RAAJ GPRAC PRIVATE LIMITED

Global Drug Master File [DMF] Submissions

[LSSSDC Accredited, ISO-29993-2017 Certified ]

Presented By: RAJNI JHA
Senior Pharmaceutical Professional
RAAJ GPRAC PRIVATE LTD.
[email protected], [email protected]
www.raajpharmaelearning.com
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 Disclaimer
Contents of this presentation are the presenters personal views and
do not necessarily represent any companies policies and position

Some images are taken – freely available from the internet for a
diagrammatic representation of the content and the source is
acknowledged

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 Global Marketing of Medicines
Role of Drug Regulatory Affairs in Pharmaceuticals
Methods for translating efforts of RnD Scientists into a safe,
efficient and cost effective medicine as a Team.
Maintaining relevant communications - both internal as well as
external to relevant stakeholders & the Regulatory Authorities
Ways to make decisions – resulting in Faster Approvals of the
Marketing Applications globally to be able to provide Quality
Medicines to the end-users[Patients].

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Introduction/Background & Principles

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 The Role of Regulatory Affairs

• Consultations with the appropriate regulatory agencies, e.g., Scientific

Advice procedures in the European Union (EU) or pre-IND meetings
with the FDA, are milestones in product development. They play an
important operational role, e.g., by considering the best processes to
follow & enable structured interaction with regulatory authorities.

• At the late stage of product development regulatory professionals are

responsible for the submission of the registration dossier, e.g.
Marketing Authorisation Applications (MAA) in the EU or New Drug
Applications (NDA) in the US.
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 Multiple Markets – Different & new
Regulations
• Emerging markets: Although the US and Europe are still the major markets,
the emerging markets of Brazil, Russia, India, China, Mexico, South Korea,
and Turkey are rapidly growing.

• The need to understand and adapt to the new complex regulatory

requirements in these emerging markets is placing new demands on
regulatory departments. Due to the still considerable differences in
documentation requirements, regulatory procedures, ways of
communication with the authorities, CMC regulations, importation
regulations, etc., local regulatory knowledge is the key to success in any
new market.

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 Introduction/Background
The Essentials & Requisites of an Effective Marketing Application:
• Regulatory affairs department translates research & development efforts of drug
development into approvable market applications inline with ever changing
global regulatory norms[ Dossier submission]
• Quality Assurance Department ensures Good Manufacturing Practices have been
followed right through drug development , scale up and commercial manufacture
as per the market applications submitted inline with most current global GMP
norms[ Certified via Facility Inspection]
• Team work involving various departments viz. Patent[IPR],Chemical Research
Analytical Research n Development, Packaging, Production, Quality control, Quality
Assurance, Purchase/Procurement, Marketing & Supply Chain.
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 Introduction/Background
Adequate and Accurate Compilation of elaborate registration
Applications for both APIs and Drug Products is very critical for
submission in different countries based on /impacted by

Regulatory and scientific knowledge regarding the drug

Adequate responses to deficiencies from different Regulatory Agencies
Implementation of regulatory strategies on a global level for the
organization
Knowledge of current regulations worldwide & experience gained by
interaction with authorities and Industry Experts expedites the approval
process.

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 Origin of Regulations
Regulations are the Rules & Directives set by Various Health Agencies &
Authorities Worldwide which maybe specific for a particular Therapeutic
Category of the Formulation or maybe Region specific .

Regulatory Affairs team is responsible for submitting the required set of

technical data regarding the medicinal product(as per the country specific
requirement) for getting its marketing approval in the respective markets
and coordinating and liasioning with the authorities during the review
process to ensure swift responses to queries raised.

It serves as an interface between the scientific and marketing expectations

in getting approvals from the relevant Health Agencies.

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 Regulations & Regulatory Affairs
The prestigious healthcare industry was the first to be significantly regulated in
the modern era.
Much of this regulation has stemmed from avoiding the repetition of disasters,
and has been led by the USA due to size of the US market and its technological
lead.
In the USA, this regulation is largely written directly into law & is codified in Title
21 of the Code of Federal Regulations (CFR)
In the late 1980s, the European Community (later the European Union) started
to harmonize the regulation of healthcare products in its member states. The
concept of regulating medicines was well established in most member countries
along lines similar to the US model.
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 Key Guidances , Directives and
References
US Food and Drug Administration (September 2004) Final Report on
Pharmaceutical CGMPs for the 21st Century- A Risk based Approach
Guidance for Industry : PAT- A framework for Innovative Pharmaceutical
Development, Manufacturing and Quality Assurance (Sep 2004)
Guidance for Industry : Q8(2) Pharmaceutical Development (November 2009)
Guidance for Industry : Q9 Quality Risk Management (June 2006)
Guidance for Industry : Q10 Pharmaceutical Quality System(Apr 2009)
Guidance for Industry : Q11 Development and Manufacture of Drug
Substances (November 2012)
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 Key ICH & Other Guidelines
Impacting Active Pharmaceutical Ingredients

Good Manufacturing Practices

Pharmaceutical Development design
Documentation requirements for APIs
Quality Risk Management
Development and Manufacture of Drug substances
Dealing with Impurities
Outsourcing Activities

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 Multi –Disciplinary Guidances
General FDA Site-http://www.fda.gov/ Drugs/GuidanceCompliance RegulatoryI nformation
/Guidances/ucm065005.htm
Q1 Stability Testing ; Q2 Methods Validation
Q3 Impurities
Q4B Evaluation and Recommendation of Pharmacopoeial Texts
Q5 Biotechnology Products
Q6 Specifications
Q7 GMPs for Active Pharmaceutical Ingredients
Q11 Development and Manufacture of Drug Substances
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM261078.pdf

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 Integrity across Cross Functional Teams

Production Team

Research n Development
IPR; Process; Analytical; Packaging Outsourced Facilities
CMO, CRO, Testing

Quality Assurance Procurement /Purchase/Supply

Change Control Management Chain , Marketing
Vendor Development & Qualification

16 August 2020 Raaj DMF Workshop August 2020 14

 APIs – Function As the Heart of Drug
Development Process For Generics
Active Pharmaceutical Ingredients [APIs]
As per the definition of ICH Q7A

An active pharmaceutical ingredient is defined in ICH Q7A as

“any substance or mixture of substances intended to be used in the
manufacture of a drug product and that, when used in the production of a
drug, becomes an active ingredient in the drug product.

Such substances are intended to furnish pharmacological activity or other

direct effect in the diagnosis, cure, mitigation, treatment or prevention of
disease or to affect the structure and function of the body”
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 APIs – Categories
There are different types of APIs defined by the Health
authorities –

APIs manufactured by
chemical synthesis,
 the fermentation process
APIs derived from plants and animals (well-characterized) and
 Semi-synthetic drug substances from plant and animal origin (well-
characterized) fall under the purview of one set of Guidance

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 DMFs

What is a Drug Master File?

Drug companies submit DMFs to FDA to provide confidential information
about facilities, processes, or articles. The DMF holder can then authorize
others to use the information within the DMF submission in support of
NDA, ANDA, and other submissions to either agency without disclosing
the information to anyone other than FDA.

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 APIs Requirements – Differences
Between EU & US-FDA
The specific data requirements for US, EU and other (non regulated) markets
may differ [wrt complexity of the API Particularly wrt key quality parameters
viz., polymorphism, Impurity profile, etc] but the basic expectation regarding
quality and compliance from the different Agencies remain the same

EU – Multiple Agencies and multiple registration procedures for the drug
product (and reviewers from different National Agencies)

US-FDA – One Agency (reviewers within the same Agency)

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 APIs Requirements – Differences
Between EU & US-FDA [Contd.]
Same set of data package to both (US & EU) will not result in the same
outcome (or review queries) because of the inherent differences in the review
style and perception of the reviewers [Europe is more detailed and stringent on
certain aspects]

GMP Expectations/Requirements are “universal” and audit or inspections

mechanisms are in place by these Agencies

Need to have global approach to regulatory issues and build a strong working
knowledge of the countries and their regulators across cross functional teams

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 APIs – The Heart of Drug Development
Process
APIs suppliers act like “partners” in the development process of the
generics drug product with the drug product manufacturer or formulator
– Use of in-house manufactured API for Products is a convenient time
saving route for drug approval process.

The ultimate goal is to sell the generic drug product to the human
population using “compliant” APIs on “Day 1”. The safety and efficacy of
the formulation is dependent upon the quality of the APIs and hence the
importance

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 APIs – The Heart of Drug Development
Process
Any change at the API Manufacturer’s end has direct impact on the formulator
– the need for “Strict” change control and involvement of the formulator

The need for “Detailed” agreement which should encompass “supply” or

“commercial” and more importantly “technical” aspects

Health Agencies are increasingly raising concerns on the carryover of

impurities and solvents to the final APIs – the need for “Strict” controls on Key
Intermediates and Key Starting Materials.

