Regulatory Affairs for Active

Pharmaceutical Ingredient
As an increased emphasis on the manufacture and
control of the active pharmaceutical ingredient (API)
With the growing requirements for chemistry,
manufacturing, and control (CMC) documentation to
support an original marketing application, as well as
inspections are frequently carried out by agencies to
ensure ongoing compliance to the marketing
application and to current good manufacturing
practices (cGMPs).
 REQUIREMENTS FOR SUBMISSION OF REGULATORY CMC
DOCUMENTS

A. Investigational Compounds
Before introduction of an experimental compound into man in
their country its require the submission of relevant
information supporting proposed clinical trials .
In the United States, the documentation is called an
Investigational New Drug Application (IND); in the U.K. its a
Clinical Studies Exemption (CTX); in other European and
international markets, the term used is Clinical Studies
Authorization (CSA); and in Canada the document is referred
to as an Investigational New Drug Submission (INDS).
 These document covers a specific clinical program for a
desired therapeutic indication in a target patient population,
and must be kept current throughout the clinical
development program and the subsequent updates are
formally reviewed by the agencies.

The investigational documentation typically includes CMC

information on the chemical characteristics, manufacture,
control and stability of the API, and any formulations planned
for evaluation in the clinic.

Periodic updates documenting other, less critical changes,

should also be submitted during the clinical program .
B. Application for Marketing

Investigational compounds that are found to be safe and effective

toward a specific indication must be registered with regulatory
agencies worldwide, prior to their being made available for sale in that
market.

The marketing application in various countries are described as NDA in

the United States, an NDS in Canada, and a Pharmaceutical Dossier in
Europe.

The registration procedure is similar and the recent adoption of the

common technical document (CTD) has begun to standardize the
format for regulatory submissions, the content of the quality (CMC)
section of the marketing application required by different countries,
particularly as it relates to information on the API, varies significantly.
The following submission of the application, certain agencies
will perform a high-level review of its content to assure that
all basic elements are contained in the submission.

Once the concerns on all aspects of the application, including

CMC, are addressed to the satisfaction of the reviewing
authority, an official ‘‘action letter’’ is typically provided to the
sponsor of the application, to formally allow marketing of the
product in that country.
C. Post approval Requirements

For the post approval it is necessary to maintain the CMC

information current and accurate.

The mechanisms to be used are often linked to the nature of the

proposed change, and it’s potential to impact the quality
(chemical and physical) or safety of the API and ultimately, the
quality, potency, safety, or efficacy of the final drug product.

These changes include API manufacturing process, (controls and

parameters), specifications (analytical test procedures and
acceptance criteria), equipment cleaning procedures, raw
materials, and/or their acceptance criteria, packaging, etc.
CONTENTS OF REGULATORY SUBMISSIONS—API SECTIONS

A. Content of Investigational Applications

 General information on the compound
 Description of key chemical and physical properties and
characteristics
 Proof of chemical structure
 List of manufacturers
 Method of manufacture (minimally a process flow diagram)
 Specifications (methods and acceptance criteria) for the finished API
 Discussion of impurities and degradation products
 Analytical test results
 Information on the analytical reference standard
 Description of the container=closure system
 Stability data
B. Content of Marketing Applications

The goals for a well-prepared API section of the application

are to convince the reviewer that the compound:

– is well characterized;
– is manufactured at production scale using a rugged and well-
controlled synthesis, which consistently provides material of
comparable or better quality than that used in the development
program;
– is tested using validated analytical procedures which show that each
batch meets meaningful, justified quality requirements (acceptance
criteria) reflecting the quality of the clinical/safety material and the
capabilities of the manufacturing process.
Under the CTD, the application should include the following API
sections

• General information
Nomenclature
Structure
General properties
• Manufacturing information
Sites of manufacture
Description of the manufacturing process and process controls
Controls on starting raw materials
Controls on critical steps and intermediates
Process validation or evaluation
Manufacturing process development
• Characterization of the API
Elucidation of the chemical structure
Discussion of impurities
• Specifications for the finished API
Acceptance criteria
Test methods
Analytical validation data
• Batch analysis results
Justification of the recommended specifications
• Reference standard information
• Container-closure information
• Stability
Summary and conclusions
Postapproval stability commitments
Stability data
C. Other Documentation Included in Marketing Applications

The CTD format allows other, regional specific information, to

be provided in a separate section of the application.

