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1.1

Guidance for Submission Version 1.0.1

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Document Control

Version Date Author Comments

1.0 Prepared on: 30.10.2018

Approved on: 5/3/2019

EXTEDO

1.0.1 Revised & Amended by Registration department:

on 4/4/2019

Maha Jaghbeer

Ahlam Abd Alaziz

Bayan Hyasat

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Table of Contents

1. ......... Introduction .................................................................................................... 5

2. ......... Scope…………… ........................................................................................... 6

......... Registration Process ...................................................................................... 7

......... Structure and Content of Submission ........................................................ 11

4.1 ......... Structure and Content of Submission: .....................................................................11

4.2 ......... Module 1: Regional Administrative Information ...................................................11

......... Presentation of the Product File ................................................................. 12

5.1 ......... Softcopy Requirements: ............................................................................................12

5.2 ......... Number of copies: ......................................................................................................12

5.3 ......... Media: .........................................................................................................................12

5.3.1 ........ System compatibility: ..........................................................................................12

5.4 ......... Security: ......................................................................................................................12

5.4.1 ........ Password protection: ...........................................................................................13

5.4.2 ........ Virus protection: ..................................................................................................13

......... Document Requirements ............................................................................. 14

6.1 ......... Legibility and Size: ....................................................................................................14

6.2 ......... Language: ...................................................................................................................14

6.3 ......... Authentication: ...........................................................................................................14

......... Inquiries ........................................................................................................ 15

......... Renewal ......................................................................................................... 16

......... Variations ..................................................................................................... 17

...... Baseline: ........................................................................................................ 18

Appendix A: JO Module 1 Administrative Information.................................... 19

Appendix B: Data Requirements .......................................................................... 21

Appendix C: Module Common Technical Documents Summaries .................. 22

Appendix D: Module 3 Quality ............................................................................. 24

Appendix E: Module 4 Nonclinical Study Reports ............................................. 35

Appendix F: Module 5 – Clinical Study Reports ................................................ 36

Appendix G: File Formats ..................................................................................... 38

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Appendix H: ICH Common Technical Document .............................................. 41

Appendix I: References ......................................................................................... 44

Appendix J: Renewal Requirements .................................................................... 45

Appendix K: Baseline Requirements ................................................................... 48

Appendix L: BE/ comparative dissolution checklists ......................................... 49

Appendix M: Abbreviations and Acronyms ....................................................... 54

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2. Introduction

The Registration Department in the Jordan Food & Drug Authority (JFDA) has developed this document, "Guidance for Submission" to assist applicants and industry in the preparation and submission of drug applications for new Marketing Authorization (MA) as well as renewals and variations to existing products to the JFDA. The guidance provides an outline of the way the Framework will be managed with respect to drug applications by the JFDA.

It is intended to provide clarification to applicants of the way in which the Registration Department in the JFDA manage information and material submitted in accordance with the Regulatory framework for Drug Approvals (version 1.0). Also, it provides assistance to comply with the requirements of filing and maintenance of their application.

Industry representatives, as well as the staff of the JFDA responsible for the drug application management, will follow this guidance and operational directions in various areas, including the handling of application information, procedure related to drug assessment, clarification and performance target of drug assessments.

To maintain its consistency and enhanced transparency, this guidance will be updated regularly to reflect the current practices in regulatory sciences. It is expected that this guidance and any amendments to it will create efficiency in the drug application management and reduce the number of clarification requests.

It should be noted that the JFDA has the right to request any information and data within the context of this guidance in order to assess adequately the safety, efficacy and quality of any medicinal products available in the Hashemite Kingdom of Jordan. The JFDA is committed to ensuring that such requests are justifiable and decisions are clearly documented.

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3. Scope

This guidance document applies to all submission types:

New submission (MA) Generics Originators New drugs Vitamins Biologics Radiopharmaceuticals Herbal medicines Renewal Variation Baseline

All submitted information and material will be screened to ensure that it is complete and of suitable quality to be reviewed. The same management principles will be applied consistently to all submission types.

This guidance document covers the preparation and filling requirements for submissions in electronic format (eCTD). It is based on the ICH CTD and the eCTD Specifications, JO M1 Specification & electronic JFDA Drug Workflow System [REGULATORY APPROVAL FRAMEWORK] .

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Registration Process

Important Note:

•All days mentioned throughout this document are Calendar days (subject to change).

All Applications will be subjected to the following procedures:

1. Online Filing of Application

The applicant shall fill up the appropriate application form in the eJDWS system. Once application form is completed, a reference number will be assigned to the application once submitted to facilitate the communication with the JFDA. Then, the applicant will be given an opportunity to book an appointment to hand over the drug application (Figure 1). An automatic reminder will be sent 2 days before the appointment. The applicant can reschedule a week before the chosen appointment. If it is missed, the applicant has to book a new appointment again. (Refer to new submission procedure steps in eJDWS).

Figure 1 A “Drug Application” includes the application form, the product file and the drug sample

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2. Acceptance of Drug Application

Phase I Validation / Screening

Phase IIValidation + Assessment

Approval / Final Decision

Online ApplicationElectronic Appointment

Figure 2 Registration Process Flow

Upon receipt of the drug application in the appointment day, a checklist for ‘Phase I Validation’/ Screening will be used to verify that the information and materials provided are complete.

If the applicant did not attend for an appointment; the screener can cancel the application after 30 minutes from appointment time by using No Show button

A. Invalid Submission:

Resubmit the file within 30 days which will be calculated through eJDWS, and the content of the CD will not be screened

B. Valid Submission Without Deficiencies:

If application is complete it will be officially received & will proceed to the next step – assessment.

C. Valid Submission With Deficiencies:

• If deficiencies are identified a deficiency letter will be generated and given to the applicant stating the deficiencies. The applicant will have a period of 30 days to complete the requirements and the drug application will not be queued. Otherwise, JFDA will securely dispose of the product file or extend the deadline for another 30 days by RA Manager Approval.

