Reagents Used in Cell Therapy Manufacturing

U.S. Food and Drug Administration

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

Keith Wonnacott, Ph.D.Division of Cellular & Gene Therapies

Office of Cellular, Tissue, and Gene Therapies

Reagents Used in Cell Therapy Manufacturing

Division of Cell and Gene Therapies

Division of Human Tissues

Division of Clinical Evaluation and

Pharm/Tox

FDA

Office of Regulatory

Affairs

Center for Biologics Evaluation and

Research

Office of Vaccines

Research and Review

Office of Blood Research and

Review

Office of Information Technology

Office of Cellular, Tissue, and Gene

Therapies

National Center for

Toxicological Research

Center for Drug Evaluation and

Research

Center For Devices and Radiological

Health

Office of the Commissioner

Office of Communication,

Outreach, and Development

Office of Management

Office of Compliance and

Biologics Quality

Office of Biostatistics

and Epidemiology

Office of Chief Counsel

Center for Veterinary Medicine

Center for Food Safety and

Applied Nutrition

Center for Tobacco Products



TerminologiesTerminologiesComponentsReagents MaterialsIngredientsExcipients



Components21 CFR 210.3(b)(3)Components21 CFR 210.3(b)(3)

“Component means any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.”



ReagentsFrom Guidance for Human Somatic Cell Therapy INDsReagentsFrom Guidance for Human Somatic Cell Therapy INDs

“Materials that are used for cell growth, differentiation, selection, purification, or other critical manufacturing steps, but are not intended to be part of the final product.”

Examples: Bovine serum, Antibodies Trypsin, Collagenase, DNAse Growth factors, Cytokines Fluorescent dye Antibiotics Media/media components



ExcipientsFrom Guidance for Human Somatic Cell Therapy INDsExcipientsFrom Guidance for Human Somatic Cell Therapy INDs

“Any component intended to be a part of the final product”

Examples: Infusion media Human serum/albumin DMSO



Other definitionsOther definitions raw material: Any ingredient intended for use in the production of APIs. These

may include starting materials, process aids, solvents, and reagents. reagent: A substance, other than a starting material or solvent, that is used in

the manufacture of an API or intermediate. active ingredient: Any component that is intended to furnish pharmacological

activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to effect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.

Active Pharmaceutical Ingredient (API): Any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body of humans or other animals. APIs include substances manufactured by processes such as (1) chemical synthesis; (2) fermentation; (3) recombinant DNA or other biotechnology methods; (4) isolation/recovery from natural sources; or (5) any combination of these processes.



Regulatory FrameworkRegulatory Framework

LAWLAW

REGULATIONREGULATION

GUIDANCEGUIDANCE



The Law



FD&C ActSection 501(a)(2)(B)FD&C ActSection 501(a)(2)(B)

“A drug or device shall be deemed to be adulterated…if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice….”



Regulations



IND Regulations 21 CFR 312.23(7)IND Regulations 21 CFR 312.23(7)

“Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary…”




“…the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance…”

“...As drug development proceeds…the sponsor should submit information amendments to supplement the initial information submitted…appropriate to the expanded scope of the investigation”




“The submission is required to contain…a list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process…”



Current Good Manufacturing Practices21 CFR 211.80Current Good Manufacturing Practices21 CFR 211.80

“There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures…”



Current Good Manufacturing Practices21 CFR 211.84Current Good Manufacturing Practices21 CFR 211.84

“Each lot of components…shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit”

“Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted…and the reliability of the supplier’s analyses [is verified].”



Guidance



Guidance for Reviewers and SponsorsGuidance for Reviewers and Sponsors

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074131.htm

Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)



Reagent Information for INDReagent Information for IND Tabulation of Reagents Used Qualification Program Determination of Removal of Reagents from

the Final Product Other Concerns



Tabulation of ReagentsTabulation of Reagents Concentration of the reagent and the

manufacturing step at which it is used Supplier Source Reagent Quality COA or Cross-reference letters



Reagent QualificationReagent Qualification Define Source, Safety, and Performance “We recommend that you use FDA-approved or

cleared, or clinical grade reagents whenever they are available.”

“If you are using a research grade (not FDA-approved or cleared) reagent as part of the manufacturing process, we recommend that you provide information verifying the source, safety, and performance of the reagent. If the vendor of the reagent has a regulatory file with the FDA, a cross-reference letter from the sponsor may be provided in the IND. If a COA from the reagent manufacturer is used, you may assess whether the testing performed is adequate and provide that information in the IND.”



