Upload
others
View
5
Download
0
Embed Size (px)
Citation preview
© 2019 Parexel International Corporation
Manufacturing challenges for commercialization of cell and gene therapy products
Mo Heidaran, PhD
Vice President, Technical, Regulatory
Parexel International [email protected]
© 2019 Parexel International Corporation
Background
Gene Therapy Opportunities
Gene Therapy Product Regulatory Considerations
Expedited Programs vs IND Phase
Special Considerations for Gene Therapy Products
Other Considerations
Manufacturing Comparability
Contract Manufacturing
Summary and Recommendations
2
Regulation and Challenges in Developing Vector-Based Gene Therapies
© 2019 Parexel International Corporation3
Opportunities in gene therapy and gene-modified cell therapy expanding
An extract from
the Quarterly
Regenerative
Medicine Global
Data Report
© 2019 Parexel International Corporation4
Opportunities in gene therapy and gene-modified cell therapy – growth in oncology and mono genetic diseases
An extract from
the Quarterly
Regenerative
Medicine Global
Data Report
© 2019 Parexel International Corporation
Remarkable growth in cell and gene therapy products
Oncology and inherited genetic disorders
Orphan drug products
Small addressable market size for ground breaking
technologies
Complex, but dynamic and responsive regulatory environment
Potential for curative products
Shift from small biotech to larger pharma and biotech (adoption by Pharma/Biotech)
Flexible Interpretation of existing regulations
Innovative Trial Design
Single arm, small patient population, ethical consideration
Large treatment effects
5
General trends
High risk, high benefit scenarios (risk mitigation strategies)
Cost is a factor
Manufacturing remains a major hurdle
Source: FDA.gov
© 2019 Parexel International Corporation6
FDA regulatory oversightOffice of Tissue and Advanced Therapies
Kymriah (CAR-T, Target CD19)Yescarta (CAR-T, Target CD19)
Carticel (Chondrocytes)Provenge (Dendritic VaccineLaviv (Fibroblast),
8 Cord Blood Manufacturers
Gentuit (Skin Substitute)TheraCys (BCG)
Cell
Undifferentiated
Stem cell or adult stem cells or Tissue Cells
Differentiated
Differentiated
HES, HSC, MSC
Cell
Peptide Pulsed
Pulsed T cells, Dendritic Cells
RNA Loaded
Tumor RNA loaded
Dendritic cells
Cell
Gene Modified
Engineered T and NK cells
Gene Edited
Gene deletion, addition
correction
Vector/
Virus
Virus
AAV
Vector
Plasmid
Tissue Engineered
Non Combination
Cell plus scaffold from
decellularized tissue
Combination
Synthetic scaffold plus
cells
Device
Combination
Catheter plus Cells
Non combination
Cell Collection & Processing
Device
Others
Xeno, Peptide, RNAi, Exosome
Luxturna (AAV RPE65)
TheraCys (BCG)
Zolgensma (AAV SMN1)
Cell therapy
Gene modified
cellsGene therapy
(in vivo)Gene edited
cellular productsCombination
productSecreted factors
Therapeutic peptide
vaccines Others
Cultured MSCs, Peptide pulsed T cells
CAR-T,IPSCs
AAV lentiviral vectors,
Plasmid vectors (AAV RPE65)
CRISPR/Cas9edited HSC
Biologic + Device Synthetic scaffold
plus MSCs
Exosomes Peptide vaccine Xenotransplantation
© 2019 Parexel International Corporation7
It is complicated and manufacturing is behindLarge
Treatment
EffectsCurative
Product is not ready
© 2019 Parexel International Corporation8
July 1, 2017 (Vol. 37, No. 13)Tony Hitchcock Technical Director Cobra BiologicsBuilding Processes for the Future
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � ! " � � � � �
� � � � � � � � � � � � � � � � � � � � � � # � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � # � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � !
$ � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � % & ' � � � � � � $ ( � � � � � � � � � � � � � � � � � �
) $ � � � * � � � + , � � ) - � � � + � � � � � , � � � � � � � � � � � � � � � � � � � � � # � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � !
* � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � + � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � + � � � � � � � � � � � � � � � � � �
� � � � � � � � � � � !
© 2019 Parexel International Corporation9
https://www.raps.org/news-and-articles/news-articles/2019/4/establishing-manufacturing-controls-a-hurdle-
for?utm_source=MagnetMail&utm_medium=Email%20&utm_campaign=RF%20Today%20|%2029%20April
Manufacturing challenges highlighted
Challenge: Establish Consistent
Manufacturing of Gene Therapy
Products at Commercial Scale Prior to
Licensing Trial and Licensure
© 2019 Parexel International Corporation
https://pink.pharmaintelligence.informa.com/PS125489/CellGene-Therapy-
Manufacturing-Readiness-Urged-As-A-Condition-For-US-Expedited-Designation
Executive Summary
Requiring that certain chemistry, manufacturing and controls conditions be satisfied
before awarding breakthrough or regenerative medicine advanced therapy status would
help ensure that the quality side of product development keeps pace with the clinical
side, says Parexel's Mo Heidaran, a former CMC reviewer in the FDA’s biologics center.
