2.2. Graham Cook

1
EFPIA EFPIA
Mock S2 Project for Drug Mock S2 Project for Drug
9 Nov. 2009 EfpiaMock S2Project 1
j g j g
Substances Substances
Graham Cook Ph.D. Graham Cook Ph.D.
Presentation at DIA Pharmaceutical Quality Forum Presentation at DIA Pharmaceutical Quality Forum
Prague, Czech Republic Prague, Czech Republic
9 November 2009 9 November 2009
Overview
The EFPIA Mock projects
Background
Objectives
Mock S2 for Biotechnology Drug Substances
Target Molecule and Process
Document structure andconcepts
9Nov. 2009 EFPIAMock S2Project 2
Document structure and concepts
Status
Mock S2 for Small Molecule Drug Substances
Status
Background
EFPIA Mock P2 discussion document (1/2006)
Illustrated QbD concepts for small molecule oral tablet
How can QbD principles be applied to the development
of drug substances?
The Mock S2 project is intended to develop discussion
documents presenting one example of enhanced QbD
concepts applied to drug substance development and
concepts applied to drug substance development and
manufacture
Two teams sponsored by EFPIA PDC ad hoc group
Formed in 2007
Informal links to PhRMA and other EFPIA working groups
Mock S2 discussion documents for:
Monoclonal antibody example - Mockestuzumab
Small molecule example - Illustrain HCl
2
Objectives
Development of the drug substance from the Quality Target Product
Profile
Development of the manufacturing process and the control strategy
The Mock S2 documents will show the application of
quality risk management considerations and enhanced
scientific understanding (Q8, Q9, Q10-like principles) to
the drug substance examples to illustrate:
How critical quality attributes (CQA) are derived, the linkage
between the critical process parameters and the CQAs, and the
development of a design space
How flexible regulatory approaches could result from an enhanced
risk based / science based submission, supported by the applicants
quality system
The application of prior knowledge and the use of tools including
Quality Risk Assessment, Design of Experiments (DoE), Scale
Down Models etc
Overview
Background
Objectives
Status
Status
Monoclonal antibody Mockestuzumab*
Fully human IgG1
No effector functionality
Fc glycosylated
N-linked at 1 Site
Charge heterogeneity
CHO cell line
Platform manufacturing strategy
Dosing
i.v. and s.c.
chronic administration
* Discussing alignment with EFPIA Mock P2 Biotech Injectable project
3
Proposed Upstream Process
Thawing of WCB
Expansion in spinner flasks or equivalent
Seed train expansion in increasing scale bioreactors
Seeding of production bioreactor
Cultivation in production bioreactor
Harvesting process
Cell free supernatant
Proposed Downstream Process
Protein A
pH inactivation
Cation exchange chromatography
UF/DF 1
Anion Exchange Chromatography (Q-Sepharose ff)
Nanofiltration
UF/DF 2
filtration and
filling of drug substance
Document structure/Concepts (1)
Introduction and discussion points
CTD structure with 3.2.S.2.6 and excerpts from S.2.2,
S.2.3, S.2.4, S.2.5 sections and Post-Approval
Management Proposals section
S.2.6 Manufacturing Process Development section
Identification of critical quality attributes of drug substance
Two approaches to be described prior knowledge vs prior
knowledge +in-vitro testing
General approach to process development and risk assessment
Design and control of selected steps:
Cell culture process production bioreactor
Anion exchange chromatography (Q Sepharose)
Final drug substance formulation by ultrafiltration/diafiltration
Overall control strategy
4
Document structure/Concepts (2)
S.2.2 Description of Manufacturing Process and Process Controls
Description of compliance elements of Manufacturing process (contrast
with S.2.6)
S.2.3 Control of Materials
Description of change management approach using decision tree and
performance in scale-down models
S.2.4 Controls of Critical Steps and Intermediates
p
Description of compliance elements of control strategy process (contrast
with S.2.6)
S.2.5 Process Validation
Description of qualification of scale-down models
Use of concepts described in FDA draft PV Guidance
Lifecycle management - Post-Approval Management Proposals
section
Status/Next Steps
Document sections being refined
Solicit feedback of consolidated draft document
from EFPIA member companies
Solicit feedback from regulatory agencies (EMEA
etc.) and other trade organisations (PhRMA etc.)
Draft to be made available to ICH Q11 team and
ICH Q8/9/10 Implementation Working Group, as
required
Publication early 2010
Mock S2 Biotech Team
Norbert Hentschel Boehringer Ingelheim(Biotech sub-group leader)
GrahamCook Wyeth (Mock S2 Project Co-Ordinator)
Stefanie Pluschkell Pfizer
Mylne Talabardon MerckSerono
Pascal Valax MerckSerono
Kimberly May Schering-Plough
Stephanie Schnicke Roche
Margaret Leahey Wyeth
Team Members and Contributors
Enda Moran Wyeth
Laure Landric-Burtin Sanofi-Aventis
Birgitte Holst NovoNordisk
Bjarne Nielsen NovoNordisk
Ronald Imhoff J ohnson & J ohnson Centocor
Alain Bayol Sanofi-Aventis
Brendan Hughes Wyeth
Sabine Wller Roche
J ason Hampson Amgen
Herv Broly MerckSerono
Karin Sewerin (formerly AstraZeneca)
5
Overview
Background
Objectives
Status
Status
Target Molecule: Illustrain HCl
N
H
+
O
Et
OMe
OMe
F
Br
Cl
Basic chemistry used as the framework for the story
Four step synthesis
Two chemical transformations (Catalytic hydrogenation and alkylation)
Plus classical resolution of enantiomers and salt formation
API for solid oral dosage form
Synthesis Scheme
OMe
N
OH
Et
OMe
OMe

