LIFECYCLE CHANGES TO THE DRUG MASTER FILE

- REGULATORY PERSPECTIVE
 WHAT’S IN A NAME ?
WILLIAM SHAKESPEARE

• DMF - Drug Master File known in US & other countries

• ASMF - Active Substance Master File as known in EU

• CEP - Certificate of Suitability to the monographs of

the European Pharmacopoeia – EDQM

• MF - Master File as known in JAPAN

DMF LIFE CYCLE - DEFINITION

NEW DRUG

APPROVAL
GENERIC
DRUG
POST
APPROVAL
FACTORS WHICH DETERMINES THE LIFE CYCLE
OF DMF

• – Manufacturability
• – Quality (Both API & DP)
• – cGMP of manufacturing site(s) of API & Intermediates
• – Business viability
• – Continuous Process Improvement
• – Business/Cost decisions (Both API & DP)
DECISIONS WHICH DETERMINE POST APPROVAL
CHANGES
• CHANGES ARE INEVITABLE
• CHANGES RELATED TO QUALITY OF THE PRODUCT
• CHANGES RELATED TO BUSINESS NEEDS
• CHANGES RELATED TO CONTINOUS PROCESS IMPROVEMENT
• CHANGES RELATED TO GLOBAL ECONOMICS
• CHANGES RELATED TO REGULATORY CHALLENGES
• CHANGES ARE HERE TO STAY
TYPES OF COMMON CHNAGES

• PRODUCTIOIN SCALE CHANGES/EQUIPENT CHANGES

• STARTING MATERIAL OR INTERMEDIATE VENDOR CHANGES
• PROCESS CHANGES RELATED TO KSM/INTERMEDIATES/API
• FINE TUNING THE PROCESS CONTROLS / CAPA
• USE OF RECOVERED SOLVENTS OR MATERIALS
• INTRODUCTION OF ADDITIONAL PRODUCTION STREAMS/SITE
TRANSFER
• CHANGES RELATED TO SPECIFICATIONS AND TEST METHODS
CLASSIFICATION OF CHANGES

• CHANGES ARE GENERALLY CLASSIFIED INTO THREE CATEGORIES

• MINOR

• MODERATE

• MAJOR
IMPACT OF POST APPROVAL CHANGES

• BASED ON THE CATEOGRY OF CHANGE, DEGREE OF IMPACT VARIES

• ANY CHANGES WILL HAVE ITS OWN BUSINESS IMPLICATIONS

• MINOR CHANGE HAVE NO IMPACT ON COMMERCIAL SUPPLY

• MODERATE CHANGES WILL HAVE LITTLE IMPACT ON COMMERCIAL SUPPLY

• MAJOR CHNAGES WILL HAVE IMPACT ON COMMERCIAL SUPPLY

IMPACT OF POST APPROVAL CHANGES

•COST IMPLICATIONS RELATED TO REGULATORY FILING

•INVENTORY

•FREQUENT CHANGES WILL HAVE IMPACT ON CUSTOMER

•MAJOR CHANGES WILL HAVE IMPACT ON PRODUCT QUALITY

HOW GLOBAL REGULATORS VIEW POST
APPROVAL CHANGES
• LIKE ONSITE INSPECTIONS, REGULATORS PERSPECTIVE RELATED TO CHANGE
IS ALSO DIFFERENT

• BASED ON REGULATORY EXPERTISE EACH REGION DESIGNED ITS OWN

REGULATIONS TO TREAT CHANGES’

• A MODERATE CHANGE IN ONE REGION WOULD BE MAJOR IN THE OTHER PART

OF GLOBE OR vice versa

• FEE PAYMENT ALSO DIFFERENT FOR DIFFERENT REGION

FDA PERSPECTIVE ON POST APPROVAL
CHANGES
• Lifecycle Changes are treated as per 21 CFR 314.70 by the FDA
• Prior Approval Changes (PAS) – High Risk
• – Review clock 4 months, Efficacy 10 months or 6 months
• Changes Being Effected in 30 days (CBE-30) -Moderate Risk
• – Review clock 6 months
• Changes Being Effected in 0 days (CBE-0) –Moderate Risk
• – Review clock 6 months
• Annual Reportable Changes- Low Risk changes
FDA GUIDANCE ON POST APPROVAL CHANGES

