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Background

As the Cell Therapy field has expanded in last decade there is an ever increasing number of industry sponsored CT products for cell therapy labs and transplant facilities to manage.

Such products can include hematopoietic stem cells, immune effector cells (ex CAR-T), gene modified and regenerative cell products that may be licensed and investigational.
There are many challenges transplant facilities face throughout the process of onboarding new products.

The objectives of this presentation include:

Identify common issues that arise when on boarding products or services developed outside your organization
Formulate mitigating strategies to resolve issues encountered in the Cell Processing lab when dealing with external Sponsors
Discuss how a Quality Agreement can be utilized to address potential quality related challenges between a transplant center and the Sponsor/manufacturer

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Objectives

The objectives of this presentation include:

Identify common issues that arise when on boarding products or services developed outside your organization
Formulate mitigating strategies to resolve issues encountered in the Cell Processing lab when dealing with external Sponsors
Discuss how a Quality Agreement can be utilized to address potential quality related challenges between a transplant center and the Sponsor/manufacturer

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Challenges - Products Galore!

Multiple Sponsors (and Investigators, CMO, CRO, Research Staff)
Multiple Cell product types

HSCs

HPC-A
HPC-M
HPC –C

Immune Effectors

CAR-T

Gene Modified
Re-Generative Cells

Licensed
Investigational

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Common Challenges

Managing the onboarding a new project from Pre-Site visit to Data monitoring
Audits- often required as part of qualifying a site

In Person - Time consuming
Virtual - Convenient but limited in actual observational review
Hybrid – some virtual, some on site or ‘face time”. Very hard to manage
NO Standardized evaluation method or tool across Sponsors

AABB/FACT accreditation doesn’t replace the need for an audit

Complying with FDA/FACT/AABB Standards

ISBT Labeling – not all Sponsors comply with ISBT standards
Donor Eligibility – can be difficult to obtain Summary of Record from the Sponsor

Managing process change

Using equipment, reagents or materials that are not validated with your lab for your intended use

Vendor Qualification – How to qualify external manufacturers
Out of Specification products

What Clinical Sites need to do when there is an OOS

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Managing all the Steps

Onboarding a new Sponsored project has many steps

Pre –Visit
Site Qualification Visit
Site Initiation Visit
Protocol Initiation Training
Compliance Review
Data review
Safety Review

All are time-consuming

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Commonalities: Sponsors want to see

SOPs

Quality

Error management
Internal Audits
Training and Competency (Procedures, Forms and records)
Equipment Management Policies

Staff qualifications ( CVs/Resumes)
Donor Eligibility

Screening
Suitability

Collection
Processing
Storage
Distribution

Equipment lists and associated records

Apheresis devices
Transport containers/carriers
Refrigerators
Freezers
Product Specific (Miltenyi devices)

Labeling processes
Facilities

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Maintaining Sanity

Pre-Planning

Hosting

Follow up

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Pre-Visit Planning

Review previous “visits” for patterns of documents requested for review
Consider compiling a folder for them to have ready for future request
Consider a file sharing system where you can place the documents and then grant temporary access for external reviewers on a case-by-case basis

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Hosting

Review previous “visits” for patterns of direct observation requests (screening area, collection area, processing lab, infusion center, etc)
Create a Facility Introduction presentation with details like names of executive management, floor plans, workflows, manufacturing numbers
Identify key Point of Contact for each area for use to check availability for proposed visit dates in the future (can be used for all modes of review)
Identify a visit coordinator, point person for all communications
Develop a “tour guide script” that can be approved in advance

Key points and highlights to mention based on questions from past visits( how many devices, types, #of staff, product /yr, etc)

Consider developing a ‘virtual tour”: video or animated tour to share in stead of walkthroughs during the visit

Cell phone video
Professional video
Engineering rendering

Preparing early and having a standardized approach facilitates reduced stress about hosting

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Follow up

Have each Point of Contact take notes during the visit

Facilitates follow up questions while reviewers are on site
Helps to avoid “surprise” findings
Start the “response” before they leave

Take notes of reviewer posed questions and follow up questions

generates ideas for process improvement that may not be reported findings but strengthens your program

Evaluate all issues and use the Change Control Process instead of immediate “fix” reflex.
Push back if you feel like a suggested change will not work in your facility or with all the products you manufacture

Examples: suggested sop changes, labeling changes, workflow changes

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Additional Challenges

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Labeling & Identifiers Challenges

