Sneh lata et al.

/ AJPSR volume 2 issue 6, June, 2012

Available online at www.ordonearresearchlibrary.com Review Article ISSN 2249-4898

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH COMPARATIVE DOSSIER FILLING PROCEDURE IN THE ASEAN, CIS AND THE GCC REGION Sneh lata*, Rajendra songara. Jaipur National University, Jagatpura, Jaipur (Rajasthan), India
Received: 23 May 2012; Revised: 4 June 2012; Accepted: 21 June 2012; Available online: 5 July. 2012

ABSTRACT Dossier is a file document submitted based on the requirement of the drug approval process. It is a comprehensive scientific document used to obtained worldwide licensing approval of a drug by diverse health authorities. Its creations, processing, compilation & dispatch to the field by a regulatory affairs department, is dependent upon many interrelated activities the filling process in the emerging markets will be depends upon the region .In the Asean region A-CTD filling procedure in GCC region CTD format and CIS countries will be NeeS filling procedure will be follow. After compilation 1 copy of the dossier will be submitted to the regulatory authorities for the registration of the drug product. Keyword: CTD-Common Technical Document. DMF-Drug Master File ICH-International Conference on Harmonisation. Dossier File Submission.

INTRODUCTION The registration procedure is different in every region .some will follow the ICH guidelines, WHO guidelines for the registration of the drug product .But some region have the country specific guidelines for the registration of the FPP. Drug regulatory affairs in pharma industries have mandated two types of dossier namely CTD (Common Technical Dossier) and ACTD (Asean Common Technical Dossier). Regulated pharma markets (eg.USA, Europe) markets require submission of dossier in CTD format which has to provide clinical trial and bioequivalence studies. As against this, semi-regulated pharma markets (South East Asian) require ACTD format which does not require exhaustive details like CTD. All of these guidelines will be considered the safety, quality and efficacy of the FP product

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 CTD (common Technical Documents)

The agreement to assemble all the Quality, Safety and Efficacy information in a common format (called CTD Common Technical Document ) has revolutionised the regulatory review processes, led to harmonised electronic submission that, in turn, enabled implementation of good review practices. For industries, it has eliminated the need to reformat the information for submission to the different ICH regulatory authorities. The CTD is organised into five modules. Module 1 is region specific and Modules 2, 3, 4 and 5 are intended to be common for all regions. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format of choice for NDAs submitted to the FDA. The CTD is organized into five modules Module 1. Administrative Information and Prescribing Information This module contains documents specific for each region specified by the Relevant regulatory authorities. - Application forms - Proposed label for use in this region Module 2. Common Technical Document Summaries

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 CTD Table of Contents CTD Introduction Quality Overall Summary Nonclinical Overview Clinical Overview Nonclinical Written and Tabulated Summaries Clinical Summary Module 3. Quality Information on quality should be presented in the structured format described in the guidance, M4Q

Module 4. Nonclinical Study Reports The Nonclinical Study Reports should be presented in the order described in the Guidance M4S Module 5. Clinical Study Reports

The modules that comprise the CTD are modules 2-5 of the submission and contain the scientific data and summaries .Modules 1 of any submission is not part of the CTD and contain region specific administrative information .the organization of the data in to modules and nodes is referred to as the granulatory of the submission

Asean ACTD format

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 . The Association of Southeast Asian Nations (ASEAN) has mandated the filing of an ASEAN Common Technology Dossier (ACTD) as the only regulatory filing for pharmaceutical companies to get approval for their drugs in the 10-member states of Singapore, Malaysia, Indonesia, Philippines, Thailand, Vietnam, Brunei, Myanmar, Cambodia and Laos, with effect from 2012. A-CTD have been organize in to 4 modules

Module 1- Administrative & prescribing information Table of Contents Application Form Letter of Authorisation (where applicable) Certifications Labelling Product Information
Module 2- Quality

Table of Contents A table of contents for the filed application should be provided. Section C: Body of Data S S1 DRUG SUBSTANCE General Information

S 1.1 Nomenclature International nonproprietary name (INN) Compendial name if relevant Registry number of chemical abstract service (CAS) Laboratory code (if applicable) Chemical name(s)

S 1.2 Structural formula

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 The structural, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided. S 1.3 General Properties A list should be provided of physicochemical and other relevant properties of the drug substance. Reference ICH Guidelines: Q6A S2 Manufacture