• Changes to an Approved NDA or ANDA

• CMC Postapproval Manufacturing Changes to Be Documented in Annual Reports

• SUPAC Guidances

• SUPAC-IR, SUPAC-MR, SUPAC-SS, SUPAC-manufacturing

• Equipment Addendum 2014

• Post approval Changes to Drug Substances Guidance for Industry

ANNUAL REPORTABLE CHANGES

• Annual Reportable Changes

• Changes that would not impact quality of the drug - low risk changes
• – e.g. -Extension of retest date based on a real time long term data
• Replacing of equipment with the same design, operating principle,
• Change in production scale
• Changes in drug substance drying equipment within the same operating principle
• Establishment of a reprocessing operation as pat of the manufacturing process
• Editorial changes
ANNUAL REPORTABLE CHANGES EXAMPLES

• Redefinition of a starting material with no change in the drug substance impurity profile

• Tightening of acceptance criteria

• Any change in an analytical procedure used for testing raw materials used in drug substance
synthesis, starting materials introduced prior to the final drug substance intermediate, in-
process materials prior to the final intermediate that provides the same or increased
assurance

• Any change in the specification made to comply with the official compendium except for any
deletion of test or widening of specification
CBE – 0 CHANGES

• CBE-0 Changes
• Changes that do not impact Quality/Safety/Efficacy in any way
• Additional Specification to controls
• Method modifications of intermediates or starting materials introduced before
• the final intermediate
• Corrections
• Missing data
CBE - 30 CHANGES

• CBE-30 Changes

• Manufacturing Facility changes to sites for which CGMP history is available

• Change in Testing Facility sites for which CGMP history is available

• The new testing facility has the capability to perform the intended testing

• Establishing a new procedure for reprocessing

• Minor Manufacturing process changes before final intermediate

• Primary container closure system changes or storage condition revision of API

• Analytical method changes of intermediates

CBE - 30 CHANGES

• For drug substances any change in process and/or process parameters except as
provided in the guidance
• An increase or decrease in production scale during finishing steps that involves
different equipment
• Replacement of equipment with equipment of different design that does not affect
the process methodology or process operating parameters
• Changes to filtration parameters for aseptic processing (including flow rate,
pressure,time or volume but not filter materials or pore size rating)
PRIOR APPROVAL SUPPLEMENT CHANGES

•Any process change made after the final intermediate processing step in DS manufacture
•Fundamental change in Drug Substance manufacturing process
•Change in the synthesis or manufacture of the Drug Substance
•Establishing a new procedure for reworking or recovery of API
•Any changes that may affect sterility assurance such as, changing to aseptic processing methods, including scales
or extend total processing time by more than 50% beyond the validated limits in the approved application
•Changing in sterilizer load configurations that are outside the validated loads
•Changes in materials or pore size rating of a filter
•Manufacturing Facility changes to sites for which no CGMP history is available
PRIOR APPROVAL SUPPLEMENT CHANGES

•Transfer of the manufacture of an aseptically processed drug substance to a newly

constructed or refurbished aseptic processing facility or area or in the existing aseptic
processing facility
•Establishing a new regulatory analytical procedure including designation of an alternative
analytical procedure that does not provide the same or increased assurance
•Changes in the drug substance drying equipment to equipment of a different operating
principle and different design for a non thermally stable intermediate or drug substance
•Changes to equipment used for particle size reduction to equipment of different operating
principle and different design
PRIOR APPROVAL SUPPLEMENT CHANGES