10
Cell/gene therapy manufacturing readiness urged as A condition for US expedited designation
© 2019 Parexel International Corporation11
CMC readiness checklist, possible solutions to CMC & manufacturing challenges
Have you performed a careful review of your manufacturing process to ensure
that you are entering Phase III trials with a product which is optimal?
Have you introduced major manufacturing changes that may require
conducting comparability studies and if so what is your plan to conduct such
comparability studies?
What is the status of your analytical method development. Have you qualified
or preferably validated your assays prior to initiation of your pivotal trial?
Do you have appropriate potency assays in place for the final drug product?
Do you have knowledge of Critical Quality Attributes (CQA), Critical Process
Parameter (CPP), and Key Process Parameters (KPP)?
Have you determined shelf life of the final drug product by conducting stability
assays using assays which are appropriate and qualified/validated?
Do you have a well-defined plan to collect materials, reserve samples, for in-
process and the final drug product?
What is your plan of action to conduct process validation to demonstrate that
the final drug product can be successfully manufactured consistently?
Have you defined Standard Operating Procedures (SOP) and protocols,
instructions for use outlining any additional manufacturing, processing,
formulation or thaw/dilution of the final drug product at clinical sites?
Do you plan to gain a better understanding of the requirements for conducting
leachable and extractable studies for materials which are in direct conduct
with your product?
What is your plan for manufacturing of the final drug product? Do you
anticipate needing to make a change to your existing facility? Do you plan for
automation, scale-out or scale-up post approval or prior to initiation of Phase
III study?
Have you made a final determination if the current release specifications are
adequate for ensuring safety and potency of your final drug product?
Have you conducted shipping validation for source materials and the final
drug product under worst case scenarios or conditions of transport?
Have you reviewed the quality of ancillary materials, reliability and
sustainability of your supply chain and do you have a plan to review your
quality agreements and SOPPs which are in place for material qualification,
vendor qualification? Have you developed an identity test for your critical
ancillary materials?
Have you finalized your choice of the final container and have a plan how to
affix the label on the final drug product?
What is your plan for testing of the source material, in process materials or the
final drug product? Do you plan to outsource your testing, or will it be
conducted in house?
Do you need to develop any in house standards (physical or performance
standards) for your assays? Do you know what standards are needed for your
product development and release testing?
Have you had an EOP2 or other meeting with the agency to assess your CMC
readiness?
© 2019 Parexel International Corporation12
What is critical in the IND review process?
Benefit to risk assessment
Product specific
Safety considerations come first
Risk and science based approach
Institutional knowledge is a factor
Team approach with product focus
Case by case
IND 30-day clock:
Cursory review
Is IND appropriate for submission
Required sections
Gap analysis
Information Request
Final assessment
Hold
Allow to proceed
Risk of Product
Benefit to patient
© 2019 Parexel International Corporation13
Benefit to risk analysis is both quantitative and qualitative
Risk of the product
Spread of communicable diseases
Lack of sterility
Immunogenicity
Contamination with adventitious
agents
Impurities
Tumorigenicity
Toxicity
Mix up
Etc.
Benefit to patient (potential)
based on animal studies
Quality of life improvement
Disease modification
Cure
Treatment benefits
Benefit
Risk
© 2019 Parexel International Corporation14
CMC information required by FDA for IND to proceed
Description of product
Manufacturing process
Mechanism of action
Analytical methods qualification
Ancillary materials (human versus animal derived)
Master cell bank (MCB) and master virus seed
(MVS) qualification
Donor screening and testing-Allogeneic Gene Modified Cells
Drug substance release specification
Drug product release specification
Sterility, identity (product characteristics that
distinguishes one product from another type in facility), purity (endotoxin level), viability, Mycoplasma if cultured, potency is optional
Other list of Release Tests (Product Specific)
Action plan for sterility failure
Container label
Stability
Shipping
Formulation
Facility information
Categorical exclusion
Evidence that product can be manufactured
© 2019 Parexel International Corporation15
Compliance approach for gene therapy products
Essential elements of CGMPs
Manufacturing controls
Prevention of contamination and cross contamination
Manufacturing consistency
Product quality
Phase based approach:
Phase I (statutory CGMPs)
Guidance for Industry CGMP for Phase 1 Investigational Drugs (https://www.fda.gov/downloads/
drugs/guidances/ucm070273.pdf)
Full CGMPs verified at time of pre-license inspection:
PHS Act, Section 351(a) and FD&C Act
Federal applicable regulations:
21 CFR 210, 211 (CGMPs)
21 CFR 600 (biological products)
21 CFR 1271, human cell, tissues and cellular and tissue based products
21 CFR 800 (device)IND phases
CGMP compliance
Phases I Licensure
© 2019 Parexel International Corporation16
Special consideration for gene therapy
Manufacturing process
Vector and plasmid sequence information
Virus Information
Special safety consideration
Replication Status
Adventitious Agent
Oncogenic activation and persistence or
other virus specific safety consideration
Virus shedding and patient follow up
Special consideration for AAV versus Lentiviruses
Guidance Documents:
Long Term Follow-Up After Administration of
Human Gene Therapy Products
Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication
Competent Retrovirus During Product Manufacture and Patient Follow-up
Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products
© 2019 Parexel International Corporation17
Technical and manufacturing challenges (gene modified cells)
Purity and Composition of Transduced cells
Efficiency of Transduction
Risk of Replication Competent Virus
Possibility of Insertional Activations
Ancillary Material and Supply chain
Manufacturing Consistency at Commercial Scale
Manufacturing Capacity
Scale Out, Automation
Chain Of Identity and Chain Of Custody
Cost
© 2019 Parexel International Corporation18
Supply chain considerations
Supply of materials (components)
Raw materials, ancillary materials, equipment, containers
Source material collection equipment
Media and growth factors, others
Manufacturing tools (flask, bags etc.)