S 2.1 Manufacturer(s) Name and full addresses including the city and country of the manufacturer of active ingredient. S 2.2 Description of Manufacturing Process and Process Controls The description of the drug substances manufacturing process represents the applicants commitment for the manufacture of drug substances. The following information should be provided to adequately describe the manufacturing process and process controls: A schematic flow diagram of the synthetic process(es) should be provided that includes molecular

formulae, weights and yields, chemical structures of starting materials, intermediates, reagents and drug substance reflecting stereochemistry, and identifies operating conditions and solvents. A sequential procedural narrative of the manufacturing process that provides quantities of raw materials, solvent, catalysts and reagent reflecting the representative batch scale, and includes process controls, equipment and operating conditions, such as temperature, pressure, pH, time etc Alternative process should be explained and described with the same level of details as the primary process. Reprocessing steps should be identified and justified S 2.3 Control of Materials Material 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. Information demonstrating that materials (including biologically-sourced materials, e.g., media components, monoclonal antibodies, enzymes) meet standards appropriate for their intended use (including the clearance or control of adventitious agents) should be provided,

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 as appropriate. For biologically-sourced materials, this can include information regarding the source, manufacture, and characterization.

Reference ICH Guidelines : Q6A

S 2.4 Controls of critical steps and intermediates Critical steps: Tests and acceptance criteria, with justification including experimental data, performed at critical steps of the manufacturing process to ensure that the process is controlled. Intermediates: Specifications and analytical procedure, if any, for intermediates isolated during the process. Reference ICH Guidelines : Q6A

S 2.5 Process Validation and/or Evaluation Process validation or evaluation studies for aseptic processing and sterilization

S 2.6 Manufacturing Process Development Description and discussion of significant changes made to the manufacturing process or manufacturing site of the drug substance used in producing non-clinical, clinical scale-up, pilot and if available, production scale batches. Reference ICH Guidelines : Q3A

S 3 Characterization

S 3.1 Elucidation of Structure and Characteristic Confirmation of structure based on e.g. synthetic route and spectral analysis. Information on the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorph should also be included. Reference ICH Guidelines : Q6A

S 3.2 Impurities Information on impurities should be provided. Reference ICH guidelines : Q3A, Q3C, and Q6A
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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

S 4 Control of Drug Substance Specification and justification of specification (s). Summary of analytical procedure and validation. S 4.1 Specification Detailed specification, tests and acceptance criteria for the drug substance should be provided.

Compendia specification are adequate. Indicate clearly whether the drug substance is purchased based on specification with a certificate of analysis, or tested by applicant. Reference ICH Guidelines Q6A S 4.2 Analytical Procedures The analytical procedure used for testing the drug substance should be provided in sufficient detail to enable reproducible testing by another laboratory. Reference ICH Guidelines : Q2A S 4.4 Batch Analyses Description of batches and results of batch analyses should be provided Reference ICH Guidelines : Q3A, Q3C and Q6A

S 4.5 Justification of Specification Justification for the drug substance specification should be provided. Reference ICH Guidelines : Q6A S 5 Reference Standards or Materials Quality information of Reference standard or material used for testing of substance should be provided. Reference ICH Guidelines : Q6A S 6 Container Closure System A descriptions of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component, and each specifications. The specifications should include
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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 description and identification (and critical dimensions with drawings where appropriate). Non-compendial methods (with validations) should be included where appropriate. 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. The suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the drug substance, including sorption to container and leaching, and/or safety of materials of construction. Stability Summary and Conclusion The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate. Reference ICH Guidelines : Q1A (R2), Q1B Post-approval Stability Protocol and Stability Commitment The post-approval stability protocol and stability commitment should be provided. Reference ICH Guidelines : Q1A (R2) Stability Data 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. Information on the analytical procedures used to generate the data and validation of these procedures should be included. Manufacturer stability data or equivalent information for generic drug Reference ICH Guidelines : Q1A (R2), Q1B, Q2A, Q2B, P P1 DRUG PRODUCT Description and Composition

A description of the drug product and its composition should be provided. The information provided should include, for example :
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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 Description of the dosage form; Composition, i.e., list of 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 manufacturers specifications) 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 : Q6A 2.Pharmaceutical Development P 2.1 Information on Development Studies The section of Pharmaceutical Development presents information and data on the development studies conducted to establish that the dosage form, the formulation manufacturing process, container closure system, microbiological attributes and usages instruction 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 (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 the Pharmaceutical Development Section. Additional supportive data may be referenced to the relevant non-clinical sections of the application. Reference ICH Guidelines : Q8(R2) P 2.2 Component of Drug Product P P.2.2.1 Active Ingredients: The compatibility of the drug substances with excipients listed in Item 2.1 should be discussed. Additionally, 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 discussed.
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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 For generic drug Literature data is sufficient.

