GMP 

Aspects of NCE Development 
for early phase INDs – CMC 
for early phase INDs  CMC
Perspective

Balaram N Rao, Ph.D.

Aurigene Discovery Technologies
Limited
Bangalore-560100
 Overview

 Introduction
 GxP in Drug Development
 Regulatory Focus and Approach
 Regulatory legal framework & Global
practices
 Early phase GMP challenges
 CMC Development
D l t&C Concerns
 Conclusion
 Introduction
R&D time and Drug Attrition rates in India

Compounds Success rate Timelines

Preclinica 214 82 1.9
Phase‐I 63 34 2.5
Phase‐II 23 4 3.4
Phase‐III 3 1 3

Edmond Differding, ChemMedChem 2017 3

 Introduction contd…
Drug Development : Risk based Approach
Drug Development Pathway

5
 GxP in Drug Development Process
Clinical trails Commercial DS/DP
Material for clinical trail
phase I to III
Non clinical DS/DP

GLP GMP GCP GMP

Study based Process based study based Process based

Certified/ claimed animal Facility approval ethics

Permission / license Permission / license for
study ethics committee committee approval
for production each production each product /
approval (Each Study)
product / not each not each batch
(Each Study)
batch

Material quality Material quality

CMC increasing control

Safety first

Efficacy next 6
 Regulatory
g y Focus
 The early phase development and manufacturing is a balance
between risk acceptance and risk mitigation
 But of what risk are we speaking?
• To the patient?
• To the manufacturing process?
• To further product development / commercialization?
• To the study reliability?
 What do we want:
• Safe product
• Meaningful results
• Further development is built on data driven knowledge
 The objectives of trials should guide the objectives in
manufacturing and development
 Regulatory Focus Contd.

 R&D / Phase I / Phase II / Phase III / Pre ‐ Commercialization
 Quality / GMP expectations for Drug Substance applied by Phase of
Quality / GMP expectations for Drug Substance applied by Phase of 
development
 Good Research and Documentation Practices
 GLPs Pre‐Clinical (Tox assessment)
G Cli i l ( )
 Early Phase cGMP expectations
 Calibrated equipment / Qualified equipment
q p q p
 Qualified Methods / Validated Methods
 Process validation
 Pre‐Commercialization cGMP expectations
Pre‐Commercialization cGMP expectations
 Process Understanding  ‐ QbD
 Risk‐Based/Science‐Based Approach to compliance decisions ICH Q8/Q9/Q10
Quality and Compliance expectations increase along with Drug
Development timeline
 Common Regulatory Creep

GLP GMP GCP

estigator 
IRB/IEC

QA
Prrinciple Inve

A & QC
Output
output Output
Output Report
Report  Material 
(DS/DP)
TFM Management Management

 Quality systems are similar but not the same

 Key stakeholder differ in their roles and responsibilities
 Outputs are not similar- report versus material
 Compliance,
p data integrity
g y and quality
q y of work are common