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 APIs – The Heart of Drug Development
Process
One of the major factors in the delays in the approval of the drug product is – API
DMF deficiencies are not answered in time- about the API, there is very limited
guidance specifically for APIs which involve more complex, hard core science and
chemistry and more detailed micro – characteristics in sync with evolving science
with modern automated tools and database.

Need for total co-operation and transparency between API Manufacturer and Drug
Product Manufacturer

Solid Manufacturing Process + GMP compliance of the manufacturing facility – Fast

Track Route for Commercialization of the Drug Product

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 APIs – The Heart of
Drug Development Process
Control of “Genotoxic” Impurities e.g. Sulfonates, Alkyl Mesylates etc. are
increasing concern areas

Qualification/Justification for levels of different solvents not listed/listed in ICH

at various stages of manufacturing

Elemental Impurities

Need to follow the “commitments” made in submission strictly & any change
need to be reported through the appropriate regulatory procedure applicable
for the respective jurisdiction
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 CFR Regulations
What are the CFR Regulations?

Data in accordance with CGMP requirements for drugs (i.e., as required by 21

CFR parts 210, 211, and 212).
Part 210 – Current Good Manufacturing Practice in Manufacturing, Processing,
Packing, or Holding of Drugs; General.
Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals
Part 212 – Current Good Manufacturing Practice for Positron Emission
Tomography Drugs.
Q7A – Active Pharmaceutical Ingredients.

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 Relevant Guidelines/Regulations
[ Refer most Updated Versions]
GCP - Good Clinical Practices
21CFR 312 Subpart D

CGMP –Current Good Manufacturing Practices GAMP

21CFR Part 211[Pharma] Good Automated Manufacturing Practices
21CFR Part 820[Waters] GAMP 5[ISPE]Guide
21CFR Part 110[Food]
21CFR 600-680[Biologics]

GALP
GLP –Good Laboratory Practices Good Automated Laboratory Practices
21CFR Part 58 EPA Directive 2185 [ 1995 Ed.]
40CFR Part 160[EPA]

16 August 2020 Raaj DMF Workshop August 2020 25

 Risk Management
(a practical example)
RISK ASSESSMENT
RISK CONTROL
Probability that collision Safe design:
happens and degree of
Build a bridge
severity of the resulting
Protection measures
damage
Trains at night
Cars in the day
Traffic lights
Warnings
Signals/noise

RISK MONITORING
Check if safety 26/
measures work
16 August 2020 Raaj DMF Workshop August 2020
 Data integrity
Data integrity is critical to regulatory compliance, and the fundamental reason for
21 CFR Part 11. It means data should be

Attributable
Legible
Contemporaneous
Original
Accurate

FDA Definition of data integrity used for internal training:

“Data are of high quality if they are fit for their intended uses in operations,
decision-making and planning . . . as data volume increases, the question of
internal consistency within data becomes paramount….”
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ALCOA EXPECTATIONS

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 Contemporaneous
Original
Attributable

Legible

Accurate ALCOA plus Enduring

Available
Retrievable

Complete
Consistent

Some more in the offing- Dynamic

*
16 August 2020 Raaj DMF Workshop August 2020 29
 Acceptance Criteria
Acceptance Criteria for impurities are Continuously Evolving due to –
Increase in Scientific Knowledge wrt inherent properties of the API
Risk Assessment by various Approaches /Tools available on date
Inclusion of DS/DP monographs in different Pharmacopoeieas
Revision of existing Monographs following toxic qualification or re-assessment of say residual solvents
or metallic residues.
Case studies following an increasing number of Applications filed with varied ROSs of APIs following
deficiencies raised by Regulatory Agencies and Responses and Justifications provided by
Pharmaceutical Industry particularly to the Different Member states of the European Union
Dosage – MDD and Duration of Treatment
Development of More sophisticated Analytical techniques to detect, resolve and quantify Impurities
adequately with acceptable LOD/LOQs
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 Regulatory Expectations and Industry Thought
Processes – The Gaps
Ref . : ISPE Presentation on QbD – November 2016
Gaps between Regulatory Expectations and Industry Thought Processes

Regulatory Authority Pharmaceutical Industry

Complex Regulations- You need to follow all Risk Aversion – Too many Regulations
our Regulations
You are not investing enough in Drug Development is already very expensive
Product/Process Understanding
You need to share more data Global Regulatory Agencies are not aligned
We need to know if you change ANYTHING The Approval process already takes so long ,
we cant afford more delays
You need to improve your processes If its not [totally] broken, we are not going to
fix it

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 “Data Integrity”
Top issues in QC Labs [ Not necessarily in the order given]

Raw Data
Software not validated
Raw Material Vendors
Equipment not validated/calibrated
Change Control/Unauthorized Access
Up dation of Validation - Most current
Reference & Working Standards
Pharmacopoiea & General Chapters for all tests

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 Introduction & Background[Contd.]
Stability testing & Packaging Development - crucial during drug development

Clinical trials are a critical and well-known part of the drug discovery, development and
approval process. Given the importance of drug safety, there are a number of additional
testing processes for the assessment of drug safety and efficacy and they are equally
important. Stability testing is one such example.

As an important step in the drug approval process, stability testing assesses how the quality
of a drug substance/product (& its packaging) varies with time under the influence of
environmental factors, including temperature , humidity & light.

The process determines whether any physical, chemical or microbiological changes affect the
efficiency & integrity of the final product, thereby ensuring that a pharmaceutical product is
safe & effective, irrespective of the market it will be supplied.
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 Introduction & Background[Contd.]

Moreover, stability testing establishes the shelf life and recommended

storage conditions of a finished pharmaceutical product and the retest
periods for a drug substance.

For the purpose of stability testing, the International Conference on

Harmonisation (ICH) divides the world into five climatic zones based on a
combination of temperature and relative humidity (RH). This division
ensures that the differences in climatic conditions in the varying regions
of the world are considered for stability studies.

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 The five climatic zones as per ICH
Zone I is defined as temperate
Zone II as Mediterranean/subtropical
Zone III as hot/dry, and
Zone IV as hot/humid.
In addition, a zone IVb was introduced relatively recently, which is defined as
hot/higher humidity and represents ASEAN (Association of Southeast Asian Nations)
testing conditions.

The climatic data that defines these regions is related to the Mean Kinetic
Temperature (MKT), which is a widely used measure in the pharmaceutical industry to
express the overall effect of temperature fluctuations during storage or transit.

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 The five climatic zones as per ICH
The five climatic zones are replicated in long-term stability studies to simulate the conditions
worldwide that a drug substance or drug product is subjected to. The ICH presents guidelines[ICH
conditions] on the conditions that should be included in a stability study. The long-term testing
conditions are shown in Table 1.

Table 1. Long-term (stability) testing conditions

Climatic Zone Temperatures Humidity
Zone I 21 °C (± 2 °C) 45% RH (± 5%)
Zone II 25 °C (± 2 °C) 60% RH (± 5%)
Zone III 30 °C (± 2 °C) 35% RH (± 5%)
Zone IV 30 °C (± 2 °C) 65% RH (± 5%)
Zone IVb 30 °C (± 2 °C) 75% RH (± 5%)
Refrigerated 5 °C (± 3 °C) None
Frozen -15 °C (± 5 °C) None
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 The five climatic zones as per ICH
During stability testing, a drug substance or drug product is evaluated under the
relevant ICH storage conditions, testing its thermal stability and its sensitivity to
moisture. The storage conditions tested and the lengths of the studies chosen
must cover the storage, shipment and use of the product.
For example, if a drug is produced in the UK (Zone I) and shipped to Egypt (Zone
IV) for distribution via Europe (Zones I and II), it would need to be tested under
zones I, II and IV.
Throughout the duration of the study, the stability of the drug is established
through physical, chemical, biological and microbiological tests. An example of
these tests is stress testing, of which photostability testing is a specific case that
assesses the effects of light exposure on the drug product or substance. A shelf
life and label storage instructions are then determined from the results of the
tests.

