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TABLE OF CONTENTSThe elephant in the classroom 4

Biopharma needs to address its workforce training methods

On the rise 15

Inside the industry’s struggle to produce gene therapies on a higher level

Redefining quality with analytical monitoring 27

How advances in biopharmaceutical characterization technologies

are improving drug quality

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www.PharmaManufacturing.com


The world can’t stop talking about

biopharma’s scientific achievements,

but the discussion often avoids

the industry’s biggest potential buzzkill:

a shortage of properly trained workers to

manufacture these new drugs.

There’s no denying that biopharma drugs

will play a vital role in the future of medi-

cine. Biologics make up about 40 percent of

the over 16,000 drugs in the global pharma

pipeline.1 These biologic hopefuls include

drugs in new therapeutic areas, such as

cell and gene therapy, that are igniting the

industry on fire with their potential to treat

the previously untreatable. The U.S. Food

and Drug Administration estimated that by

2020, they will be receiving more than 200

Investigational New Drug applications for

gene and cell therapies per year, and have

subsequently hired more clinical reviewers

to avoid approval bottlenecks.2

As these new classes of therapeutics race

towards commercialization, the industry

is grappling with the challenges of their

highly complex and specific manufacturing

processes. For years, biopharma has been

scrambling to resolve the production capac-

ity crunch created by cell and gene therapy

manufacturing. Contract manufacturers are

expanding manufacturing space while drug-

makers are building and acquiring their own

internal capacity. But facility space is only

part of the capacity crisis.

As more new therapies are approved and

the industry ramps up facility capacity, bio-

pharma needs to have a properly trained

workforce in place. Traditional training

The elephant in the classroomBiopharma needs to address its workforce training methods

By Karen Langhauser, Chief Content Director



methods are one-dimensional and simply

not producing biopharma workers who

can “hit the plant floor running.” With help

from academia, the biopharma industry is at

long last beginning to address this problem

and subsequently rethink workforce train-

ing — but is this paradigm shift happening

fast enough to keep pace with biophar-

ma’s progress?

A SLOW SHIFT IN TRAINING EFFORTSTraditional educational efforts in biopharma

look similar to those of conventional

pharma. There are ample amounts of col-

leges and universities offering applicable

degrees in areas such as chemistry or

biotechnology. Most biopharma companies

have developed in-house training programs

to get employees on board with standard

operating procedures (SOPs). Equipment

suppliers will often offer training on their

products. In addition, there are numer-

ous organizations offering online training

courses as well as virtual training environ-

ments.The combination of all of these have

been effective, but only to a degree. The

efforts share the common goal of giving

workers foundational knowledge, centered

around compliance.

“The core foundational skills for GMP and

aseptic processing haven’t changed much,”

asserts John Balchunas, who serves as

Through its flexible state-of-the-art facility, JIB provides tactile training by combining interactive presentations, workshops, hands-on lab and pilot-scale experiences.



workforce director for the National Institute

for Innovation in Manufacturing Biophar-

maceuticals (NIIMBL) in addition to his

role as assistant director of professional

development programs at the Biomanu-

facturing Training and Education Center

(BTEC). “But that doesn’t mean there isn’t

room for improvement, especially when

considering recent advances in gene and

cell-based therapies.”

BTEC at NC State University is one of a

handful of new breed training and educa-

tional centers that have stepped up within

the last decade to help biopharma tackle its

workforce challenges.

In an industry where quality is paramount,

a hyper-focus on compliance is both

logical and necessary. But it’s become

increasingly apparent that training for

today’s biopharma workforce needs to go

beyond compliance.

“Historically, training has been for FDA

compliance and simply the need to doc-

ument that your employees have been

trained. Manufacturers were focused on

ensuring that everyone in the company

read and understood the SOPs they were

responsible for,” says Balchunas. “But

lately, within the industry, there’s been a

movement towards competency-based

UP CLOSE LOOK

JEFFERSON INSTITUTE FOR BIOPROCESSING (JIB)Thomas Jefferson University Lower Gwynedd, PA

Opened: May 2019; Established in partnership

with the internationally recognized National

Institute for Bioprocessing Research and Train-

ing (NIBRT).

Facility: 25,000-square-foot training facility

Objective: To provide state-of-the-art educa-

tion and training in the fast-emerging field of

biopharmaceutical processing

Academic and professional offerings:

Offers a master’s degree program in engi-

neering with a focus in biopharmaceutical

process development and a 12-credit graduate

certificate in biopharmaceutical process devel-

opment, as well as various open enrollment

training programs. Specialized courses can be

developed to meet industry needs, delivered

either at JIB or at the company site.

What’s cool: JIB is the first — and only —

specialized education and training institute

for biopharmaceutical processing in North

America that combines commercial single-use

processing equipment with the internationally

recognized National Institute for Bioprocessing

Research and Training curriculum.



training. As the industry evolves, there’s

been a push for people at all levels to

understand the theory and concepts behind

unit operations.”

This need for competency is driving the

industry towards more hands-on training

— something that has not been the norm

— and several academic institutions have

stepped up to the challenge.

“We are seeing a transition from traditional

education to what the industry truly needs,”

says Parviz Shamlou, executive director and

head of the Jefferson Institute for Biopro-

cessing (JIB). “Hands-on training has been

missing in the industry’s education system.”

Jefferson University’s JIB, having just

opened its facility in May of this year, is the

new kid on the training block. It has the

unique distinction of being the only spe-

cialized education and training institute

for biopharmaceutical processing in North

America to offer hands-on training entirely

on state-of-the-art commercial single-use

processing equipment.

It can take biopharma employees up to

a year to get the hands-on experience

needed to do their job. Any delays in com-

mercial manufacturing — such as those

that can occur as companies struggle

to train employees or recruit additional

workers — mean delays in recouping the

With the mission of providing state-of-the-art education and training in biopharma process-ing, JIB formally opened its doors May 31, 2019.



estimated $5 billion3 it can cost to develop

a gene therapy.

“Speed to proficiency has been slow in

biopharma. It takes companies a lot of

time to get workers up to independent

performance. Hands-on training is needed

to help people to hit the ground running,”

says Balchunas.

