Cell and gene therapies will unquestionably
comprise a large part of biotech companies’
portfolios in the coming decades.
Unlike traditional large molecules, these
products have different manufacturing
and supply chain needs, requiring a fresh
look at existing regulations. Yet these challenges
will need to be addressed due to the
promise of these products to cure a variety
of diseases and disorders.
The opening talk of the 2019 PDA Cell
and Gene Therapy Conference in Long
Beach, Calif. on May 6 illustrated this
last point in particular. Tom G. Whitehead,
cofounder of the Emily Whitehead
Foundation, put a human face to the often
academic and technical discussion around
commercialization of cell and gene therapies.
At the age of five, his daughter, Emily
Whitehead, was diagnosed with acute
lymphoblastic leukemia (ALL). While
most cases have an 85 to 90% cure rate, her
case was more aggressive than usual, and
she relapsed several times to the point her
medical team recommended hospice care.
Her parents instead enrolled her in a
Phase I clinical trial where her T-cells
were reprogrammed to attack the cancer
cells and then infused back into her
bloodstream. Despite some initial setbacks,
the therapy worked. Today, Emily
remains in remission seven years later.
She is recognized globally as the first pediatric
patient cured via a T-cell therapy.
There was not a dry eye in the room after
Whitehead finished speaking, spurring
moderator and conference co-chair Michael
Blackton to state: “This is the end
result of our work, this is why it is important
for us at PDA to collaborate together
to bring these important drugs to market.
This is the reason why we are here.”
The next speaker (who had a tough act to
follow!), Thomas A. Leitch, Vice President,
Vector Manufacturing, bluebird
bio, explored what the industry needs to
do to ensure patients like Whitehead’s
daughter receive these therapies from
the perspective of a major cell and gene
“When I hear Tom share that amazing
story, I cannot help but think what amazing
times we are living in…right now
there are approved cell and gene therapies
that are helping transform lives,” he said.
“But there is a catch…for these therapies
to realize their full potential, we are going
to have to find new ways to supply them
in volumes greater than anything we have
ever seen before.”
This requires transforming current manufacturing
processes to enable manufacturing
and supplying personalized batches,
often within very short timeframes. This
scaling challenge, Leitch emphasized,
is the biggest hurdle to commercializing
these lifesaving products. He cited
the example of a personalized chimeric
antigen receptor (CAR) T-cell therapy
that requires, at a minimum, 80 staff for
ten to 14 days of batch processing. That is
for just one patient. The challenge occurs
when that is expanded out to 10,000
patients with 400 batches ongoing at a
given time. This requires almost eight million
pages of documents!
“If complexity is the opposite of compliance,
those numbers are going to be hard
to sustain,” Leitch said.
In bluebird’s case, for one such therapy,
the company turned to a contract manufacturing
organization (CMO) that had
the capacity to produce a clinical batch
right then and there. Following a positive
outcome from this initial batch, the trial
expanded, necessitating a second CMO.
In preparation for commercial launch,
bluebird began building its own suspension
platform. As the company neared
launch, bluebird brought in a third CMO
but continued to build out the suspension
platform in tandem. In addition,
the company planned to build its own
The next session delved further into the
topic of facility design. John R. Dougherty,
Lead Process Engineer, DPS Group,
explained how his firm designed a flexible
gene therapy manufacturing site using
a process-centered design. He explained
that a “flexible” facility can mean different
things to different manufacturers,
from the capability to process multiple
types of products to the ability to support
both clinical and commercial batches.
The second speaker in the session, Francesca
McBride, Director, Regulatory
Compliance, Jacobs, outlined the cGMP
considerations for cell therapy facilities,
specifically citing limited materials available
for lot release testing, fast turnaround
when it comes to administration and tracking to ensure patient-specific
lots are delivered to the correct patient.
Her presentation showed that designing
a facility for cell therapies requires a risk-based
approach to address these concerns.
