Explanatory Guidance for CTD submission
Registration Department
Jordan Food & Drug administration
Explanatory Guidanceregarding CTD Submission
(ForRegistration of Pharmaceuticals):
Version 1.0
Issue date 6/3/2011
Introduction:
-The CTD (Common Technical Dossier) provides a format for the submission of information to regulatory authorities, it does not define content,please refer to the Registration criteria for specific requirements (ex:Bioequivalence, stability, Pharmacovigilance...)so these guidance are not intended to indicate what studies are required.
- The required data for each application will differ,depending on the drug submission type, However,all the required data should be in accordance with the CTD structure.
- The check list(F1/RDP-3/2011) outlines the CTD Modules required for the submission of:
Originator drug ,New drug ,BiologicalBiosimilar drugs.
Generic Drugs,Radiopharmaceuticals
- This documentprepared to guidethe applicantswhenpreparing their applications for registration.
Detailed explanation of the CTD modules:
- Module 1:Administrative Data & certificates.
-This module contains the specific local requirements for the administrative data (e.g. the application form, the proposed summary of product characteristics, labeling and package leaflet, etc.).
-Application forms(should be signed & stamped from the applicant or fromthe marketing authorization holder)(should befilled inprintandnothandwrittenقراءة صوتية للكلمات.)
-Application forms are available on website
-For the information about:
1-Pharmacovigilance System:
Detailed description of thePharmacovigilance system must be provided
this should include proof that the applicant has the servicesof a qualified
person responsible for Pharmacovigilance and the necessarymeans for the
notification of any adverse reaction.
2-Risk-management System(plan).
A detailed description of the risk management system which the applicant will introduce should be provided, where appropriate.
-For the Specific Requirementsof Different Types of Applications:
Information for application type: If it's Originator it should be specified &
if Generic , Biosimilar…..details on the medicinal product, its active substance, pharmaceutical form, strengths, therapeutic indications, route of administration as appropriate in comparison to the reference medicinal product should be specified.
Information for submission type:(Technology Transfer, under license,contract ..)
Applicant Should give information about drug product that are manufactured contractually, or under license, or technology transfer …& documents according to registration criteria for each type should be submitted.
- Module 2:Common Technical Document Summaries
Contains summaries (the Quality Overall Summary, the Non-clinical Overview / Summaries, and the Clinical Overview / Summaries) .
Should include sufficient information from each module to provide the reviewer with an overview of all the CTD Modules should also emphasis critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed.
-Module 2.2 Introduction:
Should include its pharmacological class, mode of action and the proposed clinical use.
-Module 2.3 Quality Overall Summary:
The following points should be taken into considerations:
The Quality Overall Summary (QOS) is a summary that follows the scope
and the outline of the Body of Data in Module 3.
JFDA Stability Report Form ( F5/RDP-7\2008 ) should be included .
The QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD.
The QOS should include sufficient information from each section to provide the Quality reviewer with an overview of Module 3, the QOS should also emphasis critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed.
For Generics:Sections Required only: 2.3 Quality Overall Summaries (only JFDA Stability Report Form ( F5/RDP-7\2008 ) should be included)
2.5 Clinical Overview (the written summary(BE report or Synopsis ) of the bioequivalence has to be part of the Clinical Overview .
(Non-clinical and Clinical Summaries can be provided , but they are only mandatory if new additional studies have been provided within the documentation.)
-Module 2.4 Nonclinical Overview:
The interpretation of the data, the clinical relevance of the findings, cross-linking with the quality aspects of the pharmaceutical, and the implications of the nonclinical findings for the safe use of the pharmaceutical (i.e., as applicable to labeling) should be addressed in the Nonclinical Overview.
-Module 2.5 Clinical Overview:
The Clinical Overview is intended to provide a critical analysis of the clinical data in theCommon Technical Document, it will necessarily refer to application data provided in the comprehensive Clinical Summary ,the Clinical Overview should provide a succinct discussion and interpretation of these studies together with any other relevant information.