WHAT’S DRIVING THE SHIFT?Aside from the immediate need for more

highly trained workers to manufacture

emerging classes of therapeutics, there

are several other factors driving this shift

in mindset.

Today’s biopharma drugs have pushed the

industry towards more flexible and scalable

approaches to improving quality and con-

trolling costs. To that end, more companies

are gravitating towards single-use tech-

nologies, including single-use bioreactors.

In situations where treatments need to be

created quickly (such as vaccines in an out-

break) or in smaller, more personalized batch

sizes (such as CAR-T treatments), single-use

equipment can help reduce time spent on

cleaning and validation, thus drastically less-

ening changeover time and associated costs.

One of the challenges of emerging technol-

ogies such as single-use systems is that it’s

BTEC is a unique, cross-disciplinary instructional center that provides educational and training opportunities to develop skilled professionals for the biopharma manufacturing industry.



possible that workers enter the field without

any prior installation or operating experi-

ence. And in the field of biopharma, even

the slightest slip-up can mean thousands —

if not millions — of dollars in lost product.

“Even something as simple as the installa-

tion of a bag needs to be done perfectly

because of the value of the contents,”

says Shamlou.

JIB’s 25,000-square foot facility is fully

equipped with the most advanced single-use

technologies on the market, allowing stu-

dents to get hands-on experience with the

same equipment they will likely be seeing on

the job. JIB also teaches customized courses

for pharma companies looking to get their

workers up to speed with single-use.

“Our facility offers a place for people to

experiment and learn — and make mis-

takes,” says Shamlou.

But proficiency in advanced technologies

is just one puzzle piece in biopharma’s

big picture quest: the need for a more

agile workforce.

“As gene and cell therapies come into the

fold, they are changing the flow of the typ-

ical process development paradigm within

biopharma companies,” explains Balchunas.

Tech transfer now involves greater process

understanding from all parties involved.

Those on the R&D side need to understand

what’s in the realm of possibility for manu-

facturing, and those on the manufacturing

side need to understand how these new

Undergraduates, graduate students, and working professionals come to BTEC for hands-on learning with the latest biomanu-facturing technologies.



therapies work and how process parame-

ters influence product efficacy.

“There’s a need to break down the silos

in order to enable cross training so that

folks working in bench-scale research

understand manufacturing and vice versa,”

says Balchunas.

According to analysis drawn from BioPlan

Associates’ annual survey on biopharma

capacity, today’s biopharma professionals

need to be “broadly knowledgeable and

fully capable of independent thinking.”4 In

addition to process understanding, many

“soft” skills are needed, such as the ability

to communicate and work as a team.

“The industry is looking for a workforce that

can adapt — and one way they can adapt is

to continuously learn,” says Balchunas.

STIGMAS AND CULTURE CLASHESWorkforce woes are not limited to

UP CLOSE LOOK

BIOMANUFACTURING TRAINING AND EDUCATION CENTER (BTEC)North Carolina State University Raleigh, NC

Opened: September 2007; Established as

part of a larger grant from North Carolina’s

Golden LEAF Foundation to start a state-

wide public-private partnership now called

NCBioImpact.

Objective: To provide educational and training

opportunities to develop skilled professionals

for the biomanufacturing industry and create

the best-trained, most industry-focused work-

force possible.

Facility: BTEC operates a 82,500-square-foot

main building and a 5,000-square-foot BTEC

Annex in the Keystone Science Center.

Academic and professional offerings:

BTEC is part of the university’s College of

Engineering. BTEC offers a Master of Bio-

manufacturing and a Master of Science in

Biomanufacturing. The intitute also offers an

Upstream Biomanufacturing Graduate Cer-

tificate and a Downstream Biomanufacturing

Graduate Certificate, as well a minor in Bio-

manufacturing to undergrad and graduate

students. BTEC also offers open-enrollment

courses and specialized open enrollment train-

ing programs.

What’s cool: At the time it was built, the BTEC

building was the only facility of its kind and

scale in the U.S., and the largest in the world.

The two facilities feature more than $12.5 mil-

lion-worth of industry-standard equipment and

a simulated cGMP pilot plant facility capable of

producing biopharmaceutical products using

cell growth and expression, recovery and puri-

fication processes in a sterile environment.



biopharma. Despite recent efforts to revive

the manufacturing industry in the U.S., the

stigma attached to manufacturing jobs still

persists. A recent Deloitte study predicted

that over the next decade, nearly 2.4 million

manufacturing jobs will be left unfilled due

to a skills gap.5 Most attribute this gap to an

incorrect perception of the manufacturing

industry as a whole, which is still seen as

dirty, dangerous and not technology-based.

Careers in biopharma are typically asso-

ciated with groundbreaking laboratory

research — finding cures for cancers or

debilitating diseases like Alzheimer’s

— rather than being on the manufactur-

ing floor.

“Manufacturing has long been neglected

because research is perceived as more

glamorous,” says Shamlou.

Internal struggles are also to blame as the

wall between academia and industry is slow

to topple. Again, the focus is largely around

research. The academic scientist is wary

that pharma-sponsored research is market

driven and hinders academic freedom, while

pharma companies emphasize that risk

equates to money and drug discovery proj-

ects need to be milestone-driven.

“Many academic institutions are not

equipped to move at the rapid pace of the

biotech industry. It also is difficult for insti-

tutions to create the necessary incentives

for faculty to devote significant research

and training efforts towards collaborative

research within a traditional academic

model. This has resulted in a natural seg-

regation between academia and industry

leading to the workforce challenges we

are experiencing today,” explains Cameron

Bardliving, director of lab operations at JIB.

But fortunately, recent years have seen this

wall gradually coming down as pharma/

academia collaborations (mostly focusing

on drug development) are becoming more

common. In early 2018, Pfizer created the

Innovative Target Exploration Network

(ITEN) model designed to identify academic

research projects that had the potential

to deliver innovative therapeutic targets

within Pfizer’s core areas of expertise. The

drugmaker named University of Cambridge,

University of Oxford and University of Texas

Southwestern as the first institutions to par-

ticipate. Gilead Sciences and Yale University

have had a similar arrangement since 2011,

when the two forged a multi-year research

alliance to accelerate the discovery and

development of new drugs to treat cancer.

