Presented by – Suresh Gautam

Skbcop kamptee, Nagpur

 To assure that the drug sold to the public will
have quality attributes similar to those of the drug
demonstrated to be safe and effective.

 To assure that the quality of the drug meets

appropriate standards and is consistent.

 To assure that the drug you

are using is the drug
described onthe label.
• How and where is the drug made?
• How are raw materials tested and
monitored?
• What control procedures are in place to
assure product consistency and quality?
• Are quality attributes adequately
identified and characterized for the
product?
• Are the test methods used to monitor
product quality appropriate?
• How long does the product maintain its
quality after it is made (shelf
life/expiry)?
 Drug used in clinical studies
Safe and effective

CMC helps maintain the connection in quality between the

drug used in clinical studies and the marketed drug

Drug marketed to consumers

Commercial product
Clinical Batches
Safety and effectiveness studies

Pilot Batches
CMC information

Engineering Batches
Scale-up from pilot to commercial

Process Validation Batches

Implementation of commercial
manufacturing processes

Commercial Batches
Product marketed to consumers
• Sterile injectable product – sterility and
endotoxin concentration
• Controlled release product – release profile of
active ingredient over time
• Oral tablet – dissolution profile
• Soluble powder for drinking water – moisture
content as powder, solubility in water
It is an accurate depiction of the dynamic
world of Chemistry, Manufacturing, and
Control (CMC)(referred to by the authors as
“constantly managing change”) post
approval regulatory affairs.
 CMC regulatory affairs is concerned with the
technical characteristics of a drug molecule
and the dosage form used for its
administration. Typical list of CMC
information required for evaluation. CMC
Database or a New Drug Application : Drug
Substance – Physicochemical properties,
synthetic process, controls for starting
materials,reagents,etc.,process control for
intermediates, specifications and analytical
methods, list of impurities, stability and life to retest.
 Drug Product – Components an composition,
manufacturers, method of manufacturing and packaging,
specifications and analytical methods, stability information. In
the preapproval phase of the product life cycle, CMC
information is initially provided to FDA through and IND
application. Depending on the outcome of clinical trials
conducted under the IND, an NDA may be filed with an
additional level of CMC information.
In the post approval phase, the regulatory affairs professional
is responsible for managing changes to these conditions.
Comparison of CMC Regulatory Environments :

Preapproval Postapproval

Type of submissions INDs and NDAs Supplemental NDAs

(investigational new Annual Reports
drug application & new CMC Commitments
drug application)
Internal customer R & D (Research and Manufacturing
Development)
Customer priority Supporting INDs & Manufacturing product
NDAs

Timelines Months and years Weeks and months

Format of submission Well defined Less defined

Reference base of Being developed as part Approved conditions in

 In order to make CMC changes to the conditions of
approval in the NDA, the drug manufacturer must file
the changes with FDA through one of the various types
of post approval submissions.
Prior to 1997, the regulation governing CMC changes
to an approved NDA was 21 CFR 314.70 (Supplements
and other changes to an approved application).
This statute was established in February 1995 as part of
a comprehensive effort to improve the NDA and post
approval application process.
(1) Prior approval suppliment
(2) Changes being affected (CBE) Supplement, and
(3) Annual report
● CMC Postapproval Regulatory Submissions :
Prior approval suppliment : A prior approval
suppliment is required for a CMC changes that has a
substaintial(major) potential to have an adverse
effect on the identity, strength, quality, purity, or
potency of the product as they may relate to its safety
and effectiveness.
 A prior approval supplement may need to be approved as
soon as possible in the interest of the public health (e.g., drug
shortage). Potential impact on product quality is major.
Implementation after approval of submission.
Changes being effected supplement : A CBE supplement is
required for a CMC change that has a moderate potential to
adversely affect the drug product as to its safety or
effectiveness. The CANA (changes to an approved NDA &
ANDA) guidance provided for 2 types of CBE supplements :
(a) Supplement -Change Being Effected in 30 days (CBE -30) :
Applicant wait at least 30 days following receipt of the
submission by FDA before distributing product incorporating
the change.
(b) Supplement- Changes Being Effected (CBE-0) : Implementation
occur immediately upon FDA receipt of submission. Unlike
CBE-30 Supplement, a CBE-0 Supplement does not require a
waiting period.
(c) Annual Report : The annual report is a periodic, post
marketing submission required by 21CFR 314.81 . Potential
impact on product quality is low. Implementation occur
immediately – filled yearly within 60 days of anniversary date
of NDA approval.
Types of CMC Post approval Submission
 Types of CMC Postapproval Submission
Submission type Potential Implementation
impact on
product
quality
Prior Approval Major( After approval of
Supplement Substantial) submission