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 Regulatory Documents/Dossier
Strategy, Gap Analysis, Compilation, Regulatory Writing and
Submissions of
following application types

DMF submission in line with the GDUFA requirements to the USFDA

for APIs/Excipients
DMF in line with other global HA requirements for APIs
ASMF submission in line with the European requirements for APIs
CEP Application to European Pharmacopoeia to EDQM for APIs
API Master Files/Global Health Authorities
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 Regulatory Pre- submission Activity
Identifying the Regulatory starting material and route of synthesis for drug
substance and excipient
Designing of specifications for starting materials, raw materials, excipients,
packing materials, in-process, intermediates and drug substance/excipient
Setting the strategy and limits for genotoxic impurities and elemental impurities
Support in finalization of stability protocol, process validation protocol, hold time
study protocol, degradation study protocol and analytical method validation
protocol and review respective reports for submission
Gap analysis of submission batch documents
U.S./China /Japan agent services * Pre-assigned DMF number request
DMF/ASMF/CEP publishing in eCTD/NeeS/PDF as per current guidelines and
requirements
Addressing HA queries in stipulated
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All rights reserved for quick approvals – Wrap up
 The eCTD
To evaluate the safety and suitability of information submitted with
DMFs, Health Authorities mandated that the DMF is filed using an
electronic Common Technical Document (eCTD). Thus, the HAs can
fast track the processing, reviewing, and archiving of submissions.

Ensuring the same is practiced, the United States Food and Drug
Administration (USFDA) has set forth deadline for DMF eCTD
submissions, i.e. 05/05/2018, post which submissions will not be
received. Other Agencies have also done or in the process of doing so.

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 The eCTD
The Committee of the Eurasian Economic Union (EAEU) Mandated
Electronic Submissions

Mandatory From:
New Market Authorizations - Dec 31, 2020
- Follow-up Submissions – Dec 31, 2025

Switch to eCTD format, NOW!

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 New eCTD Requirements for FDA DMFs

As of May 5, 2018, the U.S. Food and Drug Administration (FDA) requires
electronic common technical document (eCTD) format for Type II, Type IV, and
Type V drug master file (DMF) submissions, including:
New DMFs
Annual Reports
Amendments
Supplemental Reports
FDA states that it will reject non-eCTD DMF submissions of these types.

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 New eCTD Requirements for FDA DMFs
What is eCTD?
eCTD is currently FDA’s standard submission format for new drug applications
(NDAs), investigational new drug applications (INDs), abbreviated new drug
applications (ANDAs), and certain biologics license applications (BLAs). FDA states
that DMFs are typically submissions to these applications and, as such, are subject
to electronic submission required by section 745A(a) of the Federal Food, Drug,
and Cosmetic (FD&C) Act.

When do FDA eCTD Requirements take Effect?

Type II, Type IV, and Type V DMF submissions to FDA must be in eCTD format as
of May 5, 2018. eCTD format will be required for type III DMF submissions
beginning May 5, 2020. FDA recommends using eCTD format to file Type III DMF
submissions now despite the extension.
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 New eCTD Requirements for FDA DMFs

Should I Convert My Existing DMF to eCTD?

Existing DMFs that are not in eCTD format, including those in paper
form, do not require resubmission; however, additional submissions
such as annual reports, supplements, and amendments to these
DMFs must be submitted in eCTD. Companies typically convert their
existing paper DMFs to eCTD to expedite the review process of a NDA
or ANDA that references the DMF.

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 New eCTD Requirements for FDA DMFs

How Do I File an eCTD Submission?

eCTD submissions 10GB or smaller must be sent through FDA’s
Electronic Submissions Gateway (ESG). Prior to accessing ESG, a user
must request an application number from FDA, register for an ESG
account, and configure their computer to communicate with the
gateway. FDA advises users to perform a series of tests prior to
submission. The process for ESG access may require several weeks.

Alternatively, the process can be expedited by having a Regulatory

Specialist [such as Registrar Corp]convert your DMF submissions to
eCTD format and submit them to FDA through ESG.
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 The USDMF Guidance

Docket Number:FDA-2019-D-3989 Issued by:Center for Drug

Evaluation and Research
This guidance provides FDA’s current thinking on drug master files
(DMFs), which are submissions to FDA that may be used to provide
confidential, detailed information about facilities, processes, or
articles used in the manufacturing, processing, packaging, and storing
of human drug products. DMFs can contain other types of information
as well (e.g., toxicology information, shared system REMS (risk
evaluation and mitigation strategy).

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 APIs – Drug Master File (DMF)

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 of the API
or other materials.

In the US, the DMF is generally submitted to support the IND (Investigational New
Drug), NDA (New Drug Application), ANDA (Abbreviated New Drug Application) or
other DMFs

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 APIs – Drug Master File (DMF)

In the EU, the DMF is generally submitted to support the MAA
(Marketing Authorization Application)

Filing of the DMF allows valuable confidential information of the drug

substance manufacturer to be protected at the same time allowing
the drug product manufacturer to take full responsibility for the drug
product in the market.

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 APIs – Drug Master File (DMF)

The DMF (either in the US or EU) is never “approved” or

“disapproved”. The DMF is only accessed and reviewed in support of
an application by the drug product manufacturer and ultimately the
drug product application is approved by the respective Agency. It
however is judged suitable for use wrt European region once
European product gets an approval.

The review of the new DMF does not start automatically. The review
is triggered only after the submission of the drug product application
which refers the DMF

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 APIs – Drug Master File (DMF)

Submission of the DMF for the APIs is not a mandatory requirement.

The necessary information can also be submitted in the drug product
application. However, because of the confidentiality issues and future
marketability potential, this is the preferred approach

Changes to the information provided/committed in the DMF cannot

be made without informing the Drug Product Manufacturer (or the
Agency) as it needs to be reported to the Agency accordingly by the
drug product manufacturer in line with relevant current Regulatory
Guidelines

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 LOA – for DMF Access
LOA – Letter of Access

The DMF contains confidential information about the manufacturing

process/details for the material and is submitted with the respective
authority

By submitting the LOA, the holder of the DMF basically authorizes the
respective authority to refer to the confidential information contained
in the DMF in support of the application submitted by the entity to
whom the LOA has been issued by the DMF holder

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 LOA – for DMF Access
The LOA is addressed to the respective Agency and details the
application to which the access is being given by the DMF holder

The drug product submission will be rejected in the absence of a LOA

from the DMF holder if the DMF has been referred in the application

LOA can be issued in support of multiple customers for the same

DMF

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 Differences Between Europe & US
In Europe – DMF is known as Active Substance Master File (ASMF) or the European
Drug Master File (EDMF)

The DMFs or ASMFs for APIs, consists of

Applicant’s Part (Manufacturer shares with MAH as well as Authority)
Restricted Part (Manufacturer shares with authority only) [For APIs which may or
may not be official in EP]

Certificate Of Suitability (CEP) or COS is issued by European Directorate for the

Quality of Medicines & Health Care (EDQM) for APIs /Excipients which are part
of EP monograph.
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 Differences Between Europe & US
In the USA, DMF is a single file and is categorized as follows-

Type II – Drug substances, Intermediates, Source materials,

Drug products
Type III – Packaging Materials
Type IV – Excipients , Colorants, Flavors, Essence , Source materials
Type V – FDA Accepted Reference Information
Type I – Manufacturing Site, Facilities, Operating Procedures, and Personnel
(no longer applicable)

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 Differences Between Europe & US
Basic data requirements for a DMF across the regions are designed
around the CTD (Common Technical Document) structure:

- General Information
- Manufacture
- Characterization
- Control of Drug Substance
- Reference Standards or Materials
- Container Closure System
- Stability

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 Differences Between Europe & US
The data requirements and the expectations for the above
components differ between the US and EU and warrant monitoring
the Agencies ’s websites for most recent changes in rules and
requirements

Filing of the DMF in the US is also at a cost now since October 2012
;in the EU, the CEP filing or the Amendment filing involves a certain
cost. Italy however charges for DMF filings in Europe.

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 DMFs – GMP Inspection Process for
the EU & US-FDA
On completion of review of the DMF(& the response process for the queries
raised during the review of the dossier) and the positive compliance
report/certificate of the manufacturing facility for the API, by a competent
authority, the authorization for the drug product is obtained

API manufacturing sites are routinely inspected by European Agencies or by the

US Agency -FDA. The normal frequency of the inspections are:
- US-FDA: Every 2 Years
- EU (EDQM): Every 3 Years

Frequency can be less or more - resource availability at the Agencies.

