OCTOB E R 2020#

69

Upfront
The drug dose
gender gap

In My View
Harnessing the industry’s
dark data

Business
What do the US elections
mean for pharma?

Sitting Down With
PDA President and CEO,Richard Johnson

08

10 – 1138 – 43

50 – 51

Lifting Up
a Continent
Exploring African pharma’s
pivotal role in the continent’s
economic rise18 – 27

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Our experience and solution portfolio can help customers at allstages of vaccine development, from discovery and testing to large
scale manufacturing against the novel SARS-CoV-2 outbreak.
Learn More. www.sartorius.com/covid19

Should We Fear the Virus?
The criticality of careful science communicationin the age of COVID-19

Ed i to r ial

pparently feeling better – “GREAT,” in fact
– after being hospitalized with COVID-19,
President Trump told Americans: “Don’t beafraid of Covid. Don’t let it dominate yourlife.” The comments were (typically) controversial – especiallyconsidering the death toll and the harsh reality that the
average US citizen will not receive the same standard of careas the President… But what about downplaying the risk of
COVID-19 (Trump’s preferred approach from the outset) –does it result in fewer people taking measures needed to slow
the spread of infection? The reasonable assumption here isthat a degree of public fear is a necessary motivator. Is there
an ethical case for exaggerating risk to achieve public healthoutcomes?
Research from Cornell University suggests not; threats
about dire outcomes can certainly mobilize more people totake precautions in the short term. But when catastrophic
predictions fail to acknowledge the uncertainty of the models
used to guide pandemic policy, the longer-term impact canbe an erosion of public trust – not only in the models but inscience more broadly (1). The Cornell researchers emphasized
the importance of “careful and effective science communication
for maintaining public support for science-based policies as
the scientific consensus shifts over time.”
I’ve previously discussed the problems associated withsensationalization in the other direction – when exaggerated
claims and omitted caveats feed a propaganda machine (2). In
the case of cell therapies, unproven clinics and do-it-yourself
gene editing companies tap into the hype generated to exploit
a patient’s hope of a cure. A number of these clinics are now
claiming to treat COVID-19 (3), and we’ve also seen groups
working to develop and self-administer unproven interventions
that they describe as vaccines for COVID-19 (4).
Science communication involves a degree of storytelling.
And stories inevitably tap into human emotions (fear and hopein the cases above) – I don’t think there’s a problem with that.
But issues arise when the communicators see their audience asa means to an end. Should we fear the virus? Does Company
X’s developmental therapy give us hope? The key to carefulscience communication is – while offering full transparencyof all known caveats – allowing the audience to make up theirown minds.

A

References
1.

SE Kreps and DL Kriner, “Model

uncertainty, political contestation, andpublic trust in science: Evidence from the

COVID-19 pandemic” (2020). Available
at: https://bit.ly/3lioh2d2.

J Strachan, “Science Versus Sensationalism”

3.

Healio, “Unproven ‘stem cell therapy’ claims(2018). Available at: https://bit.ly/30Wj7RZ
spread beyond arthritis into COVID-19”(2020). Available at: https://bit.

4.

ly/3lmxkPE

C J Guerrini et al., “Self-experimentation,
ethics, and regulation of vaccines” (2020).
Available at: https://bit.ly/3nkwbKq

James Strachan
Deputy Editor
www.themedicinemaker.com

C o n te n t s

5008

In My View
10

Graeme Dennis questions why
the industry refuses to make useof the significant amount of data
it generates

12

3D spheroids and organon-a-chip can help translatepreclinical data into clinicalefficacy, says Audrey Dubourg

12Standardizing single use will
help build a stronger and morecost-effective biopharma supply
chain, says Jerry Branscomb

14

A lthough contamination will
always be an issue, Massimo
Mainetti says the biopharma
industry must still strive for“zero defects”

38

03

Editorial

Should We Fear the Virus?
by James Strachan

On The Cover
Pharma’s role in Africa’s
economic rise

Upfront
06

The latest news, views andresearch – including the drug
dose gender gap, alternatives toanimal testing, and the US
allowing drug imports
from Canada

ISSUE 69 - OCTOBER 2020
Feel free to contact any one of us:
first.lastname@texerepublishing.com
Content Team
Editor - Stephanie Sutton
Charlotte Barker(Associate Content Director)
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32

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Business
38

Feature18

A frican Pharma on the Rise
How can the pharmaceuticalindustry help make theAfrican Union’s “blueprint
for transforming Africa
into a global powerhouse” areality? Here, experts discuss
brain drain, healthcare, and
COVID-19.

NextGen32

 Living Elixir?
A
Introducing the fourth
therapeutic class: live
biotherapeutics –microorganisms isolated
from the human gut with thepotential to treat many diseases

44Th e Battle for the Future ofAmerican Healthcare
Looking back at Trump’s tenure,and the potential implications of
the US elections for pharma andthe Affordable Health Act
Pacesetting Leadership
Overcoming setbacks, finding
inspiration and the art of accepting
advice: lessons learned with
Kiran Mazumdar-Shaw

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Reports
16

Focus on Quality and the Rest
Will Follow

28

Understanding the
Oligonucleotide Landscape

35

Serving a Rising Power

Sitting Down With50

 ichard M. Johnson, President,
R
and Chief Executive Officer,
Parenteral Drug Association

Management Team
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6 Up f r o n t