When it comes to partnering on work-

force development, industry organizations

such as the National Institute for Innova-

tion in Manufacturing Biopharmaceuticals

(NIIMBL), that bring together stakeholders

from both sides of the fence, have done

a lot to help break down barriers. NIIMBL,

a public-private partnership dedicated to



advancing biopharma manufacturing, has

funded the development of workforce

development and training programs fueled

by collaborations between academic and

industry experts.

But there is still work to be done.

“Pharma companies need to get more

engaged and not be afraid to talk to aca-

demic institutions about what they are up

to and what they need. Similarly, many

academic institutions are still learning how

to better listen to pharma companies in

order to provide the best training. This dia-

logue will have a huge positive impact on

academic institutions and their ability to

deliver,” says Balchunas.

SPEEDING CHANGEBut is the gradual paradigm shift towards

more hands-on biopharma training going

to be enough to sustain this burgeoning

industry? For the past 11 years, BioPlan’s

biopharma capacity survey has found that

“production operations” is the No. 1 area in

which biopharma manufacturers plan to hire

new staff — indicating an ongoing shortfall

in supply of commercial manufacturing-ex-

perienced staff.

Dissimilar to many other industries, the

pharma/biopharma industry is not creden-

tial- or certification-based. Credentials and

certifications offer standardized, formal

proof of an individual’s qualifications.

They have the benefit of indicating that all

workers that have attained them have con-

sistent skillsets.

Instead, biopharma is largely experi-

enced-based. “It’s who you know and

what you’ve done over your career,”

explains Balchunas.

In terms of workers who are new to the

field, most biopharma companies have

well-established recruiting relationships

with the academic institutions providing

training, such as BTEC and JIB. But still,

these practices are relationship-based

rather than relying on formal certifications.

Most in the field agree that the biopharma

drug pipeline is growing faster than the

workforce pipeline, and more drastic action

needs to be taken.

But in an industry that is so accustomed to

measuring employees by their experience,

the idea of certifications and credentials is a

big shift. Some past efforts have struggled,

including ISPE’s Certified Pharmaceutical

Industry Professional (CPIP) credential. ISPE

introduced the credential in 2007, revised

it in 2011, and officially halted the program

in 2013.

While Balchunas says credentialing could be

an industry gamer-changer, he also admits

it will only come when the industry reaches

a point of absolute necessity. “Industry is

going to do what makes the most sense. In



order for credentialing to be adopted by

the industry, it needs to add value over the

current state. If companies are able to find

the talent they need through current mech-

anisms, they won’t change.”

BABY STEPSAdopting a system of credentialing might

be a sprawling change for the industry, but

there are steps in between that are more

feasible. While not as structured as cre-

dentialing or certifications, there has been

a push towards more harmonized train-

ing efforts. This has come in the form of

increased collaboration among academic

institutions. In fact, many of the prominent

training institutions today have their origins

rooted in partnerships with other aca-

demic institutions.

“We have not only considered it [collabora-

tion], we have embraced it and are living it,”

says Shamlou of JIB. “Our partnership with

NIBRT in Ireland and with local community

colleges are very good examples of what

we are doing towards harmonization.”

JIB partnered with the National Institute

for Bioprocessing Research and Train-

ing (NIBRT) in Dublin, developing training

courses from the internationally recognized

NIBRT curriculum. NIBRT, which set a bench-

mark for quality training when it opened

its state-of-the-art bioprocessing facility in

2009, was itself rooted in collaboration. In

2012, the institute won an ISPE Facility of

the Year Award (FOYA) in the “Special Rec-

ognition for Novel Collaboration” category.

The same year, NIBRT won a Bioprocess

International Award in the “Manufacturing

Collaboration of the Decade” category.

But as more hands-on training institutes

pop up in the U.S., it’s natural for them to

view each other as competitors and special-

ized curriculum as proprietary.

“There is a huge need for institutions to look

for ways to collaborate more and compete

less,” says Balchunas. “This will open the

door for more sharing and harmonization

down the road. And that’s how the indus-

try takes baby steps towards credentialing

and certification.”

DISRUPTING THE STATUS QUOIf the biopharma industry grows as pro-

jected, it will need a steady supply of

well-trained workers ready to manufacture

tomorrow’s super drugs. While workforce

training has cautiously been progressing as

needed, biopharma discovery continues to

rocket forward.

The time for change is now or the industry

risks stalling the progress of new therapeu-

tic advances.

Overall collaboration within and between

industry and academia will help improve

the stigma of manufacturing and develop

more competency-based, hands-on training



programs. Ultimately, the industry may move

towards more credential-based training.

These efforts will no doubt pay off, resulting

in better trained, more effective workers

producing better and more effective treat-

ments.

REFERENCES1. Pharma R&D Annual Review 2019. Phar-

maprojects. Feb 2019.

2. Statement from FDA Commissioner

Scott Gottlieb and Peter Marks, Director

of the Center for Biologics Evalua-

tion and Research on new policies to

advance development of safe and

effective cell and gene therapies. Jan.

15, 2019.

3. The American Consumer Institute

Center for Citizen Research. “Novel

Financincing Approaches are Needed to

Capitalize on Life-Saving Gene Thera-

pies.” 2019.

4. BioPlan’s 16th Annual Report and Survey

of Biopharma Manufacturing Capacity

and Production.



The last day of an industry confer-

ence isn’t known for being crowded.

But as Friday stretched on inside

one of the large meeting rooms at the Bio-

processing Summit in Boston this August, it

remained difficult to find a seat. The focus

of the day’s full schedule of speaker ses-

sions? The vexing issues behind scaling up

production of gene therapies.

It’s no surprise that interest in this topic

is high. Although it’s only been two

years since the U.S. Food and Drug

Administration made its first approval

of a gene therapy, the market for these

often one-and-done treatments has since

expanded rapidly. In 2017, there were an

estimated 391 gene therapy companies in

the U.S. This year, nearly 100 more have

jumped into the game and every major

player in Big Pharma is now clawing for a

piece of the pie.

