www.cordenpharma.com Experts taking care. EUROTIDES November 12, 2019 Mimoun Ayoub Ph. D. VP, Global Head of Sales and Key Account Management [email protected] Stage Appropriate CMC Overview and Requirements for a Robust Dossier
www.cordenpharma.com
Experts taking care.
EUROTIDES
November 12, 2019Mimoun Ayoub Ph. D.
VP, Global Head of Sales and Key Account
Management
Stage Appropriate CMC Overview and Requirements for a Robust Dossier
Sales: € 311 million
Employees: ~ 1,500
Sales: € 115 million
Employees: ~ 870
ENKA Group
CarboTech AC
Rütgers Organics
Sales: € 635 million
Employees: ~ 1,920
Sales: € 960 million
Employees: ~ 1,200
CordenPharma
Group
WeylChem
Group
VYNOVA
Group
IT, Accounting, Finance, Human Resources, Legal
International Chemical Investors Group (ICIG)
Market Oriented PlatformsFine Chemicals Pharma EnterprisesChlorovinyls(1)
ICIG Business Services
Corporate headquarters in Luxembourg and Frankfurt
Back-office, ICIG Business Services, located in Wuppertal, 100 employees
(1) Acquisition of VYNOVA Group and CordenBioChem completed in August 2015 and April 2016, consolidated pro-forma sales 2015
CordenBioChem
Highlights
CordenPharma Group represents the Pharma
platform within ICIG
Development and manufacturing of active
pharmaceutical ingredients (APIs) and drug products
(DPs)
8 cGMP manufacturing sites and 1 R&D lab in Europe
and the United States with approximately 1,870
employees
Positioned across the value chain as full-service
provider with a broad technology portfolio and
operating in five distinctive technology platforms
Strong customer base, excellent industry recognition
and strategic partner of Big & Specialty Pharma
More than two thirds of net sales generated in the API
area, especially Small Molecules and Peptides
Net Sales Development (excl. CPL)
in €m
Net Sales Breakdown by Platform
Injectables
18%
2
CordenPharma Group: At a Glance
245259
282292
311
380
2014 2015 2016 2017 2018 FC2019
Supply Chain Positioning
CordenPharma covers the full GMP supply chain of pharmaceutical custom manufacturing (raw
materials and non-GMP pharmaceutical intermediates partially sourced from WeylChem)
API manufacturing accounts for c.62% of net sales and usually have a shorter ramp-up phase than
respective Drug Product projects
Raw MaterialsNon-GMP
Intermediates
GMP
IntermediatesAPIs DPs
Pharma
Logistics
Lifecycle Positioning
CordenPharma focuses on all stages of a drug lifecycle with competitive advantages in clinical
development and commercial production
Preclinical
12 months
Phase I
12-18 months
Phase II
24 months
Registration
12 monthCommercial Generic
Phase III
36 months
Value Chain Positioning
CordenPharma - Value Proposition
Serving Global Pharma & Biotech
Customers
Organized under 5 Distinctive
Technology Platforms
Broad Range of Expertise:
API’s: Small Molecules, Peptides,
Lipids, Carbohydrates, Highly Potent,
Cytotoxics, Conjugates
Drug Products: Oral, Liquids,
Injectables, Highly Potents, Anti-
infectives / Antibiotics
Global Coverage Allowing for Flexibility
Your Full-Service Provider from Clinical
Development to Full-Scale Commercial
Supply of APIs & Drug Products
Peptides,
Lipids &
Carbohydrates
Highly Potent
& Oncology
Injectables
Small
Molecules
Antibiotics
Compliance
Road-Map to Market
Pre-clinical
Phase 1 Phase 2 Phase 3
Non-regulated
Non-GMP
Increasing Regulatory Requirements
GMP to Full Validation
12-36 months 12-18 months 24-36 months 24-48 months
Goal of IND and Requirements
The very top objective is to demonstrate SAFETY
Need a good process understanding and impurity control, even without
a full set of QbD studies
Requires a full set of non-clinical studies
• Toxicology: Maximum Tolerated Dose (MTD), chronic and accute toxicology…
• Pharmacology: PK/PD, ADME…