EU, U.S. Regs Target CGTs
After lunch, the next two speakers
reviewed regulatory requirements. For
a Qualified Person (QP) perspective,
QP Stephanie Verbrugghe, CEO and
Founder, Farbridge Pharma Consulting,
presented, “Launching Clinical Trials in
Europe.” European regulatory requirements
in this area fall under the EudraLex
clinical trial guidelines. Manufacturing
of cell and gene therapies (referred to
as “advanced therapy medicinal products”)
must comply with GMP guidelines
geared specifically for this class of product.
Batches imported into the European
Union must have a manufacturing and
importation authorization (MIA). The
QP must audit non-EU manufacturers
and QC labs and provide a declaration to
the relevant regulatory body.
Steven Oh, PhD, Deputy Director,
Division of Cellular and Gene Therapies,
Office of Tissue and Advanced Therapies,
CBER, U.S. FDA, then provided
an FDA perspective on product lifecycle
and CMC issues. First, when it comes to
autologous products (i.e., products taken
from a patient and then administered to
the same patient) and allogeneic products
(i.e., products with cells taken from one
patient and delivered to others), there
are common concerns around material
qualification, establishing specifications,
manufacturing facilities, manufacturing
changes, supply chains, etc. For autologous
products, specific challenges are
product tracking and segregation, variability,
limited material for testing, etc., and challenges for allogeneic products
include donor eligibility, cell bank qualification,
reproducibility of cell banks,
scale up, etc.
In the face of these challenges, product
characterization is critical.
“Product characterization should occur
throughout the lifecycle, but it is expected
that investment is made at the early stage
of product development as this becomes
very important as you start making
manufacturing changes,” Oh said.
The last session of the first day delved
into the product characterization process.
Brendan G. Keenan, PhD, Associate
Director Quality Control Sciences and
Technology, bluebird bio, started off the
session with a look at analytical methods.
“There’s still the expectation that any
methods supporting your proprietary
material would be validated,” he explained,
regardless of whether the product is a traditional
biologic or a cell and gene therapy.
After Keenan’s presentation, Tam Soden,
PhD, Senior Director and Head of
Analytical Development, Kite, reviewed
analytical characterization for patient
materials, highlighting potency method
development in particular. She compared
the process to Beethoven’s 7th symphony,
which weaves together both deep and
light music in one piece.
CGT Companies Build Their Toolbox
Day 2 of the conference began with a
look at applying quality risk management
(QRM) principles to cell and gene therapies.
For the first talk, Marsha Steed,
Director Global QC Microbiology and
Contamination Control, bluebird bio, covered microbial risk assessments for cell
and gene therapies. She pointed to the
recent EU Annex 1 revision that outlines
use of QRM principles in manufacturing.
At bluebird, the company relies on a tool
called Hazard Analysis and Critical Control
Point (HACCP). Steed recognized
that companies may prefer to use different
tools but emphasized the importance
of “doing it well as patients need us to.”
HACCP is a globally recognized solution
for reducing hazard risk, originating in
World War II and developed by Pillsbury
for the U.S. space program. Since the
1970s, FDA has mandated that the food
industry use HACCP following botulism
cases due to improperly canned foods.
HACCP is a qualitative risk assessment
technique that “is a systematic, preventive
approach to identify hazards in a process
and/or system with the aim to produce
a documented plan to control these
hazards.” The tool uses risk ranking and
analysis and requires a hazard analysis
and determining critical control points,
which are then monitored extensively.
Michael Long, PhD, Senior Director Consulting
Services, ValSource, then covered a
similar risk assessment tool, the Interventions
Risk Evaluation Model (IREM). This
tool ranks the risk of interventions serves as
a kicking off point. The IREM was showcased
in the PDA Letter in 2016 (1).
The next two sessions looked at raw
material selection and control and supply
chain challenges. All of these sessions emphasized
that while there are significant
raw material and supply chain challenges
within the growing cell and gene therapy
market, there are tools available to help
At the close of the conference, Blackton
referred back to Whitehead’s power talk.
“Everything we do here results into some
outcome for the patient,” he said. “What
we are doing is going to translate to
people having better lives.”
- Baseman, H., et al. “A Line of Sight Approach for Assessing Aseptic Processing Risk: Part I.”
PDA Letter 52 (June 2016) 22-29.