On the surface, opportunities to cash in

on the explosive growth are popping up

all throughout the supply chain — from

new facility design to contract manufac-

turing. But behind the scenes there’s a

bit of anxiety about whether or not the

industry can keep up with its own efforts

to commercialize.

“If we’re talking about rare diseases, then

manufacturing will be straightforward,”

Luis Maranga, chief tech operations officer

at Voyager Therapeutics told the audience

during his presentation at the Bioprocessing

Summit. “But if you think about a disease

like Alzheimer’s — there are currently about

5 million patients, which will rise because

On the riseInside the industry’s struggle to produce gene therapies on a higher level

By Meagan Parrish, Senior Editor



the population is aging. Then, if we are

trying to treat thousands of patients, that’s

when it’s hard. As a field, we have to start

preparing for it today or we’re going to be

in a worse situation.”

Currently, there are fewer than five

approved gene therapies on the U.S.

market. But a report by the Alliance for

Regenerative Medicine showed that there

were 372 gene therapy products in clinical

trials in the first quarter of this year (a 17

percent year-over-year increase from 2018).

When looking at both cell and gene ther-

apies, the FDA has stated that it has more

than 800 active Investigational New Drug

applications on file and that by 2020, the

agency will likely receive more than 200

per year.

As this tidal wave of new treatments moves

closer to making landfall, the industry is still

working furiously to overcome the numer-

ous challenges of commercialization such

as securing raw materials, finding the right

equipment, recruiting expertise and all the

other issues associated with scaling up pro-

duction from the lab into the pharma plant.

Patients are waiting. The FDA has been

providing guidance to lead gene therapies

down a path to approval. But as more gene

therapies launch onto the scene, what will

it take for the industry to stick the landing?

BUILDING THE GENE MACHINEThere’s no question today that gene ther-

apies are one of the keys to treating and

potentially curing inherited diseases — from

genetic disorders to cancer. But it’s been

a rocky road getting gene therapies to

go mainstream.

Scientists have been tinkering with ways

to cure diseases by targeting genes for

EXHIBIT 1

Oncology dominates gene therapy drug development

Rare diseases (32%)

Rare oncologic diseases (43%)

Rare diseases non-oncologic (57%)

Cancer (32%)

Neurological (6%)

Alimentary/metabolic (6%)

Sensory (6%)

Blood and clotting (4%)

Infectious disease (4%)

Other (10%)

Source: Pharmaprojects, Informa Pharma Intelligence



the last four decades. On the heels of the

development of recombinant DNA technol-

ogy — DNA grown in a lab using genetic

material from multiple sources — a semi-

nal research paper emerged in 1972 which

laid out a groundbreaking idea for treating

genetic disorders by introducing functional

DNA into a patient.

It took 20 years of additional research

before the idea became a reality in 1990

with the approval of the first gene therapy

study in the U.S. The patient was a 4-year-

old girl with a rare genetic disease that left

her without a key enzyme for preventing

infections. As with most gene therapies in

development now, the patient was admin-

istered replacements for her faulty gene

using viral vectors. Because viruses are

so adept at invading the body, viral vec-

tors continue to be the most commonly

used way to deliver gene therapies into a

patient’s cells.

Ultimately, the first gene therapy trial was

a success and the young patient was able

to live a normal life outside of isolation. But

the field suffered a major setback eight

years later when an 18-year-old patient in

a gene therapy study died after suffering a

severe immune reaction to his treatment.

Despite the shock and public concern fol-

lowing the patient’s death, the gene therapy

market staged a careful comeback. By

2003, the first gene therapy was approved

for head and neck cancer in China. Ten

years later, Europe became a hotbed of

gene therapy R&D and now, the boom has

officially hit the U.S.

Today, gene therapies encompass a

range of treatments often referred to as

“advanced therapy medicinal products”

including genetic editing techniques and

CAR T-cell therapies, which are gene and

immuno-therapies, and work by using

engineered cells to boost a patient’s

own immune system to fight diseases

like cancer.

In 2017, the FDA approved the first CAR

T-cell therapies in the U.S.— Novartis’ Kym-

riah and Kite/Gilead’s Yescarta, which both

treat cancer. Then in December of that year,

Spark Therapeutics, a biotech upstart based

in Philadelphia, became the first company

Gene therapy buyouts Some of the biggest pharma deals driven

by gene therapies in the last year

Novartis/AveXis Therapeutics

$8.7 BILLION

Roche/Spark Therapeutics

$4.8 BILLION

Biogen/Nightstar Therapeutics

$877 MILLION

Vertex Pharmaceuticals/ Exonics Therapeutics

$245 MILLION



to ever have a gene therapy for a genetic

disease approved by the FDA.

Designed to treat a rare kind of retinal

dystrophy, Spark’s Luxturna is a one-time

injection that works by replacing a mutated

RPE65 gene that can cause complete vision

loss over time. In one study, 90 percent of

the patients treated with Luxturna expe-

rienced improvement in their functional

vision one year after treatment.

So, what’s it like when you spend years

developing a game-changing drug like

Luxturna and then finally find out if your

company has won an FDA approval that

could change the course of pharma history?

“You get a fax,” Diane Blumenthal, head of

technical operations for Spark, explains with

a chuckle. “It was right before Christmas

and Spark’s head of the regulatory board

called me to tell me it was approved, but it

was a bit anticlimactic because there were

only a few people in the office.”

But within weeks of Luxturna’s approval,

the excitement over the first FDA nod for

a gene therapy in the U.S. was quelled

somewhat by news of the treatment’s price:

$425,000 per eye.

THE PRICE ISN’T RIGHTThe approval of Luxturna not only set up

Spark to become one of the first compa-

nies to dive deep into the many challenges

A research scientist works with a roller bottle in the Spark Thera-peutics laboratory.

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of commercialization in the U.S. — it also

became the first that had to justify its price

tag for a therapy.