Reagent Qualification ProgramReagent Qualification Program “If the reagent is not FDA-approved or cleared,

additional testing may be needed to ensure the safety and quality of the reagent. We recommend that you establish a qualification program that includes safety testing (sterility, endotoxin, mycoplasma, and adventitious agents), functional analysis, purity testing, and assays (e.g., residual solvent testing) to demonstrate absence of potentially harmful substances. The extent of testing will depend on how the specific reagent is used in the manufacturing process.”



Specific Reagent IssuesSpecific Reagent Issues From human

Albumin: ensure a licensed albumin is used and “no recalled lots were used during manufacture or preparation of the product”

AB Serum: “…ensure serum is obtained from approved blood bank and meets all blood donor criteria”

From recombinant cell lines Appropriate cell line testing Viral clearance when appropriate “For monoclonal antibodies, refer to the guidance on "Points to

Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use" (Ref. 9) for further information.”



Specific Reagent IssuesSpecific Reagent Issuesporcine: “If porcine products are used,

a COA or other documentation that the products are free of porcine parvovirus.”



Specific Reagent IssuesSpecific Reagent Issues bovine: “If a reagent is derived from bovine material, you

should identify the bovine material, the source of the material, information on the location where the herd was born, raised, and slaughtered, and any other information relevant to the likelihood that the animal may have ingested animal feed prohibited under 21 CFR 589.2000. It may be that bovine material is introduced at different points in production of a reagent; the information described above should be provided for all bovine materials used.... In addition, you should provide a COA to document that bovine materials are compliant with the requirements for the ingredients of animal origin used for production of biologics described in 9 CFR 113.53.”

For more information see, "Proposed Rule: Use of Materials Derived from Cattle in Medical Products Intended for Use in Humans and Drugs Intended for Use in Ruminants," (72 FR 1581; January 12, 2007) found at http://www.fda.gov/cber/rules/catruminant.htm.



Reagent RemovalReagent Removal “You should test the final product for residual

manufacturing reagents with known or potential toxicities and describe the test procedures you use to detect residual levels of these reagents in the final product. We recommend that you determine whether a qualification study is sufficient to document their removal, or whether lot release testing is appropriate prior to initiation of clinical trials.”



Guidance For IndustryGuidance For Industry

CGMP for Phase 1 Investigational Drugs

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070273.pdf



QC FunctionQC Function “Every manufacturer should establish a written

plan that describes the role of and responsibilities for QC functions. For example, a written plan should provide, at a minimum, for the following functions. • Responsibility for examining the various

materials used in the manufacture of a phase 1 investigational drug to ensure that they are appropriate and meet defined, relevant quality standards…”



Control of Components, and Containers and ClosuresControl of Components, and Containers and Closures “You should establish written procedures

describing the handling, review, acceptance, and control of material (i.e., components, containers, closures) used in the manufacture of a phase 1 investigational drug. Materials should be controlled (e.g., segregated, labeled) until you have examined or tested the materials, as appropriate, and released them for use in manufacturing. It is important to handle and store such materials in a manner that prevents degradation or contamination.”



Control of Components, and Containers and ClosuresControl of Components, and Containers and Closures “The manufacturer should be able to identify and

trace all materials used in the manufacture of a phase 1 investigational drug from receipt to use in the manufacture of each batch. We recommend that you keep a record (e.g., log book) containing relevant information on all materials. At a minimum, recorded relevant information would include receipt date, quantity of the shipment, supplier's name, material lot number, storage conditions, and corresponding expiration date.”



Control of Components, and Containers and ClosuresControl of Components, and Containers and Closures “The manufacturer should establish acceptance

criteria for specified attributes on each material. For some materials, all relevant attributes or acceptance criteria may not be known at the phase 1 stage of product development. However, attributes and acceptance criteria selected for assessment should be based on scientific knowledge and experience for use in the specific phase 1 investigational drug. The material attributes and acceptance criteria will be reviewed in the IND application.”



Control of Components, and Containers and ClosuresControl of Components, and Containers and Closures “We recommend that you examine the certificate of

analysis (COA) and/or other documentation on each lot of material to ensure that it meets established acceptance criteria for specified attributes. For some (e.g., human and animal derived material), documentation should include information on sourcing and/or test results for adventitious agents, as appropriate. If documentation for a material is incomplete for a specified attribute, we recommend that you test for the incomplete specified attribute of the material. For each batch of the API (or drug substance), you should perform confirmatory identity testing.”