Container closures (bags or vials)
Grade of materials (CGMP) alone is not sufficient to ensure quality-CGMP grade is not verified by FDA
Manufacturers are responsible to verify that product
components are manufactured according to CGMP* (Vendor Audit)
Shipping, and storage conditions are sometime
challenging
Cost is a factor
FDA cleared devices, containers are preferred
Material qualification*
Verify safety, identity, purity and potency
Certificate of analysis is not sufficient
Quality (fit for purpose) and reliability
Regulation requires that manufacturers test the incoming materials for identity
Vendor qualification*
Vendors of critical materials should undergo a routine qualification process which may involve audit and/or
verification of their manufacturing practices
Quality agreements*
Manufacturer should have a quality agreement in place
with key vendors particularly those that perform contact manufacturing. This agreement defines the relationship between the manufacturer and contract manufacturers
Alternative sources (supply chain uncertainty)
Determine long term sustainability of the supply
Determine potential alternative Sources
© 2019 Parexel International Corporation19
Starting Biological Materials
Apheresis Procedure
Device Considerations
Collection, Apheresis
Spectra Optia, COBE Spectra (Terumo)
Cell Enrichment Step
Selection Platform
CliniMacs
Flow
Others
Purity of selected Population
Starting material characterization and
qualification
Bruce Levine in Molecular Therapies Methods and Clinical Development
The Importance of Collection,Processing and Biopreservation
Best Practices in DeterminingCAR-T Starting Material QualityLou Juliano, George Eastwood, Todd Berard &
Aby J Mathew, PhD
Qualification of collection materials & starting material qualification
© 2019 Parexel International Corporation20
Chain of identity and chain of custody
Tracking and labeling
Automated Platforms for real time tracking and scheduling
TrakCel and Vineti
Manual Platforms
Hybrid Platforms
Label Information
Label Reconciliation
© 2019 Parexel International Corporation21
Technical and manufacturing challenges (AAV products)
Background
Suitable for non dividing cells
Many isotypes AAV2,---AAV8 and AAV9
Differential tropism
Several manufacturing platforms:
Mammalian cells and insect cells
Multiple plasmid containing rep, capsid and transgene
Helper virus
Tony Hitchcock in Genetic Engineering and Biotechnology News
© 2019 Parexel International Corporation22
Special consideration AAV technology
Payload limit
Quality of Ancillary Materials
Immunogenicity (Repeat administration)
Replication Competent Virus
Durability of response
Aggregate formation and filtration
Adventitious Agent Testing (Viral Clearance)
Empty full capsid separation and testing
Method development and validation
Manufacturing capacity (adherent vs.
suspension cell Process)
Cost
AAV Quantitation Assay is Critical (how to determine patient dose accurately)
Empty to full ratio and particle to infectivity ratio
Transgene expression, potency and stability
Assay qualification and validation are very critical
Methods: qPCR/ddPCR (Viral Genome Concentration; ELISA (Viral Capsid Quantification), SDS-PAGE (VP Protein Profile, Spectroscopy, Ion Exchange Chromatography (separation between empty and full capsid), Electron Microscopy (Viral
particles as a population)
FDA does not recommend use of T antigen containing cell line since there are multiple platforms available which have
better safety profile
Test for rcAAV should include qPCR for capsid sequence in addition to rep sequence following cell amplification!
© 2019 Parexel International Corporation23
Common Platforms: Cas9/TALEN
Used for generating variety of Indels and
deletions
Review of risk benefit analysis is performed case by case and dependent on target indication, type of cells used for ex vivo
gene editing, platform(s) utility, and safety and knowledge of the final drug product.