Drug companies have long stood behind

the argument that the price of innovative

treatments are set to recoup the high, often

decades-long costs of innovation — while

funding future research, as well. Some

argue that potential one-time cures like

Luxturna could also end up being cheaper

in the long-run than a lifetime of paying for

other treatments. And of course, innovative

biotech start-ups like Spark also tackle the

time-consuming and costly research for

rare disease treatments that Big Pharma

often avoids – if they’re not going to do it,

who will?

But now, when a gene therapy comes onto

the market, it becomes the world’s new

“most expensive drug” (the crown was most

recently passed to Novartis’ Zolgensma

which treats an inherited form of spinal

muscular atrophy for about $2.1 million).

So far, gene therapy companies are coming

up with new kinds of payer plans so that

patients are not denied treatments — such

as annual payments, and/or payments tied

to the long-term efficacy of the drug.

A research scientist transferring contents from roller bottles to vials in the Spark Ther-apeutics laboratory.

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.



“Just because you can give a patient the

treatment, doesn’t mean that they will have

the desired outcome,” says Patti Seymour,

managing director of Industry Specialty

Services practice, biotechnology consulting

group at BDO, a global accounting and con-

sulting firm. “They need to show that the

gene therapy has been stably incorporated

into the patient’s genome and it has a dura-

ble response. What if they need a second

dose? Do you charge a sliding scale? [This

kind of outcome-based payment system] is

what economists are working on.”

For now, the long-term impact of these

“ultraexpensive” treatments on the insurer

and health care system are still unclear. But

one thing is for sure: Gene therapy com-

panies need to find ways to improve the

efficiency of production to help drive down

the price of their treatments.

GROWING PAINSIt’s not uncommon for the cost and

complexity of manufacturing to be high

in a nascent industry launching products

Clinical trials372 gene therapy

clinical trials in progress

P1

P2

P3

372

PHASE 1

123 (33%)

PHASE 2

217 (58%)

PHASE 3

32 (9%)(As of the end of Q1 2019)

Source: Alliance for Regenerative Medicine, “Quarterly Regenerative Medicine Global Data Report”

Once the vector production is complete, it also has to be stored and transported in temperatures

of -65 degrees Celsius or colder.



made with an innovative technology. For

the gene therapy industry, figuring out

how to now make large-scale production

run as smoothly and cheaply as possible

with the market’s existing technology is

top of mind.

“Bringing down the cost of these thera-

pies is a big goal for companies right now,”

explains Luca Mussati, vice president,

Pharma and Biotech at Exyte, a design and

engineering company. “For the industry,

the goal is to lower manufacturing costs by

ten or twenty fold.”

Inside the Bioprocessing Summit, the entire

section of the conference focused on gene

therapy manufacturing was devoted to

viral vectors — one of the hardest aspects

of gene therapy development to scale up.

For two days, dozens of companies gave

presentations on how they were finding

ways to get higher yields of viral vectors

from their process, with most focusing on

the more commonly used adeno-associated

virus (AAV). But with many companies

going about it in different ways, it was clear

that the industry has yet to settle on a stan-

dard approach.

Upstream challenges

There are several phases and platforms

involved in producing viral vectors. At the

heart of the challenge in gene therapy

manufacturing is the difference between

producing the vectors using adherent cell

lines versus suspension.

“Traditionally, viral vectors were expressed

in cell lines using adherently grown cells on

substrates, which was a very tedious pro-

cess,” explains Amanda Micklus, an analyst

with Informa Pharma Intelligence, a pharma-

ceutical research and analysis firm.

Adherent cell lines work well in an academic

setting, where gene therapies have tradi-

tionally been developed, but are typically

considered too labor- and equipment-inten-

sive for wide-scale use. Now, the focus is

“We’re expecting to see some truly transformative technologies in this space, because it needs to happen.”

— Patti Seymour, managing director of Industry Specialty Services, biotechnology consulting group, BDO



on transitioning the process to growing the

cells in suspension with bioreactors.

According to Ryan McDonough, the biotech

market sector lead for CRB, an engineer-

ing, architecture and construction firm that

works on designing and constructing biotech

facilities, suspension works better for scal-

ing up because companies don’t necessarily

have to increase the square footage of their

facility in order to boost their production.

“Suspension cell culture is more typical in

the traditional biopharma marketplace. With

suspension, scaling up requires larger bio-

reactors instead of additional bioreactors,

which is typical with adherent cell lines,”

McDonough explains.

When Spark launched Luxturna, the com-

pany used a commonly utilized adherent

process that works by attaching the cells

to the sides of roller bottles. Blumenthal

says the process has worked for Luxturna

because it treats a small patient popula-

tion. Now, the company plans to switch to

suspension for the other treatments in its

development pipeline — including gene

therapies for hemophilia A and several cen-

tral nervous system disorders.

“Roller bottles have been used for many

decades for vaccines,” Blumenthal explains.

“But if you can get the process to work in

a suspension culture, that’s a much better

way to go.”

Another unique aspect of gene therapy

manufacturing is the use of transient trans-

fection, which is how DNA is delivered to

the cell being used to make the virus. Plas-

mid DNA is the key raw material used in

transient transfection and until the process

is optimized to reduce the number of plas-

mids required, the increase in gene therapy

production is putting pressure on plas-

mid-makers to keep up.

“Everybody is now keeping a close eye

on plasmid manufacturing because there

are not many companies that have the

capability to make cGMP-grade plasmid,”

Blumenthal says.

Downstream complexity

Frustratingly, the downstream purification

process of separating viral vectors from

contaminants can also create yield losses

up to 70 percent. Often, the low vector

recovery is due to the mixture of full and

empty capsids (the protein shell of viruses).

There’s also no consensus about what to

do with empty or partially full capsids and

if they should be treated as contaminants.

In general, capsid chemistry is a part of the

process that Blumenthal says the industry is

still figuring out.

Once the vector production is complete,

it also has to be stored and transported

in temperatures of -65 degrees Cel-

sius or colder, which adds another layer

of complexity.



“Transporting larger quantities of product

under these conditions can be challenging,”

Blumenthal says.

Overall, the viral vector manufacturing pro-

cess is in need of a technology upgrade in

order to work more efficiently on a bigger

stage. In addition to the particulars of

making the vectors, McDonough says that

companies are also looking for ways to

improve process closure.