• If the applicant fails to provide the requested information within 30 days, the drug application will be rejected.

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3. Phase II Validation

(Refer to eJDWS)

The technical content of the CD will be validated to ensure that all information provided are according to the requirements of the guidelines (phase II validation) If any information is missing or incorrect, the applicant will be notified electronically by the inquiry. - The applicant will be given an opportunity to complete the file within inquiry due date. Otherwise, the file will be rejected.

4. Assessment of Application

All applications will be assessed in terms of quality, safety and efficacy – as needed – depending on the type of the product.

If issues are identified during the assessment, these issues will be resolved through electronic Inquiry Forms within inquiry due date.

5. Testing

All drug products will be subjected to appropriate testing according to the type of the application and dosage form according to lab testing bylaw.

6. Inspection

The inspection department will communicate with the applicant to decide the appropriate time for inspection – if needed, depending on the schedules of the inspectors. After the inspection is done, an inspection report will be written and a copy of this report will be sent to the applicant. In case of deficiencies, further details will follow.

7. Pricing

The pricing will be calculated according to the pricing rules outlined in the pricing guideline.

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8. Stop-clock

The stop-clock starts whenever JFDA issues an Inquiry Form. Inquiries may be raised at any time from the Phase II Validation/ Assessment. The stop-clock ends whenever JFDA receives complete and acceptable responses from the applicant.

If the applicant faces difficulties in responding to inquiries within the specified time, applicant should contact JFDA as soon as possible. A drug application will be considered rejected if the stop-clock time exceeds the JFDA deadline.

9. JFDA Decision

The final decision is made based on the outcome of JFDA's assessment, pricing, testing and inspection. The decision can be one of the following:

• Approval: when the drug application has satisfied the registration requirements for quality, safety and efficacy.

• More information is needed: when the drug application has minor deficiencies.

• Rejection: when the drug application has not satisfied the registration requirements.

10. Appeal Process

The applicant will have the right to appeal within 30 days against the JFDA decision.

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Structure and Content of Submission

5.1 Structure and Content of Submission:

The JFDA will require all applicants to submit their applications in accordance to the JO M1 specifications & ICH Electronic Common Technical Document (eCTD) format. For more information on the eCTD, please refer to appendices A-E.

The dossier requirements for each application will differ, depending on the type of application. For more details refer to appendix B.

It is important to remember that the eCTD provides a format for an MAA and does not indicate the content of a dossier and which studies should be performed. Regional and national requirements may affect the content of the dossier; therefore the dossier will not necessarily be identical for all regions.

Relevant guidelines are updated and published in the Drug Sector website, such as Stability guideline, should be followed in providing the information or studies.

5.2 Module 1: Regional Administrative Information

This module includes the required regional information specific to Jordan, such as administrative information and certificates. For more information, please refer to appendix A.

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Presentation of the Product File

A softcopy (electronic-based) of the product file shall be submitted by the applicant. The softcopy shall be eCTD.

6.1 Softcopy Requirements:

For the softcopy (electronic-based), each CD or DVD and its hard-plastic cover submitted should include the following label information, clearly presented and printed on the media with the font of 12 Times New Roman (or equivalent):

• The application number

• The company name (MAH)

• The product Trade name

• The active substance name (INN Name)

• The sequence number(s) of the submissions contained on the CD/DVD (e.g. 0002)

6.2 Number of copies:

Applicants should submit one softcopy

The submission shall be in ONE media only (CD or DVD) i.e. if the submission size was above 750MB then the applicant has to use a DVD.

6.3 Media:

The electronic submission may only be submitted in CD or DVD (single or dual layer). The disc must not be bootable or have auto-start programs.

Currently both CD-ROM and DVD ISO 9660 are considered an acceptable media standard.

However, the JFDA will not accept any hardware (laptops, desktops, thumb drives, hard drive, floppy discs, etc.) from applicants in connection with the electronic submission.

6.3.1 System compatibility:

The electronic submission (as provided) must be directly readable and usable on JFDA hardware and software.

6.4 Security:

There are various aspects related to security. The physical security of the submission during transportation/transmission is the responsibility of the applicant. Once received to the JFDA, security and submission integrity is the sole responsibility of the JFDA. In this respect, it should

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be noted that the JFDA will take appropriate measures to prevent loss, unauthorized duplication and/or access or theft of regulatory information presented both on paper and electronic media that are distributed throughout the JFDA.

6.4.1 Password protection:

One-time security settings or password protection of electronic submissions for security purposes is not acceptable during transportation/transmission from the applicant to the JFDA.

Applicants should also not include any file level security settings or password protection for individual files in the electronic submission.

Applicants should allow printing, annotations to the documents, and selection of text and graphics. The Internal security and access control processes in the JFDA maintain the integrity of the submitted files.

6.4.2 Virus protection:

The applicant is responsible for checking the submission for viruses. Checking must be performed with an up-to-date and well-recognized Anti- virus application.

After receipt of the submission at the JFDA, a similar internal virus check will be performed. If a virus is detected it can constitute grounds for refusal of the electronic submission.

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Document Requirements

7.1 Legibility and Size:

All documents should be legible. The page size, including tables, shall be uniform.

<

7.2 Language:

Information and documents supporting a drug application – such as certificates and approval letters– must be either in Arabic or English. If documents are neither in Arabic nor English, a translation to English (from an authorized translation office) and should be notarized.

7.3 Authentication:

Authentication – also known as legalization – refers to the process whereby the origins of a document are attested. Authentications of documents are made to JFDA by the Health authority and the Ministry of Foreign affairs or concerned party in the country of origin, in addition to the Jordan Embassy or Consulate where the document was issued. For more details, please refer to appendix A.