GE components can be introduced to cells
by variety of methods (Introduce expression vector or modified viruses or deliver nuclease and RNA guide)
Characterization of On target editing and allele composition
Discovery and verification of Off target Indel formation, and large inter or intra chromosomal changes (deletion, translocation, etc.) through unbiased genome wide off-target identification (orthogonal approach)
Demonstrate that ex vivo edited cellular product does not contain any nuclease activity
Demonstrate quality of gene editing components:
Stability, COA, Purity, Identity by sequencing, sterility
Description of optimization steps for components used
Detailed description of gene or protein delivery platforms
(electroporation, others)
Demonstrate adequate manufacturing experience prior to clinical product manufacturing
Characterization of GE related toxicities impacting cell phenotype
Special consideration for gene editing (GE)
© 2019 Parexel International Corporation
Background
Plasmids are commonly manufactured
by contract manufacturers
Plasmid vectors are produced with
different qualities
Recommend using CGMP grade if
possible
CGMP grade is not verified by FDA
IND holder responsibility to verify CGMP
compliance by contract manufacturer
24
Vector quality considerations
Identity Consideration
Full sequence analysis
Residual host protein and genomic DNA
Ensure purity (lack of cross
contamination)
Adherence to CGMP principles
Cross contamination control
• Line clearance
• Product specific cleaning validation of contact surfaces
• Appropriate monitoring and environmental controls and classification
Appropriate quality standards
Appropriate release testshttps://www.biopharma-reporter.com/Article/2018/07/27/US-FDA-puts-gene-therapy-on-hold-after-DNA-fragment-found-in-
plasmids#.W18o9r4gEnQ.linkedin
© 2019 Parexel International Corporation
Draft Guidance Assay Development and Validation of Immunogenicity Testing for Therapeutic Protein Products
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assay-development-and-validation-immunogenicity-testing-therapeutic-protein-products
Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of
Biosimilar Assessment (The AAPS Journal (2018) 20:25)
Analytical Methods to Measure Empty and Full Particles
https://www.beckman.tw/resources/videos/webinars/analytical-ultracentrifugation-methods-for-aav-particles
Pharmaceutical Development of AAV-based Gene Therapy Products for The Eye.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308217/pdf/11095_2018_Article_2554.pdf
USP and SCB Activities Related to the Development of Physical Standards for Gene Therapy Products
USP 2020 Workshop with focus on the development of standards for Gene Therapy Products
SCB activities related to measuring pre-existing immunity to AAV and feasibility of developing such a standard
25
Analytical method development for gene therapy products
© 2019 Parexel International Corporation
Special consideration for RCR/RCL testing, shedding and long term follow up
© 2019 Parexel International Corporation27
Testing guidance for replication competent retroviruses (RCR) or lentiviruses (RCL)
FDA recommends using Stably-transfected Vector Producer Cell (VPC) bank system
Generate MCB from VPC (VPC MCB)
Materials and sample Requirement:
See Table “Recommendation for Product Testing”
Sampling recommendation:
Both cellular and supernatant should be tested for RCR
Supernatant: FDA recommends at least 5% of the total supernatant, or 300 mL, to ensure absence of RCR.
Cell Testing: FDA recommends that you test 1% or 108 (whichever is less) pooled vector-producing cells or ex vivo transduced cells by co-culture with a permissive cell line.
Assay Requirements:
Vector supernatant assays should include culture of
supernatant on a permissive cell line for a minimum of five passages in order to amplify any potential RCR present. Similarly, cell testing should be accomplished by co-culture with a permissive cell line for a minimum of five passages in order to amplify any potential RCR present.
Guidance: Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product
Manufacture and Patient Follow-up
© 2019 Parexel International Corporation28
Long term follow up gene therapy products
Question 1: “Does your GT product utilize genome-editing technology?”
Yes, LTFU
Question 2: “Is your vector used only for
ex vivo modification of cells?”
Question 4: “Are your vector sequences integrated or is the human genome
otherwise genetically altered?”
If Yes to above 2 LTFU
Does Gene Therapy shows Persistence
Yes, LTFU
Guidance: Long Term Follow-Up After Administration of Human Gene Therapy Products
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-
products
© 2019 Parexel International Corporation29
Recommendation for patient monitoring receiving lenti viral cellular products
FDA recommends monitoring schedule to include analysis of patient samples at the following time points: pre-treatment, followed by testing at three, six, and twelve months after treatment, and yearly for up to fifteen (15) years.
However, if all post-treatment assays are negative during the first year, collection of
the yearly follow-up samples may be discontinued.
FDA recommends two methods that are currently in use for detecting evidence of
RCR infection in patients: 1) serologic detection of RCR-specific antibodies; and 2) analysis of patient peripheral blood
mononuclear cells by PCR for RCR-specific DNA sequences.
RCR testing results from production lots
and patient monitoring should be documented in amendments to the IND file. Positive results from patient
monitoring should be reported immediately as an adverse experience in the form of an IND safety report (21 CFR 312.32).
