manufacturing challenges for commercialization of cell and … · human gene therapy products...

© 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]


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


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


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


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


It is complicated and manufacturing is behindLarge

Treatment

EffectsCurative

Product is not ready


July 1, 2017 (Vol. 37, No. 13)Tony Hitchcock Technical Director Cobra BiologicsBuilding Processes for the Future

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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


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


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?


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


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


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


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


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


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


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


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


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


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


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!


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)


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


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


Special consideration for RCR/RCL testing, shedding and long term follow up


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


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


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


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


Other considerations


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


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


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


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


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



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



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



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


Thank you


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


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


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


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


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


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


QuestionsFor more information:

Mo [email protected]

Visit our Regulatory portal https://regulatory.parexel.com/


Appendix


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


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


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


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


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


Manufacturing platform and facility considerations


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


Manufacturing facility strategies

Centralized approach Decentralized approach

Decentralized point of care/near patient or bedside manufacturing


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


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


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


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