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Inquiries

An applicant may receive an inquiry from eJDWS system. When the answers are ready, applicant shall do the following:

1. in eJDWS:

a. Respond electronically to eJDWS inbox to close the inquiry by uploading validation report of the new follow up submitted sequence according to the due date specified through eJDWS (Reason: to stop the clock)

2. In the softcopy:

a. Provide JFDA with the following:

i. Section 1.9 in module 1: should include a document (letter) which lists the inquiries (questions) with the corresponding narrative text response for each question. This section will not be used for supporting technical documentation which will be included to the relevant modules. Each question should be followed by the name of section, page number and a hyperlink where the answer can be found in the concerned module.

ii. Relevant section(s) added in the right place of the submission

b. Prepare a CD/DVD including the above document(s) in the form of:

i. eCTD submission: follow the guideline “JO eCTD M1 Specifications” published in the website.

Taking into account, the labelling of the CD as mentioned in page 11 of this guidance.

Note:

• Only full answers of the inquiries are accepted.

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Renewal

An applicant shall submit a renewal request every five years – on drug products that have already received a marketing authorization from the JFDA – at least three months before the certificate expires (4 years and nine months after approval) according to appendix J through the following steps:

1. In eJDWS:

a. Choose the required drug under “Old Products” section and press ‘Renewal’ button

b. Complete the form and submit it electronically

c. Save a copy of the application form (for preparing the softcopy)

2. In the softcopy:

Prepare a CD/DVD including the required document according to appendix J in the form of:

a. eCTD submission: follow the guideline “JO M1 Specifications” published in the website.

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Variations

An applicant can submit a variation request – on drug products that have already received a marketing authorization from the JFDA – through the following steps:

1. In eJDWS:

a. Choose the required drug under “old Products” section and press ‘Variation’ button.

b. Complete the form and submit it electronically

c. Save a copy of the application form (for preparing the softcopy)

2. In the softcopy:

Prepare a CD/DVD including the required document (according to PAC requirements) in the form of:

b. eCTD submission: follow the guideline “JO M1 Specifications” published in the website.

Notes:

• The requirements of variation are available in the JFDA's website.

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Baseline:

A baseline submission is the resubmission of currently valid documents to start

the eCTD lifecycle for the submission submitted not in eCTD format.

Submission of a baseline shall be before starting a new regulatory activity or

after the end of a regulatory activity.

The compiled baseline submission is a submission of the current status of the

dossier, i.e. currently valid documents that have already been provided to JFDA

and already approved.

The baseline should be clearly stated in the cover letter of the “baseline eCTD

sequence” that the content of the previously submitted dossier has not been

changed, only the format. There is no need for the JFDA Drug Directorate to

assess baseline submissions and hyperlinks between documents are not

necessary. The submission unit ‘reformat’ should be used in the envelope for

the baseline sequence and submission type should be “none”.

The baseline submission sequence for registered product files should be

submitted as sequence (0000). However, in some cases e.g. renewals and

variations submitted as eCTD, the submission of the baseline can happen in a

higher sequence of the submission life cycle. The baseline should always be a

separate submission and should never include any changes of the documents or

content of the application.

Baseline submission composed of the currently valid documents that have

already been provided to JFDA and already approved, summary of

documentation list in addition to payment receipt, refer to appendix K

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Appendix A: JO Module 1 Administrative Information

Section Requirements Remarks 1 2 3 4 HCd

1.0 Cover letter

1.2 Application Form Taken as PDF from eJDWS

1.3 Product Information 1.3.1 Summary of Product Characteristics (SPC) and

Comparison a

1.3.2 Labeling Inner label

1.3.3 Patient information leaflet (PIL) 1.3.3.1 Arabic leaflet Mandatory for

OTC products

1.3.3.2 English leaflet and Comparison For generics: comparison with the originator + the originator leaflet.

1.3.4 Artwork (Mock-ups) Outer carton

1.3.5 Samples

1.4 Information on the experts 1.4.1 Quality 1.4.2 Non-Clinical 1.4.3 Clinical

1.5 Environmental Risk Assessment Only one subsection is applicable

1.5.1 Non-Genetically Modified Organism (Non-GMO) 1.5.2 GMO

1.6 Pharmacovigilance 1.6.1 Pharmacovigilance System 1.6.2 Risk Management Plan

1.7 Certificates and Documents 1.7.1 Manufacturing Sites Documents g c b

1.7.2 CPP or Free-salese

1.7.3 Certificate of analysis – Drug Substance & Finished Product

f f f

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1.7.4 Certificate of analysis – Excipients 1.7.5 Declaration of Ingredients from Human origin 1.7.6 Pork-content declaration 1.7.7 Certificate of suitability for TSE 1.7.8 The diluents and coloring agents in the product

formula

1.7.9 Data Protection 1.7.10 Letter of access or acknowledgment to DMF If applicable

1.8 Pricing 1.8.1 Price certificate

1.8.2 Other documents related

1.9 Responses to questions Additional data e.g. World wide

registration status e.g. Plasma master file approval from COO

1: Company original paper (not a photocopy) 2: Signature of authorized person 3: Company official stamp 4: Authentication

a) Originator Only (SPC from Health Authority) b) Certificates only c) Site Master File only d) Hard-copy e) Not required for local manufactures f) Only for Finished Product g) JFDA accreditation letter or: Accreditation requirements: - GMP/ ML for finished product manufacturer - CPPs from reference countries to substitute inspection). - SMF( section 3.2.A)

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Appendix B: Data Requirements

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.

Please refer to the following documents published in the website:

Drug registration and re-registration criteria Natural product registration criteria Biosimilar product registration criteria Bioequivalence studies regulations Post-approval changes regulations (PAC)

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Appendix C: Module Common Technical Documents 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 and 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.

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 and 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 the Electronic Common Technical Document, it will necessarily refer to application data provided in

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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 summarization of the clinical information in the eCTD.