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-
products
© 2019 Parexel International Corporation30
Special considerations (shedding studies)
“shedding” means release of VBGT or oncolytic products from the patient through one or all of the following ways: excreta (feces); secreta (urine, saliva, nasopharyngeal fluids
etc.); or through the skin (pustules, sores, wounds).
Shedding raises the possibility of transmission of VBGT or oncolytic products from treated to untreated individuals (e.g., close contacts and health care professionals).
For VBGT and oncolytic products classified as replication competent, FDA recommends that sponsors begin collecting shedding data in Phase 1 trials.
For VBGT products that are classified either as replication
incompetent or replication deficient, we recommend that sponsors collect shedding data later in product development (e.g., during Phase 2 studies), after a dose and regimen have been determined.
Preclinical shedding data may be requested for an oncolytic or a replication competent VBGT product, if:
Humans have not been previously exposed to the product, as in the
case of a non-human bacterial or viral strain.
The product has been administered to humans, but has been modified to achieve a different in vivo tropism than the parent strain.
The product has been previously administered to humans; however,
a change in the route of administration is proposed.
Humans have not been previously exposed to the product, and the route of administration differs from the natural route of exposure/infection.
Other considerations: Replication competence, Immunogenicity, Persistence and latency, Tropism, Stability of product attenuation. Route of administration
Clinical Program involves prospectively design and
incorporate the sampling plan in the clinical study to collect shedding data. Preclinical data is informative.
Other Considerations are Frequency of sample collection; Duration of sample collection; Type(s) of samples collected; and Storage
conditions for types of samples collected.
Guidance: Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products
© 2019 Parexel International Corporation
Other considerations
© 2019 Parexel International Corporation
Scale up scale out
Automation
Change of critical reagents
Manufacturing site change
Sponsors are ultimately responsible to
plan for change, report the change
and demonstrate product
comparability as needed
32
Process change is inevitable
How to deal with changes in manufacturing
Product comparability is intended to
demonstrate that a change in process
does not alter the CQA of the product.
Demonstrate product before and after
change are similar
ICH Q5E states that comparability can
be established using in vitro or non
clinical study
© 2019 Parexel International Corporation
If CQA/CPP are well known and a correlation between CQAs and product quality, safety
and efficacy can be demonstrated then testing of the product CQA before and after change
is sufficient
If knowledge of CQA/CPP is not complete then a matrix based approach is recommended
Compare all relevant product attributes before and after change (full/extended characterization)
In process and final release
Comparing Release Specifications for the product before and after change may not be sufficient
Manufacturing yield
Control of Key Process Parameters
Others
Risk assessment
Process validation ensure consistency of product after major changes are introduced
33
Tools for establishing comparability
© 2019 Parexel International Corporation34
Major considerations
What is the change?
What is the level of risk impacting product quality?
Why the change is introduced?
When is the product lifecycle the proposed change is introduced?
Essential aspects of the comparability study
A description of proposed change
Risk assessment (Impact on Product Quality)
A rationale for the proposed changes
Comparability study designs
Prioritization and assessment of key Critical Quality Attributes
Comparative assessment of quality attributes before and after change
Side by side comparison using the same biological source material is preferred
Justification for a well defined acceptance criteria
for establishing analytical comparability
Detailed analytical procedure, sample plan and statistical method and analysis
The more reflective CQAs are of clinical outcome, the easier it is to
establish product comparability
Comparability study
© 2019 Parexel International Corporation35
Special consideration contract manufacturing
Sponsors:
Applicant is ultimately responsible for quality
of the product
For BLA submission the content of MF for DS/DP/DSI can not be relied upon
If MF is not adequate IND holder or BLA holder are notified of deficiencies.
Sponsor relationship with contract
manufacturer should be established (Quality Agreement)
Contract Manufacturers:
Confidential information can be submitted to
FDA in appropriate Master File
Type II (DS/DP/DSI) , III (packaging, CC), IV (excipients) and V (Reference/Facility) (eCTD
submission requirements)
MF holder should provide LOA allowing FDA to review information in MF in relationship with a submission
CM may be inspected by FDA as part of pre license inspection
Contract
Manufacture
BLA
Holder 2
BLA Holder
3
BLA
Holder 1
FDAMF
Quality Agreement
LOA
© 2019 Parexel International Corporation36
Developing cell & gene therapy for U.S. market – key take away
Start with target disease (rare and life threatening condition) and define Target Product Profile (TPP) early on
Spend time and resources to develop candidates product(s) based on TPP and MOA
Select the right platform technologies for product development early on if possible and understand the IP landscape, your competition, pricing power and reimbursement landscape
Engage Regulatory authority early on to develop CMC and clinical strategy
Avoid major manufacturing process changes in the midst of licensing if you have
limited knowledge of the product and attributes which are key predictor of clinical outcome
© 2019 Parexel International Corporation37
Developing cell & gene therapy for U.S. market – key take away
Don’t make critical product development decisions based solely on regulatory considerations
During all stages of clinical development continue building your knowledge of the product CQA/CPP that are critical to product quality and efficacy
Don’t wait until product approval or after to develop appropriate manufacturing platforms (scale out or scale up) – anticipate success
Avoid changing manufacturing facility and plan ahead for commercial facility
Lack of attention to the quality supply chain and logistics may cause significant delay in your product launch
© 2019 Parexel International Corporation38
Developing cell & gene therapy for U.S. market – key take away
Traditional trial design used for small molecule drug products may not be applicable. When treatment effects are large innovative trial design could be acceptable by FDA.