Upfront
Research
TrendsInnovation

AnimalAlternatives
Developing in vitro methods
that help vaccine developers
reduce animal testingThough animal testing is an essential
part of vaccine R&D, Gideon Kersten,
Chief Scientific Officer at Intravacc,
believes its role in quality control isdebatable. “Not only have our analyticalcapabilities improved spectacularly,
but production processes are now
better controlled,” he says. “It should
be possible to reduce our animal use
if in vitro tests can prove a vaccine isproduced in a consistent manner.”
Intravacc, in collaboration withresearchers from Leiden University, theNetherlands, has developed a techniquethat relies on the enzyme cathepsin S
to establish the quality of vaccines (1).
Cathepsin S can be used to measure how
consistent purified native pathogens
in vaccines are inactivated. “Theinactivation step in the development ofsome vaccine types is critical and relies
often on formaldehyde,” says Kersten.
“Using mass spectrometry, we quantified
how quickly the enzyme breaks down
proteins in vaccine products. The
rate of degradation was used as anindicator of how
well forma ldehyde
inactivated the vaccines
we tested.”Though the process initially seemedstraightforward, the team soon realizedthat it would be difficult to execute.
“Using formaldehyde is really messy! The
protein fragments we studied were not
only inactivated, but extensively modified
by the compound, and we ended up witha heterogeneous mixture,” Kersten says.
“Though we mapped these modifications
in great detail, we then turned our
focus to quantifying the breakdown of
peptides that were not modifiable because

identification of
unmodified peptides
by mass spectrometry is easier.”
The change in direction allowed theteam to accurately determine the effectof cathepsin S on degradation. “We now
have a method that allows us to establish
vaccine quality without animal testing,”
Kersten says.
The team is now working towards
validating their approach before seeking
regulatory approval.
Reference
1.

TJM Michiels et al., Sci Rep, 10, 11535(2020).

INFOGRAPHICCOVID-19 Disruption
Tracelink’s survey reveals
the extent of supply chain
disruption caused by the
pandemic
Sources: TraceLink, “The Only Comprehensive Analysis of thePharmaceutical Supply Chain During the Pandemic.” Webinar;
September 24, 2020.

Pre-pandemic, 74% ofcompanies reported
average, on-time
delivery performancefrom direct material
suppliers of 98%
Now? On-time delivery
performance is down tocite persistent
supplyproblems
resulting in
drug shortages

7

Up f r o nt

BUSINESSTop Tier
Innovation

IN BRIEF

Eliminating fossil fuel emissions,embracing supercomputers, and centersof excellence… what’s new in businessfor pharma?
•••

Biogen is investing US$250
million into a 20-year “Healthy
Climate, Healthy Lives”
initiative to eliminate fossil fuelemissions across its operations.
The company plans to rely
entirely on renewable energy by
2040 and will be encouraging
and supporting its suppliers to
reduce reliance on fossil fuels.
The initiative also includes plansto advance the science aroundhow fossil fuels impact humanhealth via harmful air pollutants.
NVIDIA claims to be building
the UK’s most powerfulsupercomputer – expected tocome online by the end of theyear – to support healthcare
research. GlaxoSmithKline,
AstraZeneca, Guy’s and St
Thomas’ NHS Foundation
Trust, King’s College London,and Oxford Nanopore
Technologies all plan to takeadvantage of the system’s
capabilities.
After purchasing a new biologics
manufacturing facility in

Nominate the top
pharmaceutical technologies
in our 2020 Innovation Awards•

Despite a year marked by unprecedented
challenges, pharmaceutical equipment
companies have continued to develop
new technologies that facilitate betterand more eff icient pharmaceuticaldevelopment and manufacturing.
Continuing The Medicine Maker’s
annual celebration of innovation,
we invite you to nominate the latest
technologies that you think are making
a real difference to the pharmaceuticalindustry in our 2020 Innovation Awards.
The Awards – to be published in our
December 2020 issue – will celebrate
the highest impact pharmaceuticaldevelopment and manufact uring
technologies released in 2020. The
innovation can be a piece of equipment,
software, formulation technology, drugdelivery method, or any other advancethat you think could fit the bill. But
remember: the innovation must have beenreleased (or planned for release) in 2020.

Bloomington, Indiana, Catalentsays it will create a North
American center of excellence
for early-phase clinical biologics
formulation development anddrug product fill/finish services.
The facility is expected to begin
supporting customer programsin January 2021. The site will
integrate with the company’s
main Bloomington facility
located nearby, which recently
received a $50 million investment
to install additional high-speed
vial filling capabilities.
The FDA is launching a Digital
Health Center of Excellence
to help ensure that cuttingedge digital health technologies– including mobile healthdevices, software as a medical
device, and wearables – are
rapidly developed and reviewed
in the US. Bakul Patel, who
has been leading regulatory
and scientific efforts in digital
health devices at the FDA since2010, is to be appointed as thecenter’s first director.

Nominations close on November 3;
have your say before it’s too late!
Register your nomination athttps://tmm.txp.to/innovation2020

Primary COVID-19 challenges

5%0%Excessinventories

10%

Poor
servicelevels topatients

15%

Increased
supplychain costs

have lost
faith in theirdemandforecasts andability to plan
supplyDrugshortages

say the pandemic has/will increase problems
with diversion, theft andcounterfeiting – particularly
for test kits, vaccines andanti-viral medicines

Increased
production
costs

20%

www.themedicinemaker.com

8

 Up f r o n t

The Drug Dose
Gender Gap
Does equal always mean fair?
Across industries, women and their
allies have fought to close the gender
gap. For pharma, the problem is not
only a professional one – it affects thehealth of female patients worldwide.
And now, using data from over 2,000
journal articles, researchers from the
University of California, Berkeley andthe University of Chicago have foundthat 86 FDA-approved drugs areaffected by a drug dosing gender gap (1).
“The common practice of prescribing
equal drug doses to women andmen neglects sex d ifferences inpharmacokinetics, dimorphisms inbody weight, and risks overmedicationof women,” says Irving Zucker, thestudy’s lead author. “We discovered that
76 of the 86 drugs we investigated had
negative effects in female patients.”
The Berkeley and Chicago researchers’
analysis showed that, when given thesame dose as men, women were more
likely to experience higher concentrationsof a drug in their blood and take longer
to eliminate it from their bodies. This

