Regulatory aspects for registration of API in formulation

1. Submitted by; ARUL PACKIADHAS.Y, DEPT OF PHARMACEUTICS, Ist SEMESTER M.PHARM
Regulatory aspects for
registration of API
in formulation

2. • INTRODUCTION
• Drug Master File
• Registration procedure for API in US and EU
Definition
Regulatory authority
Division/Office handling DMF
Types
Submission requirement
Format of submission and specification
Number of copies
Fee
Language
Braille code
Accepted nations
Validity
Headquarters
Website
• References
CONTENT
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3. Abbreviations
ANDA : Abbreviated New Drug Application
AP : Applicant’s Part
API : Active Pharmaceutical Ingredient
ASM : Manufacturer of The Active
ASMF : Active Substance Master File
BLA : Biologics License Application
CEP : Certificate of suitability to the monographs of the European
Pharmacopoeia
cGMP : Current Good Manufacturing Practice
CHMP : Committee for Medicinal Products for Human use
CMDh : Co-ordination Group for Mutual Recognition and Decentralized Procedures-Humans
CMDv : Co-ordination Group for Mutual Recognition and Decentralized Procedures-Veterinary
CTD : Common Technical Document
CV : Curriculum Vitae
CVMP : Committee for Medicinal Products for Veterinary use
DCEP : Certification of Substances Division
EDMF : European Drug Master File
EDQM : European Directorate for the Quality of Medicines & Health care
EMA : European Medicines Agency
DMF : Drug Master File
eCTD : electronic Common Technical Document
FDA : Food and Drug Administration
GDUFA : Generic Drug User Fee Amendments/Act
ICH : International Council for Harmonization
IND : Investigational New Drug
LOA : Letter Of Authorisation
MA : Marketing Authorization
NDA : New Drug Application
OBI : Office of Business Informatics
OGD : Office of Generic Drug
QOS : Quality Overall Summary
RP : Restricted Part
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4. INTRODUCTION
• API is ingredient in pharmaceutical drug that is biologically active.
• Some medication product contains more than one active ingredient.
• The traditional word for Active Pharmaceutical Ingredient is pharmakon or
pharmacon.
• It is from Greek word: φáρμaKov.
• Which originally denoted a magical substance or drug.
• Their pharmacological activity plays a direct role in the diagnosis, cure, mitigation,
treatment or prevention of disease.
• API material that are the active for new drug are covered by NDA documentation.
• Innovator companies would use their IND &NDA fillings to provide the excepted
details covering API.
• While all other would establish and submit a DMF with the FDA or appropriate
country authority, such as EMA in Europe.
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5. Drug Master File
• When the drug development organization submits a NDA with the US FDA to
obtain approval for the drug, it will insert a letter from the manufacturer of the
(in)active ingredient stating that the confidential information was submitted by the
manufacturer directly – but separately from the NDA – in the form of a Drug Master
File.
• This DMF contains information about the (in)active ingredient, its manufacture,
quality specifications, in-process controls, release tests, analytical methods and
stability data.
• DMF is submitted by pharmaceutical manufacturer.
• DMF submission is not mandatory by law or FDA regulation.
• DMF is not a substitute for an IND,NDA and ANDA.
• The information in DMF is used to support IND,NDA, ANDA, other DMF or
export application.
• DMF’s are only reviewed when an ANDA or NDA references them.
• The DMF system applies to active as well as to inactive pharmaceutical
ingredients and to packaging materials.
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6. REGISTRATION PROCEDURE
FOR API IN US AND EU
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7. DEFINITION
US DMF EU DMF
“A Drug Master File 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
Chemistry, manufacturing, control,
packaging, and storing of one or more
human drugs.”
“European Drug Master File is to allow
valuable confidential intellectual property
or 'know-how' of the manufacturer of the
active substance (ASM) to be protected,
while at the same time allowing the
Applicant or marketing authorization(MA)
holder to take full responsibility for the
medicinal product.”
It is also called as Active Substance Master
File (ASMF) or European Drug Master File
(EDMF).
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8. REGULATORY AUTHORITY
US DMF EU DMF
FDA- Food and Drug Administration EU DMF handled by two agencies:
1) European Directorate for the Quality of
Medicines and HealthCare (EDQM) – CEP
2) European Medicines Agency (EMA) –
ASMF
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9. DIVISION/OFFICE HANDLING DMF
US DMF EU DMF
DMF review for Administrative
purposes by Office of Business
Informatics (OBI) staff within
Center for Drug Evaluation &
Research
Completeness Assessment is
performed by Office of Generic
Drug (OGD)/DMF Review Staff
CEP
Certification of Substances
Division (DCEP) within EDQM
ASMF
Working Group of EMA,
CHMP, CVMP, CMDh, CMDv,
EDQM
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10. TYPES
US DMF EU DMF
Type I - Manufacturing Site, Facilities,
Operating Procedures, and Personnel (now
inactivated).
Type II - Drug Substance, Drug Substance
Intermediate, and Material Used in their
Preparation, or Drug Product
Type III - Packaging Material
Type IV - Excipient, Colorant, Flavour,
Essence, or Material Used in their
Preparation
Type V - FDA Accepted Reference
Information.
