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Saravanaraja Subramanian

Regulatory Filings of Active Pharmaceutical Ingredients - An Eagle’s Eye view [US and Europe]. Saravanaraja Subramanian. WHAT IS A DRUG MASTER FILE.

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Saravanaraja Subramanian

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  1. Regulatory Filings of Active Pharmaceutical Ingredients - An Eagle’s Eye view [US and Europe] API/Regulatory Filings/Slideshow/Version-00 Saravanaraja Subramanian

  2. WHAT IS A DRUG MASTER FILE • 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. • The term Drug Master File (DMF) is commonly used to describe a submission to a competent authority that may be used to provide certain confidential detailed information about facilities, processes or articles used in manufacturing.  In Europe, such confidential information can be submitted in a so-called “Active Substance Master File (ASMF)” using the European Drug Master File procedure.  • It should be noted that there is a difference between the content and format of Drug Master Files used in the United States and Drug Master Files used for marketing authorization applications in Europe.  API/Regulatory Filings/Slideshow/Version-00

  3. Why to Submit a DMF • A DMF is prepared to support INDA, NDA, ANDA or another DMF, Export application or amendments and supplements to any of these. • In Europe, A DMF is submitted to support the Marketing Authorization Application • If your company’s API is used by a formulator who has applied for ANDA/NDA/INDA or MAA in US or EU respectively , requires a DMF to support the review of MAA in view of CMC(Chemistry, Manufacturing and Controls) . By submitting a DMF , the API manufacturer becomes part of the submission who in turn is audited by the agency(if it is for the first time or as applicable ) and approved for GMP compliances as stated in the respective agency’s regulation. API/Regulatory Filings/Slideshow/Version-00

  4. Types of Drug Master Files - US • Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel • This is no longer exist • Type II: Drug Substance, Drug Substance Intermediate, and Material Used in their preparation, or Drug Product • Most common filing • Type III: Packaging Material • For primary packing material (material that comes in direct contact with drug substance) • Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation • Raw Materials for formulation • Type V: FDA Accepted Reference Information • For example, Sterilization processes API/Regulatory Filings/Slideshow/Version-00

  5. Types of Drug Master Files Europe • API is filed as “Active Substance Master File (ASMF)” using the European Drug Master File procedure or as Certificate of Suitability (COS or CEP) for substances that are part of EP. • For excipients, Raw material or Starting Material or Packing materials , EU countries does not accept any DMF. However, a CEP can be applied if these are part of European Pharmacopeia. API/Regulatory Filings/Slideshow/Version-00

  6. Active Substance Master File (ASMF) - Europe • An Active Substance Master File (ASMF), also known as the European Drug Master File (EDMF), is the active substance section of dossiers for a marketing authorisation application or a marketing authorisation variation of a medicinal product in cases where the scientific information is divided in two separate parts – • an Applicants Part (AP) and the restricted part (RP). The AP contains information that the ASMF (EDMF) holder regards as non-confidential to the applicant/marketing authorisation holder of a specified medicinal product whereas the RP contains the information that the ASMF holder regards as confidential.   • The procedure to submit an ASMF (EDMF) allows valuable confidential “know-how” of the manufacturer of the active substance to be protected while at the same time allowing an applicant or marketing authorisation holder to take full responsibility for a medicinal product API/Regulatory Filings/Slideshow/Version-00

  7. Approval/Acceptance of DMF • US • DMF is neither approved nor disapproved. Only the Drug Product Applications /submissions are approved. A unique number is assigned to the DMF and the agency acknowledges the receipt • Europe • DMF is neither approved nor disapproved. Only the Marketing Authorization Applications /submissions are approved. However, the agency acknowledges the receipt of the DMF by document number created by the DMF holder. API/Regulatory Filings/Slideshow/Version-00

  8. Contents of DMF • The contents shall be as per CTD (Common Technical Document) format only but the details may vary based on the nature and category of the product . • Any changes to the contents filed in a DMF shall be updated annually, Amended/supplemented for US as specified in slides 10 to 17. (only certain examples of changes are specified) • Any changes to the contents filed in a DMF shall be updated through Variation Filings [Type IA, IB and Type –II ]for Europe Region as specified in slides 33 to 41. (only certain examples of changes are specified) API/Regulatory Filings/Slideshow/Version-00