Don’t Exclude
the Aged
Most clinical trials against
COVID-19 exclude the very
patients most at risk fromthe disease
Despite being at higher risk of severe
COVID-19, older adults are in dangerof being excluded from more than 50

pharmacokinetic data, Zucker andPrendergast explain, are strongly linked
to adverse drug reactions. “Not only are
women at risk of experiencing elevatedblood concentrations, but they are also
more likely to face worse drug reactions,”
Zucker says. “In 96 percent of the studies
evaluated, women experienced adverse
reactions twice as often as men. These
were often severe – causing symptoms
like depression and hallucination.”
But how can we achieve gender parity?
Zucker and Prendergast believe there
is more work to be done. “Though the
US National Institutes of Health has

mandated the inclusion of women inclinical trials, credible evidence of sex
differences in pharmacokinetics andadverse drug reactions should be madeavailable in drug labels.” The authors
added that, to attain long-term change,
it is crucial to increase awareness of sex
bias, its sources, and the countermeasuresthat can diminish gender disparities
in medicine.

percent of COVID-19 clinical trials and
100 percent of vaccine trials, according
to a review of COVID-19 trials on
clinicaltrials.gov (1). The authors evaluatedtrials based on their risk of excluding
adults over 65 years old and found thatmost trials featured either age cutoffs or
broad, unspecified exclusions.
Although they acknowledge that some
exclusion will always be necessary, theauthors argue that enrollment of greaternumbers of older adults in clinical trials
is possible with advance preparation,

staff training, and aging expertise.
Senior author Sharon Inouye, Directorof the Aging Brain Center in the Hinda
and Arthur Marcus Institute for Aging
Research at Hebrew SeniorLife, believes
that many of the exclusion criteria are “notwell-justified, and appear to be more for
expediency or convenience of the trialists.”

Reference
1.

I Zucker, BJ Prendergast, “Sex differences inpharmacokinetics predict adverse drug reactions
in women,” Biol Sex Differ, 11, 32 (2020).

Reference
1.

BKI Helfand et al., JAMA Intern Med, [Epubahead of print] (2020). DOI: 10.1001/
jamainternmed.2020.5084

Up f r o nt

IMAGE

9

OF THE MONTH

Importation
Action
FDA to allow drugs to beimported from Canada

Know Thy Enemy
Colorized scanning electron micrograph showing SARS-CoV-2
virus particles (yellow) isolated from a patient.
Credit: NIAD

Would you like your photo featured in Image of the Month?
Send it to maryam.mahdi@texerepublishing.com

QUOTE of the month

Following on from Trump’s Executive
Order in July 2020 to increase drug
importation, the FDA has issued a“final rule” that will allow certain
prescription drugs to be imported
from Canada – under specif ic
conditions. The agency has also
released Guidance for Industry,
which details procedures drug
manufacturers should follow “tofacilitate importation of prescriptiond r ugs, including biologica lproducts, that are FDA-approved,
manufactured abroad, authorized
for sale in any foreign country, andoriginally intended for sale in that
foreign country.” The imported drugs
would have to be relabeled to US
standards, and tested for authenticity,d e g r a d at ion , a nd e s t a bl i s he dspecifications and standards.
In a statement, FDA Commissioner
Stephen M. Hahn explained that theagency’s Safe Importation Action
Plan should help increase competitionin the market and lower the prices ofprescription medicines.
Reference1.

“No research team is exempt from the pressures and speed at which
COVID-19 research is occurring. And this can increase the risk of honest error
as well as misconduct. To date, 33 papers have been identified as unsuitablefor public use and either retracted, withdrawn, or noted with concern.”
Katrina A. Bramstedt writing on substandard research during
the pandemic in the Journal of Medical Ethics:
https://bit.ly/30BAKGp

FDA, “FDA Takes Actions to Help Lower
U.S. Prescription Drug Prices,” (2020).
Available at https://bit.ly/30gPZo5.

10

 I n M y V iew

In My
View
Experts from across theworld share a single
strongly held opinion
or key idea.

Harnessing
Dark Data
The pharma industry createssignificant amounts of data –so why is most of it hoarded
and never made accessible?
By Graeme Dennis, Commercial Director,
Preclinical Pharma, IDBS
Data is generally recognized as anorganization’s top asset after talent –but it is rarely treated as such. Although
the amount of data produced every day
is massive, it has been estimated that
60–73 percent goes unused for analytics,
instead relegated to storage (1). This is
known as “dark data.”
Local storage, an explosion in thenumber of users at all levels of computer
literacy, and well-intended (and justified)data security have all contributed to thevolume of dark data that companies
retain, whether or not they plan to use it.
How can the biopharma and healthcare
industries treat this data as a freestanding and central asset by making it
accessible in the long term?
Like the unexpressed parts of thehuman genome, some dark data canbe expected to have great meaning andsignificance – but not all. A key reason
this data continues to accumulate isthat there is no suitable system tohouse it. For instance, many in vivo
preclinical study results generated bycontract research organizations are inportable document formats unsuited
to analyzing or in email, an unsharedenvironment by design. This choice isdictated by convenience, but it makes
the data not only unshareable, but also
invisible to the organization. Even if
exposed, many scientists would not evenconsider using or reinterpreting the data
without significant context as to how,when, by whom, and under what precise
conditions it was gathered. They may
instead opt to rerun the study, depleting
time, money, and resources.
The antidote to the dark data morass
should go beyond just exposing it. Most
companies are guilty of data hoarding,where data is retained regardless ofquality or significance. Our goal should
not be only to find (and find value in)what is stored, but also to store less dark
data. Storage may be cheap, but it’s notalways best to keep everything.
Instead, the focus should be onretaining contextually rich data. Legacy
methods of recording and collating data
are prone to errors, but they also fail toprovide the full context in which the data
was captured. Sometimes called data
provenance, these conditions frequently
dictate the reusability or applicability ofdata for interpretation. Instrumentation,
lab location, conditions, and materials
used are just some of the many factorsthat should be considered throughout
the drug development lifecycle. Sample
origin, transport conditions, andcustody are also essential. Capturing
this information relies on advanced
infor mat ics inf rast r uct u re andsignificant forethought in system design.