A. Certificate of suitability to the
monographs of the European
pharmacopoeia (CEP)
B. Active Substance Master File (ASMF)
procedure
C. Full details of manufacture
D. Other supportive data in consideration
of the qualification of impurities.
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11. SUBMISSION REQUIREMENT
US DMF
Module I: Administrative information
• Cover letter
• GDUFA fee cover sheet
• Statement of commitment
Administrative information
• Change of address or corporate name
• Change of contact of US agent
• Debarment certificate
References
• LOA
• Statement of right of reference
• List of authorized persons to incorporate
by reference Application status
• Reactivation request
• Withdrawal of unapproved NDA/BLA/
ANDA Meetings
• Meetings request
• Meetings background material
• Communication regarding meetings
Information amendment
• Quality
• Non clinical
• Clinical
• Multiple module Other communication
• Request for comments or advice
• Environmental assessment Annual Report
• Summary of Manufacturing changes
Labeling
• Draft labeling for container.
Module II:
• QOS
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12. EU DMF
CEP
Module I: administrative information
• Cover Letter
• EDQM Application form including signed
declarations as relevant
• Information about experts, CV as
relevant
• Responses
• Additional data and revisions
Module II:
• QOS
• Experts’ report
ASMF
Module I: administrative information
• LOA
• Contents
• Application for ASMF
• Labelling and packaging
• Experts' information
• Specific requirements for different types of
applications
• Environmental assessment
• cGMP certificates
• Details of compliance with screening
outcomes
• Individual patient data
• Foreign regulatory status
• Bioequivalence trial information
• Pediatric development report
• Risk management plan
Module II:
• QOS
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13. US DMF & EU DMF Module III: format is common and in accordance with ICH M4Qguidelines
Module III: quality information of API
General Information:
• Nomenclature
• Structure
• General Properties
Manufacturer
• Manufacturer
• Description of Manufacturing Process and
Process Controls
• Control of Materials
• Controls of Critical Steps and
Intermediates
• Process Validation and/or Evaluation
• Manufacturing Process Development
Characterization
• Elucidation of Structure and other
characteristic.
• Impurities
Control of Drug Substances
• Specification
• Analytical Procedure
• Validation of Analytical Procedure
• Batch Analysis
• Justification of Specification
Reference Standards or Materials
Container Closure System
Stability
• Stability Summary and Conclusions
• Post- approval Stability Protocol and
Stability Commitment
• Stability Data
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14. FORMAT OF SUBMISSION AND SPECIFICATION
US FDA EU FDA
a) Paper format: size of paper used is 8 ½
inches ×12 inches.
Binders used:
Blue binder (Form 3316)
Red Binder (Form 3316a)
From 5th May, 2018 onwards, all Master
Files are to be submitted in eCTD format
only.
b) eCTD format: Format in accordance with
ICH guideline M4Q: Quality
CEP
a) Paper format: From June 2016 onwards,
paper format has become obsolete and all
submissions are to be made electronically.
b) eCTD format: Format in accordance with
ICH guideline M4Q: Quality and EDQM
guidelines for electronic submissions.
ASMF
eCTD ASMF is to be submitted in separate
two parts:
1.Applicant’s part (AP)
2.Restricted part (RP)
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15. NUMBER OF COPIES
US DMF EU DMF
2 COPIES 1COPIES
FEE
(FY 2020)
• New API: 57,795$
• Domestic: 44,400$
• Foreign: 59,400$
CEP
• Simple chemical certificate 5000€
• Certificate for clinical purity & sterility +
TSE 9000€
• Renewal 1500€
ASMF
• Depends on route of application
LANGUAGE
English French or English
BRAILLE CODE
Not required Required
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16. SITE REGISTRATION
US DMF EU DMF
Required Not required
VALIDITY
Valid unless inactivated or withdrawn CEP and ASMF are valid for 5years, initially
and require renewals periodically.
ACCEPTED NATIONS
China, India, Costa Rica, Chile, Belgium, and
the United Kingdom.
EMA Austria, Belgium, Bulgaria, Croatia,
Cyprus, Czech Republic, Denmark, Finland,
France, Germany, Greece, Hungary, Ireland,
Italy, Malta, the Netherlands, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain,
and Sweden
EDQM Albania, Algeria, Australia,
Azerbaijan, Canada, Georgia, Ghana Israel,
Kyrgyzstan, Malaysia, Moldova, Morocco,
New Zealand, Saudi Arabia, Singapore,
South Africa, Tunisia, and Uzbekistan
(with conditions).
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17. HEADQUARTERS
US DMF EU DMF
White Oak, Maryland EMA
Amsterdam, Netherland
EDQM
Strasbourg, France
WEBSITE
https://www.fda.gov/home CEP
https://www.edqm.eu/
ASMF
https://www.ema.europa.eu/en
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18. REFERENCE
• Global New Drug Development An Introduction by Jan A. Rosier, Mark A.
Martens and Josse R. Thomas (Page no:45-58).
• An Overview of Registration of API (DMF) in Regulated Markets
(US FDA, CANADA, EU and EDQM(CEP) by Mithun E.G. et al.
• Regulatory Requirements for Registration of API in US and EU by
Chennamstti Srilakshmi.
• Registration process of API in U.S and Europe along with comparison of
USDMF and EUDMF by Mr. Darshil Bharatbhai Shah.
• https://en.wikipedia.org/wiki/Active_ingredient
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