  9. Contents of DMF • Administrative information • Company Name, Address & Authorized persons • General characteristics of the product • Physico-chemical properties, category of drug • Chemical names and properties • Chemical name as per various classification • Manufacturing details like chemistry and flow of the process • Number of stages, ROS, Detailed process flow • Information on Key starting materials and raw materials • Commitment on KSM source [as applicable] API/Regulatory Filings/Slideshow/Version-00

  10. Contents of DMF • Quality Control and Assurance systems • Testing facility & Control Systems • Specification and testing procedures • For RM. Intermediate, In-process, API and PM • Validation of the process and analytical methods • Complete information about Process Validation and Analytical method Validation • Stability profile of the product • A minimum of 3 M accelerated stability and 3 M long term stability based on the company’s policy of filing • Data on force degradation studies API/Regulatory Filings/Slideshow/Version-00

  11. Contents of DMF • Container closure system and labels • A brief description of packing procedure and the configurations of packing the product for market and stability • Environmental Assessment • A declaration by EHS department on the impact of Environment during the manufacturing of the product • Supporting Documents • A DMF is filed with required supporting documents as specified in the guideline which includes executed BPCRs (for US), MPCRs (for US), copies of spec/STP, validation reports and so on. API/Regulatory Filings/Slideshow/Version-00

  12. Changes and Categories of filing - US • When a change is required, based on nature of the change the API manufacturer shall inform the agency and drug product manufacturer s who are using the subject API about the changes and a amendment or supplement is filed by the API manufacturer as applicable. • The API manufacturer shall update the agency annually [through ANNUAL REPORT] of minor changes which does not impact the safety, efficacy and Strength of the DP. • The Drug product manufacturer decides the filing category as PAS or CBE 0 or CBE 30 based on the impact of the change to the drug product where the API manufacturer has to file a Amendment or Supplement as applicable. • To brief, major changes as PAS; Moderate changes as CBE and minor changes as Annual Report. However, FDA has rights to ask us a PAS in place of a CBE 30 or CBE 0 or as applicable. • A few examples/conditions is portrayed in the following slides API/Regulatory Filings/Slideshow/Version-00

  13. Prior Approval Supplement (PAS) • To relax the limits for a specification (API) • To establish a new regulatory analytical method; • To delete a specification or regulatory analytical method; • To change the synthesis of the drug substance, including a change in solvents and a change in the route of synthesis. Contd…. API/Regulatory Filings/Slideshow/Version-00

  14. Prior Approval Supplement (PAS) • To use a different facility or establishment to manufacture the drug substance, where: • the manufacturing process in the new facility or establishment differs materially from that in the former facility or establishment, or • the new facility or establishment has not received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process. Contd…. API/Regulatory Filings/Slideshow/Version-00

  15. Prior Approval Supplement (PAS) • Change in equipment to a different design and different operating principles in the stage where the product is formed/synthesized for example Crystallization. (It can be either the penultimate stage or the final based on the chemistry) • Other changes on case by case API/Regulatory Filings/Slideshow/Version-00

  16. Changes Being Effected (CBE -0/CBE -30) • To use a different facility or establishment to manufacture the drug substance, where: • The manufacturing process in the new facility or establishment does not differ materially from that in the former facility or establishment, and • the new facility or establishment has received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process. • Scale up more than 10times of filed batch Size (batch Size used in Bio study) Contd….. API/Regulatory Filings/Slideshow/Version-00

  17. Changes Being Effected (CBE /CBE 30) • Contd…. • Process Optimization - Where the manufacturing operations are optimized ( this is applicable only to those operations prior to the final stage) for a better yield, better quality, Cost effectiveness with out altering finished product specification, Operating principles and mechanisms of the manufacturing, justification to be provided if altered. • Multiple changes in the manufacturing like scale up less than 10 times, Change in equipment, Optimization of manufacturing process. • Other changes on case by case basis API/Regulatory Filings/Slideshow/Version-00