9
 Regulatory Approach

 Drugs including investigational new drugs are required

t be
to b manufactured
f t d in
i accordance
d with
ith CGMPs
CGMP
• If not, considered adulterated [501(a)(2)(B) Food, Drug
andd Cosmetic
C ti Act]
A t]
 21 CFR 210, 211 Current Good Manufacturing Practices
f Finished
for Fi i h d Pharmaceuticals
Ph ti l Regulations
R l ti [1978]
 Specific regulations for GMP production
• Q7A GMP Guidance for Active Pharmaceutical
Ingredients
 Regulatory Legal Framework
FDA Guidance for Phase 1 INDs:
Recognizes some controls and the extent of controls differ between investigational and
commercial manufacturing, as well as phases of clinical studies
• Phase I Guidelines – 1991 : Doesn’t not cover all manufacturing situations of IMP
adequately
d t l
CGMPs for Phase-I (2008)
• Recommendations that provide flexibility to the manufacturers in implementing
CGMP controls appropriate to their specific situation and application.
• Exempt from compliance
• Exempt from process validation
CGMPs for Phase-II/III
• Applicability of 21 CFR part 210 & 211
• Process controls
 Global Regulatory Practices
ICH EU DCGI
[501(a)(2)(B) Food, Drug and   Directive 2003/94/EC (for  Drugs and cosmetic act 
Cosmetic Act] medicinal products and IMP  1940 from CDSCO
 CGMP for phase I  for human Use)  Schedule‐M
investigational drugs
investigational drugs  EC GMP
EC GMP‐Guide
Guide (detailed 
(detailed • Emphasis mainly on 
Emphasis mainly on
 INDs for Phase 2 and Phase  guidance) commercial 
3 studies: Chemistry,  • Part I (Finished products) +  manufacturing  
manufacturing and controls
manufacturing and controls  Annex 13 (IMPs)
Annex 13 (IMPs)  New Drugs and Clinical 
New Drugs and Clinical
 ICHQ7 for good  • Part II section 19 (APIs for  Trials Rules 2019 G.S.R. 
manufacturing practices use in clinical trials) 227(E)
• Section 19  EC : EudraLex‐Volume 4 
 Other Q & S series and M7 (GMP) and Volume 10 (CT 
material)
 Early
y Phase GMP Challenges
g
Aspect IND Commercial
GMP requirements Scope and extent may vary, no Applicable – scope and extent detailed,
uniform common regulations, change uniform common requirements
agency wise, clear guidelines missing principally, each agency advocates
in certain areas, applied at appropriate common minimum requirements and
stages applied at all the stages
Information Limited, as the stage and state are Adequate, detailed as stage and state
exploratory. is established.
Scale of manufacturing Small scale Full scale
Toxicity Limited data Toxicity qualified
Process Non-repetitive, critical parameters not Proven acceptable ranges and critical
fully known parameters established, consistent
Production Lack of fixed routines
routines, package Planned routine production
production, fixed
designs packages and designs
Labelling Blinding is a necessary aspect Always open
Validation (Analytical & More emphasis on verification All aspects of validation covered
Process)
Material Requirements Limited data and knowledge in terms Better data base as multiple API
and attributes of API as single batch may be used batches are used.
 GMP and Quality at Development stages

System R & D Toxicology Phase 1 Phase 2  Phase 3

QUALITY: • Notebook records • GLP practices are • CGMP (e.g. ICH Q7 and Annex13).
• Quality are kept of implemented as per • QA involvement by phase of
management production and regulation in specific global development
systems testing activities regions. • Quality standards
• Personal Training • Quality by Design  EU and FDA GLP • Summary development reports.
• Documentation Principles should  requirements cover the area • The bulk Drug Substance is
and records be applied to the  of released by QA
• Change selection,   Organization & personnel • Change management
management development and   Facilities • Specifications
• Deviations qualification  Equipment
/Investigations  Facility operation
• CAPA  Articles
• Auditing  Protocol and conduct
• Quality  Records and reports
Agreements  Disqualifications
• Laboratory director
 CMC Regulatory requirements at
g
IND stages
Regulations emphasize the graded nature
of CMC information needed as drug DS 
adequately
adequately 
d
development
l t progresses under
d an IND characterised
• The amount of information needed
depends on Phase of investigation DP  Impurities 
adequately
adequately  adequately
• Dosage form characterised characterised
• Duration of study Protection of 
FDA recognizes
g that CMC development
p Clinical Trial
Clinical Trial 
parallels clinical investigations subjects
• Primary objective is to assure the safety Acceptable  Manufacturing 
process 
of p
patients, during
g all p
phases of the IND quality 
q y adequately
• Phase 1 CMC evaluated mainly from the measures described
point of risk to patient. Manufacturing 
facilities 
• Phase 2 and 3 CMC evaluates safety, safety adequately
adequately 
and additionally the linkage of the clinical described
test product to the to-be-marketed product
 CMC Regulatory requirements at
g
IND stages Contd.

Phase - 1 Phase - 2 & 3

Safety is the main concern which is addressed with  Safety updates on the information provided for 
pharm/tox data phase 1
Drug substance has been tested, thus impurity  Impurities should be identified, qualified and 
profile and potency are known in animals quantified 
More detailed description of the configuration and
More detailed description of the configuration and 
Sufficient evidence to support chemical structure
chemical structure for complex organic compounds
Brief description including physical, chemical and  Complete description of the physical, chemical and 
biological properties
biological properties biological characteristics
biological characteristics
Reference standard establishment Reference standard qualification
Established specification based on tox and 
Established specification based on tox and Suitable limits based on manufacturing experience 
Suitable limits based on manufacturing experience
assurance batches. should be established
Drug substances and products are manufactured  Drug substances and products are manufactured 
g
according to CGMP for Phase 1 IND according to CGMP for Phase 2&3
g
Brief description of stability study and analytical  Detailed stability study and stability indicating 
procedure used analytical methods to be used
 Relationship between GMPs and
CMC Requirements
 The regulatory strategy used to ensure pharmaceutical
product quality involves both CMC and GMP oversight
 CMC requirements set the criteria and controls for
manufacturing and testing, as described in the submission
or dossier
 GMP requirements are derived from the regulations and
gguidelines ppertainingg to the implementation
p of p
practices and
standards in a manufacturing facility that allows for the
consistent pproduction of a qqualityy p
product with the intended
purity, safety and potency characteristics
 Synergy of GMP and CMC