ISBT128 Standards not required by FDA but are by AABB/FACT

Rare that Sponsors use ISBT unless manufacturing is At a FACT center

Product Identifiers

Not all Sponsors use Donation Identification Number (DIN) often want to use own product ID
Very few Sponsors use Chain of Identity identifier

Some use own C of I not in ISBT format

Patient identifier

If it’s for a clinical trial name and MRN not generally used
Commercial often use name DOB, MRN

Collection & Final Drug Product Labels

Not ISBT compliant; missing AABB/FACT elements

Missing ABO, Additives, collection date

Drug Product

Clinical trial -

Only Sponsor product ID, Cof I carried through - problem is name, MRN not on product label so identifying at bedside can be an issue

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Mitigation Strategies

Product Identifier

Request DIN be used from collection through to final drug product

Patient Identifier

If patient name and medical record are not used ensure there is a documentation linking the patient name and MRN to subject ID from the ordering physician

Collection Label

Determine if internal ISBT collection label can be used at apheresis collection and if necessary relabel product for export to manufacturer

Drug Product Label

Request if an additional internal label meeting AABB/FACT requirements can be used along with Sponsor’s label

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Allogeneic Products

Directed or multi-use allogeneic CT products must be accompanied with Donor Eligibility and Summary of Record

FDA Requirement
IDM and medical history screening must be tested on the donor
Licensed products are NOT exempt
Infectious disease testing off the product (ex testing the Master Cell Bank in the case of an off-the-shelf CT products) is not a surrogate for DE and Summary of Record.
IDM and medical history screening must be tested on the donor

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Mitigation – Donor Eligibility

Non-negotiable
FDA requirement - Summary of Record containing all DE requirements must be provided with each lot of drug product

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Managing Process Changes

Issue – use of equipment, reagents or materials that are not validated with your lab for your intended use

Example – The use if of an infusing via syringe pump for diluting drug product

Options

Perform your own validation studies
Evidence from the Sponsor

Request documentation from the Sponsor that process validation has been performed
Utilize their work instructions (ex Product Manual) as a controlled document that is approved through your institution’s document control process

Planned deviation (infrequent situations per FACT)

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Vendor Qualification

Qualifying external Sponsors/manufacturers?
It is a FACT Requirement

FACT B1.2 The Clinical Program shall use cell collection and processing facilities that meet FACT JACIE Standards with respect to their interactions with the Clinical Program.

In the case of multi-center trials or centralized manufacturing, the Clinical Program may have limited control over the participating collection and processing facilities; however, it is still responsible for performing some qualification of those entities to verify that tasks are performed in a reputable manner with oversight by the appropriate regulatory agency (such as the FDA).

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Qualifying External Sponsors

Strategies

Verification of an approved IND application, post-market or licensure approval
Quality assessment questionnaire
Perform a desk/paper audit of manufacturer

Request Quality Plan TOC, SOPs etc..

Request a virtual assessment

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Out of Specification Products

CT products that fail release criteria

Scenario – Your institution sent an apheresis product to CarT manufacturer and were later notified that the product did not meet lot release criteria. The product was intended to be a licensed product but is now being released as an Investigational Product under the approved FDA protocol.

The Sponsor/manufacturer will label product as investigational and perform an investigation

Your Role

Request a copy or summary of the Sponsor’s investigation and corrective measures
Investigate on your end if there were any deviations associated with apheresis, cell processing, export

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Quality Agreements

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Quality Agreements

What it is

Document that identifies and describes key quality and regulatory responsibilities between the client and the service provider
Ensures the quality and safety of product and or service

Who’s involved

Quality and Regulatory representatives from Client (eg Transplant Center) and Service Provider (Sponsor/Manufacturer)

Components of Quality Agreement

1.0 Compliance Requirements

2.0 Audits

3.0 Regulatory Inspections and Exchanges

4.0 Regulatory Filings and Regulatory Status

5.0 Documentation and Records

6.0 Change Control

7.0 Deviations

8.0 Complaints and Recalls

9.0 Personnel Training

10.0 Materials

11.0 Validation/Qualification

12.0 Transfer of Source Material

13.0 Manufacturing Controls, Packaging and Labeling

14.0 Quality Control and Assays

15.0 Storage and Distribution

16.0 Stability

17.0 Disposition of Drug Product

18.0 Packaging, Transport, and Administration of Drug Product

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Quality Agreement Template

A Quality Agreement template is available on the ISCT or AABB website.

Downloadable Word document

https://www.isctglobal.org/publications/regulatory-quality-initiatives/quality-agreement-template

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QA Agreement – Example Language