Product approval at less than commercial scale is possible but it is not sustainable commercially
Innovative approaches to process validation is required
Standard Pharm/Tox studies performed for small molecule drugs may not be applicable especially when prior evidence of safety in human exists
Manufacturing consistency established at commercial scale remains to be a major hurdle
Arguably, FDA approval does not necessarily translate to commercial success
Patient centric approaches are highly encouraged
FDA has adopted a flexible regulatory framework which is case by case, science based and depends on benefit risk analysis
© 2019 Parexel International Corporation39
Developing cell & gene therapy for U.S. market – key take away
Solving technical challenges in manufacturing of gene therapy products require government industry partnership (NIIMBL, ARMI and others)
Access to high quality and cost effective ancillary materials
Development of advanced manufacturing and analytical testing platforms
Developing appropriate standards
Successful commercialization requires consistent manufacturing of the final drug
product at commercial scale.
http://www.pharmexec.com/high-stakes-manufacturing-mitigating-risks
© 2019 Parexel International Corporation
Thank you
© 2019 Parexel International Corporation
https://regulatory.parexel.com/regulatory-blog/regenerative-medicine-versus-
regenerative-medicine-therapies-versus-regenerative-advanced-therapy-what-is-
the-difference
https://regulatory.parexel.com/regulatory-blog/qualification-as-a-step-toward-assay-
validation-for-cber-regulated-cell-and-gene-therapy-products
https://regulatory.parexel.com/regulatory-blog/points-to-consider-for-
manufacturing-biologics-at-the-clinical-site
https://regulatory.parexel.com/regulatory-blog/root-cause-why-does-regulatory-
approval-not-always-equate-to-commercial-
success?utm_source=linkedin&utm_medium=social&utm_campaign=corporatesoc
ial&kui=Cgg_t_wPV7INupo5m0TwXg
41
References
© 2019 Parexel International Corporation
https://www.parexel.com/news-events-resources/blog/key-questions-consider-
when-licensing-cell-gene-therapy-products
https://www.parexel.com/news-events-resources/blog/state-germline-gene-editing-
what-we-dont-know.
https://www.raps.org/news-and-articles/news-articles/2019/4/establishing-
manufacturing-controls-a-hurdle-for
https://pink.pharmaintelligence.informa.com/PS125489/CellGene-Therapy-
Manufacturing-Readiness-Urged-As-A-Condition-For-US-Expedited-Designation
https://medcitynews.com/2019/06/could-automating-raw-materials-production-
bring-down-gene-therapy-prices/
http://www.appliedclinicaltrialsonline.com/cmc-considerations-gene-therapy-and-
regenerative-medicine-studies42
References
© 2019 Parexel International Corporation
https://regulatory.parexel.com/regulatory-blog/benefits-of-identifying-critical-quality-
attributes-and-correlating-the-cqas-with-clinical-outcomes-for-biologic-products
https://regulatory.parexel.com/regulatory-blog/points-to-consider-for-establishing-
biotechnological-biological-product-comparability
https://regulatory.parexel.com/regulatory-blog/points-to-consider-when-referencing-
a-master-file-in-fda-regulatory-submissions-ind-bla-nda
https://regulatory.parexel.com/regulatory-blog/points-to-consider-when-designing-
a-biologics-manufacturing-facility-planning-for-success-early-on
https://regulatory.parexel.com/regulatory-blog/fda-compliance-deadline-for-stem-
cell-clinics-offering-unapproved-products-to-public
https://regulatory.parexel.com/regulatory-blog/updates-on-regenerative-medicine-
advanced-therapy-rmat-designations43
References
© 2019 Parexel International Corporation
Expedited Programs for Regenerative Medicine Therapies for Serious Conditions
Considerations for the Design of Early Phase Trial for Cellular and Gene Therapy
Products
Formal Meeting between the FDA and Sponsors or Applicants of PDUFA Products
INTERACT Meeting (Initial Targeted Engagement for Regulatory Advice on CBER
Products)
CMC Information for Human Gene Therapy INDs
Long term follow up After Administration of Human Gene Therapy Products
Testing of Retroviral Vector-Based Gene Therapy Products for Replication
Competent Retroviruses During Products Manufacturing and Patient Follow Up
Human Gene Therapy for Rare Diseases
44
References
© 2019 Parexel International Corporation
Process Validation: General Principles and Practices
Guidance for Industry Changes to an Approved Application: Biological Products:
Guidance for Industry Comparability Protocols-Chemistry, Manufacturing, and Control Information
FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic
Biotechnology-derived Products
Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC)
Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)
Guidance “Analytical Procedures and Methods Validation for Drugs and Biologics
Standard Development and the Use of Standards in regulatory Submissions Reviewed in the Center for Biologics
Evaluation and Research
CGMPs for Phase I Investigational Drugs
Potency Tests for Cellular and Gene Therapy Products
Consideration for Early Phase Clinical Trials of Cellular and Gene Therapy Products
45