  18. Annual report: • The applicant shall submit each year within 60 days of the anniversary date of U.S. approval of the application, two copies of the report to the FDA division responsible for reviewing the application. • Minor changes in manufacturing process in view of better GMP • Minor Editorial changes in specification and STP of RM, In-process, Intermediate, Packing material, and API • Minor changes in Labeling • Updated stability data • CoA of one batch; generally for the batch which is kept in stability • Changes in the equipment if it is like to like or if the difference in equipment does not make any difference materially • Contd….. API/Regulatory Filings/Slideshow/Version-00

  19. Annual report: • Contd…. • Scale up of batches up to 10 fold • Inclusion of a LoA • Other relevant information which is filed in the DMF like batch numbering system, Control numbering system, Packaging configuration, flow of materials - briefly saying, change in GMP changes • Other changes on case by case basis API/Regulatory Filings/Slideshow/Version-00

  20. Types of Marketing Application Procedures - Europe • Centralized Procedure • Decentralized Procedure (DCP) • National Procedure • Mutual Recognition procedure (MRP) • Certificate of Suitability (COS) API/Regulatory Filings/Slideshow/Version-00

  21. Authorisation procedures in the European Union • Medicines can be authorized in the European Union by using either the centralised authorisation procedure or national authorisation procedures. • 1. Centralised authorisation procedure • The European Medicines Agency is responsible for the centralised procedure (also known as the 'Community authorisation procedure'). This procedure results in a single marketing authorisation (called a 'Community marketing authorisation') that is valid across the European Union, as well as in the EEA/EFTA states Iceland, Liechtenstein and Norway. The centralised procedure is compulsory for human medicines that are: API/Regulatory Filings/Slideshow/Version-00

  22. Centralised authorisation procedure • Contd…. • derived from biotechnology processes, such as genetic engineering; • intended for the treatment of HIV/Aids, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions; • officially designated 'orphan medicines' (medicines used for rare diseases). API/Regulatory Filings/Slideshow/Version-00

  23. Centralised authorisation procedure • For medicines that do not fall within these categories (the 'mandatory scope'), companies have the option of submitting an application for a centralised marketing authorisation to the EMEA, as long as the medicine concerned is a significant therapeutic, scientific or technical innovation, or if its authorisation would be in the interest of public health. • Applications through the centralised procedure are submitted directly to the EMEA. Evaluation by the Agency's relevant scientific committee takes up to 210 days, at the end of which the committee adopts an opinion on whether the medicine should be marketed or not. This opinion is then transmitted to the European Commission, which has the ultimate authority for making decisions on marketing authorizations in the EU. API/Regulatory Filings/Slideshow/Version-00

  24. National authorisation procedures • Each EU Member State has its own procedures for the authorisation, within their own territory, of medicinal products that fall outside the scope of the centralised procedure. Information about these national procedures can normally be found on the website of the national competent authority in the country concerned. • However, there are also two possible routes available to companies for the authorisation of such medicinal products in several countries simultaneously: (DCP and MRP) API/Regulatory Filings/Slideshow/Version-00

  25. Decentralised procedure • Using the decentralised procedure, companies may apply for simultaneous authorisation in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralised procedure. API/Regulatory Filings/Slideshow/Version-00

  26. Mutual-recognition procedure • In the mutual-recognition procedure, a medicine is first authorised in one EU Member State, in accordance with the national procedures of that country. • Following this, further marketing authorisations can be sought from other EU countries in a procedure whereby the countries concerned agree to recognise the validity of the original, national marketing authorisation. API/Regulatory Filings/Slideshow/Version-00

  27. Certificate of Suitability (COS) • The other name of COS - Certificate of Suitability to the Monograph of the European Pharmacopoeia (CEP) • The active substance and/or raw and starting material or excipients are subject of a monograph of the European Pharmacopoeia the CEP can be used by the manufacturer of medicinal product in its application for marketing authorisation to demonstrate the compliance of the substance used with the monographs of the European Pharmacopoeia • The active substance manufacturer should submit documentation to the European Pharmacopoeia Secretariat with a view to evaluating the suitability of the pharmacopeial monograph in relation to the manufacturing method actually used. API/Regulatory Filings/Slideshow/Version-00