©Raaj GPRAC, All rights reserved

 DMFs – GMP Inspection Process for
the EU & US-FDA
If a new manufacturing site is being proposed through any drug
product filing, the respective Agency normally inspects the facility
prior to granting the approval of the drug product

If the manufacturing site is already inspected and the subsequent

filing is done from the same manufacturing site (with similar type of
operation), the approval is generally granted based on the
documentation review

©Raaj GPRAC, All rights reserved

 GMP Inspections for the API- Salient Points

The Agencies expect the manufacturer to apply cGMPs to the API

process beginning with the use of starting materials and to validate
the critical process steps that impact the quality and purity of the final
API

Controls over material quality are expected to increase as the process

approaches the final API

©Raaj GPRAC, All rights reserved

 GMP Inspections for the API- Salient Points

The Agencies expect the manufacturer to apply cGMPs to the API

process beginning with the use of starting materials and to validate
the critical process steps that impact the quality and purity of the final
API

Controls over material quality are expected to increase as the process

approaches the final API

©Raaj GPRAC, All rights reserved

 GMP Inspections for the API- Salient Points
The general approach by the Agencies for auditing the manufacturing site
for the API consists of the following:

Quality System assures overall compliance with cGMPs and internal procedures and
specifications

Facilities and Equipment System includes activities which provide an appropriate

physical environment and resources used in the production of APIs

Materials System includes measures and activities to control starting materials,

intermediates and containers. It includes validation of computerized and inventory
control processes, storage, and distribution controls

©Raaj GPRAC, All rights reserved

 GMP Inspections for the API- Salient Points
 Production System includes measures and activities to control the
manufacture of APIs, including in-process sampling and testing, and process
validation

 Packaging and Labeling System includes measures and activities that control
the packaging and labeling of intermediates and APIs

 Laboratory Control System includes measures and activities related to

laboratory procedures, testing, analytical methods development and methods
validation or verification, and the stability program

©Raaj GPRAC, All rights reserved

 APIs – Change Management
There is a Continuous Evaluation of Product and does not end
after initial submission-

Each component API or Formulation submitted to Agencies have significance as

defined by different Agencies & changes to these have implications in terms of
additional data generation & reporting mechanisms to the respective Agencies

The changes proposed by the drug substance manufacturer need to be submitted

as an amendment to the DMF along with the necessary data to both the
Applicant[ drug product Manufacturer]and relevant agencies.

©Raaj GPRAC, All rights reserved

 APIs – Change Management

The drug product manufacturer in turn has to submit the necessary

variation application with the respective Agency for the approval of
this change along with the required data so that they are free to use
the revised API

API manufacturer has the “obligation” to update/inform the

customers regarding the changes being implemented so that the drug
product manufacturer acts accordingly

©Raaj GPRAC, All rights reserved

 Drug Master Files

A Drug Master File (DMF) is a submission of information to the FDA

to permit the FDA to review this information in support of a third
party’s submission without revealing the information to the third
party.

DMFs usually cover the Chemistry, Manufacturing and Controls (CMC)

of a component of a drug product e.g. drug substance, excipient ,
packaging material.

Drug product information or non-CMC information may be filed in a

DMF.
©Raaj GPRAC, All rights reserved
 Information Sources
DMF Web site http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ Forms
Submission Requirements/DrugMasterFiles DMFs/ default.htm
Contains current list of DMFs, links to supporting guidances and, most
importantly, advice for DMF holders not in DMF Guidance (1989) Guidance link:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Forms Submission
Requirements/Drug Master Files DMFs/default.htm
DMF questions: General: dmf [email protected]
GDUFA specific: [email protected]
Technical questions e.g. about amount of stability data needed, designation of
compound as a starting material are review issues and not DMF issues. Send
inquiries to [email protected]
©Raaj GPRAC, All rights reserved
 Laws and Regulations
Laws - Food Drug and Cosmetic Act (FD&C Act)
Food and Drug Administration Safety Information Act (FDASIA) including the
Generic Drug User Fee Act (GDUFA) and Prescription Drug User Fee Act (PDUFA)

Regulations: Section 21 of the Code of Federal Regulations (21 CFR)

Required information 314 New Drug Application (NDA) and
Abbreviated NDA (ANDA)314.50 Content and format of an application
314.70 Changes to an Approved Application
314.420 Drug Master Files

©Raaj GPRAC, All rights reserved

 Requirement & Reasons for DMFs
Who Must File a DMF?- NOBODY !

There is no legal or regulatory requirement to file a DMF. Same Information can

be submitted in an Application (NDA or ANDA).

Then why do we file a DMF? Reasons for a DMF!

Maintain confidentiality of proprietary information (e.g., Manufacturing

procedure) for the holder
Permit review of information by reviewers at FDA to support applications
submitted by one or more applicants

©Raaj GPRAC, All rights reserved

 Clarification of Some Relevant Terms
Registration: In many parts of the world a company ”Registers” an application or a “dossier.”
In the US, only manufacturing sites are “registered” in the Drug Registration and Listing
System (DRLS)

Active Pharmaceutical Ingredient (API) = “drug substance.”

Letter of Access: In some cases a DMF holder will call the permission to reference a DMF a
“Letter of Access.” (Phrase used in Europe). In the US, this is called a “Letter of Authorization”
(LOA). An LOA does not permit anyone except FDA to “Access” i.e. “read” the DMF

Transmittal Letter = Cover Letter

Annual Report = Annual update

©Raaj GPRAC, All rights reserved
 Initial Submission - Paper DMFs
Holder sends the DMF in two copies to
Central Document Room
Center for Drug Evaluation and Research
5901-B Ammendale Road
Beltsville, MD 20705-1266

Use recommended binders

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRe
quirements/DrugMasterFilesDMFs/ucm0 73080.htm

Fasteners must be obtained separately. 2 Piece Prong Fasteners, 8 1/2" Center to

Center, 3 1/2" Capacity
©Raaj GPRAC, All rights reserved
 Initial Submission – Electronic DMFs
Electronic Submission Gateway (ESG)–Holder sends the DMF in Electronic
Common Technical Document (eCTD) format through the ESG
http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default. htm
- Choose "CDER" as the Center and "eCTD" as the submission type"

Physical Media (CD-ROM, DVD or USB drive)–Holder sends the DMF on physical
medium in eCTD format to the address on previous slide
–See the Transmitting Specifications website when transmitting via physical
media (CD\DVD)
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Forms
SubmissionRequirements/ElectronicSubmissions/UCM163567.pdf
Acceptance of digital signatures the same as for any other submission to FDA

©Raaj GPRAC, All rights reserved

 Initial Submission – Electronic DMFs
Guidance

Follow the DMF Guidance and additional information on DMF Web site.

Pre-assigned Number

A pre-assigned number is required for an EDMF. May also be obtained for paper
DMF. See “Requesting a Pre-Assigned Application number”

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequi
rements/Electronic Submissions/ucm114027.htm

©Raaj GPRAC, All rights reserved

 Initial Submission – Components
Transmittal (cover) letter, including pre-assigned number, where applicable

Administrative information. For complete list of information to include see DMF Web site. Make
sure to include Telephone number, fax number and e-mail address for the responsible individual
(contact person)

A Statement of Commitment (Recommended in the DMF Guideline : “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.”)

NEW !! on Web site: List of Referenced applications e.g. DMF for intermediates
Technical information

©Raaj GPRAC, All rights reserved

 How the System Works
DMF entered into FDA’s database (DARRTS) and assigned a number
Status = PENDING Not available for review
Reviewed for administrative purposes ONLY by the Office of Business
Informatics (OBI) staff. If incomplete, OBI sends a request for
additional information.
If administratively complete, OBI sends an acknowledgement letter
Status = ACTIVE Available for review.
Usual processing time is 2-3 weeks
E-mail: [email protected]

©Raaj GPRAC, All rights reserved

 Acknowledgement Letter
Notifies holder of DMF number and type.
Includes Title(Subject) & Holder of DMF.
Will appear on list posted on web site
“SUBJECT OF DMF as manufactured in CITY, STATE or CITY,COUNTRY.”
Reminder of obligations of holder. Submit all changes as amendments. Notify FDA
of change in holder name or address
Notify FDA of change in agent/representative
Notify authorized parties of changes
SUBMIT ANNUAL REPORT
Submit Letter of Authorization (LOA) for each item referenced for each customer
©Raaj GPRAC, All rights reserved
 Guidances for Technical Information
Format: Common Technical Document (CTD)
CTD is a structured format that permits efficient life-cycle management,
which is important for DMFs and for electronic submissions

Guidance for Industry M4Q: The CTD – Quality

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM073280.pdf
Drug Substance Guideline for Submitting Supporting Documentation in
Drug Applications for the Manufacture of Drug Substances
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM070632.pdf
ICH Quality Guidances: See next Slide

©Raaj GPRAC, All rights reserved

 Key ICH and other Quality Guidances
General FDA Site -http://www.fda.gov/Drugs/GuidanceCompliance
RegulatoryI nformation /Guidances/ucm065005.htm
Q1A- Q1F Stability Testing
Q2 Analytical Validation
Q3A- Q3D Impurities
Q4- Q4B Evaluation and Recommendation of Pharmacopoeial Texts
Q5A-Q5E Quality of Biotechnology Products
Q6A-Q6B Specifications
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients
Q8 Pharmaceutical Development
©Raaj GPRAC, All rights reserved
 Key ICH and other Quality Guidances
Q9 Quality Risk Management
Q10 Pharmaceutical Quality Systems
Q11 Development and Manufacture of Drug Substances
Q12 Lifecycle Management

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInf
ormation/Guidances/UCM261078.pdf
Other guidances relevant to the specific market

Always refer to the most updated Guidance on the respective country site
©Raaj GPRAC, All rights reserved
 Letter of Authorization (LOA)
The DMF will be reviewed ONLY when it is referenced in an
Application or another DMF.
An LOA does two things: Grants FDA authorization to review the
DMF
Grants the Authorized Party the right to incorporate the
information in the DMF by reference.