The CTD format also specifies sections for inclusion of

references and attachments, as appropriate.

The CTD includes a quality overall summary (QOS) of the

more detailed information provided in the application
 REGISTRATION SAMPLES

• Samples of the API, reference standards, and key impurities

will be requested by certain agencies so that they can perform
the test methods contained in the marketing application.

• Certificates of analysis, and sometimes the analytical columns

and reagents required for testing, are often sent to the
reviewing agency or their designated testing laboratory
shortly after submission of the marketing application.
 THE REVIEW AND APPROVAL PROCESS

• The review of various contents of the marketing application

can be very dynamic, visible, and sometimes intense.
• To satisfying the reviewer query there should be a definite
strategy for developing responses to agency reviewer
questions.
• Questions from regulatory agency reviewers are valuable
learning tools, and often aid the company in the preparation
of future applications for a particular market or markets.
These learning’s should be communicated back to the
development areas, as much of the content of the application
has its origins in early development.
• The United States adopted a process known as the
Prescription Drug User Fee Act (PDUFA), which defines the
expected length of time for review of an original application.
• In the EU, marketing applications must be submitted for
approval through one of two processes, the centralized
procedure (CP) reserved for applications serving major
therapeutic needs, and the mutual recognition procedure
(MRP), used for all other applications.
 PREAPPROVAL INSPECTIONS

During the approval process for marketing applications,

regulatory agency are engaged for the site inspection which
emphasis on the readiness of the site to manufacture and test
the specified API or process intermediate. This ensures that the
inspected companies complies the CGMP & GLP guidelines.

Most companies will attempt to assure site readiness through

internal audits of company and contract facilities prior to
submission of the filing. Sites specified in the application
should have manufactured the API or intermediate at the time
of filing, or at least be suitably equipped and prepared to do so.
 POSTAPPROVAL CHANGE EVALUATIONS

• The most of the agencies place as much emphasis on post

approval activities as they do on approval of the original filing
because the agencies are charged with assuring the drugs being
marketed in their country are and remain safe and effective.
• Thus, changes to the information approved in the marketing
application must be reviewed with or at least communicate to
the respective agencies, often before drug product containing API
made or tested under the change can be placed on the market.
• The content of a postapproval submission reporting a change to
the manufacture or control of the API is dictated by the
requirements of the different regulatory agencies, as
documented in published guidelines.
• These guidelines list the type of changes that can be
submitted as Type I (minor) variations, and contain the
necessary information and documentation required to
support the proposed change.
• Any change not specifically defined as Type I in the EU
guidelines, must be filed as a Type II (major) variation.
• The EU further defined minor changes that can be
implemented as soon as documentation is provided to the
agency (Type IA) and those, which require a brief waiting
period to allow an initial broad review before implementation
(Type IB).
In US FDA Changes, which present a moderate degree of
potential adverse impact, could be implemented upon
submission of the required documentation to FDA, or 30 days
after that submission [changes being effected (CBE) or CBE-30].

A tool recently introduced in the EU to facilitate more efficient

postapproval change control is the certificate of suitability (CoS).
To obtaining a CoS involves the review and approval by the
European Pharmacopoeial Commission of the current API
characterization, manufacturing and control data for an already
registered API.
Drug Master File (DMF) for Abbreviated New Drug
Application

A Drug Master File (DMF) is a submission to

the Food and Drug Administration (FDA) that
may be used to provide confidential detailed
information about facilities, processes, or
articles used in the manufacturing, processing,
packaging, and storing of one or more human
drugs.
• Drug Master Files are submissions to US FDA
on
 Overseas (non- US) Pharmaceutical Mfg. Facilities
 Active and Inactive components.
 Articles used in manufacturing, processing.
 Materials used in packing etc.
 Processes
 Supporting to various applications:
 IND
 NDA
 ANDA
 Another DMF
 Supplemental Applications / Amendments
 DMFs are approved or disapproved
 TYPES OF DRUG MASTER FILES

I. Type I: Manufacturing Site, Facilities, Operating

Procedures, and Personnel.
II. Type II: Drug Substance, Drug Substance Intermediate,
and Material Used in Their Preparation, or Drug Product.
III. Type III: Packaging Material.
IV. Type IV: Excipient, Colorant, Flavor, Essence, or Material
Used in Their Preparation.
V. Type V: FDA Accepted Reference Information. Each DMF
should contain only one type of information and all
supporting data.