  28. Notes on National Procedure • This procedure is applicable when the medicinal product is not approved by any member state of EU and when the medicinal product wants MA from a particular country. (Independently of other European regulatory agencies, the quality, efficacy and safety of the medicinal product for which marketing authorisation has been requested in any one of the EU country). This type of MAA is called as National procedure. • This type of procedure is, in general, only applicable to medicinal products which have not yet received marketing authorisation in any member state of the European Union (EU) or the European Economic Area (EEA). • A EDMF is submitted to the concerned EU country only from the API manufacturer to support the MAA (Marketing Authorization Application) . API/Regulatory Filings/Slideshow/Version-00

  29. Notes on Mutual Recognition Procedure (MRP) • This procedure is applicable only when the medicinal product has a approved MA (Marketing Authorization) by a National procedure from any one EU country. • Mutual recognition means that EU countries may approve the decision made about a medicinal product by another EU country. • The pharmaceutical company submits their application to the country chosen to carry out the assessment work, which then approves or rejects the application. The other countries have to decide within 90 days whether they approve or reject the decision made by the original country. • If the Member State(s) fail to reach an agreement during the 60-day procedure of the pre-referral, a referral to the CHMP/CVMP for arbitration may be made through its secretariat at the EMEA. API/Regulatory Filings/Slideshow/Version-00

  30. Notes on Centralised Procedure • The centralised procedure (CP), one of the marketing authorisation procedures in Europe, results in a Community authorisation. Medicinal products approved by this procedure is accepted by the EU countries and some other countries which choose EU decisions. • A Community authorisation is valid for the entire Community which means that the medicinal product may be marketed in all Member States.  • Marketing authorisation applications for medicinal products which have been developed by means of biotechnological processes (i.e. rDNA technology) must use the centralised procedure.  • Applications for medicinal products containing a new active substance or innovative medicinal products with novel characteristics may optionally use the centralised procedure. API/Regulatory Filings/Slideshow/Version-00

  31. Notes on Decentralized Procedure • Decentralised procedure is used for applying for a market authorisation in cases where the product is not authorised in any EU member state. The decentralised procedure is based on the same fundamental idea as the mutual recognition procedure (the “MR procedure”). (210 Days) • In contrast to the MR procedure, however, the decentralised procedure does not require a national marketing authorisation to have been granted for the medicinal product. API/Regulatory Filings/Slideshow/Version-00

  32. Notes on Decentralized Procedure • On the contrary, the pharmaceutical company applies for marketing authorisation simultaneously in all the required member states of the European Union (EU) or European Economic Area (EEA). • If the Member State(s) fail to reach an agreement during the 60-day procedure of the pre-referral, a preferral to the CHMP/CVMP for arbitration may be made through its secretariat at the EMEA. • The review flow chart of MAA by DCP is indicated in the next slide to understand as to why & how the regulatory approvals are considered time bound. API/Regulatory Filings/Slideshow/Version-00

  33. API/Regulatory Filings/Slideshow/Version-00

  34. Variation Filings - Europe • Type - 1 A • Type - 1 B • Type - 2 API/Regulatory Filings/Slideshow/Version-00

  35. TYPE – I A VARIATION • Change in the name and/or address of the marketing authorisation holder • Change in name of the active substance • Change in the name and/or address of a manufacturer of the active substance where no European Pharmacopoeia certificate of suitability is available • Change in the name and/or address of a manufacturer of the finished product • Change in ATC Code API/Regulatory Filings/Slideshow/Version-00

  36. TYPE – I A VARIATION • Change to batch release arrangements and quality control testing of the finished product • Change in batch size of active substance or intermediate up to 10 fold • Tightening of specification limits • Minor changes to an approved test procedure • Change to comply with an update of the relevant monograph of the European Pharmacopoeia or national pharmacopoeia of a Member State • Tightening of in-process limits • Change in shape or dimensions of the container or closure API/Regulatory Filings/Slideshow/Version-00