The holder MUST submit an LOA (2 copies for paper) to the DMF
THEN send a copy to the APPLICANT
APPLICANT submits copy of LOA in their Application. ONLY
mechanism to trigger complete technical review of the DMF.

©Raaj GPRAC, All rights reserved

 Letter of Authorization (LOA)
LOA must contain a specific reference to a particular item in the DMF.
Specify the item by its code name, page number and, most
importantly, DATE OF THE SUBMISSION as it appears on the cover
letter of that submission (not an internal document date) Volume
number not useful
When the Authorized Party (AP) changes its name, the DMF holder
should issue a new LOA and send a copy to new AP.
When holder changes name the DMF holder should issue a new LOA
and send a copy to all APs.

©Raaj GPRAC, All rights reserved

 Letter of Authorization (LOA)
It is not necessary to resubmit an LOA on a periodic basis. However,
the list of authorized parties should be submitted in the Annual
Report

Withdrawal of Authorization: If a DMF holder withdraws

authorization for a customer to reference the DMF this should be
submitted as a “Withdrawal of Authorization” document.

©Raaj GPRAC, All rights reserved

 Electronic DMF (EDMF)
ALL electronic applications MUST follow the Electronic Common Technical
Document (ECTD), unless a waiver is granted. No waivers granted for DMFs

How to submit: http://www.fda.gov/downloads/Drugs/GuidanceComplian

ceRegulatoryInformation/Guidances/UCM149705

Can convert paper DMF to EDMF but once electronic, cannot submit paper,
even for LOA.

~12% of Type II DMFs submitted since 01/01/2001 are electronic

©Raaj GPRAC, All rights reserved

 Electronic DMF (EDMF)
Submitting a DMF using Electronic Common Technical Document
(eCTD)

Contact [email protected] for DMF-related submission

questions.

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, storing of one or more human
drugs.

©Raaj GPRAC, All rights reserved

 Electronic DMF (EDMF)
Beginning on May 5, 2018, new DMFs, as well as all documents submitted
to existing DMFs, must be submitted using the Electronic Common
Technical Document (eCTD). DMF submissions that are not submitted in
eCTD format after this date will be rejected.

Pre-assignment of DMF Numbers

DMF holders wishing to submit an electronic DMF must obtain a pre-
assigned number. See “Requesting a Pre-Assigned Application number.”

For conversion of a paper DMF to electronic CTD format, see Electronic

DMF Guidance

©Raaj GPRAC, All rights reserved

 Electronic DMF (EDMF)

ELECTRONIC DMFs

The FDA has published a Final Guidance, "Providing Regulatory

Submissions in Electronic Format — Certain Human Pharmaceutical
Product Applications and Related Submissions Using the eCTD
Specifications" (5/15/2015) regarding electronic submissions. The
compliance date for submitting a DMF in electronic format is May 5,
2018.

©Raaj GPRAC, All rights reserved

 Electronic DMF (EDMF)
CONVERSION OF PAPER DMFs TO ELECTRONIC DMFS
An existing DMF number may be used when converting a paper DMF
to electronic format. If the existing number is 4-digits, e.g. 1234, the
DMF holder should pad left with zeroes to convert to a 6-digit format,
e.g. 001234.

Read - Electronic Submissions Gateway guidance on the US FDA site

©Raaj GPRAC, All rights reserved

 Annual Reports (ARs)
Not required under any regulation .
Regulations require that the DMF “…contain a complete list of each
person currently authorized to incorporate by reference any
information in the file…” See 21 CFR 314.420(d).

Recommended in Guidance to permit DMF holders to fulfill this

requirement on an annual basis, rather than submitting a new list
whenever a new Authorized Party is added.

©Raaj GPRAC, All rights reserved

 Annual Reports (ARs)
Should contain List of authorized Parties
List of all changes reported since last AR
If no changes, include a statement to that effect
The list of “authorized parties” is a list of the customers. It is NOT a
list of individuals who work for the holder or their agent who are
authorized to ADD material to the DMF
All changes in technical or administrative information (including
updates to stability data) MUST be reported as amendments when
they occur. See 21 CFR 314.420(c).

©Raaj GPRAC, All rights reserved

 Reporting Changes to a DMF
A DMF can be reviewed at any time when a review is triggered by
reference in an APPLICATION.

Therefore, DMF must be up-to-date at the time of review.

If changes have been made but not reported to DMF, reviewer can
waste valuable time (on the APPLICANT’s clock) reviewing obsolete
information.

©Raaj GPRAC, All rights reserved

 Closure & Reactivation of DMFs

Closure by Holder: Holder submits a Closure request to DMF

Entry into database changes status to “Closed.” Unavailable for
review.
Closure by FDA : If a DMF has not had an Annual Report in three
years, FDA issues an Overdue Notice Letter(ONL).
After ONL issued, holder can retain activity of DMF ONLY by
submitting an Annual Report.
If no response to ONL in time period specified in ONL (90 days),
FDA can change the status to “Closed.” Unavailable for review

©Raaj GPRAC, All rights reserved

 Closure & Reactivation of DMFs
Reactivation of a Closed DMF :
Holder submits a “Reactivation”
Should contain a complete copy of the DMF, containing any revisions since
the last submission.
Contact DMFQuestion for a request for an exception to the recommendation
to resubmit the entire DMF.

 Entry of a Reactivation into DARRTS changes status to “Active” and the DMF
is available for review.

Status of DMF shows up on DMF Web site list

©Raaj GPRAC, All rights reserved

 Review of DMFs

DMFs ARE NEITHER APPROVED NOR DISAPPROVED

A DMF is reviewed to determine whether it is adequate to support the

particular Application that references it.

©Raaj GPRAC, All rights reserved

 DMF Review and Communications Procedure

DMF is reviewed using same regulatory and scientific criteria as

review of Application

If more information is needed to complete the review, a list of the information
needed is communicated to the holder in an Information Request (IR) Letter

If the information in the DMF cannot support approval of the application that
references it FDA sends a Deficiency Letter (DEF) or Complete Response (CR)
Letter (specific for Type II DMFs under GDUFA), and then [next slide]

©Raaj GPRAC, All rights reserved

DMF Review and Communications Procedure

The APPLICANT is notified that information has been requested for the DMF.
The letter to the APPLICANT is either an IR or CR Letter.

The nature of the information requested in the DMF letter is not

communicated to the APPLICANT.

If no information needed for DMF, No letter to DMF holder except for “No
Further Comments” letter specific for Type II DMFs under GDUFA.

Applicant not notified.

©Raaj GPRAC, All rights reserved

 Agents for DMFs
Not required, although recommended to facilitate communication for foreign
company

Holder appoints agent in Agent Appointment Letter on the holder’s letterhead.

Responsibilities of agent should be defined in Agent Appointment Letter

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInfo
rmation/DrugRegistrationandListing/ucm084014.htm

Do not use the word “authorize” in appointing an agent. This can be easily
confused with a Letter of Authorization. Use the word is “appoint.”
©Raaj GPRAC, All rights reserved
 New GDUFA DMF Requirements
DMF fee – when and how to pay

New DMF correspondences and meetings DMF Complete

Response letter
DMF Incomplete letter
DMF No Further Comments letter
DMF 10-day teleconference
Available for Reference List
http://www.fda.gov/downloads/ForIndustry/UserFees/G
enericDrugUserFees/UCM332875.pdf

©Raaj GPRAC, All rights reserved

 New GDUFA DMF Requirements
FEES
GDUFA requires DMF fees for Type II DMFs for drug substances
(Active Pharmaceutical Ingredients (APIs)) used to support
Abbreviated New Drug Applications (ANDAs).

Since GDUFA does not apply to any other type of DMF or to Type II
DMFs used to exclusively support NDAs or INDs, there are no fees for
these types of DMFs.