P 2.2.2 Excipients The choice of excipients listed in Item P 1, their concentration and characteristics which influence the drug product performance should be discussed relative to their respective function.

P 2.3 Finished Product P 2.3.1 Formulation Development 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 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.

P 2.3.2 Overages Any overages in the formulation(s) described in Item P 1 should be justified.

P 2.3.3 Physicochemical and Biological 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 immunological activity should be addressed

P 2.4 Manufacturing Process Development The selection and optimization of the manufacturing process described in Item P 3.2, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified. Differences between the manufacturing process(es) used to produce pivotal clinical batches and the process described in Item P 3.2 that can influence the performance of the product should be discussed.

P 2.5 Container Closure System The suitability of the container closure system used for the storage, transportation (shipping) and use of the drug product should be discussed as necessary. This discussion should consider e.g. choice of materials, protection
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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 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.

P 2.6 Microbiological Attributes Where appropriate, the microbiological attributes of the dosage form should be discussed including the rationale for not performing microbial limits testing for non-sterile products, and the selection and effectiveness of preservatives systems in product containing anti microbial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.

P 2.7 Compatibility 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. reference

P3

Manufacture

P 3.1 Batch Formula 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: The actual quantities (g, kg, liters) etc. of ingredient should be stated. Overage: Supporting data and the reason for including the overage shall be enclosed. The total number of dosage unit per batch must stated. A description of all stages involved in the manufacture of the dosage form is required.

P 3.2 Manufacturing Process and Process Control 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.
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The full description of manufacturing process must sufficient details to cover the essential point of each Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 stage of manufacture. For sterile product the description includes preparation and sterilization of components (i.e. Containers, closures, etc).

P 3.3 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 P3.3 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 : Q2A and Q6A

P 3.4 Process Validation and/or Evaluation 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). Reference : Q6A or Asean guidelines for Process validation

P4

Control of Excipients

P 4.1 Specification The specification for the excipients should be provided. P 4.2 Analytical Procedures The analytical procedure used for the testing of critical excipients i.e. substances which affect stability and bioavailability of finished product (e.g. preservative, buffer

components, dissolution enhancer)should be provided. Reference ICH Guidelines : NCE : Q2A and Q5A P 4.3. Excipients of Human and Animal Origin For excipients of human or animal origin, provide information of sources (e.g gelatin, enzyme, etc), specifications,
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description,

viral safety data)

regarding

adventitious agents (e.g., TSE,

viruses,

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 mycoplasma).Reference ICH Guidelines : NCE : Q5A, Q5D ; P 4.4 Novel Excipients For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization and controls, with cross references to supporting safety data (nonclinical or clinical) should be provided P 5 Control of Finished Product Specification and justification of the specification, summary of the analytical procedure and validation, and characterization of impurities.

P 5.1 Specification The specification for the finished product should be provided. Reference ICH Guidelines : NCE : Q6A; P 5.2 Analytical Procedures. The analytical procedures use for the testing the finished product should be provided. Reference ICH Guidelines : NCE : Q2A P 5.3 Validation of Analytical Procedures Analytical validation information, including experimental data for the analytical procedures use for the testing the finished product should be provided. ReferenceICH Guidelines : NCE : Q2A and Q2B Reference : ASEAN Guideline P 5.4 Batch analyses Description (including size, origin and use) and test result of all relevant batches e.g pre-clinical, clinical pilot, scale-up, and if available production-scale batches) used to in manufacturing should be provided. Reference ICH Guidelines : NCE : Q3A, Q3C, and Q6A establish specification and evaluate consistency