PRODUCT QUALITY
PRODUCT QUALITY  ICH Q8-10

CMC CGMP

Focus:  Submission/Dossier  Facility/Manufacturing/Testing

Industry Role: Setting manufacturing  quality  Implementing manufacturing and testing 
criteria  and controls  practices designed to meet manufacturing 
and Quality Standards 
Guidance :  ICH Q1‐6, M4  ICH Q7
Agency Role :  Assessment and Approval of   Verification of conformance to CGMP and to 
manufacturing and Quality  regulatory submission/dossier standards 
standards and controls through facility
Inspections; Evaluation of Quality system 
 GMP Creep
p into CMC
 Because they are both critical pillars of product quality, there
are often
f areas off overlap
l between
b CMC considerations
d and
d
GMPs.
 Examples of areas of overlap include:
 Process development

 Validation

 Continuous process improvement.

 Resolution of the overlap can be achieved by viewing CMC

development as a “process, criteria and controls setting
activity” and GMPs as an “implementation activity”
 CMC Concerns

• Reasons for selection, 
y, p y
stability, physicochemical  Polymorphs
properties of various forms • No agreement on starting 
material
Key starting
• Lack of information on key 
materials
starting materials
• Insufficient stability data
Stability
• Unstable Molecule
Safety
• No
No Stability indicating 
Stability indicating
method • Inadequate control of 
impurities from KSMs
Impurities • Impurities not covered in tox
• In‐process controls • Mutagenic impurities at 
• Reproducibility issue higher levels
• Inconsistent data between lot to lot • Lack of control strategy to 
limit impurities
• Manufacturing variability
 Clinical Hold

 Unknown or Impure component's

 Chemical structure of known or highly likely toxicity
 Product that cant remain chemically stable for through
out the testing program proposed
 Product with an impurity profile indicative of a potential
health hazard or impurity profile insufficient defined to
assess potential health hazard
 Poorly characterized reference standard
 Process control strategy for process degradants
 How to overcome Failures

Drug Failures related to clinical safety,

quality,
quality efficacy,
efficacy safety issues w
w.r.t
r t API and
Drug product can be overcome by
establishing control strategy of the Drug
from
f starting
t ti to
t ending
di

22
 CMC Development Elements
Deliverables 

Intended use
Quality Target 
Route Define desired quality characteristics  of the product 
Product 
Product Product Profile
Dosage
Understanding 
Critical Quality  Impurities
Attribute  Perform risk assessment to link  quality attributes to 
Particle size
Assessment  Clinical Safety and Efficacy 
stability
Process 
Performance  PPIs and Ranges 
Indicators 
Pre‐
Characterization  Characterization Plan  Study the impact of  deliberate variation in process 
Study the impact of deliberate variation in process
Process  Assessment parameters and raw materials (inputs) on proposed CQAs 
Understanding  Characterization  and determine process parameter  and raw material 
Process  criticality 
Characterization  Data  

Process Critically  CPPs / CRMs/ CMAs 
Assessment   and Ranges 

Process 
Process controls
Control Strategy
l
Control of DS & DP Derived based on understanding and control of sources of 
Control Strategy 
Analytical  Control  In process testing variability to ensure product Quality and Consistency  
Strategy  Container systems
 Conclusion
 Graded nature of CMC information from Phase 1 to Phase 3 studies

 CGMP should be applied for Phase 1 drugs do not need full CGMP but
do need good manufacturing controls

 IND regulatory oversight focused on safety as primary review objective.

 A
Amount
t off CMC information
i f ti depends
d d on the
th phase
h off IND,
IND duration
d ti off
study

 Need for a harmonized drug regulations globally, especially the

regulatory
g y requirements
q for fastening
g the lengthy
g y drug
g development
p for
unmet medical needs
24