Food and Drug AdministrationCenter for Biologics Evaluation and Research

The Office of Cellular, Tissue, and Gene Therapies Web Seminar Series

presents:

Cellular Therapy Products

Keith Wonnacott, PhDChief, Cellular Therapies Branch

Division of Cellular and Gene Therapies

Office of Cellular, Tissue, and Gene Therapies

Presentation Outline

• Introduction • Tips and references for IND preparation• Manufacturing information to put in an

IND– Starting Material and Reagents– Product Manufacturing– Product Testing and Characterization – Product Stability

• Summary and concluding remarks

I. Introduction

I. Introduction Somatic Cell Therapy Defined

• “autologous, allogeneic, or xenogeneic cells that have been propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics ex vivo to be administered to humans and applicable to the prevention, treatment, cure, diagnosis or mitigation of disease or injuries”

• October 14, 1993. 58 FR 53248• Do not meet the criteria in 21 CFR 1271.10 to

be regulated solely under PHS Act section 361 and regulations under 21 CFR 1271

I. Introduction

• Stem cells and stem cell-derived products– hematopoietic, mesenchymal, embryonic,

umbilical cord blood, etc• Cancer vaccines and immunotherapies

– E.g., dendritic cells, activated T lymphocytes (TIL, LAK), B lymphocytes, monocytes, cancer cells chemically modified or unmodified

Examples of cellular therapies

• Pancreatic islets• Chondrocytes• Keratinocytes• Hepatocytes• Xenotransplantation products• Combination Products• Gene therapy modified cells

I. IntroductionMore examples of cellular therapies

OPPORTUNITIES• Cells are dynamic. They migrate,

proliferate, differentiate, and respond to their environment in vitro and in vivo

• Multiple cell types and mechanisms of action can be involved

• Therapeutic outcome can be curative and permanent– Repair, replace, regenerate

I. IntroductionCell therapy opportunities

I. Introduction

CHALLENGES• No terminal sterilization• Limited shelf life (due to cell viability)• Small lot size/limited sample volume• Limited availability of starting material for

process, product, and test method development

• Patient to patient variability and cellular heterogeneity

Cell therapy challenges

II. IND Preparation

II. IND Preparation

• Learn and follow the regulations• Know what’s in your product• Be data driven and include the relevant

data in your submission• Present your information clearly and

concisely. Tables, figures, and flow-charts can be very helpful.

• Provide complete, well-organized, and internally consistent information

Helpful hints

II. IND PreparationSelected regulations for cell therapyRegulation DescriptionHCT/Ps Tissue rules intended to

prevent the spread of infectious disease

21 CFR 1271

Biologics Biologics product testing standards21 CFR 600

Drugs IND requirementsCurrent good manufacturing practices

21 CFR 31221 CFR 211

II. IND PreparationExamples of topics covered in guidance• CMC content and format for cell therapy• Donor Eligibility• CGMP for Phase 1• Potency• Aseptic Processing• Cell Banking• Stability• Process and test method validation

III. Product Manufacturing

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)  4/9/2008

III. Product Manufacturing

• Choose an appropriate cell source– Know the history, if applicable– Determine appropriate screening and

testing for autologous and allogeneic donors

– Minimize variability where possible

Cell source

III. Product Manufacturing

AUTOLOGOUS• Donor eligibility determination not required• However, labeling requirements may apply

– “NOT EVALUATED FOR INFECTIOUS SUBSTANCES” (21 CFR Part 1271.90 (b)(2))

– “FOR AUTOLOGOUS USE ONLY” (21 CFR Part 1271.90 (b)(1))

• Processing shown not to support propagation of infectious agents

Cell Source - Autologous

III. Product Manufacturing Cell Source - AllogeneicALLOGENEIC• Donor screening and testing required

– Screened and tested per 21 CFR Part 1271 – Sample timing for DE testing

• Within 7 days of cell harvest/collection• Except peripheral blood stem/progenitor cells

or bone marrow up to 30 days before recovery 21 CFR1271.80(b)

III. Product Manufacturing

• HIV-1 (antigen and NAT)• HIV-2• HCV (antigen and NAT)• HBV (surface & core Ag)• Syphilis

• HTLV-1• HTLV-2• CMV

All Leukocyte rich

Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 8/8/2007

Cell Source - Required Donor Testing

III. Product Manufacturing Cell Source – Cell Banks• Master Cell Bank

– In vivo, in vitro, and human virus testing (and potentially animal virus testing)• CMV, HIV-1 & 2, HTLV-1 & 2, EBV, HBV,

HCV, B19– Bacterial, fungal, mycoplasma,

endotoxin– Identity, purity, and activity testing

III. Product Manufacturing

• Working Cell Bank– In vitro virus testing– Bacterial, fungal, mycoplasma,

endotoxin– Limited identity testing

Cell Source – Working Cell Bank

ICH Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin - 9/24/1998

III. Product Manufacturing Components/Reagents/Excipients• Reagent table

– Source, supplier, grade, concentration• Qualification program

– Qualify reagent suitability (performs as expected)

– Ensure reagent quality • Establish specifications for safety, purity,

potency or reference a master file• Approve each new lot of reagents through

in-house testing or review and verification manufacturer testing (COA)

III. Product Manufacturing• Choose a robust manufacturing process

– Establish standard operating procedures (SOPs)• Do performance runs to ensure process consistency• Establish procedures to prevent:

– Product mix-ups– Product cross-contamination

• Qualify procedures for safety– killing of tumorigenic cells, viral clearance, absence of

replication competent virus, removal of unwanted residuals, etc.