  37. TYPE – I B VARIATION • Replacement or addition of a manufacturing site for part or all of the manufacturing process of AS • Minor change in the manufacturing process of the active substance • No change in qualitative and quantitative impurity profile or in physico-chemical properties. • The synthetic route remains the same, i.e. intermediates remain the same. API/Regulatory Filings/Slideshow/Version-00

  38. TYPE – I B VARIATION • Change in batch size of active substance or intermediate - More than 10-fold compared to the original batch size approved at the grant of the marketing authorisation • Any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-sized equipment. • Test results of at least two batches according to the specifications should be available for the proposed batch size. • ٱ The active substance is not a biological substance. • The change does not affect the reproducibility of the process. • The change should not be the result of unexpected events arising during manufacture or because of stability concerns. API/Regulatory Filings/Slideshow/Version-00

  39. TYPE – I B VARIATION • Change in the specification of an active substance or a starting material/intermediate/reagent used in the manufacturing process of the active substance • Addition of a new test parameter to the specification of an active substance or a starting material/intermediate/reagent used in the manufacturing process • Other changes to a test procedure, including replacement or addition of a test procedure of API specification API/Regulatory Filings/Slideshow/Version-00

  40. TYPE – I B VARIATION • Change in the manufacturer of the active substance or starting material/reagent/intermediate in the manufacturing process of the active substance where no European Pharmacopoeia certificate of suitability is available • Change in site of the already approved manufacturer (replacement or addition) • New manufacturer (replacement or addition) • Change in: • the re-test period of the active substance • the storage conditions for the active substance API/Regulatory Filings/Slideshow/Version-00

  41. TYPE – I B VARIATION • Change of specification(s) of a former non-European pharmacopeial substance to comply with European Pharmacopoeia or with the national pharmacopoeia of a Member State • Other changes to a test procedure, including replacement or addition of a test procedure • Scale up more than 10 fold API/Regulatory Filings/Slideshow/Version-00

  42. TYPE - II VARIATIONS • Change in Specification limits – relaxation of limit for a test. • Change in ROS • Change in impurity profile (New Impurity) • For example, a case when Unknown impurity is characterized and the limit is revised (NMT 0.10% to NMT 0.15%) API/Regulatory Filings/Slideshow/Version-00

  43. References • Guidance for Industry : BACPAC-I Intermediates in Drug Substance Synthesis -Bulk Actives Post approval changes : Chemistry, manufacturing , and Controls Documentation • Guideline for submitting supporting drug applications for the manufacture of DRUG SUBSTANCES • Guide to Inspections of Bulk Pharmaceutical chemicals • Guidance for Industry – Changes to an approved NDA or ANDA • Guidance for Industry – Scale-up and post approval changes : CMC, In vitro dissolution testing, and In Vivo Bioequivalence Documentation API/Regulatory Filings/Slideshow/Version-00

  44. References • http://www.emea.europa.eu/index/authorisation.htm • http://www.emea.europa.eu/htms/human/raguidelines/pre.htm • http://www.emea.europa.eu/htms/human/raguidelines/post.htm • GUIDELINE FOR DRUG MASTER FILES • EUROPEAN DRUG MASTER FILE PROCEDURE FOR ACTIVE SUBSTANCES Disclaimer: The whole power point presentation is intended to give a basic idea of regulatory filings of API in US and EU region to all readers. This does not confer any rights or privileges by any body to propose or decide the filing category of changes to approved marketing authorization. This presentation is the part of knowledge sharing management and not for implementation. API/Regulatory Filings/Slideshow/Version-00

  45. About the Author Mr.Saravanaraja Subramanian is employed with Enaltec Laboratories Limited, India, as Dy.General Manager – Quality Assurance and Regulatory Affairs. He is having good amount of experience and vast knowledge in the areas of Quality Assurance, Quality control, Validation and Regulatory Affairs. He is specializes in Pharmaceutical Microbiology. He can be reached by on his mobile phone at 0091-9699995911, and via at e-mail at:ssaravanaraja@enalteclabs.co.in 45 API/Regulatory Filings/Slideshow/Version-00

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