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 P 5.5 Characterization of Impurities Information on the characterization of impurities should be provided, if not previously provided in Item 1.3.2 Impurities. Reference ICH Guidelines : NCE : Q3B and Q6A P 5.6 Justification of Specification Justification for the proposed finished product should be provided Reference ICH Guidelines : NCE : Q3B and Q6A P 6 Reference Standards or Materials Requirement : Quality information and tabulated presentation of Reference standard or materials used for testing of drug product should be included. P 7 Container closure system A descriptions of the container closure systems should be provided, including the identity of materials of construction of each primary and secondary packaging component, and each specifications. The specifications should include description and identification (and critical dimensions with drawings where appropriate). Noncompendial methods (with validations) should be included where appropriate. 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. Suitability information should be located in P 2 P 8 Product Stability 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.

Stability Summary and Conclusion:

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 All criteria under ICH Guidelines are acceptable with the exception of real time storage conditions which should be 300C, 70% RH. Provision of moisture protection of the packaging should be taken into consideration. Reference ICH Guidelines: Q1A (R2), Q1B, Q2A, Q2B and Q5C ASEAN Guideline on Stability Study Post-approval stability protocol and stability commitment the post-approval stability protocol and stability commitment should be provided. References ICH Guidelines : NCE, ASEAN Guideline on Stability Study Stability Data 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. reference : ASEAN Guideline on Stability Study, ASEAN Guideline on Validation of Analytical Procedure P 9 Product Interchange ability The type of studies conducted, protocol used and the result of the studies should be presented in the study report. Type of studies conducted should refer to ASEAN (proposed) Bioavailability and Bioequivalence requirement, Guideline for Bioavailability and Bioequivalence Studies or WHO Manual for Drug Regulatory Authority. Reference: - WHO, Regulatory Support Series No 5,"Bioequivalence Studies in Humans." - ASEAN Guideline on Bioequivalence Study Section D: Key Literature References Key literature references should be provided, if applicable.

Module 3-Non clinical study report Module 4- clinical study report

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GCC- CTD registration procedure

The data requirements for each application will differ, depending on the drug submission type. However, all the required data should be in accordance with the CTD structure. Section Module 1 1.0 1.1 1.2 1.3 1.3.1 1.3.2
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Requirements Regional Administrative Information Cover letter Comprehensive Table of content Application Form Product Information Summary of Product Characteristics (SPC) Labeling

R R R

R R Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 1.3.3 1.3.3.1 1.3.3.2 1.3.4 1.3.5 1.4 1.4.1 1.4.2 1.4.3 1.5 1.5.1 1.5.2 1.6 1.6.1 1.6.2 1.7 1.7.1 1.7.2 1.7.3 1.7.4 1.7.5 1.7.6 1.7.7 1.7.8 1.7.9 1.7.10 1.8 1.8.1 1.8.2 1.9 Package Leaflet Arabic leaflet English leaflet /French leaflet Artwork (Mock-ups) Samples Information About The Expert Quality Non-Clinical Clinical Environmental Risk Assessment Non-Genetically Modified Organism (Non-GMO) GMO Pharmacovigilance Pharmacovigilance System Risk Management Plan Administrative information GMP Certificate CPP or Free-sales Certificate of analysis Drug Substance Certificate of analysis Excipients Alcohol-free declaration Pork-free declaration Certificate of suitability for TSE The diluents and coloring agents in the product formula Patent Information Letter of access or acknowledgment to DMF Pricing Price certificate Other documents related Pricing list Responses to questions R O O R R R R R R R R O R R O O O O O O R R R R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 Module 2* 2.1 2.2 2.3 Common Technical Document Summaries Table of Contents of Module 2-5 Introduction Quality Overall Summary Introduction 2.3.S 2.3.S.1 2.3.S.2 2.3.S.3 2.3.S.4 2.3.S.5 2.3.S.6 2.3.S.7 2.3.P 2.3.P.1 2.3.P.2 2.3.P.3 2.3.P.4 2.3.P.5 2.3.P.6 2.3.P.7 2.3.P.8 2.3.A 2.3.A.1 2.3.A.2 2.3.A.3 2.3.R 2.4 Drug substance General Information Manufacture Characterization Control of Drug Substance Reference Standards or Materials Container/Closure System Stability Drug Product Description and Composition of the Drug Product Pharmaceutical Development Manufacture Control of Excipients Control of Drug Product Reference Standards or Materials Container/Closure System Stability Appendices Facilities and Equipment Adventitious Agents Safety Evaluation Novel Excipients Regional Information Nonclinical Overview ONLY 2.5
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R R R