-Module 2.6 Nonclinical Summary
The primary purpose of the Nonclinical Written and Tabulated Summaries should be to provide a comprehensive, factual synopsis of the nonclinical data.
-Module 2.7 Clinical Summary
The Clinical Summary should provide a detailed factual summarisation of the clinical information in the CTD.
- Module 3:Quality.
3.2 Body of Data
3.2.S DRUG SUBSTANCE
-The information on the drug substance can be submittedin the following order:
1-Valid European Certificate of Suitability (CEP) with all appendices(copy) for drug substancemanufacturer/s.
The Drug Substance sections should refer to the Certificate of Suitability in therelevant sections in Module 3.2.S,the Certificates of Suitability are deemed toreplace the data of the corresponding sections(S.2.2, S.2.3, S.2.4 and S.2.6) and therefore in principle no furtheradditional information is necessary except concerning technical characteristics of the substance where not covered by the Certificate of Suitability (e.g. when the Certificate of Suitability does not describe a specific technical grade, information and data for the re-test period).
2-If theCertificate of Suitability (CEP) is not available all the Drug Substance sections in Module 3.2.S should be full-filled& a valid copy of GMP certificate (for drug substance manufacturer/s) should be included.
The information from the Open Part of the DMF should be provided in
drug application.
Information in sections (S.2.2, S.2.3, S.2.4 and S.2.6) may not be available to the holder of the drug product,they will be in the closed part of the DMF which will be available from the drug substance supplier ,so the supplier of the drug substance can send a Drug Master File (closed part of the DMF) directly to authority .
*COS or CEP: Certificate Of Suitability: A Certificate issued from EDQM (European Directorate for the Quality of Medicine) to
demonstrate the compliance of the substance used with the monograph of the European Pharmacopoeia.(not issued for biological)
GMP certificate: issued from health authorities, the firm follow GMP, should mention the name of drug substance.
DMF: drug master file.
3.2.S.1 General Information (name of the active ingredient, manufacturer)
Information on the nomenclature of the drug substance (INN),
chemical name,USAN….),Structure(structural formula, molecular formula..).
General properties:A list should be provided of physicochemical and other relevant properties of the drug substance, including biological activity for biotech,shouldbespecified.
For Biotech:
The schematic amino acid sequence indicating glycosylation sites or other posttranslational modifications and relative molecular mass should be provided, asappropriate.
3.2.S.2 Manufacture (name of the active ingredient, manufacturer)
3.2.S.2.1 Manufacture name , address.
The name, address, and responsibility of each manufacturer should be provided.
Name should comply with (CEP or GMP certificate provided).
3.2.S.2.2 Description of Manufacturing Process& process controls .
The description of the drug substance manufacturing process represents the applicant’s commitment for the manufacture of the drug substance. Information should be provided to adequately describe the manufacturing process (flow diagram) and process controls.
For Biotech:
Information should be provided on the manufacturing process, which typicallystarts with a vial(s) of the cell bank, and includes cell culture, harvest(s),purification and modification reactions, filling, storage and shipping conditions.
Batch (es) and scale definition:
An explanation of the batch numbering system, including information regardingany pooling of harvests or intermediates and batch size or scale should be provided.
Cell culture and harvest:
A flow diagram should be provided that illustrates the manufacturing route fromthe original inoculums (e.g. cells contained in one or more vials(s) of the WorkingCell Bank up to the last harvesting operation. The diagram should include all steps(i.e., unit operations) and intermediates. Relevant information for each stage, suchas population doubling levels, cell concentration, volumes, pH, cultivation times,holding times, and temperature, should be included. Critical steps and criticalintermediates for which specifications are established (as mentioned in 3.2.S.2.4)should be identified.
A description of each process step in the flow diagram should be provided ,information should be included on, for example, scale; culture media and otheradditives (details provided in 3.2.S.2.3); major equipment (details provided in3.2.A.1); and process controls, including in-process tests and operationalparameters, process steps, equipment and intermediates with acceptance criteria(details provided in 3.2.S.2.4). Information on procedures used to transfer materialbetween steps, equipment, areas, and buildings, as appropriate, and shipping andstorage conditions should be provided. (Details on shipping and storage providedin 3.2.S.2.4.)