IDBS has a longstanding presencein the data space and I have observed
a proliferation of standalone systems
across siloed specialties and disciplines.
When it comes to realizing the benefitsof data, I have three central pieces ofadvice: recognize data maturity, explore
integration approaches, and embrace a“data first” cultural shift.
First, classifying data according to
its level of maturity is wise because it
enables assignment of resources, effort,“Legacy methods ofrecording andcollating data areprone to errors, butthey also fail toprovide the fullcontext in which thedata was captured.”I n M y V iew

and priority to align with broader
company goals. For instance, data may
be considered fully dark or sequestered,shared (perhaps on a shared drive or
SharePoint), structured (stored in a
database), and ultimately standardized(both structured and harmonizedwith internal or industry standards).
Stratifying data this way and thenfunctionally – perhaps according to
the most active project, candidate, or
biological relevance – can make theprocess manageable.
Second, it is important to explore
integration approaches. The nearer datais captured to the moment of acquisition,
the less likely it is to become sequestered.
Vendor assessments must raise integration
capabilities early and often in theevaluation of candidates. Data pipelining
tools, database replication, or scripting

can close these gaps, but the best solutions
eliminate the gap via integration.
F ina l ly, a “ data f i rst ” st rateg yacknowledges the importance of data,socializes it, and provides the tools thatenable success. The F.A.I.R. (findable,
accessible, interoperable, reusable) data
principles provide broadly accepted
guidelines for when such a program may
be implemented. This type of program
will succeed when it is visibly endorsedby leadership and prioritized at thebench. And you should absolutely invite
not only champions, but also skeptics toparticipate – they will provide some ofyour most valuable input!
Big pharma is increasingly turning
to third-party R&D firms to accelerate
the early stages of drug development.
Today, the most effective of these firms
are technology-focused, with a cultural

 11mindset that recognizes the power ofdata. Method execution and sample
management – approaches with origins
in manufacturing and QC – haveextended into drug development.
By revealing dark data, optimal
conditions and processes can be
replicated, workload reduced, andefficiency increased. Error detection,for example, becomes much easier when
one can pinpoint when and where acertain context changed. By rolling backto this point, it is possible to resumedevelopment, rather than starting theentire process again. In essence, dark data
can shine a light on the best way forward.
Reference
1.

1. Forrester, “Hadoop Is Data’s Darling
For A Reason,” (2016). Available athttps://bit.ly/3bRlyJU.

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12

 I n M y V iew

A ModelExperiment
Harnessing the potential of
microphysiological systems
to advance drug discovery

By Audrey Dubourg, Product Manager at
CN Bio Innovations Ltd., Cambridge, UK
With just one in 10 preclinical candidates inphase I trials likely to gain market approval,
the pharmaceutical industry must find ways
to develop effective therapeutics faster andmore cost-effectively. Pipelines include
a mix of drug discovery, redevelopment,
repurposing, combination therapeutics,
and new modalities, such as gene therapies
or regenerative medicines. When it comesto success, however, the translatability ofpreclinical data into clinical efficacy is only as
good as the predictivity of the test models…
Drug discovery traditionally involves
two-dimensional monolayer cell culture
experiments followed by testing inanimals to ensure results translate invivo. Unfortunately, these models sufferfrom well-documented inefficiencies andinaccuracies, including oversimplification,
insuff icient representation of theunderly ing pathophysiolog y, andinterspecies differences – all of which canlead to poor translatability into the clinic.
Microphysiological systems (MPS) area relatively new approach that combines
bioengineering and cell biology to provide
more physiologically relevant data in earlyR&D stages. MPS build on the conceptsof traditional two-dimensional assays,
but improve physiological relevance by
mimicking aspects of organ function.
Systems such as 3D spheroids, organoids,organ-on-a-chip, multi-organs on chips,
static micropatterned technologies, andphysiome-on-a-chip models combine
living cells and microfluidic technologies
with drug delivery, stimulation, or sensing
tools to gain a clearer picture of how suchtools will function in a living organism.
The technology’s broad applications
extend into modelling healthy or diseasedorgans, studying multi-organ interactions,investigating ADME and toxicity, andscreening, identifying, and ranking drugcandidates. Single- and multi-organ MPS
technologies are designed to mimic specificaspects of organ function or crosstalk;for instance, an MPS that incorporates
liver tissue with another organ offers theopportunity to concurrently study efficacy
and susceptibility to toxicity. For highly
prevalent diseases with well-established
impacts on public health, they can alsoenable investigations into host genetics,
treatment responses, novel therapeutictargets, and additional biomarkers. Suchinvestigations are increasingly importantfor conditions such as non-alcoholicsteatohepatitis (NASH), for which there
are currently no therapies on the market.
Microtissue models of human NASH
demonstrate key hallmarks of the disease,giving researchers the opportunity to
mimic the stages of disease and elucidate
its pathophysiological mechanisms on acellular level.
By improving risk predictivity overstandard research tools, or by providing
a more comprehensive model that is nototherwise available, MPS could bridge
the gap between traditional cell culture
and human studies. But, to maximize theirpotential, insights gathered from thesemodels should be considered alongsidein vivo data – both to provide confidence
in the data derived from MPS models
and to offer insight into the mechanisms
underlying differences and adverse eventsin animal models. Ultimately, single- andmulti-organ MPS could yield efficiency
gains, reduce costs, and potentially reduceanimal usage.
As MPS technology continues to evolve,
advances in the field are extending thelifespan of models, enabling a greater
window for long-term experiments,
compound dosing, and observations ofdisease progression – and edging us evercloser to a true simulation of humanbiological conditions.