FOR ORIGINATORS

Overview of the Nonclinical Testing Strategy Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 2.5.1 2.5.2 2.5.3 2.5.4 2.5.5 2.5.6 2.5.7 2.6 Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology Overview of Efficacy Overview of Safety Benefits and Risks Conclusions References Non clinical written and tabulated summaries: Pharmacology, pharmacokinetics Toxicology FOR ORIGINATOR ONLY 2.6.1 2.6.2 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.5 2.6.2.6 Section 2.6.2.7 2.6.3 2.6.4 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6 2.6.4.7 2.6.4.8 2.6.4.9
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Introduction Pharmacology Written Summary Brief Summary Primary Pharmacodynamics Secondary Pharmacodynamics Safety Pharmacology Pharmacodynamic Drug Interactions Discussion and Conclusions Requirements Tables and Figures Pharmacology Tabulated Summary Pharmacokinetics Written Summary Brief Summary Methods of Analysis Absorption Distribution Metabolism (interspecies comparison) Excretion Pharmacokinetic Drug Interactions Other Pharmacokinetic Studies Discussion and Conclusions Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 G

Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 2.6.4.10 2.6.5 2.6.6 2.6.6.1 2.6.6.2 2.6.6.3 2.6.6.4 2.6.6.5 2.6.6.6 2.6.6.7 2.6.6.8 2.6.6.9 2.6.6.10 2.6.7 2.7 2.7.1 Tables and Figures Pharmacokinetics Tabulated Summary Toxicology Written Summary Brief Summary Single-Dose Toxicity Repeat-Dose Toxicity Genotoxicity Carcinogenicity Reproductive and Developmental Toxicity Local Tolerance Other Toxicity Studies (if available) Discussion and Conclusions References Toxicology Tabulated Summary Clinical Summary Summary of Biopharmaceutic and Associated Analytical Methods 2.7.1.1 2.7.1.2 2.7.1.3 2.7.1.4 2.7.2 2.7.2.1 2.7.2.2 2.7.2.3 2.7.2.4 2.7.2.5 2.7.3 2.7.3.1 2.7.3.2 Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Appendix Summary of Clinical Pharmacology Studies Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Special Studies Appendix Summary of Clinical Efficacy Background and Overview of Clinical Efficacy Summary of Results of Individual Studies

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 2.7.3.3 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3 2.7.3.4 Comparison and Analyses of Results Across Studies Study Populations Comparison of Efficacy Results Across All Studies Comparison of Results in Sub-Populations Analysis of Clinical Information Relevant to Dosing

Recommendations 2.7.3.5 2.7.3.6 Section 2.7.4 2.7.4.1 2.7.4.1.1 2.7.4.1.2 2.7.4.1.3 2.7.4.2 2.7.4.2.1 2.7.4.2.2 2.7.4.3 2.7.4.4 2.7.4.5 2.7.4.5.1 2.7.4.5.2 2.7.4.5.3 2.7.4.5.4 2.7.4.5.5 2.7.4.5.6 2.7.4.5.7 2.7.4.5.8 Persistence of Efficacy and/or Tolerance Effects Appendix Requirements Summary of Clinical Safety Exposure to the Drug Overall Safety Evaluation Plan and Narratives of Safety Studies Overall Extent of Exposure Demographic and Other Characteristics of Study Population Adverse Events Analysis of Adverse Events by Organ System or Syndrome Narratives Clinical Laboratory Evaluations Vital Signs, Physical Findings, Observations Related to Safety Safety in Special Groups and Situations Intrinsic Factors Extrinsic Factors Drug Interactions Use in Pregnancy and Lactation Overdose Drug Abuse Withdrawal and Rebound Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability 2.7.4.6 Post-Marketing Data G