Purification and modification reactions
A flow diagram should be provided that illustrates the purification steps (i.e., unitoperations) from the crude harvest(s) up to the step preceding filling of the drugsubstance. All steps and intermediates and relevant information for each stage(e.g., volumes, pH, critical processing time, holding times, temperatures andelution profiles and selection of fraction, storage of intermediate, if applicable)should be included. Critical steps for which specifications are established asmentioned in 3.2.S.2.4 should be identified.
A description of each process step (as identified in the flow diagram) should beprovided. The description should include information on, for example, scale,buffers and other reagents (details provided in 3.2.S.2.3, major equipment (detailsprovided in 3.2.A.1), and materials.
For materials such as membranes andchromatography resins, information for conditions of use and reuse also should beprovided. (Equipment details in 3.2.A.1; validation studies for the reuse andregeneration of columns and membranes in 3.2.S.2.5.) The description shouldinclude process controls (including in-process tests and operational parameters)with acceptance criteria for process steps, equipment and intermediates. (Details in3.2.S.2.4.).
Reprocessing procedures with criteria for reprocessing of any intermediate or thedrug substance should be described. (Details should be given in 3.2.S.2.5.).
Information on procedures used to transfer material between steps, equipment,areas, and buildings, as appropriate, and shipping and storage conditions should beprovided (details on shipping and storage provided in 3.2.S.2.4.).
Filling, storage and transportation (shipping)
A description of the filling procedure for the drug substance, process controls(including in-process tests and operational parameters), and acceptance criteriashould be provided. (Details in 3.2.S.2.4.) The container closure system(s) usedfor storage of the drug substance (details in 3.2.S.6.) and storage and shippingconditions for the drug substance should be described.
3.2.S.2.3 Control of Materials.
Materials used in the manufacture of the drug substance (e.g., raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided.
For Biotech:
-Control of Source and Starting Materials of Biological Origin
-Source, history, and generation of the cell substrate
-Cell banking system, characterization, and testing
3.2.S.2.4Control of Critical Steps& intermediates.
Critical Steps: Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.
Intermediates: Information on the quality and control of intermediates isolated during the process should be provided.
3.2.S.2.5Process Validation
Process validation and/or evaluation studies for aseptic processing and sterilization should be included.
For Biotech:
Sufficient information should be provided on validation and evaluation studies todemonstrate that the manufacturing process (including reprocessing steps) issuitable for its intended purpose and to substantiate selection of critical processcontrols (operational parameters and in-process tests) and their limits for criticalmanufacturing steps (e.g., cell culture, harvesting, purification, and modification).
The plan for conducting the study should be described and the results, analysis andconclusions from the executed study(ies) should be provided. The analyticalprocedures and corresponding validation should be cross-referenced (e.g.,3.2.S.2.4, 3.2.S.4.3) or provided as part of justifying the selection of critical processcontrols and acceptance criteria
3.2.S.2.6Manufacturing Process Development.
A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the drug substance used in producing nonclinical, clinical, scale-up, pilot, and, if available, production scale batches.
For Biotech:
The description of change(s) made to the manufacture of drug substance batches used in support of the marketing application (e.g., nonclinical or clinical studies) should include.
Testing used to assess the impact of manufacturing changes on the drug substance(s) and the corresponding drug product(s) can also include nonclinical and clinical studies. Cross-reference to the location of these studies in othermodules of the submission should be included.
3.2.S.3 Characterization (name of the active ingredient, manufacturer)
3.2.S.3.1 Elucidation of Structure and other Characteristics.
Confirmation of structure based on e.g., synthetic route and spectral analysesshould be provided. Information such as the potential for
isomerism, theidentification of stereochemistry, or the potential for forming polymorphs shouldalso be included.
For Biotech:
For desired product and product-related substances, details should be provided onprimary, secondary and higher-order structure, post-translational forms (e.g.,glycoforms), biological activity, purity, and immunochemical properties, whenrelevant.