Guidance for Industry: CGMP for Phase 1 Investigational Drugs - 7/15/2008

Procedures

III. Product Manufacturing

• Tracking of all products from the donor to the consignee or final disposition, and from consignee or final disposition to donor (21 CFR 1271.290(b))

• Appropriate patient identifiers and procedures to prevent product mix-ups

• Procedures in place to ensure product segregation

Procedures - Tracking

III. Product Manufacturing

• Establish adequate facility and equipment performance standards and monitoring plans– Ensure aseptic environment for cell processing

through design and monitoring– Use closed systems where possible– Use disposable equipment and process aids

Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing -- Current Good Manufacturing Practice - 9/29/2004

Facilities

III. Product Manufacturing

• Written procedures for ensuring manufacturing oversight– Review and approval of procedures, testing,

acceptance criteria– Release/rejection of lots– Investigating manufacturing deviations

• Prevent, detect, and correct deficiencies• QC recommended to be independent of

production• Audit procedures and schedule

Quality systems

IV. Product Testing

IV. Product Testing

• Provide meaningful insight into process and product quality

• Contribute to the safety and quality of the final product

In process testing

IV. Product Testing

• Needs to be performed on the final product, not intermediate

• All relevant tests should be performed • Establish meaningful measures of

sterility, identity, purity, and potency

Final product testing

IV. Product Testing

• Define critical product attributes• Define and monitor/control all cell

types present in the product• Establish proper specifications

– Ensure the safety and consistency of product lots

– Base acceptance criteria on experience– Agree with current FDA standards

Product characterization

IV. Product Testing

• Methods – Must be adequate to assess safety – Must include aerobic, anaerobic, and fungal– 610.12 or USP <71> generally accepted– Alternative methods possible under 21 CFR

610.9 • Method Qualification

– Bacteriostasis and fungistasis data required if antibiotics are used in culture

Sterility Testing

IV. Product Testing Microbiological Testing – Rapid Release• Product may be released before 14 day

culture on final product if:– In-process test (48-72 hr) is negative at

time of release– Rapid method, such as Gram stain, is

negative– Final product testing is initiated– Sterility failure plan is in place to ensure

appropriate action and reporting

IV. Product Testing Mycoplasma• Testing should be done after pooling of

cultures but before washing• Recommend rapid method (PCR or other) If

unable to have results of culture based assay prior to administration (21 CFR 610.9 applies)

Draft Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals 7/12/1993

IV. Product Testing Identity Testing• Distinguish from other products

processed in same facility• Ensure labeling is accurate• May also help to characterize the

product– Distinguish between the multiple cell lines

used– Define product composition through

phenotypic analysis

IV. Product Testing Purity Testing• Freedom from extraneous material in the

finished product, whether or not harmful (21 CFR 600.3(r))

• Residuals contaminants– Reagents not intended to be in the product– Unwanted cellular subsets

• Pyrogenicity/Endotoxin– Rabbit pyrogen method required (21 CFR 610.13),

LAL is an alternative method (21 CFR 610.9 applies)

IV. Product Testing Potency Testing• The word potency is interpreted to mean the

specific ability or capacity of the product…to effect a given result. 21 CFR 600.3 (s)

• A quantitative biological assay or correlated to a quantitative biological assay

Draft Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products - 10/9/2008

IV. Product Testing Other Tests• General Safety

– Cellular therapy products are exempt• Viability

– Generally >70% – If not, data showing dead cells do not

affect safety• Cell number/dose

– Minimum, maximum?

IV. Product Testing

• Inappropriate timing of sample collection

• Unacceptable or unqualified test method

• Inadequate description of test method• Inadequate specification• Test not performed

Common Problems

V. Product Stability

V. Product Stability Stability Testing• Required for IND (21 CFR 312.23(a)(7)(ii))

– Data generated at appropriate time and conditions– Minimally will cover time period proposed for

clinical trial– Method, sampling times, temperature, assays

• Should cover shipping, storage, and holding of cells at all phases of manufacturing

• Stability at later phases designed to collect data to support final formulation and dating period

Summary

• Cellular therapies pose unique opportunities and challenges

• CMC information should ensure quality of:– Starting Material and Reagents– Product Manufacturing– Product Testing and Characterization – Product Stability

• Many additional resources are available

Thank you for your attention.