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 2.7.4.7 2.7.5 2.7.6 Module 3 Section 3.1 3.2 3.2.S 3.2.S.1 3.2.S.1.1 3.2.S.1.2 3.2.S.1.3 3.2.S.2 3.2.S.2.1 3.2.S.2.2 3.2.S.2.3 3.2.S.2.4 3.2.S.2.5 3.2.S.2.6 3.2.S.3 3.2.S.3.1 3.2.S.3.2 3.2.S.4 3.2.S.4.1 3.2.S.4.2 3.2.S.4.3 3.2.S.4.4 3.2.S.4.5 3.2.S.5 3.2.S.6 Appendix References Synopses of Individual Studies Quality Requirements Table of Contents of Module 3 Body of data Drug Substance General Information Nomenclature Structure General Properties Manufacture Manufacturer(s) Description of Process and Process Controls Control of Materials Control of Critical Steps and Intermediates Process Validation and/or Evaluation Manufacturing Process Development Characterization Elucidation of Structure and Other Characteristics Impurities Control of Drug Substance Specifications Analytical Procedures Validation of Analytical Procedures Batch Analyses Justification of Specification Reference Standards or Materials Container/Closure Systems R R R R R R R R R R R R R R R R R R G R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 3.2.S.7 3.2.S.7.1 3.2.S.7.2 3.2.S.7.3 3.2.P 3.2.P.1 3.2.P.2 3.2.P.2.1 Stability Stability Summary and Conclusions Post-approval Stability Protocol and Commitment Stability Data Drug Product Description and Composition of the Drug Product Pharmaceutical Development Components of the Drug Product Drug substance 3.2.P.2.1.1 Excipients 3.2.P.2.1.2 3.2.P.2.2 Drug Product Formulation Development 3.2.P.2.2.1 Overages 3.2.P.2.2.2 Physiochemical and Biological Properties 3.2.P.2.2.3 3.2.P.2.3 3.2.P.2.4 3.2.P.2.5 3.2.P.2.6 3.2.P.3 3.2.P.3.1 3.2.P.3.2 3.2.P.3.3 3.2.P.3.4 3.2.P.3.5 3.2.P.4 Manufacturing Process Development Container Closure System Microbiological Attributes Compatibility Manufacture Manufacturer(s) Batch Formula Description of Manufacturing Process and Process Controls Controls of Critical Steps and Intermediates Process Validation and/or Evaluation Control of Excipients R R R R R R R R O R R O R R R R R R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 3.2.P.4.1 3.2.P.4.2 Specifications Analytical Procedures R R

Section 3.2.P.4.3 3.2.P.4.4 3.2.P.4.5 3.2.P.4.6 3.2.P.5 3.2.P.5.1 3.2.P.5.2 3.2.P.5.3 3.2.P.5.4 3.2.P.5.5 3.2.P.5.6 3.2.P.6 3.2.P.7 3.2.P.8 3.2.P.8.1 3.2.P.8.2 3.2.P.8.3 3.2.A 3.2.A.1 3.2.A.2 3.2.A.3 3.2.R 3.2.R.1 3.2.R.2 3.2.R.3 3.3
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Requirements Validation of Analytical Procedures Justification of Specifications Excipients of Human or Animal Origin Novel Excipients Control of Drug Product Specifications Analytical Procedures Validation of Analytical Procedures Batch Analyses Characterization of Impurities Justification of Specifications Reference Standards or Materials Container/Closure System Stability Stability Summary and Conclusions Post-Approval Stability Protocol and Stability Commitments Stability Data Appendices Facilities and Equipment Adventitious Agents Safety Evaluation Excipients Regional Information Alcohol Content Declaration Porcine/Pork content/origin The diluents and coloring agents in the product formula Literature References

G R R R R

R R R R R R R R

R R R

O O R

R R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

Modules 4 is not required for the Gucc country for the registration of the generic drug. Section Module 5 5.1 5.2 5.3 5.3.1 5.3.1.1 5.3.1.2 5.3.1.3 5.3.1.4 5.3.2 5.3.3 5.3.4 5.3.5. 5.3.6 5.3.7 Requirements Clinical study report Tabular listing of all clinical studies Comprehensive Table of content Clinical study reports Report of biopharmaceutical studies Bioavailability(BA) study report Comparative bioequivalence(BE) and BA study report In vitro in vivo correlation study report Report of Bioanalytical and Analytical Method R R R R NR R NR NR G

Report of studies pertinent to pharmacokinetic using human NR Biomaterials Report of human pharmacokinetic (PK )studies Report of human pharmacodynamic (PD )studies Report of Efficacy and safety study Report of post marketing Experiences Case report forms and individuals patients listings Key literature references NR NR NR NR NR