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Appendix D: Module 3 Quality

3.2 Body of Data 3.2.S Drug Substance The information on the drug substance can be submitted in the following order: 1. Valid European Certificate of Suitability (CEP) with all appendices (copy for drug substance

manufacturer/s. The Drug Substance sections should refer to the Certificate of Suitability in the relevant sections in Module 3.2.S ,the Certificates of Suitability are deemed to replace the data of the corresponding sections (S.2.2, S.2.3, S.2.4 and S.2.6) and therefore in principle no further additional 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 the Certificate of Suitability (CEP) is not available all the Drug Substance sections in Module 3.2.S should be full-filled and a valid copy of GMP certificate (for drug substance manufacturer/s) should be included in section (3.2.R). 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. 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, should be specified. For Biotech: The schematic amino acid sequence indicating glycosylation sites or other posttranslational modifications and relative molecular mass should be provided, as appropriate. 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).

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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 typically starts 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 regarding any 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 from the original inoculums (e.g. cells contained in one or more vials(s) of the Working Cell Bank up to the last harvesting operation. The diagram should include all steps (i.e., unit operations) and intermediates. Relevant information for each stage, such as population doubling levels, cell concentration, volumes, pH, cultivation times, holding times, and temperature, should be included. Critical steps and critical intermediates 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 other additives (details provided in 3.2.S.2.3); major equipment (details provided in 3.2.A.1); and process controls, including in-process tests and operational parameters, process steps, equipment and intermediates with acceptance criteria (details provided in 3.2.S.2.4). Information on procedures used to transfer material between steps, equipment, areas, and buildings, as appropriate, and shipping and storage conditions should be provided. (Details on shipping and storage provided in 3.2.S.2.4.) Purification and modification reactions A flow diagram should be provided that illustrates the purification steps (i.e., unit operations) from the crude harvest(s) up to the step preceding filling of the drug substance. All steps and intermediates and relevant information for each stage (e.g., volumes, pH, critical processing time, holding times, temperatures and elution profiles and selection of fraction, storage of intermediate, if applicable) should be included. Critical steps for which specifications are established as mentioned in 3.2.S.2.4 should be identified. A description of each process step (as identified in the flow diagram) should be provided. The description should include information on, for example, scale, buffers and other reagents (details provided in 3.2.S.2.3, major equipment (details provided in 3.2.A.1), and materials. For materials such as membranes and chromatography resins, information for conditions of use and reuse also should be provided. (Equipment details in 3.2.A.1; validation studies for the reuse and regeneration of columns and membranes in 3.2.S.2.5.) The description should include process controls (including in-process tests and operational parameters) with acceptance criteria for process steps, equipment and intermediates. (Details in 3.2.S.2.4.).

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Reprocessing procedures with criteria for reprocessing of any intermediate or the drug 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 be provided (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 criteria should be provided. (Details in 3.2.S.2.4.) The container closure system(s) used for storage of the drug substance (details in 3.2.S.6.) and storage and shipping conditions 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.2.4 Control 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.2.5 Process 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 to demonstrate that the manufacturing process (including reprocessing steps) is suitable for its intended purpose and to substantiate selection of critical process controls (operational parameters and in-process tests) and their limits for critical manufacturing steps (e.g., cell culture, harvesting, purification, and modification). The plan for conducting the study should be described and the results, analysis and conclusions from the executed study(ies) should be provided. The analytical procedures 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 process controls and acceptance criteria 3.2.S.2.6 Manufacturing Process Development.

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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 other modules 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 analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included. For Biotech: For desired product and product-related substances, details should be provided on primary, secondary and higher-order structure, post-translational forms (e.g., glycoforms), biological activity, purity, and immunochemical properties, when relevant. 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 analytical procedures 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)

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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-unit basis (including overages, if any) the function of the components, and a reference to their quality standards (e.g. compendia monographs or manufacturer’s specifications)

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.2.1.1 Drug 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).

NAMES OF INGREDIENTS UNIT FORMULA

Percentage

formula FUNCTION

REFERENCE TO

STANDARDS ACTIVE SUBSTANCE

EXCIPIENTS

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3.2.P.2.1.2 Excipients (name of the finished product, dosage form) The functions of Excipients, their concentration and 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, ionic strength, 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). 3.2.P.2.5 Microbiological Attributes (name of the finished product, dosage form) Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed. 3.2.P.2.6 Compatibility (name of the finished product, dosage form)

The compatibility of the drug product with: The reconstitution diluent(s) or Dosage devices (e.g., precipitation of drug substance in solution, sorption on injection

vessels, stability)

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3.2.P.3 Manufacture (name of the finished product, dosage form) 3.2.P.3.1 Manufacturer(s) (name of the finished product, dosage form) The name, address, and responsibility of Finished product manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. 3.2.P.3.2 Batch Formula (name of the finished product, dosage form) A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process and their amounts on a per batch basis. 3.2.P.3.3 Description of Manufacturing Process and Process Controls (name, 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. A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Equipment should, at least, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity, where relevant. Steps in the process should have the appropriate process parameters identified, such as time, temperature, or PH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g., low humidity for an effervescent product) should be stated. 3.2.P.3.4 Controls of Critical Steps and Intermediates (name of the finished product,

dosage form) Critical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 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. 3.2.P.3.5 Process Validation and/or Evaluation (name of the finished product, dosage form). Process validation protocol (should outline the formal studies planned for the production scale batches) or / and Process Validation Report should be provided. (Which include Description, documentation, and results of the validation studies for critical steps or critical assays used in the manufacturing process). Validation of the sterilization process or aseptic processing or filling should be provided. 3.2.P.4 Control of Excipients (name of the finished product, dosage form) 3.2.P.4.1 Specifications (name of the finished product, dosage form) The specifications for excipients should be provided.

