Draft Guidance for IndustryMinimally Manipulated, Unrelated, Allogeneic

Placental/Umbilical Cord Blood Intended for Hematopoietic

Reconstitution in Patients with Hematological MalignanciesCTGTAC meeting March 30, 2007

Overview• Background/History• Purpose/Scope of Guidance• License Application Procedure• Chemistry, Manufacturing & Controls• Applicable Regulatory Requirements

HCT/Ps, Compliance with cGMPs• Postmarketing activities • Next steps

Background (1)• History of promulgation of HCT/P

regulations– Proposed a tiered approach– Implemented by promulgating 3 final rules

• Unrelated allogeneic hematopoietic stem/progenitor cells including cord blood (HPC-C) meet criteria for regulation as biological products under PHS Act (systemic effect)– Subject to IND and BLA requirements

Background (2)

• Summary of 1998 FR notice: Request for Proposed Standards– Requested submission of comments

• Establishment controls• CMC controls-processing & product standards• For minimally manipulated unrelated allogeneic

cord blood and PBSC

Background (3)

• Summary of 2003 BRMAC on cord blood– FDA provided analysis of clinical outcome

data– Committee discussed safety & efficacy issues

• CBER task force determined data submitted to docket and published literature permit development of recommendations for applying for licensure

• Published draft guidance January 2007

Draft Guidance

• Open for public comment

• Comment period ends April 17, 2007

• Represents FDA’s current thinking; does not establish legally enforceable responsibilities

• Recommendations, unless specific regulatory or statutory requirements cited

• Can use an alternative approach

Purpose

• Recommends ways for cord bank to apply for licensure for specified indications

• Explains applicable regulations in Title 21 of the Code of Federal Regulations

• Provides other information about the manufacture of HPC-C and how to comply with the applicable regulatory requirements

Scope (1)

• Covers cord blood products that are:– Minimally manipulated; and– Intended to be used in recipients unrelated

to the donor

Scope (2)

• Does not cover:– PBSC– Other cord blood products (e.g. more than

minimally manipulated, and/or for other indications)

– Cord blood for autologous/family-related use (though encourage following these recommendations)

Indication specified in Draft Guidance

• Hematopoietic reconstitution (engraftment) outcomes defined in 1998 FR notice

• Preponderance of data submitted to docket describing cord blood transplant outcomes in patients with hematologic malignancies (approximately 65-70%)

• Numerous other indications – much less data (all genetic disease 25%, SAA/FA 5%)

Data needed to support other indications

• Data demonstrating safety and efficacy of HPC-C for transplantation in patients with other diseases/disorders, for example– Engraftment– Survival– Measures of mitigation of defect (e.g. immune

reconstitution; increase in level of metabolic enzyme; correction of hemoglobinopathy)

• Subject of committee discussion

Use of this Guidance to apply for a Biologics License

• Manufacturer demonstrates in application that they have followed guidance recommendations

• Manufacturer may modify any procedure in guidance– Evidence demonstrating modification will provide

assurances of safety, purity, potency, and effectiveness

• Guidance provides specific recommendations if manufacturer wishes to rely on data in the docket

• Biologics license would apply to HPC-C manufactured at time of and subsequent to approval of the license application

Do cord blood manufacturers have to use this Guidance when

applying for a license?

• No. However, a manufacturer who does not use this guidance must submit a BLA for their HPC-C containing the following data:– Studies demonstrating that the product meets

requirements of safety, purity, and potency (21 CFR 601.2)

• nonclinical laboratory studies• clinical studies

• Recommend consultation with CBER about alternative approaches

License Application Procedure

License Application Procedure

• Form FDA 356h – Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use

• Where to submit – Document Control Center (address provided)

• Guidance describes information to include and

• What action FDA will take

Information to Include• Index• Representative draft labeling• Summary of information submitted• CMC – 21 CFR 314.50(d); § 601.2

– Full description of manufacturing process and SOPs for critical procedures, assays

• Summary validation data• Establishment description – § 600.10• Other attachments, including citation to

data in docket

What action will FDA take?