3.2.S.3.2 Impurities.Specify impurity profile.
3.2.S.4 Control of Drug Substance(name of the active ingredient, manufacturer):
3.2.S.4.1 Specification (name, manufacturer)
The specification for the drug substance should be provided.
( if pharmacopoeial a copy of the monograph should be included).
3.2.S.4.2 Analytical Procedures (name, manufacturer)
The analytical procedures used for testing the drug substance should be provided.
3.2.S.4.3 Validation of Analytical Procedures (name, manufacturer)
Analytical validation information, including experimental data for the analyticalprocedures used for testing the drug substance, should be provided.
Verification used for Pharmacopoeial methods.
Validation used for Non- Pharmacopoeial methods.
3.2.S.4.4 Batch Analyses (name, manufacturer)
Description of batches and results of batch analyses should be provided.
3.2.S.4.5 Justification of Specification (name, manufacturer)
Justification for the drug substance specification should be provided.
( if pharmacopoeial a copy of the monograph should be included).
3.2.S.5 Reference Standards or Materials(name of the active ingredient, manufacturer)
Standard name and its manufacturer (provide COA of API reference standard).
3.2.S.6 Container Closure System (name of the active ingredient, manufacturer)
Mention the type of the container, closure.
3.2.S.7 Stability (name of the active ingredient, manufacturer)
Results of the stability studies (e.g., forced degradation studies and stress conditions)
should be presented in an appropriate format such as tabular, graphical, or narrative.
Conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.
Include stability data minimum of:6 months at accelerated conditions and 12 months at long term conditions for three batches.
3.2.P DRUG PRODUCT (NAME OF THE FINISHED PRODUCT, DOSAGE FORM)
3.2.P.1 Description and Composition of the Drug Product (name of the finished product, dosage form)
A description of the drug product and its composition should be provided.
List of all components of the dosage form, and their amount on a per-unitbasis (including overages, if any) the function of the components, and a reference to their quality standards (e.g.compendia monographs ormanufacturer’s specifications)
NAMES OF INGREDIENTS / UNIT FORMULA / Percentage formula / FUNCTION / REFERENCETO
STANDARDS
ACTIVE SUBSTANCE
EXCIPIENTS
3.2.P.2 Pharmaceutical Development(name of the finished product,dosage form)
This section should contain information on the development studies conducted to establish the dosage form, the formulation, manufacturing process, container closure system, microbiological attribute, usage instructions.
3.2.P.2.1 Components of the Drug Product (name of the finished product, dosage form)
3.2.P.2.1.1Drug Substance (name of the finished product, dosage form)
The compatibility of the drug substance with Excipients should be justified. Physicochemical characteristics for Drug Substance that can influence the performance of the drug product should be discussed (e.g., water content, solubility, particle size distribution or polymorphic form).
3.2.P.2.1.2 Excipients (name of the finished product, dosage form)
The functions of Excipients, their concentrationand their characteristics that can influence the drug product performance should be discussed for each Excipient.
3.2.P.2.2 Drug Product (name of the finished product, dosage form):
3.2.P.2.2.1 Formulation Development (name of the finished product, dosage form)
A brief summary describing the development of the drug product, Including pre formulation studies or justification if not needed.
3.2.P.2.2.2 Overages (name of the finished product, dosage form)
Any overages in the formulation should be justified.
3.2.P.2.2.3 Physicochemical and Biological Properties (name of the finished product, dosage form)
Parameters relevant to the performance of the drug product, such as pH, ionicstrength, dissolution, redispersion, reconstitution, particle size distribution, aggregation,polymorphism, rheological properties, biological activity or potency, and/or immunological activity, to be addressed if needed.
3.2.P.2.3 Manufacturing Process Development (name of the finished product, dosage form)
-Specify the critical steps of Manufacturing
- Any differences between pivotal clinical batches and the production batches should be mentioned with its justification(ex:scaling up from pilot to production).
3.2.P.2.4 Container Closure System (name of the finished product, dosage form)
The suitability of the container closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the drug product should be discussed.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).