• Equipment changes made during or after the final solution step

• Redefinition of a starting material resulting in a change in the impurity profile of the

drug substance

• Changes made after the formation of the final intermediate (new crystallization solvent)

• Changes in the synthesis with adverse effect to the impurity profile (e.g., introduction of
genotoxic impurity)
EU PERSPECTIVE ON POST APPROVAL CHANGES

•CEP PROCEDURE IS APPLICABLE FOP EXISTING SUBSTANCES REPORTED IN EP MONOGRAPH

•AUTHORITY COMPETENT FOR THE ASSESSMENT OF CEP IS EDQM
•CEPS are accepted by the signatory parties of the Convention on the Elaboration of the European Pharmacopoeia, i.e. all the
member States of the European Union. Other countries accept CEP, e.g. Canada, Australia, New Zealand…..
•ASMF PROCEDURE IS APPLICABLE FOR EXISTING SUBSTANCES NOT REPORTED IN EP MONOGRAPH OR FOR
NEW CHEMICAL ENTITIES
•AUTHORITY COMPETENT FOR THE ASSESSMENT OF ASMF IS EMA
• ASMF: accepted across all the EU members depending on the route of application
•REVIEW PROCEDURE INCLUDES, CENTRALIZED PROCEDURE, DECENTRALIZED PROCEDURE, MUTUAL
RECOGNITION PROCEDURE
EU GUIDANCE ON POST APPROVAL CHANGES

• FOR CEP, “GUIDELINE ON REQUIREMENTS FOR REVISION/RENEWAL OF

CERTIFICATES OF SUITABILITY TO THE EUROPEAN PHARMACOPOEIA
MONOGRAPHS, PA/PH/CEP (04) 2, 7R corr”

• FOR ASMF, Guidelines of 16.05.2013 on the details of the various categories of variations, on
the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission
Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations
to the terms of marketing authorisations for medicinal products for human use and veterinary
medicinal products and on the documentation to be submitted pursuant to those procedures.
POST APPROVAL SUBMISSION OF CEP

• ANNUAL NOTIFICATION
• IMMEDIATE NOTIFICATION
• MINOR REVISION
• MAJOR REVISION
• SISTER CEP
• NEW CEP
ANNUAL NOTIFICATION

• Change in the name and/or address of a manufacturer of a starting material used

• Deletion of a manufacturer of a starting material used in the manufacture
•Minor change in the manufacturing process of an intermediate or the final
substance that is not expected to impact the quality
• Up to 10-fold increase or decrease compared to the original approved batch size
• Tightening of the limits /Addition of a new in-process test excluding CPP
• Deletion of a non-significant specification parameter
IMMEDIATE NOTIFICATION

• Change in the name and/or address of the certificate holder

• Change in the name and/or address of a manufacturing site or a quality control testing
site for the final substance
• Change in the name and/or address of a manufacturer of an intermediate used
• Deletion of a manufacturer of intermediate or of a manufacturing site
• Change in the manufacturer of a starting material is part of the same group as the
currently approved manufacturer
• Change in the manufacturer of an intermediate is part of the same group
IMMEDIATE NOTIFICATION

• Do and Tell change. Notification fee is 1000 Euros

• Tightening of specification limits for the final substance
• Addition of a specification parameter for the final substance
• Minor changes to a test procedure for the final substance. Editorial changes to a method
description annexed to a certificate of suitability
• Change in the composition of the immediate packaging of the final substance
• Removal or reduction of an approved re-test period
• Change to more restrictive storage conditions
MINOR REVISION TO CEP

• Approval time line 1M. Minor revision fee is 1500 Euros

• Change in the manufacturer of a starting material or intermediate is not part of the same group
• Starting material vendor uses a different route of synthesis or manufacturing conditions
• Any other minor changes in the manufacturing process of an intermediate or the final substance
• Change in batch size which is more than 10-fold increase compare to the originally approved
batch size
• Change of a limit for a mutagenic impurity in starting material /intermediate/ reagent/API
inline with ICH M7
MINOR REVISION TO CEP