Raw material quality. Avoid processes using toxic starting materials
Testing methods: drug substance, drug product, bioanalytical methods…
Product stability: the product should be stable during the duration of the
non-clinical/clinical studies
IND Project Road-Map
Budget
Quality
Time
Alignment between Budget-Quality-
Time
Compromising one will impact the
other, consequences beyond IND
Risk assessment and mitigation
approach
Pay now or pay later but more…
Program Team
CMC API CMC DP
Packaging labeling logistics
Non-clinical End-points
Various and complex steps
Multiple stakeholders with different skills
Project predictability. Expect challenges and be
prepared to manage them: Contingency Plan
with Time and Budget extension
Program Team
CMC API CMC DP
Packaging labeling logistics
Non-clinical End-points
The big Disconnect…
There are disconnects within each of the two pilars: between API and
DP as well…Multiple partners involved
Performing non-clincial studies to nearly perfection with gaps in CMC
doesn’t help
Non-clinical
Tasks
CMC
API
& DP
Key Milestones
Avoid time-gaps between milestones
Data and supporting documentation
generated to be ready to transit to
next stage
Results vs. Expectations at each
milestone. Gaps and mitigation plans
Project teams for each milestone with
an overall program management
Final dossier: compiling data as you
progress
FDA Submission
API Devpt. Manufact.
DP Devpt. Manufact.
Labeling, Packaging
Pre-clinical tox. And
pharmaco.
Compiling Documents
Review
Project
Plan
Project
Team
For Each Milestone…Ex. API Synthesis
1
1
Execution, monitoring
and controling
Project Closing
Follow up, improvement
• Feasibility evaluation
• Targets/milestones
• Definition of scope
• Cost calculation
• Proposal preparation
• Quote submission
• PO
• Definition of tasks
• Ressources and
capacities
• Scheduling
• Project team
building
• Kick-off
• Process research and
dev´t• Analytical dev´t• Supply chain
• EHS study
• Manufacturing
• QC/QA release
• Regulatory services
• Stability study
• Reporting
• Final report
• Delivery
• Project review
• Lession learned
• Further optimization
• Cost savings potential
• Know-how management
• Commercial potential
Phase appropriate development, risk assessment
Process Development
12
Technology
Transfer
Manufacturing
Familia-
risation
Design for
Manufacturability
Process Parameter
Screening
Analytical
Development
Technical
Package
Route
Scouting
Report
Master
Batch
Record
Batch Analysis
Method
Optimisation /
Validation
Process
Optimisation &
CharacterisationUpdated
Master Batch
Record
Route
scouting
Campaign
Report
Commercial Manufacturing
Process
Validation
Before Initiating the Work…
Put together a good document for the Target Product Profile TPP
What needs to be achieved to end up with a good and safe drug
TPP provide a basis for a good planning of the activities and how they
should be performed to address the requirements
TPP will helps identify the risks and mitigate them
• Drug substance risks
• Drug product risks
• Non-clinical study risks, study design etc
• Regulatory strategy
Mode of adminitration
Expected formulation: IV, SC, Oral (capsule, tablet, granules…), Patch…
• The requirements will depend on the formulation
TPP is a living document and can be updated based on the progress and
challenges
Assumptions, Paper Work…
Clear the intellectual property
For the product itself
For the planned experiments. Some of the technologies intended could be
patent protected. Seek an FTO statement
Plan for enough API and finished product
Anticipate potential solubility issues and other physical and chemical
challenges based on the product structure/peptide sequence:
Can the drug be formulated based on its chemical formula/structure.