Standardize
for Success

By Jerry Branscomb, Senior ProductManager of Single-Use Technology forStandardization and Harmonization at
Thermo Fisher ScientificWe’re making progress on
standardizing single-use
systems – and it could mean amore cost-effective supply chain

Recent years have seen considerable
growth in the adoption of single-use
technologies in the biopharmaceuticalindustry. By eliminating the long,resource-intensive decontaminationand sterilization steps associated withmulti-use equipment, single-use has
proven that it can help biopharmaceuticalorganizations boost operational efficiency,
improve product quality and consistency,
and reduce costs. However, increased
demand for single-use is straining supply
chains and delivery timelines – an issue
I believe standardization can alleviate.
Standardization has historically provenchallenging because biopharmaceuticalorganizations typically require highly
specialized (often custom) single-use
designs to meet their workflow needs.
And if standardization practices are notproperly executed and managed, it can bedifficult to control configurations that havebeen functionally optimized and qualified
for use in multiple applications. If thesame design is being used across different
workflows and facilities, for example, wemust employ appropriate processes toensure that any subsequent revisions will
not impact the various applications.
Today, there is increasing focus on
combining the attributes of several
custom designs into one system for use
as standard across different bioprocessing
workflows. This helps to establish shorter
lead times for single-use and simplify
purchasing and inventory efforts,
making these technologies more readily
and sustainably available. Importantly,
standardization also removes the risk ofvariation in the manufacturing process byenabling biopharmaceutical companies
to implement more efficient, repeatable,
and consistent processes that are quick to
deploy and maintain – thereby boostingproductivity. Ultimately, standardization
can help biopharmaceutical organizations
eliminate production bottlenecks andaccelerate the release of new therapeutics
to market.
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Group (BPOG) standard methods,
for example, are designed to enforce
industry-wide leachable and extractable
testing protocols for components used in
the manufacture of single-use systems.
Typically, manufacturers of single-use go
to great length and investment to perform
leachable and extractable testing of theirproducts, a burden that standardizing
on specific components could reduce.
Following the BPOG standards has also
made it easier for biopharmaceuticalorganizations to directly compare
different components using the relevant
test data to verify suitability for use in
their operations. Ultimately, relianceon BPOG standards simplifies andaccelerates the adoption of single-use
technologies in the safest and mosteffective way.
The progress that has been made so far
in standardizing single-use technologies
has unlocked significant productivity
gains for the biopharmaceutical industry– and I believe there is more innovation
to come! Developers of single-use systems
are constantly devising new technologies
and optimized designs that offer thehighest standards of performance,
consistency, reliability, and safety. And,
as we look to the future, single-use
standardization will play a vital rolein building a stronger and more costeffective biopharma supply chain.
www.themedicinemaker.com

14

 I n M y V iew

Zero Defects
Biopharma companies
must minimize defects andcontamination

By Massimo Mainetti, Global Head ofMarketing and Product Management,
Datwyler
As the COVID-19 pandemic continues to
unfold, the industry is working tirelessly toidentify effective treatments and vaccines.
There is intense pressure to produce a
vaccine in a short time frame, which
demands efficiency on all fronts. Naturally,large molecules are being considered astreatments, but manufacturers face thechallenge of ensuring that such drugs havezero defects and do not contain silicone
contamination from packaging and delivery.
Although silicone contamination has been
an issue for decades, it can be commonly
found in the plungers and stoppers ofsyringes, cartridges and vials. Because of
its ubiquity, the default tendency among
pharma manufacturers is to “work around”
the possibility of silicone contaminationin drug formulation, rather than address
the issue head-on. Such contamination
challenges are surmountable; indeed,
solutions in this space can save time, money
and stress, while delivering a better productto the patients.
When producing parenteral packaging
for vulnerable or sensitive products,
medicine manufacturers should always aim
for zero defects. The zero-defect approachbetter preserves the drug, protects thepatient, and upholds the reputation of the
drug manufacturer. Injectable biologics haveemerged as chief drivers of sales growth in
the pharmaceutical industry, but are costly