Mandelic Acid
.
N
OH
Et
OMe
OMe
N
OH
Et
OMe
OMe
OH
O
OH
IPC
Dryi ng
H2,
Pd/C,
EtOH
Mandel ic Aci d
Ol efin
Mandel ate Salt
Rac-Ami nol
IPC
Rxn
Toluene
NaOH (aq.)
Stage 1
Stage 2
Post Approval change
envisaged:
Asymmetric catalytic
hydrogenation in Stage 1
(based on existing
N
OH
Et
OMe

N
O
Et
OMe
OMe
F
Br
N
H
+
O
Et
OMe
OMe
F
Br
Cl
Cl
F
Br
IPC
Dryi ng
IPC: In-Process Control
PTC: Phase Transfer Catal yst
Ami nol
Benzyl Chl ori de
Il l ustrai n Free Base
Ill ustrai n Hydrochlori de
PTC
NaOH (aq.)
Toluene
Heptane
Methyl ethyl ketone
HCl (conc.)
Illustrain HCl (seed)
Stage 3
Stage 4
laboratory-scale data)
leaving existing resolution
as an upgrading step to
achieve same quality of
intermediate
6
Document Structure
Introductory Letter
Mock S.2.6
Design Selection/Development History
Definition of Illustrain CQAs
Control of Illustrain CQAs
Design and Control of Stage 1(Rac-Aminol)
Design and Control of Stage 1 (Rac Aminol)
Design and Control of Stage 2 (Mandelate salt)
Design and Control of Stage 3 (Illustrain Free base)
Design and Control of Stage 4 (Illustrain HCl)
Control Strategy for Illustrain HCl
Post Approval Changes/Lifecycle Management
Each section on Stage 1-4 also contains a
process description excerpt from S.2.2
Key Aspects (1)
Application of QbD concepts to small molecule API
development and manufacture, including:
Derivation of critical quality attributes (CQAs) for the drug
substance fromthe Quality Target Product Profile defined for the
drug product
Rational design of the manufacturing process and the development
of process understanding
Identification of critical process parameters (CPPs)
Development of design spaces for process operations, with some
Development of design spaces for process operations, with some
discussion of operational considerations
Design of control strategy, including a variety of different controls
Use of tools, including:
Application of prior knowledge, including first principles knowledge
Use of Quality risk assessment tools to prioritise development
efforts and develop a control strategy
Use of Design of Experiments (DOE) in process development
Use of process analysers in small-scale experiments to gain
process understanding
Key Aspects (2)
How Quality by Design information could be presented in a
regulatory submission including:
Outcomes of Quality Risk Assessments
Representation of a design space
Finished Drug Substance specifications
Compliance commitments relating to the description and continual
improvement of the manufacturing process
How flexible regulatory approaches could result from an enhanced
science and risk baseds bmission s pportedb the applicants
science- and risk-based submission, supported by the applicants
quality system, in the areas of changes to:
The operating conditions of the process
The design of early stages of the synthesis
Manufacturing scale
Manufacturing equipment
Manufacturing site
Raw materials
7
Stage 1 Hydrogenation
N
OH
Et
OMe
OMe

