Dossier Requirements for Active Pharmaceutical Ingredients –U.S&E.U :Dossier Requirements for Active Pharmaceutical Ingredients –U.S&E.U Guided by: Submitted by: Mr. Santosh Kashyap, G.L.Pramod, Asst.general manager, MS.c (ph.regulatory affairs) Global regulatory affairs, MCOPS, Microlabs limited, Manipal university, Bangalore. Manipal.


Contents :Contents Objective of study Introduction of API in pharmaceutical industry API registration in U.S API registration in E.U Differences between U.S DMF & EDMF Conclusion References API: Active pharmaceutical ingredient


Objective of study :Objective of study The objectives of this minor project are listed below: 1. To review the regulatory requirements for API dossier in U.S &E.U 2. To analyze various types of API regulations. 3. To suggest the drug marketing authorization regarding the necessary documents required For API filing in U.S&E.U


Introduction of API in Ph.industry :Introduction of API in Ph.industry 1.API makes a drug product effective and provides the pharmacological activity of any drug 2.cGMP is main requirement for manufacturing of API’s. cGMP certificate


Introduction of API in Ph.industry :Introduction of API in Ph.industry Three overall activities that bring an API to Market:- Development of chemical process Manufacturing activity utilizing that process Governmental regulations


API Registration in U.S :API Registration in U.S Requirement is DMF A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.


Overview :Overview


US DMF :US DMF Type 1: Facilities Type 2: Drug Substance Type 3: Containers & Closures (screw caps, glass, bottles, syringes, rubber stoppers, etc.) Type 4: Colors, Flavors, Excipients Type 5: FDA Accepted Reference Information


US DMF :US DMF Purpose:- DMFs are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party the contents of the file. When an applicant references its own material, the applicant should reference the information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF


US-DMF: Registration requirements-1 :US-DMF: Registration requirements-1 Submission of USDMF: 1.Each DMF submission should contain A transmittal letter Administrative information Specific information 2.The DMF must be in the English language. Whenever a submission contains information in another language, an accurate certified English translation must also be included. 3.Each page of each copy of the DMF should be dated and consecutively numbered. An updated table of contents should be included with each submission


US-DMF: Registration requirements-2 :US-DMF: Registration requirements-2 TRANSMITTAL LETTERS Transmittal letters to the FDA accompany the DMF to the Agency and instruct the Agency as to the nature of the submission. A transmittal letter serves one of three purposes. It instructs the Agency that this is: 1. An original submission and the Agency should assign a DMF number and hold the DMF for future reference in the filing of an application for a drug product. 2. The submission is an amendment to a DMF on file with the Agency. The letter provides instructions on updating the DMF. 3. The letter is an affirmation that the DMF holder has reviewed the DMF and found that no amendment is necessary.


US-DMF: Registration requirements-3 :US-DMF: Registration requirements-3 Administrative information: a. Names and addresses of the following: DMF holder. Corporate headquarters. Manufacturing/processing facility. Contact for FDA correspondence. Agent's, if any. b. The specific responsibilities of each person listed. c. Statement of commitment. d. A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.


US-DMF: Registration requirements-4 :US-DMF: Registration requirements-4 Specific information Quality part of CTD Batch Production Records Raw material certificate of Analysis Specimen Label Reprocessing batch record


U.S DMF-Format :U.S DMF-Format CTD-Q format The DMF is submitted as original and duplicative jackets, collated, assembled, paginated and jacketed. The jacket covers are purchased from the government printing office and are specifically provided for the DMF’s.


U.S DMF-Format :U.S DMF-Format The DMF must be submitted in two copies, one with a blue cover and one with a red cover.


U.S DMF-Assembly & Delivery :U.S DMF-Assembly & Delivery Multiple volumes are numbered, the paper must be standard U.S paper(8 1/2 by 11 inches) Address:- Drug Master File Staff Food and Drug Administration 5901-B Ammendale Rd. Beltsville, MD 20705-1266 Fees : There are no fees or charges for filing a DMF


Processing &reviewing polices-U.S-DMF :Processing &reviewing polices-U.S-DMF Original DMF: An original DMF submission will be examined on receipt to determine whether it meets minimum requirements for format and content. 2 If the submission is administratively acceptable, FDA will acknowledge its receipt and assign it a DMF number.


Processing &reviewing polices –U.S DMF :Processing &reviewing polices –U.S DMF 3.once accepted, the DMF is entered into agency database and the holder or its agent should receive an acknowledgement letter. 4.If the submission is administratively incomplete or inadequate, it will be returned to the submitter with a letter of explanation from the Drug Master File Staff, and it will not be assigned a DMF number


Processing &reviewing polices-U.S DMF :Processing &reviewing polices-U.S DMF Drug master file review: 1.A DMF is never approved or disapproved. 2.The agency will review information in a DMF only when an IND sponsor, an applicant for an NDA, ANDA, or Export Application, or another DMF holder incorporates material in the DMF by reference.