to manufacture and often highly sensitive
to extraneous contamination, such as
silicone, cellulose, or other particles. If the
drug includes unsatisfactory levels of any ofthese contaminants, the whole batch must
be disposed of, representing a significant
monetary loss and, as we are reminded amid
today’s pandemic, precious time wasted in
moments of potential crisis. Despite all
the industry-standard quality audits andthird-party oversight, contamination oflarge molecule drugs is still commonplace.
What best practices reduce incidenceof drug contamination? In the case ofsilicone in parenteral drug packaging,it can start with complete coverageof any plunger or stopper with a nosilicone fluoropolymer coating. Creating
a robust barrier between the drug andrubber minimizes the impact posed byextractables and leachables. Additionally,
drug and device manufacturers canseek ready-to-use components in rapidtransfer port (RTP) bags, so that drug
manufacturers do not have to sterilize theirown components. Pushing the washingand sterilization of components further
upstream to component manufacturers
reduces the manufacturing footprint in abiologics facility, and also keeps the focus
on the core competency of manufacturing
and filling the drug product rather thanon component processing – which itself
requires meticulous attention to detail.
Another best practice is to establish clear,transparent channels of communication
between key parties – the drug company,
the packaging manufacturer, and otheressential suppliers. By working moreclosely, specifiers can easily identify
and troubleshoot potential sources ofcontaminants and eliminate common
defects throughout the supply chain; acrucial endeavour when you consider thatvisible particles accounted for 22 percent of
all injectable drug recalls between 2008 and2012, and that recall events due to visible
particulates have been steadily increasing
since 2009. Component manufacturers
should consider redesigning production

facilities for packaging and delivery systems
used in large molecule drug applications
to eliminate the presence of identified
contaminants.
Perhaps the most common contaminantsin pharmaceuticals are cellulose (cottonand paper) fibers, synthetic fibers, silicone,
plastics, rubber, metal particles andcorrosion products, glass particles andvial delamination flakes, skin flakes, andchar particles. Eliminating cellulose fromthe vicinity of production is particularly
difficult. Cellulose can be introduced via
wood pallets, paper and bags present nearproduction environments. Eliminating
paper from the production floor – and, if
possible, in the surrounding offices andother areas – by transitioning a facility to allelectronic records and communications, cango a long way to reducing cellulose particles
that can circulate. Substituting wood pallets
with non-contaminating versions made ofplastic substrate is also recommended.
Finally, it’s necessary to improve productinspection. Camera inspection adds a layer of
security the naked eye cannot achieve alone.
Cameras do not get tired and do not misseven the smallest anomaly. For regulators,
the trend is toward increased stringency.
Recently, the FDA set the bar even higher
for injectable drug manufacturing by
calling for implementation of improved
specifications, increased inspection,and improvement in analytical andinspection techniques.
Meanwhile, the creators and end usersof large molecule drugs are relying onparenteral drug packaging companies to
get as close to zero defects as possible.
Anytime there is a market recall, it is
not just a financial liability, but a hugerisk to the reputation of pharmaceuticalcompany partners and to the health of
waiting patients.
The harsh reality? Contamination will
always be an issue, and so “zero defects”
represents a truly aspirational or idealistic
goal; we in the industry must tackle thisengineering challenge head on so that we
can at least get as close as possible.

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16

 S p o ns o r e d F e a tu r e

Focus on Quality– and the Rest
Will Follow
Amgen developed the MultiAttribute Method (MAM) toobtain high-fidelity understandingof the quality of its own biologics– which is raising the bar acrossthe biopharmaceutical industry
Da Ren is Scientific Director, Jette Wypych is
Executive Director, Attribute Sciences, andTing Song is Senior Scientist, all at Amgen,
Thousand Oaks, California, USA.
Amgen has always had one overriding
goal: to serve patients. With an emphasison diversity, collaboration and, above all,quality, the company aims for continuous
improvement in every sector of thebusiness (see “Building a Culture of
Innovation.”). “In fact, quality was theforemost driver behind the developmentof multi-attribute method (MAM),” says
Amgen’s Scientific Director, Da Ren. “Wewanted to develop a holistic control tool
applicable along the entire bioprocess,including release and stability testing.”
Using a whole set of conventional
characterization and control methods,
which of ten assess each attributewith a different assay, did not fit thebill. Enter high-resolution accurate-mass(HRAM) mass spectrometry (MS) and its
potential to directly identify andquantify relevant attributes
in a single assay.

“The old view was that ‘the process isthe product’ – but we turned that on
its head by defining the product by its
critical quality attributes (CQAs) and theirassociated desired levels, which is the“blueprint” for designing the processes tomanufacture the most safe and efficacious
product. In other words, we start withthe final desired product in mind, and theprocess design follows,” says Jette Wypych,
Executive Director of Attribute Sciences.
MAM is an ideal analytical tool to enable
this approach, as MAM has the capabilityof measuring a large number of posttranslational modifications in the productat the molecular level.
Challenges and rewards
The original concept of MAM wasconceived by Izydor Apostol at Amgenin 2010. Richard S. Rogers (then memberof the Amgen MAM team) and othercolleagues went on to demonstrate thepotential of MAM and published Amgen’s
work in a scientific paper in 2015 (1). Though
MAM showed clear scientific and technicalpromise, the challenge of driving the
project from concept to an accepted QC
release tool in a GMP setting still lay ahead;channeling the significant power of HRAMMS into a method capable of robustly,
accurately, and routinely measuring CQAs
relevant to safety and efficacy in a cGMP
environment. This process was no small
task. “The transition required and improved
implementation and robustness analysis,”says Ren. Other constraints included theneed to control costs (without resorting
to inadequate instruments) and minimize
footprint (so that multiple instruments could
fit in a single QC lab).
Solving these problems, says Ren,required collaboration across multiple
teams and departments – and the need
to work closely with instrument