References
© 2019 Parexel International Corporation
ICH Q2(R1) – Includes Validation of Analytical Procedures
ICH Q5E – Includes concepts of comparability and how to establish comparability
ICH Q6 – Includes concepts of quality standards, acceptance criteria and specifications
ICH Q8 – Pharmaceutical Development:
Includes concepts of critical quality attributes and critical process parameters
Includes concepts of Quality by Design and examples of design space
ICH Q9 – Quality Risk Management
Describes a systematic process for the assessment, control, communication and review of
quality risks
ICH Q10 – Pharmaceutical Quality Systems
Describes systems that facilitate establishment and maintenance of a state of control for
process performance and product quality46
References
© 2019 Parexel International Corporation
QuestionsFor more information:
Visit our Regulatory portal https://regulatory.parexel.com/
© 2019 Parexel International Corporation
Appendix
© 2019 Parexel International Corporation
Donor Eligibility Requirements.
US Patients can not be treated with products manufactured from donors
which do not meet the requirement as defined in 21 CFR 1271 subpart C.
Donor screening requirements: Medical health record and questionnaire for
relevant communicable disease agents and diseases
Donor testing requirements: Test is performed using CLIA certified lab or
equivalent and FDA cleared test kits
Product Comparability is required if there is a significant
manufacturing changes (i.e., change of donor materials, facility
etc.)
Shipping qualification for starting materials, product and stability
considerations
Import export considerations
49
Points to consider:
Special considerations for IND submitted to US FDA based on product manufactured outside of US
© 2019 Parexel International Corporation 50
Regulatory considerations from source tissue to patient delivery
Bruce Levine et al., Molecular Therapy Method and Clinical Development
At clinical site there must be facility and capability to prepare the product within its allowed shelf life and deliver to patients.
Instruction for use must be accompanied.
Collection: apheresis -Donor eligibility for allogeneic product
(screening and testing) requirements country specific to national
authority where clinical trial is performed.
Transport of Tissue: From collections site to manufacturing site, experience with donor tissue transport would be needed.
Delivery: In some cases, administration of product may require special
considerations such as specific catheters or delivery devices, Additional Safety Considerations for
Potentially Biohazardous Materials
Transport of the Final Drug Product:Fresh products have the most difficult logistics! Product must remain stable during shipment and
must be used within its recommended shelf life. Import export considerations are factors to keep in mind
© 2019 Parexel International Corporation 51
Supply of materials (components)
Raw materials, ancillary materials, equipment, containers
Source material collection equipment
Media and growth factors, others
Manufacturing tools (flask, bags etc.)
Container closures (bags or vials)
QC test platforms
Grade of materials (CGMP) alone is not sufficient to ensure quality
Shipping, and storage conditions are sometime challenging
Cost is a factor
FDA cleared devices, containers are preferred
Material qualification
Verify safety, identity, purity and potency
Certificate of analysis is not necessarily sufficient
Quality (fit for purpose) and reliability
Regulation requires that manufacturers test the incoming materials for identity (Licensure)
Vendor qualification
Vendors of critical materials should undergo a routine qualification process which may involve audit and/or
verification of their good manufacturing practices
Quality agreements
Manufacturer should have a quality agreement in place
with key vendors particularly those that perform contact manufacturing. This agreement defines the relationship between the manufacturer and contract manufacturers
Alternative sources (supply chain uncertainty)
Determine long term sustainability of the supply
Determine potential alternative Sources
Supply chain considerations
© 2019 Parexel International Corporation52
Cell and gene therapy shipping logistics
-20°C 15-25°C2-8°C- 80°C
Shelf life of cell and gene therapy productsLong Short
- 196°C
Site
Depot? Site
2-8°C
Manufacturer
Shelf life
Import
Export
Donor
Donors eligibilityDetermination
© 2019 Parexel International Corporation
Manufacturing is defined as all steps in propagation or
manufacture and preparation of product and includes but not
limited to processing, filling, testing, labeling, packaging and
storage by the manufacturer. Processing refers to any
manufacturing steps that is performed which may affect its
safety, purity and potency of the product (21 CFR
600.3(u)(Z)).
Manufacturing at the clinical site may include for example
collection of the starting biological materials, formulation of
the final drug product, thaw and wash of the final drug
product or addition of other agents including small molecule
to the final drug product to affect the drug product potency.