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(if compendial provide the monographs). 3.2.P.4.2 Analytical Procedures (name of the finished product, dosage form) The analytical procedures used for testing the excipients should be provided (if compendial provide the monographs). Also provide Certificate of Analysis of each excipient. 3.2.P.4.3 Validation of Analytical Procedures (name of the finished product, dosage

form) For Pharmacopoeial Excipients (Not Applicable). For non-compendial excipients, Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate. 3.2.P.4.4 Justification of Specifications (name of the finished product, dosage form) For Pharmacopoeial Excipients (Not Applicable). For non-compendial excipients, Justification for the proposed excipient specifications should be provided, where appropriate. 3.2.P.4.5 Excipients of Human or Animal Origin (name of the finished product, dosage

form) For excipients of human or animal origin, EDQM certificate of TSE/BSE free certificates or certificate from health authorities should be provided. 3.2.P.4.6 Novel Excipients (name of the finished product, dosage form) If included in the drug formula (full details if used for the first time in a drug product.) 3.2.P.5 Control of Drug Product (name of the finished product, dosage form) 3.2.P.5.1 Specification(s) (name of the finished product, dosage form) The specification for the drug product should be provided.

PARAMETER SPECIFICATIONS METHOD & REFERENCE

3.2.P.5.2 Analytical Procedures (name of the finished product, dosage form) The analytical procedures (Method of Analysis) used for testing the drug product should be provided. 3.2.P.5.3 Validation of Analytical Procedures (name of the finished product, dosage form)

Validation of method of analysis, including experimental data, for the analytical procedures used for testing the drug product, should be provided (Assay, impurities, dissolution.)

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Note: if the analytical procedures used in the control of the drug product are Pharmacopoeial then verification is required which include:

System suitability (tailing factor, resolution, stability of solution, theoretical plates, …) Selectivity including spiking (to prove resolution from excipients), stress conditions testing and purity of the peak (the method used to prove the purity of the peak should be stated).

Linearity and Accuracy 3.2.P.5.4 Batch Analyses (name of the finished product, dosage form) A description of batches and results of batch analyses should be provided, Description of batches as the following: Results of batch analyses:

DRUG NAME & CONC.

BATCH

NO.

MANUFACTURING DATE

MANUFACTURING SITE

PACKAGE

TYPE BATCH SIZE &TYPE

(Pilot, Production)

Results of batch analyses

Test Parameters

Acceptance criteria

BATCH NO.

BATCH NO.

BATCH NO.

Results Results Results

A copy of the original analysis certificates for all these batches are included at the end of Part 3.2.P as regional information (3-2-R). 3.2.P.5.5 Characterization of Impurities (name of the finished product, dosage form) Information on the characterization of impurities should be provided, it could be referred to Module 3, Drug substance section "3.2.S.3.2 Impurities". 3.2.P.5.6 Justification of Specification(s) (name of the finished product, dosage form) Justification for the proposed drug product specification should be provided (if not compendial). 3.2.P.6 Reference Standards or Materials (name of the finished product, dosage form) Refer to Module 3, section "3.2.S.5 Reference Standards or Materials". 3.2.P.7 Container Closure System (name of the finished product, dosage form) A description of the container closure systems should be provided (and critical dimensions, with drawings where appropriate), along with specification and Method of Analysis (Where appropriate).

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For non-functional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided. 3.2.P.8 Stability (name of the finished product, dosage form) 3.2.P.8.1 Stability Summary and Conclusion (name of the finished product, dosage

form) The types of studies conducted (Accelerated, Long term…), protocols used, and the results of the studies should be summarized. The summary should include, conclusions with respect to storage conditions (labeling statement) and shelf-life that will be applied on the product indented to be marketed in our country. and, if applicable, in-use storage conditions and shelf life. Provide Special stability tests for different dosage forms (e.g. inverted stability study,…) if applicable. Summarize Forced degradation studies and stress condition (i.e. Photo stability studies) if applicable. 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (name of the

finished product, dosage form) The post-approval stability protocol and stability commitment should be provided: 1. To Complete Real Stability Data (to cover shelf life) on pilot batches (if not completed at

time of submission) and Real Stability Data on production batches (if not submitted with file) once they are available as annual report.

2. Ongoing stability (Real data as annual report). 3.2.P.8.3 Stability Data (name of the finished product, dosage form) Results of the stability studies should be presented for 3 batches: Accelerated (40 ± 2 °C / 75 % RH ± 5 %) minimum time period at submission (6 months) Long term (30 ± 2 °C / 65 % RH ± 5 % Zone IV a) minimum time period at submission (12 months) with a commitment to cover the shelf life once available. Provide Supportive stability data (if available). For biosimilars: the quality sections (should include comparative studies with reference drug, beside his own) in section 3.2.R (or according to international practice). 3.2.R: Certificate of Analysis for drug substance from supplier/s

& from Drug Product manufacturer. (COA should be Stamped & Signed, or electronic signature).

Valid certificate of suitability [CEP] from EDQM for drug substance [from each supplier]

(copy).

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Valid GMP certificate for drug substance manufacturer(copy)[ from each manufacturer ] Only if CEP is not available (note that in this case all drug substance sections will be required).

Raw data and chromatograms for stability study. Summary of production & Quality control protocol. PMF 3.2.A SMF

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Appendix E: Module 4 Nonclinical Study Reports

4.1 TABLE OF CONTENTS

A Table of Contents should be provided that lists all of the Nonclinical Study Reports and gives the location of each study report in the Common Technical Document.

4.2 STUDY REPORTS

The study reports should be presented in the following order

4.2.1Pharmacology

4.2.2Pharmacokinetics

4.2.3Toxicology

4.3 LITERATURE REFERENCES

For Generic: Module 4 (Not applicable ).Literature References may be included.

For the biosimilars: non-clinical studies are required in section (to be specified later according to international practice).

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Appendix F: Module 5 – Clinical Study Reports

5.1 TABLE OF CONTENTS

A table of contents for the study reports should be provided.