CBE Supplement – Moderate 30 days after FDA

30 days receipt of submission

CBE Supplement- 0 Moderate Immediately upon FDA

day receipt of submission

Annual Report Minor (low) Immediately – filed

yearly within 60 days
of anniversary date of
 CMC Post approval Guidance : 21 CFR 314.70 be
revised to streamline the regulatory process for CMC
post approval changes. Two years later 21 CFR 314.70
expired without an updated version in place. FDA
issued an interim guidance document, guidance for
industry: changes to an approved NDA or ANDA
(CANA),that has been the reference for determining
the appropriate regulatory submission for CMC post
approval changes.
 In April 2004 , the revised 21 CFR 314.70 rule was
published, and the CANA guidance was updated.
 The revised rule and CANA guidance provide
recommended filing categories for changes to the
following : (a) components and composition , (b)
manufacturing sites, (c) manufacturing process, (d)
specification, (e) packaging, (f) labeling, (g)
miscellaneous changes, & (h) mutiple related changes.
 The revised rule and guidance also increased the
regulatory burden for other types of changes. For
example, a change in a packaging component that controls
the dose delivered to the patient (e.g., the valve of a
metered dose inhaler) now requires a Prior Approval
Supplement, whereas under the original 21 CFR 314.70
Rule it was possible to file this change in an Annual
Report.
Change control is required by 21 CFR 211.180(e)
and entails proper review, assessment,
implementation, and adherence to written
procedures for making CMC changes.
An effective change control system is the
foundation for successful management of CMC
postapproval changes. Four steps are
conducted by the CMC postapproval regulatory
affairs professional :
This required interactions with the manufacturing site in
order to understand the changes.
E.g. a change request may specify that the site is
considering a batch size change.
(2) Established the regulatory basis for the change :
once the true extent of the changes is elucidated, the
change scenario needs to be evaluated against the context
of the approved conditions in the NDA file and current
FDA guidance.
The initial response describe the submission requirement,
regardless of filling categories, and includes a statement
that the reporting category will be determined when the
data and information package has been assessed.
Upon submission of the assessment, a second (final)
response is provided confirming the appropriate filling
category for the proposed change.
 Change control proposal received by CMC
postapproval
Regulator
y Initial regulatory response (Potential filing
experience categories and assessment requirements) FDA
Regulatio consultation
n
guidance
document
s Assesment
Additional
testing
Adverse required?
affect?
Final regulatory response
Prior approval supplement
CBE suppliment(0 or 30 days) Conforman
Equivalen
Annual report ce to
t
No submission required (i.e. cGMP Changes) specificatio
pre/post
change? n?
The initial response describe the submission
requirement, regardless of filling categories, and
includes a statement that the reporting category
will be determined when the data and
information package has been assessed.
Upon submission of the assessment, a second
(final) response is provided confirming the
appropriate filling category for the proposed
change.
All regulatory submission are accompanied by FDA from
356h singed by the regulatory affairs professional acting
as a “responsible agent "for the drug manufacturer.
The form includes a number of certification statements
that define the scope of responsibility associated with
this role. The role of acting as a
responsible agent is what differentiates the CMC
regulatory affairs professional from other functional
groups involved with compiling and submiting
postapproval application.
THANK
YOU…