Hydrophobicity. Is the preclinical formulation going to be the long-term
approach? Potential gaps to be assessed
Anticipated stability issues? Oxidation, ester cleavage, hydrolysis…
Manufacturing: scalability and COGS. Competitive landscape
Drug Substance CMC Requirements
The very least you need to provide:
Nomenclature and product description
Physical and chemical characteristics
Manufacturer and relevant documents
Method of synthesis: detailed flow diagram including reagents, solvents…
Structure justification, chirality, sequence
Impurities and justification. Genotoxic impurities
Specify limits for ID, purity, assay, impurity level, KF, etc. Justify why
Analytical methods: ensure the methods are aligned with the process and
can detect and quantify process and stability related impurities
Container/packaging specifications. Stability
Drug Substance Recommendations
Anticipate and identify the RSM and the criticality of their
specifications
If ALREADY MADE the Phase 1 material, provide the CoA of both Tox
and phase 1 material. Explain, justify the differences if any
Understanding the process. Process impurities vs. Stability impurities,
methods, impact of raw materials (use-test?), replacing class I
solvents. No need to characterize impurities for PC studies
Planning for enough material…
Primary reference standard
Method development, qualification
Stability
Formulation development
Retain samples
Drug Substance Recommendations
Qualifying higher process impurities through toxicology studies. Use of
a less pure API (~95%)
Purity may drop during formulation
Scale-up may lead to less pure material due batch size and difficulties to
keep process parameters under control
Ideally long-term process should not change too much but only
optimized. Synthetic route to be optimized and ideally not changed.
Scalability of current Tox batch process to be considered
Partner should have the capacity to support throughout the
product life-cycle. Switching only if really needed. Tech transfer
costs, new partner not familiar with the process challenges, time for
transfer…
Drug Product Requirements
Similar to API with more Drug Product specific information
Components in the DP
• Excipients including novel actives (formulation technologies, delivery systems)
• Primary packaging: suppliers to be listed
– For injectables:vials, stoppers, pre-filled syringes, cartridges…
– Solids: blister packaging specifications, bottles…
Manufacturer, licenses
Process flow diagram with emphasis on the sterilization steps
Analytical methods and specifications
• Excipients and packaging materials
• API
• Finished product
Stability data: 1 month for US and 3 months for Europe
Container closure integrity test (CCIT): to be validated for sterile products
Drug Product Requirements
Importance of the dosage form:
Intravenous and Sucutaneous: sterile liquid or lyophilized to be
reconstituted
Sterility is key and needs to be validated: sterile filtration, heating
cycle, container closure
Inhaled products, provide information on:
• Particle size
• Bioavailability
• Dilution
• Complex formulation (lipids nanoparticles, liposomes…): Process information
• Device functionality
Oral delivery: Dissolution profile, Blend Uniformity, process information on
coated, un-coated tablets, capsule…
Switching from one dosage form to another needs to be carefully
assessed and risk-mitigated
Compressing Timelines
Good design of the studies
Target indication once IND filed
Plan for phase 1 studies: healthy volunteers vs. Patients (oncology)
Plan to be cross-checked by a toxicologist and confirmed by a KOL
Route of administration, dose
Pre-IND meeting with FDA
CMC: no need for GMP API. Recommend less pure API for Tox.
Leverage on synergies between API and DP
• Analytical methods
• Timelines
• Understanding of the API characteristics will help DP development and
manufacture
• Stability data on API will help anticipate DP stability
Compressing Timelines
Overriding the requirements generates more work and causes delays
Lean project planning and avoid leaving too much gaps between
the activities. The time required is usually under estimated
The required data for filing should be generated as the project
progresses. Compiling 12-18 months of data afterwards can be a
challenge.
Analysis of the CMC risks: scale-up, stability, methods, contingency
Simple formulation possible but need to assess the risk of switching
later on.
Project management, project management, project management…
CMC Supply Chain Complexity
No matter how many CMC partners involved, there will be ONE FDA Reviewer!!!