5.4

CIS-NeeS format

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

REGISTRATION CHART IN RUSSIA COUNTRY

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012

REGISTRATION CHART IN BELARUS COUNTRY

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 REGISTRATION CHART IN KAZAKHASTAN COUNTRY

Registration file (or dossier) represents the documents submitted to State Regulatory Authority for registration. Russian registration file consists from 6 parts: Administrative documents Description of pharmaceutical properties Data about manufacturing of pharmaceutical product Data about quality control of the finished pharmaceutical product Data about PRE-CLINICAL pharmacological and toxicological studies of pharmaceutical product Data about CLINICAL studies of pharmaceutical product European registration file consists from 5 modules. The structure of Russian and European registration files is very similar. If manufacturer has European registration file it is not necessary to prepare separated docs for Russia. All data required for Russian dossier are available in European file. Russian registration file must be presented to State Regulatory Authorities in Russian language. The country will follow the CTD format for the registration of the drug product 1. Module 1 Administrative part 2. Common technical document Summaries
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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 3. Quality 4. Non Clinical Report 5. Clinical Report Modules 4 is not required in the filling of the Drug product in the Ukraine

Section Module 1 1.1 1.2 1.3 1.3.1 1.3.2 1.3.3 1.3.3.1 1.3.4 1.4 1.4.1 1.4.2 1.4.3 1.5 1.6 1.7 1.7.1 1.7.2 1.7.3 1.7.4

Requirements Regional Administrative Information Table Of Content Application Form Product Information Summary of Product Characteristics (SPC) Labeling Package leaflet English leaflet /French leaflet Artwork (Mock-ups) Information About the Experts Quality Non-Clinical Clinical Specific Applications Environment Risk Management Plan Administrative Information GMP Certificate CPP or Free-sales Manufacturing License Patent Information Requirement For Different Types Of

R R R R R NR R R

R R R R R

R R R R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 Modules 2 Requirement is same as in the GCC countries.

Module 3 Section 3.1 3.2 3.2.S 3.2.S.1 3.2.S.1.1 3.2.S.1.2 3.2.S.1.3 3.2.S.2 3.2.S.2.1 3.2.S.2.2 3.2.S.2.3 3.2.S.2.4 3.2.S.2.5 3.2.S.2.6 3.2.S.3 3.2.S.3.1 3.2.S.3.2 3.2.S.4 3.2.S.4.1 3.2.S.4.2 3.2.S.4.3 3.2.S.4.4 3.2.S.4.5 3.2.S.5 3.2.S.6 3.2.S.7

Quality Requirements Table of Contents of Module 3 Body of data Drug Substance General Information Nomenclature Structure General Properties Manufacture Manufacturer(s) Description of Process and Process Controls Control of Materials Control of Critical Steps and Intermediates Process Validation and/or Evaluation Manufacturing Process Development Characterization Elucidation of Structure and Other Characteristics Impurities Control of Drug Substance Specifications Analytical Procedures Validation of Analytical Procedures Batch Analyses Justification of Specification Reference Standards or Materials Container/Closure Systems Stability R R R R R R R R R R R R R R R R R R G R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 3.2.S.7.1 3.2.S.7.2 3.2.S.7.3 3.2.P 3.2.P.1 3.2.P.2 3.2.P.2.1 3.2.P.2.1.1 3.2.P.2.1.2 3.2.P.2.2 3.2.P.2.2.1 3.2.P.2.2.2 3.2.P.2.2.3 3.2.P.2.3 3.2.P.2.4 3.2.P.2.5 3.2.P.2.6 3.2.P.3 3.2.P.3.1 3.2.P.3.2 3.2.P.3.3 3.2.P.3.4 3.2.P.3.5 3.2.P.4 3.2.P.4.1 3.2.P.4.2 Section 3.2.P.4.3 3.2.P.4.4 3.2.P.4.5 Stability Summary and Conclusions Post-approval Stability Protocol and Commitment Stability Data Drug Product Description and Composition of the Drug Product Pharmaceutical Development Components of the Drug Product Drug substance Excipients Drug Product Formulation Development Overages Physiochemical and Biological Properties Manufacturing Process Development Container Closure System Microbiological Attributes Compatibility Manufacture Manufacturer(s) Batch Formula Description of Manufacturing Process and Process Controls Controls of Critical Steps and Intermediates Process Validation and/or Evaluation Control of Excipients Specifications Analytical Procedures Requirements Validation of Analytical Procedures Justification of Specifications Excipients of Human or Animal Origin R R G R R R R R R R R O R R R R R O R R R R R R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 3.2.P.4.6 3.2.P.5 3.2.P.5.1 3.2.P.5.2 3.2.P.5.3 3.2.P.5.4 3.2.P.5.5 3.2.P.5.6 3.2.P.6 3.2.P.7 3.2.P.8 3.2.P.8.1 3.2.P.8.2 3.2.P.8.3 3.2.A 3.2.A.1 3.2.A.2 3.2.A.3 3.2.R 3.2.R.1 3.2.R.2 3.2.R.3 3.3 Alcohol Content Declaration Porcine/Pork content/origin The diluents and coloring agents in the product formula Literature References NR NR NR R Facilities and Equipment Adventitious Agents Safety Evaluation Excipients NR NR NR Stability Summary and Conclusions R Novel Excipients Control of Drug Product Specifications Analytical Procedures Validation of Analytical Procedures Batch Analyses Characterization of Impurities Justification of Specifications Reference Standards or Materials Container/Closure System R R R R R R R R R