Holder obligations :Holder obligations Notice Required for Changes to a Drug Master File : 1.A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the DMF 2.Notice should be provided well before Making the change in order to permit the sponsor/applicant to supplement or amend any affected application's as needed.


Holder obligations :Holder obligations Annual Update : 1.The holder should provide an annual report on the anniversary date of the original submission. 2.This report should also identify all changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF. 3.If the subject matter of the DMF is unchanged, the DMF holder should provide a statement that the subject matter of the DMF is current. 4.Failure to update or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF


Authorization to refer to a DMF :Authorization to refer to a DMF Letter of Authorization to FDA : 1.Before FDA can review DMF information in support of an application, the DMF holder must submit in duplicate to the DMF a letter of authorization permitting FDA to reference the DMF. 2.If the holder cross references its own DMF, the holder should supply in a letter of authorization the information designated by items 3, 5, 6, 7, and 8 of LOA.


Letter of Authorization :Letter of Authorization The letter of authorization should include the following: The date. Name of DMF holder. DMF number. Name of person(s) authorized to incorporate information in the DMF by reference. Specific product(s) covered by the DMF. Submission date(s) of 5, above. Section numbers and/or page numbers to be referenced. Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it. Signature of authorizing official. Typed name and title of official authorizing reference to the DMF


Follow up to U.S- DMF :Follow up to U.S- DMF FDA database contains lists of DMF’s as well as information concerning submission and status of DMF’s. “A” = Active. This means that the DMF was found acceptable for filing, administratively, and is up-to-date. “I” = Inactive “N” = Not an assigned number “P” = DMF Pending Filing Review


Inactive status of DMF’s :Inactive status of DMF’s There are three reasons for a DMF to be listed as INACTIVE: CLOSED BY THE HOLDER:  The holder requested that the DMF be closed (or retired, closed, inactivated, or withdrawn.) CLOSED BY THE FDA:  The holder did not respond to an Overdue Notification Letter within 90 days to update the DMF. OVERDUE FOR UPDATE: For DMFs submitted before June 30, 2006, a DMF is considered OVERDUE FOR UPDATE when there have been no technical amendments or annual reports submitted since that date.


Overdue notification letters :Overdue notification letters 1.FDA is in the process of sending “Overdue Notification Letters” (ONLs) to DMF holders for DMFs that are OVERDUE FOR UPDATE. 2.If a DMF holder does not respond to this letter within 90 days, the DMF will be considered “CLOSED BY THE FDA.”  It will then be RETIRED. 3.A RETIRED DMF is unavailable for review


Retaining the activity of a DMF :Retaining the activity of a DMF A DMF holder that wants to retain the activity of a DMF that is listed as Inactive and that was not CLOSED BY THE HOLDER or CLOSED BY THE FDA should Use the following process 1.Condition - no changes Documentation – submit an annual report include authorized party information.


Retaining the activity of a DMF :Retaining the activity of a DMF 2.Condtion -If there have been CHANGES and these CHANGES have not been reported to the DMF . Documentation -submit a combined ANNUAL REPORT and report of changes in technical/and/or administrative information 3. Condition -If there have been CHANGES and these CHANGES HAVE been reported to the DMF Documentation -Annual Report and authorized party information.


API REGISTRATION IN E.U :API REGISTRATION IN E.U Depends on classification of substances New active substances Existing active substances not described in the European pharmacopoeia. Existing active substances described in the European pharmacopoeia.


Feasible ways :Feasible ways a. Certificate of suitability to the monograph of the European pharmacopoeia (CEP). b. Active substance master file procedure. c. Full details of manufacture d. Other supportive data in consideration of the qualification of impurities. New active substances-option (b) or (c) would apply Existing substances-option (a) would apply .(c), (d) also apply.


CEP :CEP The DMF is submitted to the European Directorate for the Quality of Medicines (EDQM) in France. Similar to USDMF excluding the details of the plant in detail. Two copies along with Admn information to be sent to France office. Certificate will be issued from France office mentioning the product name, Holder and Final solvents used. The DMF has to be updated every 5 years incase there are no major changes.


CEP-Submitting new applications :CEP-Submitting new applications The applicant should send the following documentation to the EDQM: A complete application form including the fee form. A single copy of dossier in CTD format A single copy of the Quality Overall Summary in word format.


CEP-Validation of new applications :CEP-Validation of new applications All applications are screened at reception to check whether they are acceptable and can be validated The evaluation clock can start only once the application has been validated. Otherwise, it is blocked and a deficiency letter is sent to the applicant together with a deadline. The clock will start only if the required information is received in time.