• Widening of the approved specification limits for the final substance to be in line with the limits of
the Ph. Eur. monograph
• Introduction or revision (non-editorial changes) of a RMS (Risk management summary) regarding
elemental impurities
• Change in the re-test period or storage conditions of the final substance
• Addition of a re-test period for the final substance and/or change in the storage conditions for the
final substance
• Extension of the re-test period of the final substance and/or change in the storage
conditions for the final substance
MAJOR REVISION TO CEP

• Approval time line 2M. Major revision fee is 2000 Euros

• The proposed manufacturer of the starting material uses a different route of synthesis or
manufacturing conditions which impact the specifications of the final substance

• The proposed manufacturer of the intermediate uses a substantially different route of synthesis or
manufacturing conditions which are likely to change the specifications (qualitative and/or
quantitative impurity profile) of the final substance (e.g. change in synthetic strategy, new reagents,
solvents, materials are introduced into the synthesis)
MAJOR REVISION TO CEP

• Replacement of the manufacturing process with substantial changes likely to change the
qualitative and/or quantitative impurity profile of the final substance also including the
introduction of a ‘telescoped process’ (where multiple chemical transformations are run
without isolation of intermediates)

• Change in the manufacturing process of an intermediate or the final substance concerning

the sterilisation step(s), including changes in batch size of a sterile substance

• Changes in the manufacturing process of a herbal substance related to geographical

source or production
MAJOR REVISION TO CEP

• Addition of a new in-process test and limit regarding a critical parameter

• Widening of in-process test limits applied during the manufacture of the final substance
or specification parameter for a starting material / intermediate / reagent which may have
a significant effect on the overall quality of the final substance

• Deletion of in-process test limits applied during the manufacture of the final substance,
which may have a significant effect on the overall quality of the final substance

• Deletion of a specification parameter which may have a significant effect on the overall
quality of the final substance
WHEN SISTER CEP IS REQUIRED????

•Approval time line 3M. Sister CEP fee is 5000 Euros

•SF procedure is intended to facilitate the submission of similar dossiers and to allow applicants
benefit from a fast-track procedure and harmonised assessments
•SF procedure is applicable to cover an alternative manufacturing process, manufacturing site or
an alternative grade). This new application can be submitted as a “sister file”, provided that the
conditions listed in the guideline are fulfilled
•Advanced intermediate vendor changes should be reported as a SF
•If changes results in any potential impact on the quality of the final substance
•Introduction of a change (e.g. new class 2 solvent) in penultimate step >10% of ICH limit
WHEN NEW CEPT IS REQUIRED????

• Change that are considered substantially different = can the change impact the quality /
specifications of the final substance such as
Example 1: introduction of a new solvent which is not demonstrated absent in the final substance

Example 2: introduction of an additional solvent in the last step (even if already used in the previous
steps; and even if demonstrated absent)  substantial change since the impurities in the final
substance are different
Example 3: change in the manufacturing process that modifies the final substance impurity profile
Example 4: introduction of a new intermediate manufacturer that uses a different catalyst than the
approve intermediate manufacturer substantial change since leading to a different impurity profile in
the final substance.
POST APPROVAL CHANGES TO ASMF

• ASMF holders shall not modify the contents of their ASMF (e.g. manufacturing process or
specifications) without informing each Applicant/MA Holder and each competent
Authority. This obligation remains valid until the LoA has been withdrawn by the ASMF
holder

• Any change to the ASMF should be reported by every MA holder to the Competent
Authority by means an appropriate variation procedure
TYPES OF VARIATIONS

Following categories of variations, defined in Article 2 of the Variations

Regulation:

