# Presentation: 064959

## Draft Guidance for IndustryMinimally Manipulated, Unrelated, Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in Patients with Hematological Malignancies

- CTGTAC 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- Published draft guidance January 2007

## Draft Guidance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## Indication specified in Draft Guidance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**

## 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

- 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