CEP-Acknowledgement of receipt :CEP-Acknowledgement of receipt After completion of verification of dossier , the certification secretariat sends an acknowledgement of receipt with in 8 days. Once the dossier is received, and if acceptable, the secretariat has four months to designate two assessors for examination, one month to implement the conclusions, to deliver the certificate of suitability.


CEP-Designation of assessors :CEP-Designation of assessors For each dossier, the secretariat designates two assessors for examination. The assessors examine the dossier submitted and prepare a report in three parts: Report A or confidential report Report B or request for revision of the monograph Report c or comments for the inspectors.


CEP-Assessment :CEP-Assessment The assessment will be done by the assessors, assisted by the certification secretariat. The assessors finally present one of the four conclusions. 1.The monograph is able to control the quality of the substance and/or the substance meets the criteria of the criteria of the monograph products with risk of transmitting agents of animal spongiform encephalopathies. consequently-certificate of suitability is granted.


CEP-Assessment:- :CEP-Assessment:- 2.The monograph is not able fully to control the quality Of the substance, but the information provided (new, validated, analytical method and/or additional tests) nevertheless guarantees that the quality of the substance Is adequately controlled (note: this situation is not Applicable for cases of TSE risk assessment). Consequently: The certificate of suitability is granted.


CEP-Assessment :CEP-Assessment 3. The information supplied is incomplete and does not allow a conclusion. Consequently -The certificate of suitability is not granted as long as the information is still incomplete 4. The monograph is not suitable to control the quality of the substance and an agreement on testing methods for (a) given impurity (ies) or an agreement on the TSE risk assessment has not been reached or the information provided (even after several requests) do not demonstrate compliance with the current requirements. Consequently – justification for the decision not to grant a certificate of suitability will be given


CEP -Follow up activities :CEP -Follow up activities Failure to comply with the following will render the certificate void. Any change (administrative or technical) that may or may not affect the quality, safety or efficacy. Update after five years with at least a statement that no changes Incase of revision of monograph, the manufacturer shows compliance with the new requirements


CEP-Revision :CEP-Revision The holder of a CEP must inform the EDQM of any change (s) by sending all necessary documents. A complete application form + fee form A single copy of dossier. Classification of changes:- Notification Minor Major


CEP- Renewal :CEP- Renewal The certificate of suitability is valid for five years from the date when the original certificate was granted. Holder of a certificate of suitability shall ask for the renewal of the certificate of suitability six months prior to expiry date by providing an update of the certification dossier.


CEP-Revision & Renewal dossier :CEP-Revision & Renewal dossier 1.Application form General information Names and addresses Specific information 2. Technical data Certification of analysis (CoA) Validation data Analytical method data Accelerated stability data 3.Comparative table of changes/comparative data


CEP- Timetables :CEP- Timetables


CEP- Registration fees :CEP- Registration fees


CEP- Sister files :CEP- Sister files 1.There are cases when a manufacturer has been granted a CEP For a substance and where they apply for a second CEP for the Same substance to cover an alternative process, generally because the existing one cannot cover the new process/ conditions …i.e. sister files. 2.Time tables and fee-3 months & 3000 euros. 3.Conditions: original application should already have been approved by EDQM and CEP granted. Manufacturer should be same for both applications.


EU ASMF: Principle :EU ASMF: Principle 1.Marketing Authorisation Holder (MAH): Full responsibility for the medicinal product and the quality and quality control of the active substance 2.Active Substance Manufacturer (ASM): Allowance of valuable confidential intellectual property of know how to be protected Applicants Part (AP) Restricted Part (RP)


Restricted (confidential) Part :Restricted (confidential) Part 1.Manufacture Detailed description Control of Materials Control of critical steps and intermediates Process Validation Manufacturing Process Development 2.Impurities: for those impurities which do not need to be controlled in the final active substance and which are related to detailed description of the manufacturing process. 3.Justification of specification: for information related to detailed description of manufacturing process, control of materials and process validation.


Restricted (confidential) Part :Restricted (confidential) Part Exceptions Validation data of sterilisation process may be required in Applicant’s part when no further sterilisation process of the final product


EDMF-Procedure - Use :EDMF-Procedure - Use ASMF can only be submitted in relation with a MA Can also be used when no confidentiality issue between MAH and ASM MAA: either CEP or ASM should be submitted Additional information might be requested from the Applicant by the Authorities in addition to the ASMF: e.g. particle size (when not present in a ASMF)


EDMF-Procedure – Use :EDMF-Procedure – Use ASMF holders → Applicant/MA Holder Copy of latest version of the AP Copy of QOS (latest version of AP) Letter of access: Permission of ASMF holder to competent Authorities to access the data in the ASMF in relation to a specific application


EDMF-Procedure – Use :EDMF-Procedure – Use ASMF holder → Competent Authorities The ASMF (applicant + restricted part) either once or for each MA (depends on national requirements) Letter of access Discussion between ASMs and competent authorities/ EMEA related to ASMF “legally” not possible however ………..


