kg, liters) etc. of ingredient should be stated.
o Overage: Supporting data and the reason for including the overage
o The total number of dosage unit per batch must stated.
o A description of all stages involved in the manufacture of the dosage form is required.
· Production of each antigen in the vaccine (i.e. fermenter or culture volumes for each bulk batch size as applicable and typical bulk volumes per production run) should be described.
· Batch formula for each batch size and final formulated bulk product should be provided.
· Lot numbering system for intermediates and final product should be described.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
· 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.)
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 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:
o Test performed
o Stages at which test is done
o Frequency of sampling & no. of samples taken each time
o Acceptance criteria
o Tests and acceptance criteria
· Specifications for quality assurance of the product should be supplied
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
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 aseptic processing or filling).
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
· Specifications for all excipients
· Reference for specifications (Compendial/Manufacturer)
· Source (manufacturer and country of origin)
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
· Control tests performed on raw materials, with appropriate
· characterization:
· List of raw materials meeting compendia specifications, indicating the pharmacopoeia;
· List of raw materials meeting in-house specifications including the tests performed and specifications;
· List of biological starting materials (human or animal origin) with information on the provisions to avoid risk of Transmissible Spongiform Encephalopathies (TSEs) and human diseases (HIV, hepatitis, etc) in the final product; give tests and specifications by supplier and repeated by QC. Certificates for bovine and human derived products used in production indicating the supplier, source, supplier tests for risk contaminants and results should be provided.
· List of media with ingredients, tests performed and specifications.
· Give the in-house expiry date or retest policy for raw material chemicals.
Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.
Please refer:
ICH 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.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
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
For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterisation, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format.
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.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
*Please refer to Section E12
*Please refer to Section E13
- Description (including size, origin and use) and test results of all relevant batches (e.g preclinical, clinical pilot, scale-up, and if available production-scale batches) used to establish specification and evaluate consistency in manufacturing should be provided
o A tabulated summary of the batch analysis, with graphical representation where appropriate should be provided.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
- 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.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
Justification for the proposed drug product specification(s) should be provided.
Compendial requirements or appropriate information from the manufacturer.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
Please refer:
ICH Q5A(R1): Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin
Applicable for Blood Products only.
Applicable for Blood Products only.
(i) Batch 1
(ii) Batch 2
Applicable for Blood Products and Vaccines only.
(i) Batch 1
(ii) Batch 2
Applicable for Vaccines and Plasma-derived Products only.
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.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
Container Closure System
- Identity of materials of construction of each primary and secondary packaging component & its specifications
- The specifications include:
o drawings where appropriate)
o Control of primary and secondary packaging material - give a description of the QC tests and specifications for primary (glass vials, stoppers, caps) and secondary packaging material (boxes) from each supplier. Give a description of the QC checks, tests and approvals regarding pre-printed materials: colours, content, etc, on each lot from each supplier of pre-printed vial labels/boxes/cartons, leaflets, shipping labels, and any other vaccine-specific printed material.
o Package size
o Details of packaging inclusion e.g. dessicant, vaccine vial monitor (VVM), etc.
o For non-functional secondary packaging components (e.g. those that do not 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.
o Suitability information should be located in P 2
- Reports of stability studies should provide details of the batches placed under study (a minimum of 2 batches are required):
o conditions of storage during study (temperature, humidity, upright, inverted position etc) - for liquid product, stability should be generated on stoppered vials stored both upright and inverted.
o duration of study and frequency of the tests/observations
o tests performed (including degradation products being monitored) and acceptance limits; specifications and rationale for the choice of tests for determining stability
o should include real time and accelerated studies
- Stability report – data demonstrating 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.
- Assigned shelf life and storage conditions
- In addition to final product stability data at the recommended storage temperature, the accelerated stability data at elevated temperatures should be sufficient to justify the choice of Vaccine Vial Monitor for the use with the product. The use of VVM is not mandatory but strongly recommended.
- Results of quantitative assays must be expressed as a numerical value with the appropriate limits and not as “pass” or “fail”.
- 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. Provide for each presentation (doses/vial), a list of the lots numbers on test, batch size, scale of production, vial size, vial orientation, and dates of manufacture. Justification of the choice of these lots is requested. Tables of accelerated stability data are required to define the VVM category to be used with the specific vaccine (stability data at 2 different temperatures are required and these are usually 2-8°C and 37°C or 45°C), however real time data establishes the expiry dating.
- Conclusions on stability and the claimed shelf life of the vaccine(s) should be presented.
- Stability testing of diluents and reconstituted vaccine in case of lyophilized vaccines. For lyophilized vaccines, the stability of the diluent in vials/ampoules should be presented to establish the expiry date. Lot numbers, dates of manufacture, tests, specifications and numerical results should be provided as for vaccine - tables are acceptable.
- The stability of the vaccine after reconstitution with the diluent should establish the stability of the vaccine after first entry for at least up to 6 hours after reconstitution. Multiple entry of the vial should be simulated. The same criteria and parameters for stability studies on the final product should be followed.
- Any post-approval stability protocol and commitment should be stated.
Please refer:
ICH Q6B: Specifications: Test procedures and acceptance criteria for biotechnological/ biological products
WHO TRS 962 Annex 3: Guidelines on stability evaluation of vaccine
Malaysian/ ASEAN Guideline for stability studies
Applicable for Biosimilar product