“The industry needs the ability to manu-

facture these cell and gene therapies in a

manner where the process is never exposed

to the environment,” he says.

Several industry experts also say there is a

huge push to bring more automation and

robotics into vector manufacturing to min-

imize the need for human intervention and

speed the process along.

“There’s also a need for a more robust

analytics package to test products and

improved formulations to keep them stable

for long periods of time,” Seymour says.

So far, the general consensus is that equip-

ment vendors aren’t always keeping up

with the pace of commercialization. But the

demand for new technologies is there and

the race is on.

“We’re expecting to see some truly trans-

formative technologies in this space,

because it needs to happen,” Seymour says.

THE PATH TO COMMERCIALIZATIONOne common refrain from companies that

have now “been there, done that” in gene

therapies is that drug developers should

make decisions about how they want to

scale up early in the process. It’s a tricky

proposition, particularly because it’s difficult

to predict how much capacity they’ll need

to meet future demand.SOURCE: PHARMAPROJECTS, INFORMA PHARMA INTELLIGENCE

EXHIBIT 2

Top 20 gene therapy companies by pipeline sizeVolume of gene therapies in development

16REGENXBIO

14Juno TherapeuticsGenethon

12Sangamo TherapeuticsCRISPR Therapeutics

9Spark TherapeuticsMolMedKite PharmaIntrexonEditasInnovative Cellular TherapeuticsCureVacCellular Biomedicine Group

11Sarepta TherapeuticsOrchard TherapeuticsBluebird Bio

10NovartisApplied

Genetic Technologies4D Molecu-

lar Therapeutics

13Benitec Biopharma



“One of the biggest challenges for manufac-

turers is that they don’t know yet what the

rate of production will be, or what technol-

ogy they’ll need to produce their medicine,”

says Stefan Kappeler, technology manager,

Life Sciences at Exyte. “Companies want

to make sure they have the best process

laid out. Often, they just use the technol-

ogy that’s on the market at the moment.

But one year later, there might be a big

advancement in that technology that they

then need to stay competitive.”

In addition to seeking out the right tech-

nologies, drug developers also have a big

decision to make when it comes to finding

a facility.

“It helps to develop a commercialization

strategy that starts with a ‘make versus

buy’ analysis — i.e., building a facility for

your own use versus buying manufacturing

capacity from another company,” Seymour

says. “This has to be done early in the pro-

cess, very often before you have a clinical

signal. It’s a big decision with multimil-

lion-dollar consequences.”

Of course, companies can also consider

working with an outsourced manufactur-

ing partner, and several CMOs have been

working to increase capacity, often through

mergers. In fact, rising demand for viral

vectors was a catalyst behind two of the

industry’s biggest acquisitions this year

— Thermo Fisher’s $1.7 billion purchase of

Brammer Bio and Catalent’s $1.2 billion deal

to buy Paragon Bioservices.

But Seymour cautions that at the moment,

CMO capacity for gene therapy manufac-

turing is stretched thin because demand is

high, and it could be several years before

contract manufacturers catch up.

When a company decides to construct

its own facility, several new options have

emerged to help drug developers design a

space with the right kind of flexibility for the

gene therapy market. And if CRB’s business

is any indication, it’s a direction that many

companies are choosing to go.

According to McDonough, the design and

construction firm has seen a 25 percent

uptick in gene therapy inquiries since the

first wave of approvals in 2017. McDonough

says CRB, which worked on the largest ded-

icated cell and gene therapy facility in the

world, also has several gene-related proj-

ects in the pipeline that are over 200,000

square feet.

“We can also do operations improvement

to help companies understand how to get

more out of their manufacturing process

with a minimal amount of facility modifica-

tions,” he says.

This fall, Exyte is also launching a brand-

new, pre-fabricated gene therapy facility

called Rita. The company says that the idea



is for Rita to work much like Lego blocks

with standard components that are highly

customizable and can fit together smoothly

in whatever way a company needs.

“It’s a concept made up of cells with stan-

dard arrangements that can be assembled

in various ways for virtually any layout,

whether it’s a segregated or ballroom

approach,” Mussati says.

The Rita facilities will also be designed so

that the customer’s unique facility features

and technologies can easily fit into the

spaces within the cell.

“Rita is about creating a platform for utilities

and infrastructure that can vary from one cus-

tomer to the next,” Mussati explains. “Rather

than adapting the process to the facility — it’s

a facility that adapts to the process.”

Mussati and Kappeler say that Exyte pre-

dicts that the demand for Rita — along

with an equivalent platform the company is

launching for monoclonal antibodies — will

be so high that it will comprise 20 percent

of the company’s revenue stream for its Life

Sciences division next year.

WHAT THE FUTURE HOLDSThe industry has faced similar challenges

before. In fact, several experts pointed out

that right now, the gene therapy market

looks a lot like the market for monoclonal

antibodies after they first started hitting the

scene. As drug developers worked to transi-

tion their process from the lab to the plant,

the challenges of scaling up created several

stumbling blocks.

“I would see the gene therapy market as

being a bit chaotic for the next few years,”

McDonough says.

Among all the experts interviewed for this

article, the prediction of when the gene

therapy industry will find its groove was the

same: about five years.

For now, companies are mobilizing

quickly to fill in the gaps for gene therapy

“Rita is about creating a platform for utilities and infrastructure that can vary

from one customer to the next.” — Luca Mussati, vice president, Pharma and Biotech at Exyte



commercialization. Mergers and acquisitions

have increased throughout the supply chain

so that companies can marry their capabil-

ities to develop the right tech and quickly

increase capacity.

As the industry moves forward, the overar-

ching goal is to create a repeatable platform

for gene therapy manufacturing that many

companies can replicate. And equipment

manufacturers are also working together at

an increased rate to innovate new solutions.

“I think the collaboration has been remark-

able, especially for the speed at which the

market is growing,” McDonough says.

Many involved in the gene therapy market

also say that the FDA has been effective at

creating a roadmap for companies looking

to commercialize gene therapies.

“I think the FDA is providing appropriate

guidance and is a great partner with the

industry right now,” Seymour says.