Supply Chain and Compressing Timelines
API and Drug Product Development and manufacture
Automated synthesis vs. Semi-automated or manual
Drug product: level of automation in filing, labeling, packaging, inspection
Experience developing processes and similar APIs. Synergies with other
similar APIs can help reducing the process development timelines
CMO/CRO level of outsourcing. The more outsourcing, the complex
is the supply chain and overall project overview
Does the set-up of API and DP sourcing allows for easy use of the
synergies? Integrated project plan?
Delay in API impacts the start of the formulation. Am I going to have
another formulation slot soon? Impact on overall project timelines…
API and DP under the same roof. Delays in API are easier to handle in
case of integrated supply. Aligning multiple partners can be a challenge
Supply Chain and Compressing Timelines
CDMOs and CROs must have a very good blend of knowledge and
expertise in such services
True integrated services, no silos! CDMOs and CROs with the
capabilities but working in silo mode!
Overall project management: overviewing all of the activities API, DP,
coordinate with non-clinical services…
Project team with clear duties and responsibilities keeping an eye on the 3
pilars: timelines, quality and budget
One Project Team: Easy transition from one stage to the next
Partner reliability: can deal with challenges. Solution oriented
The CMC gaps may have a big impact on product due dilligence for
partnering or out-licensing
ProcessDevelopment
Scale-UpAPI
Manufacturing
FormulationDevelopment
Scale-UpDrug ProductManufacturing
Compressing the Timelines Through Project
Integrated Services
Leverage on API know-how to transition to drug product:
Analytics, product characteristics
Integrated Project Management, overview on the overall Project Plan
Time and Costs saving
In vitro, ADME, Bio-
methods
Toxicology, Pharmacology
Quality & Regulatory Support
Selecting the CMC Partner
Supply of API and DP under the same roof
Scientific skills and know-how in line with your project requirement
Available capacity to support far beyond IND and avoid switching
and associated risks
Capabilities: manufacturing and analytics including later stages
Regulatory history and quality system
Can manage multiple projects. Resource flexibility, can adapt to
changing scenarios
Strong project management and communication
Transparency
Pricing
Pre-IND Meeting (few months before submission)
The Agency is a Partner. Work collaboratively. They provide
guidance for the project
Compiling a list of questions to be addressed during the meeting. Can
the data be compiled or is it spread over various CDMOs and
CROs?
Few thoughts: very short summary of the dossier
Product information: small molecule, peptide, biologic, vaccine…
Therapeutic indication
Dosage form and route of administration
EXPECTATIONS FROM THE PRE-IND MEETING. What are the
questions/uncertainties to be clarified?
Data to date
CMC plan
Non-clinical plan
Phase 1 protocol, at least an idea of the next stage
IND Submission and Review Process
IND Submission
Do you have all the information required. Check-list, tick the boxes
Do you have the resources to put together the required documents
Do you have project management capabilities to feed all necessary
information generated over several months
Do you have a clear idea of the target filing date and how to get there
Don’t hesitate to seek help from consultants having experience with
filing
Summary
Connecting CMC development with pre-clinical development
Even not completely optimized, the process strategy should be able
to supply clinical and commercial quantities after optimization
Interdependent activities. Project plan is key. Integrated services are
a big plus in accelerating the program and saving costs
Planning time to compile the data, usually underestimated
Some CMC activities cannot be compressed without jeopardizing the
dossier (stability, development API and DP)
Specifications to be set based on process data rather than what can
be done or internal capabilities. Alignment between CQAs and
CPPs
Work closely with the agency and the reviewer. Multiple CDMOs
and CROs can be involved but there will be one reviewer!!! Dossier
should be comprehensive
www.cordenpharma.com
Experts taking care.
THANK YOU
Mimoun Ayoub, Ph.D.
VP, Global Head of Sales and Key Account Management
Cell: +41 79 937 5302
www.cordenpharma.com