N
OH
Et
OMe
OMe
H2, Transition
Metal Catalyst
Rac-Aminol Olefin
High level of process understanding
C t l ti h d ti d l i l l ti ll t bli h d h i l
Catalytic hydrogenation and classical resolution are well established chemical
processes
Highly selective hydrogenation yielding racemic product
Focus is on achieving reaction rate by avoidance of deprivation of hydrogen leads
to scale-independent process controls and assurance of quality
Limited detail of process parameters and operating conditions to support
current and proposed future process
e.g. Solvent not specified since hydrogenation in variety of solvents is successful
Facilitates future process change (e.g. moving to asymmetric hydrogenation) under
company quality systemcontrol without prior approval
Change management plan proposed includes criteria to be met
Stage 2 Resolution
N
H
+
OH
Et
OMe
OMe
OH
O
O
N
OH
Et
OMe
OMe

OH
O
OH
racemic
(R)-Mandelic Acid Rac-Aminol Mandalate Salt
+ (R)
(R)
(R)
(R)
(R)
(R)
Process exploits differential solubility of diastereomeric salts in
multiple solvents
Crystallisation temperature and concentration controlled to limit
undesired isomers
Residual solvents purged in downstreamprocessing
Future change in solvent supported
Control strategy involves focus on achieving chiral and achiral purity
Input material (chiral purity of mandelic acid plus known impurity profile
of stage 1 product using defined stage 1 controls)
Important process parameters crystallisation temperature, stoichiometry
and concentration
Stage 3 Alkylation
N
OH
Et
OMe
OMe

Mandelic Acid
.
N
OH
Et
OMe
OMe
N
O
Et
OMe
OMe
F
Br
Cl
F
Mandelate Salt Aminol
Toluene
NaOH (aq.)
Illustrain Free Base
Phase
Transfer
Catalyst
NaOH (aq.)
Toluene
Heptane
Cl
Br
Benzyl Chloride
High level of understanding of science of phase-transfer catalysis
Potentially critical impurities present in stage starting materials or generated
during stage include genotoxic benzyl chloride
Evaluation of reagents and solvents
Impurity purging studies to determine acceptable input levels
Predictive understanding of effects of equipment change and scale-up of
biphasic reaction included in Design Space
Control strategy focus on control of these critical impurities to safety-based
limits in API
8
Stage 4 Salt Formation
N
O
Et
OMe
OMe
F
Br
N
O
Et
OMe
OMe
F
Br
HCl
MEK, HCl (aq.)
.
All critical aspects of purity of the drug substance are met in the free base
Solvent selection for crystallization needs to maintain purity profile
Solvent selection for crystallization needs to maintain purity profile
Salt formation focussed on important physicochemical attributes
Solid form(monomorphic)
Particle size distribution
Science and risk-based screening approach to solvent selection and
parameter ranges
Predictive understanding of nucleation/crystal growth provides scale-
independence
Design space established which ensures API meets particle size distribution
as required for content uniformity of tablet drug product
PAT analyser used for process understanding not required for process
control in commercial manufacture
Status/Next Steps
First draft circulated to EFPIA member companies
for comment 9/2008
Final draft document circulated 11/2009 to solicit
feedback from EFPIA member companies
Solicit feedback from regulatory agencies (EMEA
g y g (
etc.) and other trade organisations (PhRMA etc.)
Draft to be made available to ICH Q11 team and
ICH Q8/9/10 Implementation Working Group
Publication targeted for late 2009/early 2010
Mock S2 Small Molecule Team
Frank Montgomery Astra Zeneca (Small Molecule sub-group Leader)
GrahamCook Wyeth (Mock S2 Project Co-Ordinator)
Luc J anssens J &J Tibotec (EFPIA PDC ahg Sponsor)
Michael OBrien Wyeth
Ron Ogilvie Pfizer
Heinz-Hermann Bokel Merck KGaA
Paul Collins Eli Lilly
Michael Saegebarth Novartis
Team Members and Contributors
Alain Duguet Sanofi Aventis
Ricardo Giralt Boehringer Ingelheim
Subodh Deshmukh Wyeth
Shanthi Sethuraman Eli Lilly
Chris Beels (formerly GlaxoSmithKline)
Danielle Giron (formerly Novartis)
Kevin Wall (formerly J &J Noramco)
9
Thank You

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