©Raaj GPRAC, All rights reserved

 When A DMF fee is not Required

For ANDAs that are part of the backlog

For submissions not part of GDUFA (INDs, NDAs, Changes Being
Effected (CBE) 0 or 30 supplements)
For any non-Type II DMF (Type IV DMF for an excipient)
For any Type II DMF that is not referenced as the APIDMFs for API
intermediates
DMFs for drug product manufacturing intermediates
DMFs for Drug Products

©Raaj GPRAC, All rights reserved

 The DMF Fee under GDUFA

Fee collection is processed in FDA for GDUFA by OFM

(Office of Financial Management), who manage the payment
infrastructure and OM (Office of Management) who manage and track
the user fee obligations

Two common cases for fee payment:

 Paying DMF fees for DMFs which are not yet filed with FDA
 Paying DMF fees for DMFs which are already filed with FDA

©Raaj GPRAC, All rights reserved

 DMF Fee payment triggers Completeness
Assessment

DMF Fee is a one-time fee & is different from the facility fee related to the drug
substance manufacturing facility
Payment of the DMF fee triggers the Completeness Assessment process in OGD
DMF Fee is required when referencing ANDA is submitted
DMF Fee may be paid independent of a referencing ANDA in order to get a
completeness assessment and be to listed on the FDA’s “Available for Reference”
webpage.
There are risks of delaying the ANDA filling if DMF fee has not been paid

©Raaj GPRAC, All rights reserved

 Characteristics of the DMF CR Letter

The DMF CR Template has been in use since mid-October

2012 and contains the following sections

Chemistry Deficiencies (if applicable)

Microbiology Deficiencies (if applicable)
Facilities information (if available)Standard language approved by the Office
of Compliance
No further questions if facilities acceptable
Inspections/evaluations pending

©Raaj GPRAC, All rights reserved

 Characteristics of the DMF CR Letter

The DMF letters will issue before the ANDA CR letter for a given review cycle to
comply with ANDA CR requirements.
DMF CR letters will be referred to in the ANDA CR letter along with instructions to
the applicant not to respond until the DMF holder has indicated that they have
submitted a complete response to the DMF CR letter.
DMF responses from the holder must address all issues raised in the Chemistry
and Microbiology sections of the letter or they will not be reviewed.
Note that statements in the DMF amendment deferring response to a future
submission are not acceptable.
DMF must notify the ANDA sponsor when they submit their response

©Raaj GPRAC, All rights reserved

 DMF No Further Comments Letter
The Commitment letter states: “Once a DMF has undergone a complete
review & the ANDA referencing same is either approved or tentatively
approved – at such time there being no further outstanding deficiencies to the
DMF
– FDA will issue the DMF holder a letter to indicate that the DMF does not
have any further open matters as part of the review associated with the
referencing ANDA.”

Issued at approval of the ANDA, not when the DMF is first deemed adequate

©Raaj GPRAC, All rights reserved

 DMF Incomplete Letter
Issued to communicate issues discovered during Completeness Assessment.
Comments in the letter will describe any issues and the additional information
that is needed to address the issues

DMF holders need to respond with an amendment as quickly as possible to avoid

adversely impacting the filing of an ANDA

Cover letter of the amendment should indicate that the submission is a

“Response to DMF Incomplete”

Notification instructions in the fax coversheet need to be followed to avoid delays

in updating the Completeness Assessment

©Raaj GPRAC, All rights reserved

Completeness Assessment focuses on “Complete”
New requirement in the GDUFA legislation :Drug substance (Type II) DMFs must
be deemed “available for reference” by the HHS Secretary to be referenced by an
ANDA.

Two things must happen for the DMF to be considered “available for reference”
 DMF Fee must be paid
 DMF must pass a “completeness assessment”

ANDAs can only be filed by OGD if all DMFs for the drug substance(s) are “available
for reference” .

©Raaj GPRAC, All rights reserved

 New Market Authorizations - APIs
Filing Active Pharmaceutical Ingredient (API)/Excipient information separately to
Health Authorities (HAs) is not mandatory.

However, to maintain the confidentiality and to refer the same information for
multiple drug product applications, as a practice, manufacturers of API/Excipients
file the information as Drug Master Files (DMFs), Active Substance Master Files
(ASMFs), and Certificates of Suitability (CEPs) as per the region-specific
requirements.

Once API/Excipient information is filed with HAs and is accepted, same can be
referred through Letter of Access (LoA) to multiple applications to avoid
duplication of API information for different drug product submissions.
©Raaj GPRAC, All rights reserved
 New Market Authorizations - APIs
Regulatory submission requirements for API (Drug Substance)/ Excipients are very
specific and different for every Health Authorities .

Hence, expertise and experience in filing DMFs, ASMFs, CEPs, and active
ingredient master files to global Health Authorities help in quick review approval
of drug product applications.

Organizations need very strong Regulatory team with expertise in handling new
submissions to all major Health Authorities.

©Raaj GPRAC, All rights reserved

 Major Health Authorities
The United States Food and Drug Administration (USFDA)
The European Medicines Agency (EMA),
The European Directorate for the Quality of Medicines (EDQM)
The Therapeutic Products Database (TPD)
The Pharmaceuticals and Medical Devices Agency (PMDA)
The Therapeutic Goods Administration (TGA)
The Medicines Control Council (MCC),
Ministry of Health (MoH) of Russia,
Latin America (LATAM), Middle East and North Africa (MENA)
 Asia Pacific (APAC), Association of Southeast Asian Nations (ASEAN),
Commonwealth of Independent States (CIS) regions and
World Health Organization (WHO).
©Raaj GPRAC, All rights reserved
 API Registration in Japan
The active pharmaceutical ingredient (API) market in Asia is growing at an
increasingly rapid pace. From 2007 to 2011, it went from 24.5 to 28.5 percent of
the world market. From now through 2017, it should expand at a rate of 8.2
percent annually. This puts Asia’s API market — worth $33 billion currently — at
more than $50 billion by 2017. [ Covid!!!!!]
Many foreign API firms from India, Europe and the US are actively selling their
APIs on the Japanese market.
Japan’s share of innovator APIs is high, and demand is growing especially in the
biotech drug sector. But API generics are also starting to gain ground in Japan.
Chinese and Indian firms have recently flooded Japan’s market with inexpensive
APIs. The accompanying price competition has forced some Japanese API
manufacturers out of their own domestic market
©Raaj GPRAC, All rights reserved
 API Registration in Japan
API REGISTRATION
In order to register an API with the Japanese Pharmaceuticals and Medical
Devices Agency (PMDA), manufacturers must first apply through Japan’s Drug
Master File (DMF) system.

The Japanese DMF system is similar to the one run by the US Food and Drug
Administration (FDA). The Japanese DMF system makes it possible for API
manufacturers to register their products with the PMDA directly. In this way, API
manufacturers avoid having to turn over sensitive information when finished drug
manufacturers use their product. For each finished drug application involving the
API, the PMDA simply pulls the information it needs from the DMF.

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 API Registration in Japan
DMF registration is a voluntary process in Japan. Items such as APIs and new
excipients (those that have different composition ratios from existing excipients)
can be registered. According to the PMDA, drug substances, intermediaries and
materials in OTC drugs do not need to be registered.

In Japan, the API or excipient manufacturer is in charge of DMF registration. If the
manufacturer lacks its own office in Japan, it must appoint a person or a business
entity called an In-Country Caretaker (ICC) to apply for them. The ICC must fill out
the DMF application and answer all PMDA questions, both during and after API
registration.

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 API Registration in Japan
Registration materials should be submitted in Japanese and must include:
The name of the API or drug substance
The name and location of the manufacturing site
The manufacturing license number and type
The name and address of the ICC
Drug ingredients * Manufacturing methods
Manufacturing process controls
Specifications and test methods
Non-clinical studies (in the case of new excipients)
Quality control tests , Stability tests & Storage methods
Safety information
The dates of expiration ©Raaj GPRAC, All rights reserved
 API Registration in Japan
DMF registration is free. There are no additional government fees. The PMDA
suggests that applicants submit all materials prior to the submission of finished
drug applications that use their product.[Covid !!!]

Finished drug manufacturers must cite all relevant DMFs during their own drug
registration. They are encouraged to attach DMF registration certificate copies to
their own applications. In the course of the PMDA review for the finished drug
product, all questions about the DMF products are directed to either the DMF
license holder or to the ICC.

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 API Registration in Japan
If any changes are made to the production process of DMF products, a “minor
change notification” or an “application for change in registration” should be filed
with the PMDA. The API manufacturer also needs to discuss any such changes
with the manufacturer of the finished drug product, as the finished drug
manufacturer also needs to file a “partial change notification” or a “partial change
approval application” for any changes in the API production process.
The PMDA provides simple consultation sessions for matters relating to DMF
registration.
FOREIGN COMPANIES IN JAPAN
An increasing number of foreign pharmaceutical companies are selling APIs on
the Japanese market. Sometimes they sell to domestic drug manufacturers and
sometimes they sell to foreign drug companies manufacturing products in Japan.