Despite the challenges, the payoff for

successfully navigating the gene therapy

market and commercializing a new product

will likely be big — both for the company

and patients.

“Throughout my career, I’ve overseen the

approval of six new drugs. It never gets

old,” Blumenthal says of making it to the

finish line with Luxturna. “But this one was

particularly special.”



Advances in the use of biological

structures and processes to target

human disease have resulted in the

development of a broad range of innova-

tive biotherapeutics, spanning recombinant

protein-based products such as monoclonal

antibodies (mAbs), cytokines and enzymes,

through to drug molecules generated by

microbial fermentation. The specific tech-

nologies and processes used to manufacture

each of these biopharmaceutical products

are diverse and specialized. However, they

are all highly sophisticated and must be

carefully optimized to deliver the intended

results, as small changes in manufacturing

conditions can have a significant impact on

the quality and consistency of the product.

Consequently, to ensure the release of safe

and effective products, advanced analytical

methods must be employed to closely mon-

itor the critical quality attributes (CQAs) for

every batch.

Due to the way in which these drugs

are manufactured, the impurities that

are present often have very similar

characteristics to the active ingredient

itself. This can make the identification

and quantification of impurities highly

challenging, especially using conventional

analytical techniques. Fortunately, advances

in the analytical technologies used for

routine workflows are helping to support

the efficient manufacture and release of

high-quality biotherapeutics in line with

regulatory requirements. Here, we highlight

how advances in biopharmaceutical

characterization technologies are helping

manufacturers efficiently and effectively

Redefining quality with analytical monitoring How advances in biopharmaceutical characterization technologies are improving drug quality

By Jingli Hu, Senior Applications Chemist and Jeff Rohrer, Director, Applications Development, Thermo Fisher Scientific



monitor CQAs and deliver safe, high-quality

medicines to patients.

MORE CONSISTENT CHARACTERIZATIONmAbs are an increasingly important bio-

therapeutic product class that have grown

steadily in use over the past three decades.

Like other types of recombinant pro-

tein-based therapeutics, mAbs are large

and highly complex molecules that are man-

ufactured using sophisticated production

and purification processes. However, this

complexity necessitates robust and reliable

characterization techniques to screen for a

broad range of impurities and post-trans-

lational modifications (PTMs) introduced

during manufacturing steps.

Peptide mapping is a well-established

method for the characterization of mAbs

and other recombinant protein-based

drugs, providing primary sequence confir-

mation and enabling the identification and

quantification of PTMs such as deamida-

tions, glycosylations and oxidations. The

technique involves enzymatically or chem-

ically digesting mAbs to generate peptide

fragments that are separated and analyzed

by liquid chromatography-mass spectrome-

try (LC-MS) techniques.

The enzyme of choice within peptide

mapping digestion workflows is trypsin.

However, trypsin-based approaches are

often associated with poor reproducibil-

ity, limiting confidence in results. Studies

have shown that small changes in digestion

conditions can result in significant varia-

tions in the number and type of PTMs, with

high buffer pH and long digestion times

resulting in greater concentrations of deam-

inated peptides.1 Additionally, trypsin-based

digestion protocols typically require

EXHIBIT 1

Tandem LC or LC-MS channel time savingsAchieving time savings using dual channel UHPLC for tandem LC or LC-MS applications.

Analytical gradientApplication 1








Application switch time


Reconditioning

Reconditioning

Reconditioning

Reconditioning Reconditioning Reconditioning

Reconditioning Reconditioning

Single channel LC

Tandem LC or LC-MS

Flow path 1 |

Flow path 1 |

Flow path 2 |

Time savings| |

Compared to single channel LC



time-consuming manual sample handling

steps that cannot be easily automated,

further increasing the potential for inconsis-

tencies in results.

Improvements in automated trypsin-based

protein digestion protocols are helping to

overcome these challenges by streamlining

peptide mapping workflows and improving

the consistency of results. The advent of

commercial trypsin digest kits that include

thermally stable, immobilized trypsin has

enabled high-temperature protein dena-

turation workflows that do not require the

addition of denaturants. This has resulted

in faster and more reproducible protein

digestion workflows that reduce post-trans-

lational modifications and deliver more

consistent results. Some trypsin digest kits

also enable automated sample prepara-

tion and digestion workflows, accelerating

the delivery of consistent characterization

data by simplifying or even eliminating

error-prone manual steps. As such, these

workflow innovations are helping to boost

throughput and efficiency while also

increasing confidence in results.

IMPROVING THROUGHPUTAnother bottleneck for manufacturers oper-

ating peptide mapping workflows is LC-MS

analysis. Despite the breadth and depth

of information that can be obtained from

LC-MS workflows, these methods typically

require lengthy column reconditioning or

washing steps to re-equilibrate the column

for the next sample. These steps are import-

ant to remove residues that may remain on

the column, ensure stable backpressures

and achieve consistent and reliable sep-

aration performance, especially if mobile

phases contain buffers or ion-pair reagents.

Although individual reconditioning steps

may only take a matter of minutes, over

the course of a typical peptide mapping

sequence they can extend workflows by

hours, during which time the MS instrument

stands idle.

EXHIBIT 2

Dual LC channel time savingsAchieving time savings using dual channel UHPLC for simultaneous orthogonal characterization using multiple applications.











Single channel LC

Dual LC

Flow path 1 |

Flow path 1 |

Flow path 2 |

Time savings| |

Compared to single channel LC






Modern dual channel ultra-high perfor-

mance liquid chromatography (UHPLC)

systems are helping manufacturers of

biopharmaceutical products apply their

resources more efficiently. These innovative

systems are highly flexible and enable the

use of a second channel that is supported

by a separate pump and detector system.

The two channels can be configured

according to the needs of the applica-

tion, enabling either tandem LC or LC-MS

applications, or alternatively, simultaneous

orthogonal characterization depending on

the system set-up.

When configured to operate in tandem

LC-MS mode, dual channel UHPLC sys-

tems allow the same validated method to

be run across two pumps, saving consid-

erable time compared to a single channel

system (Exhibit 1). This set-up allows one

channel to be used to collect data, while

the second is simultaneously used to condi-

tion the column for the next analytical run.