– Minor variations of Type IA

– Minor variations of Type IB

– Major variations of Type II

MINOR VARIATIONS TYPE IA

• Change in the manufacturer of a starting material/reagent/intermediate used in the

manufacturing process of the active substance when the proposed manufacturer is part of the
same pharmaceutical group (IN)

• Up to 10-fold increase / decrease compared to the originally approved batch size

• Tightening of in-process limits

• Addition of a new in-process test and limits

• Minor changes to an approved test procedure

MINOR VARIATIONS TYPE IB

• Change in the manufacturer of an intermediate

• Minor change to the restricted part of an Active Substance Master File
• More than 10-fold increase compared to the originally approved batch size
• Addition or replacement of an in-process test as a result of a safety or quality issue
• Changes to a test procedure (including replacement or addition) for the active substance
or a starting material/intermediate
• Addition or replacement of a specification parameter as a result of a safety or quality
issue
• Extension or introduction of a re-test period/storage period supported by real time data
MAJOR VARIATIONS TYPE II

• Alternate KSM or Intermediate manufacturer uses a substantially different route of

synthesis or manufacturing conditions, which may have a potential to change important
quality characteristics of the active substance
• Substantial change to the API manufacturing process of the active substance which may
have a significant impact on the quality, safety or efficacy of the medicinal product
• Widening of the approved in-process test limits, which may have a significant effect on
the overall quality of the active substance
• Deletion of an in-process test which may have a significant effect on the overall quality
of the active substance
MAJOR VARIATIONS TYPE II

• Change outside the approved specifications

limits range for the active substance
PMDA PERSPECTIVE ON POST APPROVAL
CHANGES
• MHLW ordinance determine minor or major changes
• There is no annual reportable changes concept in Japan
• Major Changes require customer acceptance and a partial change application would get filed
• Minor changes are those which are not specified explitly in the Ordinance
• Article 47, The minor changes specified by MHLW Ordinance pursuant to the provisions of
Article 14, Paragraph 10 of the Act shall be changes other than provisions of Article 14,
Paragraph 10 of the Act shall be changes other than those specified below
PMDA PERSPECTIVE ON POST APPROVAL
CHANGES
• (1) Changes in the manufacturing methods, etc. that will affect the nature, properties,
performance, or safety of a product
• (2) Deletion of items from the specifications and changes in the specifications
• (3) Changes concerning methods for the inactivation or elimination of pathogenic factors
• (4) Addition, changes or deletions concerning the dosage and administration, or the
indications
• (5) In addition to those specified in the preceding items, any changes that could potentially
affect the quality, efficacy, or safety of a product
PMDA PERSPECTIVE ON POST APPROVAL
CHANGES
• POTENTIAL CHANGES IN THE NATURE OF DRUG SUBSTANCES DUE TO
CHANGES IN REGISTERED ITEMS REQUIRES A “NEW
APPLICATION” FOR REGISTRATION (Which is not limited to the
following)

• MAJOR CHANGE IN THE ROS OF API OR INTERMEDIATE

• CHANGE IN THE APPROVE API SPECIFICATIONS

OTHER REGULATORS (INCLUDING EM)
PERSPECTIVE ON POST APPROVAL CHANGES
• OTHER REGULATORY MARKETS SUCH AS CANADA, AUSTRALIA, SOUTH
AFRICA, CHINA, BRAZIL AND REST OF THE EM COUNTRIES DO HAVE THEIR
OWN RULES AND REGULATIONS
• REGULATORS FROM CHINA, SINGAPORE, KOREA, AUSTRALIA CANDA HAVE
THEIR OWN STRINGENT REGULAOTRY REVIEW MECHANISM ON CHANGE
MANAGEMENGT OF DMFs FILED WITH THESE AUTHORITIES.
• REGULATORY INSPECTION FROM THESE AUTHORITIES IS COMPARBLE TO
US, EU AND JAPAN
REGULATORY PERSPECTIVE ON POST APPROVAL
CHANGES

• Let us do some case study based on Q&A!