Post-Approval Stability Protocol and Stability Commitments R Stability Data R

Section Module 5 5.1 5.2 5.3 5.3.1

Requirements Clinical study report Tabular listing of all clinical studies Comprehensive Table of content Clinical study reports Report of biopharmaceutical studies

R R R R

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 5.3.1.1 5.3.1.2 5.3.1.3 5.3.1.4 5.3.2 5.3.3 5.3.4 5.3.5. 5.3.6 5.3.7 Bioavailability(BA) study report Comparative bioequivalence(BE) and BA study report In vitro in vivo correlation study report Report of Bioanalytical and Analytical Method Report of studies pertinent to pharmacokinetic using human Biomaterials Report of human pharmacokinetic (PK )studies Report of human pharmacodynamic (PD )studies Report of Efficacy and safety study Report of post marketing Experiences Case report forms and individuals patients listings Key literature references NR R NR NR NR NR NR NR NR NR

5.4

Comparative study in Asean ,GCC and CIS country Asean Filling Procedure A-CTD GCC CTD CIS NeeS

Approval timeline

110 working days

140 working days

It will be differ from the country to country Russia-210 working days Belarus-180 working days Kazakhstan-227 days

Administrative Data (LETTER OF

REQUIRED

NOT REQUIRED

NOT REQUIRED

AUTHORIZATION) Pharmacovigilance Mock speciman Package leaflet Required(English) Required(Arabic/En Not required glish) up Not required Required Required required required

and Not required

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 Information about the Not required experts Quality summary Stability (condition) studies 300C2/755%RH 300C2/755%RH 300C2/655%RH overall Not required Required required Not required required

Conclusion:From the above point we have concluded the registration procedure will be differ in minor variation there is further needs for harmonization so the applicant does not modify the individual format & the information will be become unambiguous and the transparent to facilitate the review and help a reviewer to become quickly oriented References 1. http://reg-info.com/ctd-guidelines 2. http://www.ich.org/products/ctd.html 3. www.ich.org/about/organisation-of-ich/coopgroup/asean.html 4. http://www.moh.gov.bn/pharmacyservices/download/ASEAN%20Common%20Technical%20Docume nt%20(ACTD).pdf 5. http://www.ectdblog.com/2008/05/asean-ctd-actd.html 6. www.ich.org/about/organisation-of-ich/coopgroup/gcc.html. 7. www.fda.gov/cder/regulatory/application/ind_page_1html 8. www.nccmerp.org 9. www.ismp.org

10. http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf 11. http://aspe.hhs.gov/sp/reports/2010/GenericDrugs/ib.shtml 12. www.jyoungpharm.in/article.asp?issn=0975-1483;year...

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Sneh lata et al. / AJPSR volume 2 issue 6, June, 2012 13. http://www.ipapharma.org/Regulations.aspx 14. http://leavefreedom.blogspot.in/2010/01/asean-harmonises-drug-registration.html

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