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports:

For Generic: Provide Bioequivalence Study report (format & content submitted according to the data specified in BE registration criteria) which includes:

Table of content of BE (BE checklist appendix L)

BE Additional requirements in appendix L

Summary report

In-vitro testing

In-vivo study design

Assay methodology Validation

Pharmacokinetic Parameters of BE

Statistical Analysis

Appendices (for Detailed Analysis)

5.3.1.3 In vitro-In vivo Correlation Study Reports

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

For Generic: Summary Bioequivalence tables:

Reanalysis of Study Samples

Summary of Standard Curve and QC Data for Bioequivalence Sample Analyses

SOPs Dealing with Bioanalytical Repeats of Study Samples

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5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

For Generic: Not Applicable

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

For Generic: Should be provided, if BE study not submitted (Justified)

5.3.4 Reports of Human Pharmacodynamic (PD) Studies

For Generic: Should be provided, if BE study not submitted (Justified)

5.3.5 Reports of Efficacy and Safety Studies

For Generic: Not Applicable

5.3.6 Reports of Post-Marketing Experience

Risk management Plan (where appropriate).

PSUR to be submitted after product placed in the market of the country of origin.

5.3.7 Case Report Forms and Individual Patient Listings

For Generic: Not Applicable

5.4 Literature References

For originator drugs: only the Literatures Pertinent to the Claimed Indication(s) are required.

For Generic: Optional, the Literature References for the originator drug (Pertinent to the Claimed Indication(s)) should be included in case where originator drug is not registered in Jordan.

For biosimilars: the clinical studies (comparative) are required in section (to be specified later according to international practice).

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Appendix G: File Formats

General requirements:

Generally, the relevant information must be structured according to the requirements of the Common Technical Document (CTD). The following files formats are accepted:

• PDF

• For graphics: Joint Photographic Experts Group (JPEG), Portable Network Graphics (PNG), Scalable Vector Graphics (SVG) or Graphic Interchange Format (GIF).

Portable Document Format:

PDF is an open, de facto, published format created by Adobe Systems Incorporated (http://www.adobe.com). It is not necessary to use a product from Adobe or from any specific company to produce PDF documents. PDF is accepted as a standard for documents defined in this specification. The following recommendations support the creation of PDF files that agencies can review effectively. To ensure that PDF files can be accessed efficiently, PDF files should be no larger than 100 megabytes. Optimize PDF files for fast web view.

The following points can be made in relation to PDF files:

• Files must be legible with PDF version 1.4 or higher

• PDF files produced from an electronic source document are highly preferred over PDF files produced from scanned paper, since those 'electronic' PDF files provide the maximum functionality to the reviewers in terms of search and print capabilities, and copy and paste functionality. The overviews/summaries in the CTD Module 2 should always be generated from an electronic source document.

• If scanning is unavoidable, readability and file size must be balanced; the following is recommended: resolution 300 dpi (photographs up to 600 dpi), avoid gray scale or color where possible, use only lossless compression techniques.

• If colors other than black are used, the colored pages must be tested on a black and white printer for acceptable reproduction and legibility prior to submission.

• Print area for pages must fit on an A4 sheet of paper; margins must allow binding in multi-ring binders without affecting readability.

• Landscape-oriented tables must automatically appear in landscape on screen.

Text Searchable Files:

Applicants are requested to ensure that all submissions contain the maximum amount of text searchable content. Documents with searchable text will aid the assessor, or any other user, in searching for specific terms and also in copying and pasting information into another document, such as an assessment report. JFDA recognizes that not all documents need to be text searchable.

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This appendix provides some guidance about what must be text searchable and the ways to ensure that files are created appropriately.

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Documents that must always be text searchable:

The PDF should be produced wherever possible from a text source, such as MS Word, but if sourced from a scanned original then they must be OCR’d.

• Key administrative documents in Module 1 including, the cover letter, application form, SPC, labeling and PIL documents

• The main body of text of Risk Management Plans

• Any document in Module 2 of the submission (QOS, Nonclinical Overview and Summaries, Clinical Overview and Summaries).

• The main body of text in any reports, methods, analytical procedures, etc. supplied in Module 3 of the submission

• The main body of text and main tables in modules 4 and 5.

Documents that do not need to be text searchable:

The PDF should be produced wherever possible from a text source, such as MS Word, but if sourced from a scanned original then there is no need for OCR.

• Any original Certificate of Pharmaceutical Product

• Any original Certificate that confirm that the product is free from BSE/TSE

• Any original GMP certificate

• Any original certificate of analysis

• Any manufacturer’s licenses

• Any certificates of suitability

• Any Manufacturing Authorization

• Any literature references sourced from journals, periodicals and books (except when these are used in a bibliographic application so support the main claims of the application).

• Any page with a signature that does not contain other information key to the understanding of the submission

• Applicants should consider providing signatures on separate pages from key text in reports, overviews, etc.

Use of Electronic Signatures:

The use of advanced electronic signatures (digital signatures) will be crucial in achieving pure electronic communication between the pharmaceutical industry and regulatory agencies, particularly for authentication of electronic submissions and documents contained therein.

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Appendix H: ICH Common Technical Document

Common Technical Document (CTD)

The Common Technical Document is an internationally agreed format for the preparation of a marketing authorization (MA) that is to be submitted to the regulatory authorities in the three ICH regions (USA, EU and Japan) and in some other countries and regions. The CTD provides a common format for the preparation of a well-structured dossier. It uses a modular framework described in ICH Topic M4 (http://www.ich.org/). This guidance document should be read in conjunction with the most recent version of the ICH CTD guidance documents.

It is important to remember that the CTD provides a format for an MAA and does not indicate the content of a dossier and which studies should be performed. Regional and national requirements may affect the content of the dossier; therefore, the dossier will not necessarily be identical for all regions.

The CTD is applicable for all types of products (new chemical entities, biologicals, herbals etc.)

The CTD is organized into five modules (Figure 3Figure 3). Module 1 is region specific. Modules 2, 3, 4, and 5 are intended to be common for all regions.

• Module 1: Administrative Information and prescribing Information

• Module 2: Common Technical Document Summaries

• Module 3: Quality

• Module 4: Non-Clinical Study Reports

• Module 5: Clinical Study Reports

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Figure 3: Diagrammatic representation of the organization of the ICH CTD

eCTD

The eCTD is defined as an interface for industry to agency transfer of regulatory information while at the same time taking into consideration the facilitation of the creation, review, lifecycle management and archival of the electronic submission.