• Review application

• Schedule prelicense inspection as soon as possible after receiving complete application

• If application not complete, FDA will identify/advise establishment of additional information that they will need to submit

Chemistry, Manufacturing and Controls (CMC)

CMC: HPC-C Description and Characterization (1)

Table A: Required and recommended tests and results

• Safety– ID testing – required (maternal blood sample)

• All tests negative except for non-treponemal test for syphilis when confirmatory test negative; CMV

– Sterility testing – required (cord blood* and pre-cryopreservation sample)

• Negative– Hemoglobin (cord blood sample)

• No homozygous hemoglobinopathy

*Cord blood = cord blood before undergoing volume reduction

CMC: HPC-C Description and Characterization (2)

Table A: Required and recommended tests and results

• Purity and potency (pre-cryopreservation sample)– TNC ≥ 5.0 x 108/HPC-C

• Based on 20 kg recipient dose of ≥ 2.5 x 107/kg and 70% post-thaw recovery = 1.7 x 107/kg

– Viable nucleated cells ≥ 85%– Viable CD34+ cells ≥ 1.25 x 106/HPC-C

• Based on CD34+ cells ≥ 0.25% prior to freezing

CMC: HPC-C Description and Characterization (3)

Table A: Required and recommended tests and results

• Identity– HLA typing (cord blood sample)– Confirmatory HLA typing (attached segment)– ABO/Rh (cord blood sample)

CMC: Manufacturer information (1)

• Identification– Name(s), address(es), FDA registration

number(s), other organizational information for each manufacturer

• Including those under contract, agreement, other arrangement to perform a manufacturing step; for example,

– Collection sites– Laboratories performing donor testing for relevant

communicable disease agents and product sterility testing

CMC: Manufacturer information (2)

• Contamination precautions– Description of in-process controls to prevent or

identify contamination or cross-contamination• Avoid simultaneous manipulation of more than one HPC-C in

a single area• Precautions taken to prevent contamination and cross-

contamination by equipment

– Narrative description of procedures/facility/equipment design features

– Narrative description of manufacturing area – collection, volume reduction, packaging, labeling, cryopreservation, storage, and shipping

CMC: Methods of manufacturing (1)

• SOPs to submit with license application– Collection– Processing

• Volume reduction; cryopreservation; frozen storage; lot release

– Selection• Data management; search request; donor matching to

candidate recipients; selection of HPC-C– Shipping and handling

• Shipping to transplant center; thawing and preparation for administration; emergency product recovery

• Validation data summary– Recommend data from 3 consecutive, separate

HPC-Cs

CMC: Methods of manufacturing (2)

• Flow charts– Complete visual representation of manufacturing

process flow, including list of in-process controls, and tests performed at each step

– Includes information on transfers• Microbiology

– Includes description of presterilized equipment and containers

• Control of aseptic manipulations– Includes description of process parameters that are

monitored; procedures used to monitor bioburden/sterility; conditions and time limits for process steps

Other Important CMC Information

• Description of container closure system– Can reference NDA, 510(k), or MF– Provide evidence of container and closure

integrity for duration of proposed storage period

• Environmental assessment – 21 CFR Part 25– Applicant may submit request for categorical

exclusion

Other Important CMC Information

• Methods validation/verification– Infectious disease tests –

licensed/approved/cleared– Other tests – sterility, TNC, HLA, ABO/Rh,

other

• Labeling – see Guidance Section VII.B.2

HPC-C previously manufactured

• Subject of committee discussion

HPC-C previously manufactured using the same procedures

• License would apply to HPC-C previously manufactured in accordance with the information provided in the license application, where documentation is provided to demonstrate their comparability to HPC-C currently manufactured

HPC-C previously manufactured using different procedures

• Cord blood processing methods have changed over time• Any change has potential to affect safety and quality

To include under BLA:• Must demonstrate comparability of previously

manufactured HPC-C to the currently manufactured HPC-C

• Must provide evidence that methods, facilities, and controls used for manufacture conformed to CGMP and other applicable regulatory requirements

Recommended approach for demonstration of comparability

• Separate validation summaries

• Data on product characteristics:– TNC count– Viable CD34+ cell content– Colony forming units (CFU)

• Alternative methods

• Clinical outcome data

• Medical literature citation

Correlations among TNC, CD34+ cells, and CFU in HPC-C

• TNC and CD34+ cell dose have been shown to correlate with engraftment

• Increase in TNC associated with shortened time to engraftment

• CD34+ cell dose associated with incidence and rate of neutrophil recovery

• Correlation between viable CD34+ cell number and CFU reported

Correlation of CFU and CD34+ cells in HPC-C

Log CD34+ (x 104)

Log All CFU (x 104)

Cairo et al. 2004; Blood, 104:11, Abstract #406.