These highly efficient workflows even allow

analysts to implement additional washing

steps without extending total run times,

helping to improve the quality of peptide

mapping data obtained, without adding

additional time to analytical runs.

BOOSTING ANALYTICAL EFFICIENCYOther characterization workflows are

widely used for the analysis of mAbs and

other recombinant protein-based products.

Commonly used techniques include

strong cation exchange (SCX) chroma-

tography, size exclusion chromatography

(SEC), and reversed-phase chromatogra-

phy. Each technique depends on specific

chromatography column chemistries and

gradient methods, allowing manufacturers

to monitor a comprehensive range of prod-

uct CQAs.

EXHIBIT 3

Gentamicin and sisomicinSeparation of gentamicin and sisomicin using a Thermo Scientific Dionex ICS-5000+ HPIC system (inset: chemical structure of the main components of gentamicin).

Minutes

400

nC

50 • • • • • • • • 0 10 20 30 40 50 65

Peaks:1. Sisomicin2. Gentamicin C1a3. Gentamicin C24. Gentamicin C2b5. Gentamicin C2a6. Gentamicin C1

1

2

3

4

5 6

Gentamicin

OH

HOHOHN

H2N

H2NNHR1

HN2

R3

R2

O

OO

O

R1 R2 R3

C1a H H H

C2 H CH3 H

C2b CH3 H H

C2a H H CH3

C1 CH3 CH3 H



Despite the excellent analytical per-

formance offered by the latest UHPLC

systems, meeting the high throughput

demands of routine biotherapeutic charac-

terization workflows remains challenging.

To perform the full range of characteriza-

tion studies required to support regulatory

guidelines, manufacturers must often per-

form separate analytical runs sequentially,

setting up each new method after the

previous workflow has been completed.

This necessarily involves time-consuming

application switching steps, extending the

total analysis time required (Exhibit 2).

One way for biotherapeutics manufactur-

ers to improve throughput and capacity

is to increase the number of instruments

they use for characterization workflows.

However, for many organizations, lim-

ited budgets and laboratory space mean

that investing in additional equipment is

not feasible.

The latest dual channel UHPLC systems are

helping biopharma manufacturers obtain

the reliable characterization results they

need, using the same resources. When con-

figured to support simultaneous orthogonal

characterization, separate characterization

techniques can be used to analyze the same

sample, increasing the quantity of information

that is obtained while improving productiv-

ity and cost per sample. By reducing sample

preparation requirements and eliminating the

need to change validated experimental condi-

tions, dual channel UHPLC systems offer time

and cost savings compared to single channel

instrument set-ups.

SAFEGUARDING QUALITY AND CONSISTENCYAlthough many of the largest categories of

biotherapeutics are recombinant proteins,

these are by no means the only biopharma

products that require robust character-

ization workflows to ensure therapeutic

safety and efficacy. Broad-spectrum ami-

noglycoside antibiotics are manufactured

by bacterial fermentation processes and

typically have a relatively narrow therapeu-

tic range.2 The aminoglycoside antibiotic

gentamicin, for example, is used for the

treatment of serious infections caused

by gram-negative bacteria. However, its

application is limited due to the potential

for renal and otovestibular toxicity. The

small difference between the effective

and toxic concentration means careful

therapeutic monitoring of aminoglycoside

levels is necessary to minimize the risk of

adverse effects, particularly in patients with

renal failure.

Gentamicin consists of a mixture of struc-

turally similar components, the most

abundant being gentamicin C1, C1a, C2, C2a

and C2b (Exhibit 3). Because the antibiotic

is manufactured by a microbial fermen-

tation process, other structurally similar

products may be formed in small amounts

during synthesis. Given the variation in the

potencies and toxicity between the various



gentamicin components, robust product

characterization is essential.

Ion-pairing reversed-phase liquid chro-

matography combined with pulsed

amperometric detection (PAD) is widely

used for the analysis of aminoglycoside

antibiotics and related impurities. How-

ever, the number and structural similarity

of the impurities that are present makes

characterization challenging if high-reso-

lution chromatographic separation is not

maintained. With routine high-throughput

laboratories under pressure to produce

accurate results while maximizing through-

put and operational efficiency, fast,

robust, and reliable analytical solutions

are required.

Fortunately, improvements in modern

high-performance ion chromatography

(HPIC) systems are helping to deliver fast,

sensitive analyses without compromising

on resolution. The advanced high-pres-

sure capabilities of the latest HPIC systems

enable excellent separation resolution to

be achieved using small diameter particle

columns (Exhibit 3), supporting high-con-

fidence identification and quantification of

impurities by PAD.

Furthermore, the availability of dedicated

fast ion chromatography columns designed

for rapid analysis is also boosting workflow

productivity by reducing the time taken to

deliver results. When these analyses are run

using dual channel HPIC systems, through-

put can be optimized further, cutting

through routine characterization workflow

bottlenecks and helping manufacturers of

biotherapeutics achieve more using the

same resources.

CONSISTENT AND RELIABLEToday’s sophisticated biopharma

production workflows demand the use

of robust and reliable analytical methods

to monitor product CQAs and ensure

the release of safe, high-quality batches.

In addition, with manufacturers under

sustained pressure to deliver confident

results cost-effectively, the technologies

used within routine biopharmaceutical

characterization workflows must support

efficient, high-throughput analyses.

Fortunately, the latest advances in

technology are helping to overcome

workflow bottlenecks, helping pharma

companies collect consistent and reliable

biopharmaceutical characterization data

faster and more efficiently.

REFERENCES1. Ren D, Pipes GD, Liu D, et al. (2009) An

improved trypsin digestion method min-

imizes digestion-induced modifications

on proteins. Analytical Biochem.; 392(1):

12–21.

2. Begg, E.J., Barclay, M.L. and Kirkpatrick

C.J.M. (1999) The therapeutic monitor-

ing of antimicrobial agents. Br. J. Clin.

Pharmacol.; 47(1): 23–30.



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2020 BIOPHARMA TRENDS - Pharmaceutical Manufacturing...mercial manufacturing — such as those that can occur as companies struggle to train employees or recruit additional workers