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 API Registration in Japan
Drug Master File System in Japan
Ref :
Master File Management Group Division of Pharmacopoeia and Standards for
Drugs Office of Review Management Pharmaceuticals and Medical Devices
Agency (PMDA)

In Japan, the Drug Master File (DMF) is called “Master File” or “MF”.

Part 1. How to register to MF in Japan

Part 2. Generic Drug Review System, MF System

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 API Registration in Japan
Foreign manufacturers applying for MF registration must appoint an in-country
caretaker for drug substances (APIs), etc. Pharmaceuticals and Medical Devices
Agency (PMDA)
Approval application for pharmaceutical products marketing authorization
applicant PMDA APIs manufacturer CTD-3 Disclosed(Open) Part Restricted(Closed)
Part
Select an in-country caretaker for drug substances (APIs) etc., who lives in Japan
and will undertake clerical work for the relevant registration, etc. Foreign
manufacturer(MF Holder) cannot submit “CTD-3” of API manufacturing methods
to PMDA directly.
Foreign manufacturer (MF Holder) In-country caretaker PMDA the Act on
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices,
Regenerative and Cellular Therapy Products, Gene Therapy Products, and
Cosmetics Pharmaceuticals and
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 Different Items for MF registration
Drug substances, intermediates (for medical use)

New excipients and pre-mix excipients with different composition ratios from the
existing ones

Materials used for manufacturing Cellular and Tissue-based Products （Cell,

Medium, Medium Excipient, etc.）

Others Pharmaceuticals and Medical Devices Agency (PMDA) PFSB / ELD

Notification No.11173 December 11, 2014 12 Pharmaceuticals and Medical
Devices Agency (PMDA)

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 The Regulations
It is important for the MAA/MAH, the MF Holder and the incountry caretaker to
understand the Japanese regulation (PFSB / ELD Notification No. 0210001
February 10, 2005) and the guidance.

[Disclosed(Open) part] The MAA/MAH, the MF Holder and the in-country

caretaker must communicate with each other.

[Restricted(Closed) part] The MF Holder and the in-country caretaker must

communicate with each other.

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 API Registration in China
While there is no DMF system in China currently, there is a limited registration
system for drug companies manufacturing their APIs in China and for foreign
companies exporting APIs into China.
If a domestically manufactured API is part of any product sold in China, then the
API must be registered. Registration requirements follow guidelines established by
the International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
Registration materials must include:
The product name ; The product structure ;The manufacturing site name
Manufacturing methods, including process control ;Quality control tests and data
Specifications, test methods ; Stability tests and data
Packaging methods ; Storage methods
Dates of expiration ©Raaj GPRAC, All rights reserved
 API Registration in China

In China, API applications may be submitted together with applications for the
finished drug product. When this occurs, the API application may pull clinical data
and test results from the application for the finished drug product.
However, foreign manufacturers of finished drugs that are imported do not have
to submit their foreign DMFs to the CFDA. If they so choose, they may provide
information from foreign DMF filings to take the place of their CPP (Certificate of
Pharmaceutical Product).

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 API Registration in China
DRAFT DMF SYSTEM
The CFDA released a draft proposal in September 2010 for setting up a comprehensive
Chinese DMF system. That draft was revised, and was followed by another draft that was
released in November 2011.
According to the most recent draft, DMF filings would be mandatory for APIs and
excipients (as well as for auxiliary materials like packaging) included in drugs marketed in
China. Export-only drugs, on the other hand, would not require DMF filings for either their
APIs or their excipients.
The CFDA’s Center for Drug Evaluation (CDA) would oversee all DMF filings. Similar to
officials at Japan’s PMDA or the US FDA, CDE representatives would keep sensitive DMF
information secret from finished drug manufacturers. These manufacturers would need to
cite the DMF registration numbers for APIs and excipients used in their finished drug
product, during product registration. This would enable the CDE to pull relevant
information from the DMF for evaluation of the finished drug product.

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 API Registration in China
Also included in the draft regulations are guidelines for change notifications. For
example, whenever a change occurs in the API production process, that
manufacturer would need to notify all finished drug product manufacturers using
their product. These finished drug manufacturers then bear responsibility for
auditing the API manufacturer to make sure that all changes are accurate.

Finally, the draft regulations also require that domestic API manufacturers
periodically conduct quality audits of their suppliers. These audit reports would
need to be included along with the DMF application.

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 API Registration in China
Since January 1, 2018, CFDA has not been accepting Active Pharmaceutical
Ingredients (APIs), Pharmaceutical Excipients and Pharmaceutical Packaging
Materials registration application independently. The Active Pharmaceutical
Ingredients (APIs), Pharmaceutical Excipients and Pharmaceutical Packaging
Materials are now reviewed/approved as part of a drug product application.

CFDA, now NMPA, had a pre-market approval policy that allowed APIs, excipients
and packaging materials to be registered separately with pharmaceutical product
application. The process usually took longer and was expensive. The new system
allows these manufacturers to file the DMF reducing the approval time and
respective cost involved. Pharmaceutical manufacturers can refer to the DMF
code while submitting the drug application making the process more efficient.

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 API Registration in China
Who Can File a Drug Master File (DMF)?
The following category of companies indenting to export to Chinese drugs
manufacturers can file the DMF
Active Pharmaceutical Ingredients manufacturers
Excipient manufacturers
Packaging Material manufacturers
What is the Process for Filing the DMF
NMPA has established an electronic platform for APIs, excipients and
pharmaceutical packaging DMFs submission and registration.

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 API Registration in China
Does DMF Application need a Local Representative?
Yes, in order to file the DMF in China with NMPA, a manufacturer will require a
local legal representative. The DMF application need to be filed in Chinese
Language; therefore, if foreign manufacturers have their DMF in English or other
language, they need to get the document translated in Chinese as per NMPA
guidelines and format.

Documents Required for DMF Registration in China

The application for Drug Master File (DMF) must be in Chinese language
translated from original foreign language. The content for DMF includes:

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 API Registration in China
Company Basic Information such as name, registration details etc.
Basic information of pharmaceutical package materials such as package name,
composition and ingredients (all ingredients) with information on physical and
chemical properties, basic characteristics of the package, protective and
functional features.
Current approval and marketing situation in China and overseas with relevant
supporting documents, summary of production, sales and usage
Include National Standard and Pharmacopeia Record information (Domestically
and Overseas)
Manufacturing information such as production process and process control,
material control, key procedures, verification, validation and evaluation

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 API Registration in China
Documents related to quality control, quality standard, analytical
method validation and related documents
Documents related to patch testing and reports, stability analysis
Provide safety and comparability analysis study reports
The documents need to be submitted electronically and usually it
takes about 15 days for NMPA response post submission of
application. (However, it takes often longer for CDE review to
complete and respond).

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China Amends DMF System on Drug Packaging
China first established a Drug Master File (DMF)-type system for the registration of
drug packaging materials, active pharmaceutical ingredients (APIs), and drug
excipients in Announcement No. 146 of 2017, published by the former China Food
and Drug Administration (CFDA). Under the registration system, a company first
needs to submit to the Center for Drug Evaluation (CDE) the registration dossier for a
packaging material, API, or drug excipient and obtain a registration number. The
registration dossier will later be reviewed together with the application for the
correlated pharmaceutical product.

A significant update to the registration dossier procedures was announced on July 16

and became effective on August 15, when China's National Medical Products
Administration (NMPA) issued Announcement No. 56 of 2019, which clarifies and
simplifies the procedure and requirements for the registration of drug packaging,
APIs, and drug excipients in China.
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China Amends DMF System on Drug Packaging

With respect to drug packaging, the Announcement amends the registration dossier
requirements.

Notably, data requirements for certain categories may be reduced for drug
packaging materials where the data needed for registration are determined
according to the risk level and use information about a particular drug packaging
material.

For example, if a drug packaging material has not been used in pharmaceutical
applications but has lawful use in direct contact with food as food packaging
materials, there may be a reduction in data requirements.