EDMF-General considerations-1 :EDMF-General considerations-1 Responsibility of ASMF holder: One identical ASMF in EU for same API (for different applications in different member states) Version number AP MP dossier should be most recent and identical to version number AP ASMF: responsibility of the applicant Request for harmonisation requested by member states possible Update of ASMF Responsibility of ASMF holder Information to applicant and competent authority Full supplier chain described in finished product file


EDMF-General considerations-2 :EDMF-General considerations-2 The quality control methods should be kept in line with the current regulatory and scientific requirements Compliance with GMP Responsibility of Manufacturing Authorisation Holder (finished product) MAH can use different QC methods full description needed in application file In case of more than one supplier, there should be one single compiled specification for each supplier: responsibility MAH


EDMF-General considerations-3 :EDMF-General considerations-3 MA holder legally bears full responsibility MP on the market MA holder also responsible for the active substance MA holder cannot share this responsibility with ASMF MA holder responsible that active substance from any source is continuously manufactured and controlled in conformity with MPD Thus variations to ASMF can legally only be initiated by MA holder Thus ASMs should continuously inform MA holders of any changes New Variation Regulation in EU: Classification guideline not yet definitively adopted by EU Commission ASMF holders should precisely know with MA holders are linked to their ASMFs!


EDMF-Recommendation to API industry :EDMF-Recommendation to API industry Keep the information the same for all MA-holders Keep a clear administration of MA holders/countries connected to a certain ASMF Inform MA-holders and authorities in case of variations directly “As for medicinal products, EDMF holders should keep the content of their EDMFs updated with respect to the actual synthesis/manufacturing process”


Structure -CTD :Structure -CTD Module 1 regional administrative Module 2 QOS/summaries Module 3 quality Module 4 non-clinical Module 5 clinical 3.1 table of content 3.2 body of data 3.3 literature references 3.2.S substance 3.2.P drug product 3.2.A appendices 3.2.R regional information name ASMs MA holders specifications, methods & validation MA holders batch analyses if relevant reference to ASMF / data from AP ASMF copy AP ASMF LoA from ASMF holder to MA holder for named product MA dossier CTD


Regulatory Affairs :Regulatory Affairs USDMF contents: Facilities Description Production Process Description Quality Control Stability studies Analytical methods validation Batch Cards Technical Information on Key Starting Materials EDMF contents: Open part Brief Process Description Quality Control Stability studies Analytical methods validation Closed part Detailed Process Description Quality Control


Slide 58:Poll at “1st European GMP Conference on APIs” (Brussels, 9-11 September 1998) PROCEDURES VOTES European DMF 0 USA/FDA DMF 0 CEP all INDUSTRY’S OPINION WHY ?


Slide 59:WHAT THE API INDUSTRY LIKES ABOUT CEPs Vs OTHER PROCEDURES OVERVIEW OF FEATURES OF EDMF Vs CEP


Slide 60:FEATURES OF CEP VS EDMF PROCEDURE


Slide 61:A T Y P I C A L C E P F L U O X E T I N E Reference number Title Holder + manufacturing site(s) Referred monograph


Slide 62:Quality Assurance system applied Starting Validity Date A T Y P I C A L C E P F L U O X E T I N E


Conclusion :Conclusion The drug master file is a critical document used to support a drug application. Deficiencies in the drug master file can result in the delay of approval of the drug application It is important that the DMF be filed in a timely manner and that the standards used to compete it are of the same quality as actual drug application.


References :References 1.Guideline for drug master file, http://www.fda.gov/drugs/development approval process/forms submission/drug master files DMF’s/ucm 073164.htm 2. Active pharmaceutical ingredients development, manufacturing, and regulation-edited by stanely H.nusim 3. Encyclopedia of pharmaceutical technology, third edition-edited by james swarbrick. Volume 2- drug master file, page no 14701-14705.


References :References 4. Directives 2001/83 EC as amended 5. Guidelines: Active Substance Master File Procedure (ASMF) Summary of Requirements for Active Substances in the Quality Part of the dossier Various guidelines in relation to the Active Substance 6. Active Substance Master File (ASMF)/European Drug Master File (EDMF): synonymous 7. See EMEA website: www.emea.europa.eu


pramod.lakshmana@gmail.com grandhe.lakshmana@learner.manipal.edu :pramod.lakshmana@gmail.com grandhe.lakshmana@learner.manipal.edu