www.cordenpharma.com
Experts taking care.
TIDES USAMay 2019
Mimoun Ayoub Ph. D. Head of NA and Emerging Markets
Peptide CMC Approaches for a Fast and Successful IND Filing
Sales: € 380 millionEmployees: ~ 2000
Sales: € 115 millionEmployees: ~ 870
ENKA Group
CarboTech AC
Rütgers OrganicsSales: € 700 millionEmployees: ~ 2000
Sales: € 960 millionEmployees: ~ 1,200
CordenPharma Group
WeylChem Group
VYNOVA Group
IT, Accounting, Finance, Human Resources, Legal
International Chemical Investors Group (ICIG) Market Oriented Platforms
Fine 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
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.60% of net sales and usually have a shorter ramp-up phase than respective Drug Product projects
Raw Materials Non-GMP Intermediates
GMP Intermediates APIs DPs Pharma
Logistics
Lifecycle Positioning
CordenPharma focuses on all stages of a drug lifecycle with competitive advantages in clinical development and commercial production
Preclinical12 months
Phase I12-18 months
Phase II24 months
Registration12 month Commercial GenericPhase 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
SmallMolecules
Antibiotics
Road-Map to Market
Pre-clinical Phase 1 Phase 2 Phase 3
Non-regulatedNon-GMP
Increasing Regulatory RequirementsGMP 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 theother, consequences beyond IND
Risk assessment and mitigationapproach
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
The big Disconnect…
There are disconnects within each of the two pilars: between API andDP as well…Multiple partners involved
Performing non-clincial studies to nearly perfection with gaps in CMC doesn’t help
Non-clinicalTasks
CMCAPI & 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 Dept. Manufact.
DP Devpt. Manufact.Labeling,
Packaging
Pre-clinical tox. And
pharmaco.
Compiling Documents
Review
Project Plan
Project Team
For Each Milestone…Ex. API Synthesis
9
Execution, monitoring
and controlingProject 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
10
Technology Transfer
Manufacturing
Familia-risation
Design for Manufacturability
Process Parameter Screening
Analytical Development
Technical Package
Route Scouting Report
MasterBatch Record
Batch AnalysisMethodOptimisation / Validation
ProcessOptimisation & CharacterisationUpdated
Master Batch Record
Route scouting
CampaignReport
Commercial Manufacturing
ProcessValidation
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 help you 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
Before Initiating the 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 your RSM and the criticality of their specifications
If you have 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. 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: Process information on coated, un-coated tablets, capsule…
Switching from one dosage form to another after preclinical needs tobe 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 IND 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 Easy transition from one activity / stage to the next, one project team
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-Up API
Manufacturing
FormulationDevelopment Scale-Up Drug Product
Manufacturing
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-
methodsToxicology,
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 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, not only to complete the work 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.Director, Head of North America and Emerging [email protected]: +41 79 937 5302www.cordenpharma.com