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 Challenges regarding Development and
Optimization of APIs
Patent Infringement
Appropriate Filing Stage [ Route of Synthesis]- Key/Regulatory Starting Material Justification
Degradation pathway of the API via stress testing
Dosage Form Specifications most of the time control only the API degradation products and
additionally ensure controls of solvents involved in preparation of the DP, API-Excipient and API-
API Interactions.
Control of Impurities- all categories at release as well as Stability studies
Physico-chemical properties
Deriving the appropriate Packaging for the API
Incorporating Regulatory Updation –Monographs , etc

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 Challenges regarding Development and
Optimization of APIs
Deriving the appropriate Storage conditions for the API
Assigning Retest Date aligned with the stability studies generated
Writing adequate Development Reports, Scale up Reports, Technology transfer
document, Addenda and Supplements to these
Vendor Development and Qualification for Key Starting Materials and Critical Raw
materials
Relevant SOPs at the Research & Development stage
Incorporation of Quality by Design Elements
Incorporation of Risk assessment and Mitigation Strategies
Change Management
Good Documentation and Distribution practices within the CFT
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 Challenges regarding Development and
Optimization of APIs
Establishing the Critical Operating Steps
Establishing the Critical Operating Parameters
Establishing the Critical Quality Attributes
Identifying and Controlling unknown impurities
Ensuring likelihood of Genotoxic impurities , their actual presence
Development and Validation of appropriate and sensitive enough analytical test methods for
testing of impurities and other relevant test parameters
Control of Metallic and other impurities as per latest guidances
Incorporation of Pharmacopoieal Monograph, General Chapters , Latest Guidances or directives,
etc while establishing specifications for impurities.
Outsourcing of KSM or analytical testing

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Regulatory & cGMP requirements- Key Guidances
and References
International conference on harmonisation of technical requirements for registration of
pharmaceuticals for human Use

Q3A(R2) Impurities in new drug substances

Q3B(R2) Impurities in new drug Products
Q3C(R5) Impurities : Guidelines for Residual Solvents
Q3D: Impurities: Guideline for Metal Impurities

Some regulatory guidance on specification limits for residues of metal catalysts and reagents is in
EMA only. An ICH guideline Q3D ensures that new requirements have the necessary input of the
regional regulatory authorities, to the benefit of regulators, industry, and public health.

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 Q3D: Impurities: Guideline for Metal Impurities
A new harmonised guideline was developed to provide a global policy for limiting metal
impurities qualitatively and quantitatively in drug products and ingredients

The existing ICH Q3A guideline classifies impurities as organic, inorganic, and residual
solvents.

The Q3A and Q3B guidelines effectively address the requirements for organic impurities.

An additional guideline Q3C was developed to provide clarification of the requirements
for residual solvents.

The new guideline Q3D provides similar clarification of requirements for metals, which
are included in the ICH inorganic impurities classification.
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 Q3D: Impurities: Guideline for Metal Impurities
A harmonised approach for control of metal impurities, including the
list of specific metals to be limited.

Appropriate limits for these to help avoid the uncertainty and

duplication of work for industry to meet requirements that may
otherwise differ between the ICH regions.

A harmonised guideline to provide appropriate safety-based limits for

the control of metal impurities, along with consistent expectations for
test requirements and regulatory filings.

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 Q3D: Impurities: Guideline for Metal Impurities
Appropriate controls for those metals with clearly established toxicological
concerns.

These metal impurities may arise from the drug substances, excipients, or
manufacturing processes used for drug products, and may include catalysts,
reagents, ligands, heavy metals or other residual metals, such as those due to the
material source (e.g. Pb, Hg, As,Cd).

Earlier control of metal impurities is primarily based on pharmacopoeial

requirements for Heavy Metals, which have been widely used for routine
screening of pharmaceutical ingredients since the early 20th century.

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 Q3D: Impurities: Guideline for Metal Impurities
The commonly used methodology was mainly intended to control metals which form a
sulphide precipitate, such as lead, copper and other metals which were potential
contaminants from water pipes, manufacturing equipment, processes, and other
common sources.

Although the risk factors for metal contamination have changed dramatically, the
standards for their control have changed little for more than 50 years, and most Heavy
Metals limits have little basis in toxicology.

So, arose the potential need and benefit of a harmonised guideline for metal impurities.
Previously, the Expert Working Group on Quality developed the Q3A, Q3B,and Q3C
guidelines in order to provide a harmonised approach to limiting impurities. Toxicologists
also provided input on the subject of impurities, particularly with regard to toxicity of
process-related impurities and residual solvents.
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 Regulatory requirements- Key Guidances and
References
CTD sections related to Stability Testing

Section 2.3.S.7.1(a)/ 2.3.P.8.1(a): Stress Testing

Section 2.3.S.7.2/ 2.3.P.8.2: Post approval Stability commitments
Storage conditions
Section 2.3.S.7.3/ 2.3.P.8.3: Stability Data
Stability data
Other stability studies

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 CTD sections related to Stability Testing
Module 3: Quality

General Structure/Drug Substance 3.2 S Drug Substance 3.2 S.1 General

Information 3.2 S.2 Manufacture 3.2 S.3 Characterisation 3.2 S.4 Control of Drug
Substance 3.2 S.5 Reference Standards or Materials 3.2 S.6 Container Closure
System 3.2 S.7 Stability

General Structure/Drug Product 3.2 P Drug Product 3.2 P.1 Description and
Composition of the Drug Product 3.2 P.2 Pharmaceutical Development 3.2 P.3
Manufacture 3.2 P.4 Control of Excipients 3.2 P.5 Control of Drug Product 3.2 P.6
Reference Standards or Materials 3.2 P.7 Container Closure System 3.2 P.8 Stability

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 Regulatory requirements- Key Guidances and
References
ICH Guidelines for Stability Testing:
1) ICH Q1A (R2): Stability testing of new drug substances and products
[ASEAN, US-FDA, WHO and EMA have derived/aligned their guidelines with this one ]
2) ICH Q1B: Photo-stability testing of new drug substances and products

3) ICH Q1C: Stability testing of new dosage forms

 4) ICH Q1D: Bracketing and matrixing designs for stability testing of new drug substances and
products

5) ICH Q1E: Evaluation for stability data

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 API- Summary of stress testing

CTD section 2.3.S.7.1 (a)

Stress testing: can help identify the likely degradation products

which, in turn,
Can help establish the degradation pathways and subsequently the
intrinsic stability of the molecule
This also facilitates the validation of the stability-indicating power of
the analytical procedures used.
Stress testing may be carried out on a single batch of the API made by
the validated manufacturing process for production batches .
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 European Regulatory Procedures for APIs
The ASMF Procedure and the CEP Procedure
Maintaining Regulatory Submissions
Vendor Development and Qualification
Change Management Handling
Updates , Supplements and Renewals- Regularization with
Authorities

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 DMFs – Requirements for Europe & USA
Basic data requirements for a DMF across the regions are designed around the
CTD (Common Technical Document) structure:

- General Information
- Manufacture
- Characterization
- Control of Drug Substance
- Reference Standards or Materials
- Container Closure System
- Stability

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 DMFs – GMP Inspection Process for
the EU & US-FDA
Upon completion of the review of the DMF (and the response process for the
queries raised during the review of the dossier) and the positive compliance
report/certificate of the manufacturing facility for the API, by a competent
authority, the authorization for the drug product is obtained

The API manufacturing sites are routinely inspected by European Agencies or by

the US Agency -FDA. The normal frequency of the inspections are:
- US-FDA: Every 2 Years
- EU (EDQM): Every 3 Years

The frequency can be less or more - resource availability at the Agencies.

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 DMFs – GMP Inspection Process for
the EU & US-FDA
Upon completion of the review of the DMF (and the response process for the
queries raised during the review of the dossier) and the positive compliance
report/certificate of the manufacturing facility for the API, by a competent
authority, the authorization for the drug product is obtained

The API manufacturing sites are routinely inspected by European Agencies or by

the US Agency -FDA. The normal frequency of the inspections are:
- US-FDA: Every 2 Years
- EU (EDQM): Every 3 Years

The frequency can be less or more - resource availability at the Agencies.

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 DMFs – GMP Inspection Process for
the EU & US-FDA
If a new manufacturing site is being proposed through any drug
product filing, the respective Agency normally inspects the facility
prior to granting the approval of the drug product

If the manufacturing site is already inspected and the subsequent

filing is done from the same manufacturing site (with similar type of
operation), the approval is generally granted based on the
documentation review

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 Drug Product Filing Routes - EU
The application procedures through which the drug product are approved in
the EU are different from the US

In the year 1995, the European Union (EU) established an organization called the
European Medicines Evaluation Agency (EMEA, now known as EMA) for a
centralized approval process. The EMEA co-ordinates drug license applications
within the European Union (EU)

For the EU, it is for the drug products filed through the following procedures:
 - DCP (Decentralized Procedure)
 - Mutual Recognition Procedure (MRP)
 - CP (Centralized Procedure)
 - National Procedure

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Design it Right Do it Right
Present it Right

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 Rajashri Survase-Ojha
9819125208, 9821144706
[email protected], [email protected]
www.raajpharmaelearning.com