In United States because the manufacturing at clinical sites
is not normally inspected, FDA expects that the manufacturer
demonstrates in their BLA that they are in full control of any
manufacturing performed at the clinical site. The essential
elements of demonstrating manufacturing control at the
clinical site is not trivial and in some cases not well
understood by many drug developers.
53
Special consideration for manufacturing at the clinical sites
Any manufacturing performed at the clinical must be fully
validated and validation of the procedures performed should
be performed using worst case scenarios.
Training of the staff that are involved in any manufacturing
steps at the clinical site should be performed by individuals
who are considered to be well qualified. The training should
be done at regular frequency and documented accordingly.
Manufacturers should establish a robust quality system to
identify any deviation from SOP and perform CAPA as
needed.
Implement a quality system that ensures chain of custody
(COC) and chain of identity (COI) of the source biological
materials, product intermediates and the final drug product
during all stages of manufacturing.
The state of facility in which any manufacturing is performed
at the clinical site is also expected to impact the quality of the
final drug product. Manufacturers should ensure that
manufacturing is performed in a suitable environment
anticipating worst case scenarios
© 2019 Parexel International Corporation
Companion diagnostics are increasingly being used to identify certain responsive
patient population or potentially to develop tumor specific vaccine based on the
patient and tumor specific neoantigens
https://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm511
178.htm
This draft guidance is intended to assist with the codevelopment of a therapeutic
product and an accompanying IVD companion diagnostic
54
Companion diagnostics
© 2019 Parexel International Corporation
Manufacturing platform and facility considerations
© 2019 Parexel International Corporation56
Product specific considerations:
Cell therapy, tissue engineering, gene therapy
Contamination and cross contamination control:
Appropriate clean room classification
Manufacturing platform (open vs. closed)
Isolators in clean room
Complexity of process
Multi product use or single product type use
Personnel and material flow
Other facility design considerations:
Appropriate use of pressure bubbles, pressure sinks, gowning de-gowning
One pass air or not
Importance of change over, cleaning etc.
Centralized versus decentralized manufacturing
Manufacturing facility considerations
© 2019 Parexel International Corporation57
Manufacturing facility strategies
Centralized approach Decentralized approach
Decentralized point of care/near patient or bedside manufacturing
© 2019 Parexel International Corporation
Trend toward single use disposables
Automated functionally closed platforms
Shift from adherent to suspension culture
Consideration of the manufacturing
environment (use of isolators)
58
Manufacturing platforms
CPPCPP
© 2019 Parexel International Corporation
Standard Development in Regenerative Medicine
21st Century Cure Act Title III, Section 3033-3036
Section 3036: Direct Department of Health Services (HHS), in consultation with National Institute of Standard and Technologies (NIST) and stakeholders, to facilitate efforts around development of standards for regenerative medicine therapies and regenerative advanced therapies
Develop physical and Performance Standards to facilitate development of Regenerative product manufacturing and testing
Guidance on “Standards Development and the Use of Standards in Regulatory Submissions Reviewed in the Center for Biologics Evaluation and Research”
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/UCM589416.pdf
Standard Coordinating Body (SCB)
SCB is a not for profit organization began as an initiative of the Alliance for Regenerative Medicine (ARM). In September
2016, the National Institute of Standards and Technology (NIST) and SCB established a Memorandum of Understanding (MOU).
https://www.standardscoordinatingbody.org/
Standard Development Bodies (Consensus and Non Consensus)
ISCT, ASTM, ISO, USP
National Institute of Standards and Technologies (NIST)
59
Standard development activities
© 2019 Parexel International Corporation 60
Consider defining manufacturing and process validation in terms of unit
operation(s)
Manufacturing platforms (continued)
Unit Operations 1
Unit Operations 2
Unit Operations 3
Unit Operations 4
© 2019 Parexel International Corporation
CBER Advanced Technologies Team (CATT)
https://www.fda.gov/vaccines-blood-biologics/industry-biologics/cber-advanced-technologies-team-catt
National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) https://niimbl.force.com/s/
Focus of developing technology to facilitate manufacturing of biologics (NIST)
Work force training and grant for projects to develop scale up manufacturing and rapid testing for release
Gene Therapy Roadmap, Vaccine Roadmap and Bispecific roadmaps
Advanced Regenerative Medicine Institute https://www.armiusa.org/
Focus on Tissue Engineering and 3D printing (DOD)
Georgia Tech Manufacturing Institute http://www.manufacturing.gatech.edu/
National Institute of Health https://www.nih.gov/research-training/medical-research-initiatives/rmi
FDA/CBER Enhancing Innovations in Emerging Technologies for Advanced Manufacturing of Complex Biologic
Products (R01) https://grants.nih.gov/grants/guide/rfa-files/rfa-fd-18-023.html
Continuous Manufacturing https://www.fda.gov/Drugs/NewsEvents/ucm557448.htm
61
Manufacturing initiatives