Types of samples available for comparability studies (1)

• Segment– Cell sample attached to HPC-C container– Advantage:

• Exposed to same processing, freezing and storage conditions as HPC-C

• Low risk of mislabeling between segment and HPC-C

– Disadvantage:• Limitation on the amount of sample for testing• Finite number of segments

Types of samples available for comparability studies (2)

• Cryovial sample – Processed similarly as HPC-C but separate

aliquot– Advantage:

• Increased number of aliquots may be stored• Cryovial sample retrieval does not affect HPC-C

– Disadvantage:• Sample may not be representative of HPC-C• May be exposed to different freezing and storage

conditions• Increased risk of mislabeling between cryovial and

HPC-C

Types of samples available for comparability studies (3)

• HPC-C unit– Advantage

• Most representative of product received by patients

• Sufficient samples for testing

– Disadvantage:• HPC-C unit cannot be used for transplant

Establishment Description

Establishment Description (1)

• General Information– Floor diagram, location of major equipment– Description of processing areas– Activities in adjacent areas– Product, personnel, equipment and waste flows

• Specific Systems– Source of water used in processing, if applicable– Heating, ventilation, and air conditioning– Facility controls

• Including environmental monitoring program– Computer systems

• Information and validation summaries for systems that control critical manufacturing processes; examples provided

Establishment Description (2)

• Contamination/Cross-Contamination Issues – supplements information in the CMC section– Equipment cleaning procedures and

validation• Certification of cleaning validation for removal of

product residues

– Containment features• Air handling (where appropriate)• Procedures for decontamination and equipment

cleaning when there is a breach in container integrity

Applicable Regulations and

Post marketing Activities

Applicable Regulatory Requirements (1)

• Manufacturer and product subject to all applicable regulatory requirements: – Prelicense inspection (42 U.S.C. § 262)– 21 CFR Parts 210 and 211 (CGMP)– 21 CFR Part 600 (Biological Products: General)– 21 CFR Part 601 (Licensing)– 21 CFR Part 610 (Biological Products Standards)– 21 CFR Parts 201, and 610 Subpart G (Labeling)– 21 CFR Part 202 (Advertising)

Applicable Regulatory Requirements (2)

• 21 CFR Part 1271 HCT/P regulations:– Establishment Registration and Listing– Donor Eligibility– Current Good Tissue Practice (CGTP)

• More specific regulations supersede more general• Compliance with CGMP would result in compliance

with applicable CGTP requirements, with some exceptions

Applicable Regulatory Requirements(3)

• CGTP (not covered under CGMP)– Donor eligibility– Prevention of spread of communicable

disease– Manufacturing arrangements– Exemptions and alternatives

Applicable CGMPs (1)

• Quality control unit• Personnel• Buildings and facilities• Equipment• Predistribution shipments and control

of components, containers, and closures

• Production and process controls -process validation

Applicable CGMPs (2)

• Packaging and labeling controls– Includes physical separation from other operations;

distinct identification code; expiration dating determined by stability testing; shipping containers and conditions to be maintained during transit

• Label and labeling content to be submitted– Prescription drug labeling– Package label – partial label may be used– Subject to bar code label requirements

Applicable CGMPs (3)

• Holding and distribution• Laboratory controls

– Testing for safety, potency, identity; stability program

• Records and reports• Failure investigations• Tracking• Complaints• Returned and salvaged HPC-C

Postmarketing Activities (1)

• Clinical Outcome Data Collection– Recommend analysis of clinical data from

transplant centers as quality indicator– Should evaluate data to determine

whether adverse experiences or other unexpected outcomes may be due to manufacturing problems

Postmarketing Activities (2)

• Changes to be Reported (21 CFR 601.12)

• Adverse Experience Reporting -

(21 CFR 600.80)

• Biologic Product Deviation Reporting -

(21 CFR 600.14)

Next steps

Review and address comments to docket

• Finalize Guidance– Intend to include date for implementation of

IND/BLA requirement (ending period of delayed implementation of IND requirement)

• License applications accepted at any time

Unrelated allogeneic PBSC (HPC-A)

• Also subject of 1998 FR notice• Considerations for HPC-A regulatory approach:

– HPC-A often requires limited manufacturing beyond recovery, testing, labeling, distribution

– Post-recovery manufacturing steps may be performed in laboratory at transplant center

– Most HPC-A manufacturing performed by establishments participating in the NMDP registry

– Other issues: Donor mobilization, cell selection/depletion, DLI

• Subject of committee discussion