manufacturers. But the results
have been extraordinarily gratifying. “In
addition to quantitation of predefined
CQAs, MAM’s new peak detection
capability is outstanding,” says Ren. “Itis capable of detecting any new peak (apotential impurity that is not predefined)
in the sample against a reference standard.
The high resolution and accurate mass
features allow it to detect co-eluting
peaks with very small mass shifts, such as
those associated with deamidation, whichconventional methods and low-resolution
instruments simply cannot identify.”
Another issue faced by the team
involved data processing and presentation– the volume of information generated
by MAM was incompatible with a visual
output. Again, the cross-functional, teambased approach triumphed: today’s MAM
uses a bespoke computational algorithm
that evaluates observed masses frameby frame, assigns them to the previously
identified attributes, and alerts users toabove-threshold new peaks.
However, the team was well awarethat intelligent solutions are of little use
if operators cannot apply them in a highthroughput environment. “The technology
had to be used by QC specialists, not mass
spec specialists,” says Wypych. “And thatmeant robust methods and user-friendly
software were essential.”
It often takes a lot of effort to makesomething feel easy, comments Ting
Song, Senior Scientist at Amgen, but theteam was committed and motivated. The
resulting user-friendly and automatedsystem was able to rapidly process large
volumes of data into actionable information.
“The best part,” says Song, “is hearing my
QC colleagues saying how easy it is to use!”
For Wypych, one of the most rewarding
moments was seeing MAM fulfil therequirements for a release and stability tool;
namely, user-friendly, accurate, quantifiable
CQA monitoring and new peakS p o ns o r e d F e a tu r e

detection. “At that point, I knew we hada scientifically defensible method that we
could apply and implement in release andstability testing and share with regulators.”
Perfect timing, perfect fit
MAM is becoming increasingly accepted
as a better testing strategy within theindustry; several biopharmaceuticalcompanies have been evaluating it in
QC, and others are planning to do so.
The trend is reflected in the growth of the
MAM Consortium (www.mamconsortium.
org), a network co-led by Rogers andRen. The Consortium – which has over
300 members, including pharmaceuticalcompanies, regulatory agencies, CDMOs,
and instrument/software vendors – meets
monthly to discuss MAM and related mass
spectrometry technologies.
“At first, many people in the industry
questioned the utility of MAM for the QC
environment,” says Ren. “But now people
don’t ask why they should use MAM; instead,they ask how to implement the technology.”
The credibility of MAM has been further
enhanced, says Wypych, by technicalpublications from regulatory agencies (2),
who have acknowledged the importanceof MAM’s ability to detect new peaks –and thus unexpected product degradants
or impurities.
MAM also fits perfectly with ICH
Quality by Design (QbD) guidelines.
“ The abilit y to char ac ter ize andquantitatively measure CQAs and guideprocess development to obtain target
levels of CQAs is essential for QbD
in biologics,” says Wypych. An added
benefit for sponsors and regulators
alike was MAM’s flexibility. If it becomes
necessary to monitor additional CQAs
for a given product, MAM can easily
accommodate the change. Companies
that rely on conventional methods, bycontrast, would need to add a new
assay to the release specifications.
“Industry and many regulatory bodies
now accept that MAM can measurecomplex challenges involved in MAM
development. “We have a lot of highly
talented people – but they are also teamplayers and adept at cross-functional
collaboration.” The open, supportive
culture contributes to the collaborativeenvironment within Amgen, says Ren.
“Everybody helps each other and, in theend, the best ideas prevail!”
Ren also pays tribute to external
collaborators. “ When combining
different components in a brand-new
system, vendor support is critical.”Working closely was essential to ensure
acceptable and usable technology
outcomes, says Wypych. “We had
to develop technical QC solutions
that would also be acceptable toregulators. Putting MAM into the cGMP
environment raised issues regarding
robustness, functionality, consumables
and software requirements – addressing
them required close collaboration withthe vendor. And that’s why choosing
a vendor with a long-term view isimportant – biomanufacturers want toavoid the need to change instrumentation
every few years.”

Building
a Culture of
Innovation
How is it that some companies
always seem to be at the leading edgeof technology development? Amgen
attributes its success to a consistent,
sustained approach: employ talented
individuals, place them in a supportive
corporate culture, and encourage them
to focus on quality. The evolution of MAM
from concept to QC tool is a testament
to what this philosophy can achieve.
Ren notes that employee diversity
also plays a key role. “People of different
backgrounds approach the same problem
in different ways – and this inspires
innovation.” Wypych agrees and notes
how Amgen’s culture gives anyone –from any background – the opportunity
to grow and blossom.
A second ingredient in the Amgenrecipe for success is teamwork. This,says Ren, was fundamental in solving thean almost unlimited number of specific
CQAs related to post-translational
modifications at the molecular level,
which are deemed relevant to safety andefficacy,” says Wypych.
By exploiting the known advantagesof HRAM-MS, Amgen has changed
the QC testing toolkit forever. “Now,
we can monitor CQAs in an end-toend approach,” says Ren. “We identify
CQAs during characterization and then– following QbD principles – monitor
and control them from development torelease.” And this – just as Amgen always
intended – is bringing about the desired
improvements to product quality.

 17

References
1.

RS Rogers et al, “Development of aquantitative mass spectrometry multiattribute method for characterization,
quality control testing and disposition of
biologics,” MAbs, 7, 881 (2015). PMID:
26186204

2.

S Rogstad et al, “Multi-attribute method for
quality control of therapeutic proteins,” Anal
Chem, 91, 14170 (2019). PMID: 31618017

3.