The eCTD is an electronic version of the CTD. The structure, folder and file names correspond to those of the CTD. As a submission format, however, it contains additional technical components which enable the lifecycle of individual files in the application, and the lifecycle of the product itself, to be managed.

An eCTD has the following components: Folder structure, Contents (files) and XML backbone.

The folder structure has a hierarchical organization reflecting that of the CTD, and it holds the scientific and technical contents of the eCTD (divided into many files which are the same as those in the non-eCTDs, usually in PDF format).

The XML backbone is recognizable as ‘index.xml’ at the root level of the submission folder of an eCTD and provides two useful functions:

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• It provides a hyperlinked table of contents of the entire submission when viewed in a web browser with a suitable style sheet

• It provides descriptive information (‘metadata’) on the files that make up the actual contents of the eCTD.

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Appendix I: References

JFDA Reference Documents:

Regulatory Framework for Drug Approvals (eJDWS)

JO Module 1 Specifications The latest versions of JFDA's guidance documents are available on the website at the following address:

http://www.jfda.jo

ICH Reference Documents:

M4: The Common Technical Document

Organization of The Common Technical Document for the Registration of Pharmaceuticals for Human Use

Implementation Working Group – Questions & Answers (R3)

Electronic Common Technical Document Specification (version 3.2)

The Common Technical Document for The Registration of Pharmaceuticals for Human Use: Quality – M4Q(R1)

The Common Technical Document for The Registration of Pharmaceuticals for Human Use: Safety – M4S(R2)

The Common Technical Document for The Registration of Pharmaceuticals for Human Use: Efficacy – M4E(R1)

These documents and more are found at the ICH website at the following address: http://www.ich.org/

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Appendix J: Renewal Requirements

J1: First Renewal

Section Description Remarks

1.0 Cover letter CL from applicant requesting re-registration in addition to

Cover letter from MAH requesting re-registration

1.2 Application Forms

1.3 Product Information

1.3.1 Summary of Product Characteristics (SPC) and comparison

Legalized SmPC for originator

1.3.2 Labelling

1.3.3 Patient information leaflet (PIL)

1.3.3 ar Arabic leaflet

1.3.3 en English leaflet and Comparison For generics: comparison with originator leaflet

1.3.4 Artwork (Mock-ups)

1.7 Certificates and Documents 1.7.1 Manufacturing Sites Documents Copy of JFDA API and

finished product manufacturer approval

1.7.2 CPP or Free-Sales Legalized CPP/FSC 1.7.3 Certificate of analysis - Drug Substance &

Finished Product

1.7.4 Certificate of analysis - Excipients 1.7.5 Declaration of Ingredients from human origin List of human or animal

origin substances entering in the composition of the product and its source and the related certificates

1.7.6 Pork-content declaration 1.8 Price 1.8.1 Price Certificate Legalized price certificate

1.8.2 Other documents related Copy of JFDA pricing certificates

Additional Data Copy of JFDA MA

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certificate Copy of all JFDA approval on any variation submitted Comparison table between registered dossier & renewal dossier

Registration status world wide

Declaration letter from manufacturer with no changes (Manufacturing process, MoA, formula, packaging material, specifications, ….) if change it should be submitted.

Updated technical agreement in case of contract manufacturing

Copy of COO approval for plasma master file

Module 3 :

3.2.P.1 Description and Composition of the Drug Product

Composition certificate

3.2.P.5.1 Specification(s) Release and shelf life specification mentioning the last one approved (number, date).

3.2.P.8.3 Stability Data Ongoing stability study for at least one new production badge

3.2.R Updated plasma master file 3.2.R If applicable

Module 5

5.3.6 Reports of Postmarketing Experience Updated post marketing safety reports/ PSUR (if applicable)

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J2: Second Renewal

Section Description Remarks

1.0 Cover letter CL from applicant requesting re-registration in addition to

Cover letter from MAH requesting re-registration

1.2 Application Forms

1.7.2 CPP or Free-Sales Legalized CPP/FSC (not required for local products)

1.8 Price 1.8.1 Price Certificate Legalized price certificate

(not required for local products)

1.8.2 Other documents related Copy of latest JFDA pricing letter

Additional Data Copy of JFDA renewal

certificate

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Appendix K: Baseline Requirements

Module 1: Regional Administrative Information

1- Cover letter

2- Application Form

3- Product Information

a. Summary of Product Characteristics (SPC) and comparison

b. Labelling

c. Patient information leaflet (PIL)

i. Arabic leaflet

ii. English leaflet and comparison

d. Artwork (Mock-ups)

4- Certificates and Documents

5- CPP or Free-sales

Module 3: Quality

1- Drug Substance

2- Drug Product

3- Appendices

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Appendix L: BE/ Comparative dissolution checklists

L1: BE Check List

Agent Name …………… Date of submission:..............................

Administrative part Title Page Declaration from product manufacturer of the following:

* Name of test product/dosage form/conc ------------------------ * Name of reference product/dosage form/conc ----------------- * Bio-batch manufacturer…………………………………………… * Finished product manufacturer…………….. * MAH……………… * Source of the API of the bio-batch……………. * Bio-batch size & type ( production /pilot) * Bio-analysis date ( start-end) * Declaration from MAN/MAH that no change in formula of test product since study time. * Study title/Date of study : ------------------------------------------------------------- * Study type (fed .fast ) ------------------------------------------------------------------------ * Name and address of sponsor………………………….. * Name and address of CRO ( clinical site) * Name and address of clinical laboratory( bio-analytical site)

Name, address of the clinical investigator----------------------------------------- Copy of GMP certificate of the bio-batch manufacturer if it's not approved ------ If approved copy of health authorities approval of the site --------------------------

Approval of following GCP from Health Authorities of country of clinical investigator /or inspection reports of the study according to adopted BE guidance

Approval of following GLP from Health Authorities of country of clinical laboratory/or inspection reports of the study according to adopted BE guidance

Copy of protocol approval from health authorities if the CRO is in Jordan or copy of protocol approval by IRB committee

Composition of the bio-batch /copy of the recent CPP of test product Certificate of analysis of study batches (T&R)

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Technical part Table of contents Study resumes.