Advice and Conclusions



AdviceAdvice Know the source material and manufacturing

process used to produce all reagents (particularly biological reagents)

Be aware that the materials used to prepare/generate the reagents could present a potential riskPurification of protein Bacterial fermentation

Ask the right questions



ConclusionsConclusions Laws, regulations, and guidance help to

define the appropriate use of reagents in cell therapy manufacturing

The choice of reagents used as well as the qualification of those reagents in an IND is the responsibility of the sponsor

Appropriate documentation of the evaluation and control of all reagents is essential for your IND



CBER UpdatesFinal RulesCBER UpdatesFinal Rules Final Rule - Amendments to Sterility Test Requirements for

Biological Products; Correction 5/24/2012 Final Rule - Revision of the Requirements for Constituent

Materials 4/13/2011 Final Rule - Administrative Practices and Procedures; Good

Guidance Practices; Technical Amendment. 4/1/2010 Expanded Access to Investigational Drugs for Treatment Use,

Final Rule (Federal Register) 8/13/2009 Charging for Investigational Drugs Under an Investigational

New Drug Application, Final Rule (Federal Register) 8/13/2009 Final Rule - Current Good Manufacturing Practice and

Investigational New Drugs Intended for Use in Clinical Trials 7/15/2008

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ActsRulesRegulations/General/default.htm



CBER UpdatesGuidancesCBER UpdatesGuidances Draft Guidance of Industry: Preclinical Assessment of Investigational Cellular

and Gene Therapy Products November 2012. Guidance for Industry: Preparation of IDEs and INDs for Products Intended to

Repair or Replace Knee Cartilage December 2011. Guidance for Industry: Clinical Considerations for Therapeutic Cancer

Vaccines October 2011. Guidance for Industry and FDA Staff: Investigational New Drug Applications for

Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications. June 2011

Final Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products January 2011.

Guidance for Industry: Cellular Therapy for Cardiac Disease October 2010. Guidance for Industry - Minimally Manipulated, Unrelated Allogeneic

Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications 10/2009

Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products 09/2009

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



Licensed Products

http://www.genzyme.com/

(sipuleucel-T)

http://dendreon.com/

Fibrocell Science, Inc

http://mylaviv.com/

HPC, Cord Blood

http://www.nybloodcenter.org/

http://druginserts.com/lib/images-other/gintuit/gintuit-figure1.jpg








Approval DocumentsApproval Documents http://www.fda.gov/BiologicsBloodVaccines/C

ellularGeneTherapyProducts/ApprovedProducts/default.htm

Posted Documents Include:Package InsertApproval LetterSummary Basis for Regulatory ActionApproval History, Letters, Reviews, and Related

Documents



Advisory Committee DiscussionsAdvisory Committee Discussions Posted documents include:

Agendas Briefing Documents Questions Presentations Roster Summary Transcripts Webcasts

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/CellularTissueandGeneTherapiesAdvisoryCommittee/default.htm



Investigational ProductsInvestigational Products



Total Active Investigational Cell and Gene Therapy Products (IND, IDE, MF)Total Active Investigational Cell and Gene Therapy Products (IND, IDE, MF)

0

200

400

600

800

1000

1200

1400

1600

Fiscal Year



Yearly New IND and IDE Submissions to OCTGTYearly New IND and IDE Submissions to OCTGT

0

50

100

150

200

Cell Therapy Gene Therapy Other Total



New IND and IDEs Submitted to OCTGT:Commercial or Research SponsorsNew IND and IDEs Submitted to OCTGT:Commercial or Research Sponsors

0

20

40

60

80

100

120

140

160

commercial research



Cellular product manufacturing questions Keith M. Wonnacott, Ph.D. (Cell Therapies Branch Chief) [email protected] 301-827-5102

Regulatory Questions: Contact the Regulatory Management Staff in OCTGT at [email protected] [email protected] or by calling (301) 827-6536

OCTGT Learn Webinar Series: http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

OCTGT Contact InformationOCTGT Contact Information



Public Access to CBERPublic Access to CBERCBER website:http://www.fda.gov/BiologicsBloodVaccines/default.htm

Phone: 1-800-835-4709 or 301-827-1800

Consumer Affairs Branch (CAB) Email: [email protected]: 301-827-3821

Manufacturers Assistance and Technical Training Branch (MATTB)Email: [email protected]: 301-827-4081

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Reagents Used in Cell Therapy Manufacturing

Documents

Transcript of Reagents Used in Cell Therapy Manufacturing