Name, and signature of the investigator (s). Name, and signature of the clinical investigator (s). Product information (Pharmacology, Pharmacokinetic) Summary of Bioequivalence study. Summary of bioequivalence data. Figure of mean plasma concentration-time profile (Log, Normal). Figure of mean cumulative urinary excretion (if used). ( Log ,Normal Figure of mean urinary excretion rates (if used). ( Log ,Normal)

In vitro testing. 1. Certificate of analysis of study batches (T&R) by the sponsor 2. Full composition of bio-batch of test product 3. Dissolution method and validation 4. Comparative dissolution profile 5. Content uniformity testing.

Study designs. 1. Introduction. 2. Summary and type of the study. 3. Signature of IRB committee 4. Study Protocol.(no of subjects, exclusion and inclusion criteria) 5. Demographic characteristics of the subjects. 6. Informed consent form. 7. Details of clinical activity. 8. Deviations from protocol. 9. Adverse reactions report.

Assay Methodology and Validation. 1. Assay method description (including description of the order analyzing real

samples and quality control samples.

2. Method Validation with chromatograms. 3. Data on linearity of standard samples. 4. Data on inter-day precision and accuracy of low, intermediate & high

concentration.

5. Data on intra-day precision and accuracy 6. Calibration / standard curves. 7. QC Chromatograms for low/ high ranges.

8. Chromatograms of standard and quality control samples. Complete serial chromatograms for 5- 20% of subjects.

9. Data demonstrating stability of samples. 10. Short-term stability of the lowest concentration.

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11. Long-term stability of the lowest concentration. 12. Limit of Quantification. 13. Freeze- thawing stability of lowest concentration 14. Discussion and Conclusion.

Pharmacokinetic parameters. Table and figure of mean plasma concentration-time profile( Log ,Normal). Table and figure of individual subject plasma concentration time profiles. Figure of mean accumulative urinary excretion (if applicable). Figures of individual subject cumulative urinary Excretion (if applicable). Figure of mean-urinary excretion rates (if applicable). Figures of individual subject urinary excretion rates. Results of analyzed data arranged by, Drug/period, Drug/sequence for volunteers.

Statistical Analysis 1. Statistical consideration. 2. Summary of statistical significance. 3. Summary of statistical parameters. 4. Analysis of variance (ANOVA). 5. Parametric and additional nonparametric optional 90% confidence Intervals

(lower limit, upper limit and point estimate)

6. Two one-sided t-test (lower limits, upper limits of the calculated test statistics and the tabulated t-value).

Appendices 1. Analytical raw data (copies of chromatograms should be provided as obtained

from the instrument showing retention time and integrated peak areas)

2. Medical record and clinical reports. 3. Print out of pharmacokinetic analysis (optional). 4. Print out of statically analysis (optional)

* Please fill with data where is possible

1. I declare that all the documents which refer to in this check list are attached & number of files Submitted for this application…………………………………

- Name & Sign of responsible Pharmacist:……………………………

2. For office health authorities (use : I declare that I received the files Submitted for this application…………………………………

- Name & Sign of responsible Pharmacist in registration Department:………………………………….

- Application Number:………………………… Date:………………… - Fees 400JD Date:…………………

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L2: Comparative In vitro dissolution checklist

3. I declare that all the documents which refer to in this check list are attached & number of files Submitted for this application

- Name & Sign of responsible Pharmacist:…………………………… Date:…………………

Page No. Item

Declaration from product manufacturer of the following: *Name of test product/dosage form/conc ------------------------ * Name of reference product/dosage form/conc ----------------- * Bio-waiver batch manufacturer…………………………………………… * Finished product manufacturer…………….. * MAH……………… * Source of the API of the bio-waiver batch……………. * Bio-waiver batch size & type ( production /pilot) * Declaration from MAN/MAH that no change in formula of test product since study time * Reason for Biowaiver request (BE for another strength, BCS Class I or III,.. others)

Composition of each product /R&T /copy of the recent CPP of test product.

Proof of Linear Pharmacokinetics covering the dosage range of interest/(in case of strength waivering )

Proof of dosage proportionality (in tabular format) between the test & reference drug products. /(in case of strength waivering )

Proof of BCS classification (BCS Class I or III) regarding solubility & permeability with solubility study. /(in case of BCS waivering )

Proof of similarity with the reference drug product composition according to JFDA adopted BE\BW guidelines/(in case of BCS waivering )

Certificate of analysis of bio-waiver batch & Certificate of analysis of reference batch

No of media/ Type of media

No of dosage form tested.. Method of analysis /validation Dissolution/ in-vitro test … condition /speed….. Details of results / tabulated F2 value /Similarity calculation Graphs

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4. For official (use : I declare that I received the files Submitted for this application…………………………………

- Name & Sign of responsible Pharmacist in registration Department:…………………………………

- Application Number:………………………… Date:………………………

- Fees 100 JD

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Appendix M: Abbreviations and Acronyms

API Active pharmaceutical ingredient

CEP/COS Certificate of Suitability

COO Country of Origin

CPP Certificate of Pharmaceutical Product

CTD Common Technical Document

DMF Drug Master File

EDQM European Directorate for Quality of Medicines Certification unit.

eJDWS electronic Jordan Drug Workflow System

EXF Ex-factory price

FPP Finished pharmaceutical product

GMP Good manufacturing practices

INN The International Non-proprietary Name

JFDA Jordan Food and Drug Authority

MAA Marketing Authorization Application

NCE New Chemical Entity

PIL Patient Information Leaflet

SPC Summary of Product Characteristics

TSE CEP Transmissible Spongiform Encephalopathy.

WSP Whole Sale Price