D Ren, “Advancing mass spectrometry
technology in cGMP environments,” Trends
Biotechnol (2020), In Press

To find out more, visit https://themedicinemaker.com/amgenmam
thermofisher.com/learnMAM

18

Feature

o n

t h e

By Maryam Mahdi
A sh a red c ont i nent a l v i sion i s d r iv i ng ch a nge i n A f r ic a .
O ver t he nex t fou r dec ades, mem bers of t he A f r ic a n Un ion
hope to ach ieve t he goa l s out l i ned i n Agenda 2 0 6 3 –t he bluepr i nt for t ra n sfor m i ng A f r ic a i nto a globa lp owerhouse. But t he road to ec onom ic suc cess a nd t hec ont i nent ’s g row t h i s l it tered w it h hu rd les t h at c a n on ly beclea red i f c ompa n ies ac ross i ndus t r ies play t hei r pa r t .
W h at does t h i s mea n for t he ph a r m aceut ic a l i ndus t r y ?
Here, ex per ts g ive t hei r t a ke on ph a r m a’s role i n A f r ic a’s
f ut u re a nd d i sc uss how c ompa n ies c a n overc ome bot hh i s t or ic a nd new ch a l lenges.

20

FeatureS T E M M I N G
t h e

B R A I N
D R A I N
C a n A f r ic a n profe s sion a l s b e p er s u ade dt o pu r s ue opp or t u n it ie s at home?
By Kelly Chibale
Africa is suffering from a skills exodus. Reports estimate that one
in three skilled professionals from Africa now live and work in thedeveloped world (1). This loss of talent has serious ramifications,
not only for the continent’s economy but also for the growth of
its innovative R&D pharmaceutical industry. Africa imports
many of the drugs it consumes and has yet to cement itself as acenter for R&D. With such heavy reliance on foreign products,
how will the continent move toward a more independent future?
The answer lies in dismantling the negative perceptions that hold
Africa in a vicious cycle of dependence. For the most part, Africa
is viewed through the lens of poverty – and its high disease burden
makes it appear like foreign medical innovation is the best optionthat African governments have to offer patients. Though there issome truth to this notion, it, unfortunately, adds fuel to the fires ofafro-pessimistic sentiment. Many pharmaceutical stakeholders bothwithin and outside the continent have yet to see African innovationand the benefits it can bring to patients. And without evidence
of innovative pharmaceutical prowess, Africa cannot attract theexpert workforce needed to build its pharmaceutical infrastructure.
But even if there were examples of African innovation – andthere are – the idea that foreign goods are somehow superior seems
hardwired. For example, if asked to choose between a pair ofleather shoes made in Italy and a pair made in Zambia, how many
people would opt for shoes made by an African craftsman – even
if the quality was better? Shoes may seem a trivial example, butthey highlight a more serious issue. Even if African companies
were developing more high-quality medicines, would patients athome and abroad feel confident in using them?
Though it is impossible to say with certainty how people will
respond to Africa’s future innovative pharmaceutical offerings,
stakeholders from across the continent have the opportunity toconfront the perceptions that plague the industry. It will requirea multifaceted approach – but, from my own experience, I’ve
realized that we all have a role to play in creating a positive
perception of the industry.

A

j o u r n e y

h o m eAs an African academic, I have faced the challenging decisionof leaving home to pursue educational opportunities. Like manyothers, the attraction of advanced facilities and thorough training
pushed me to pursue international education. My doctoral studies
at the University of Cambridge were invaluable – not only was I able
to pursue my research interests in a way that would not have beenpossible in Africa, but I also had the chance to build my network andwork alongside individuals at the cutting edge of science. Though I
had every intention of returning to my native Zambia once my studies
were completed, I found that, without the appropriate infrastructure
for research and development, my options would be limited.
The frustration I felt wasn’t unique – many other African
students and postgraduates have found themselves in similar
situations. I chose to return to help support the academic careersof young professionals and launch a drug development center,
H3D, at the University of Cape Town. The center focuses on
the discovery of potential medicines for disease indications
that predominantly affect Africans and developing technology
platforms that allow customization of medicines to African
patients’ needs. Though my decision has brought much value tomy life, those who choose different paths cannot be blamed formaking the decisions most appropriate for their professional goals.
Nonetheless, we found it difficult to fill positions in the center’s
early days. We were embedded into the University of Cape
Town’s ecosystem and our expert team had a wealth of industry
experience – but the local professionals we wanted to hire simply
weren’t there. Advertisements for postgraduate positions, forexample, were answered by international applicants. Though
it would have been wonderful to have greater South African
representation, we found that the people who did apply wereattracted to the center because we had managed to create an
R&D environment like those found in Europe and the USA.
As the center matured, we were able to showcase ourcapabilities as a biopharmaceutical operation. This, in turn,
attracted a more diverse pool of candidates, and we now have
many talented individuals of African heritage working with us.
Ultimately, having the right infrastructure in place helps build
influence. And that helps drive change not only at the local levelbut also on a regional and international scale.

A d v i s i n g
g o v e r n m e n t
The inability to retain talent across the continent has caused some topoint the finger at governments. “Are our ruling bodies doing enoughto prevent the mass departure of skilled professionals?” It’s a question

Far right: Kelly Chibale

that arises often. But such a complex issue has no simple answer. I
believe that the responsibility for preventing the brain drain does notlie solely with our political institutions. Governments across Africa
are investing in the training of their citizens, often sending people
abroad to study. But if those who benefit from this funding choose
not to come back, there is no return on investment. This, again, feeds
into the cycle of dependence that prevents us from reaching our fullpotential. People rightly have the choice not to return – but if Africa
is to develop a drug discovery and manufacturing ecosystem thatrivals those elsewhere, it needs a critical mass of talent.
The lack of innovative pharmaceutical manpower also means that
African governments haven’t seen many scientists and entrepreneurs
setting up their own organizations. And despite investing in young
talent, they often fail to see the importance of allocating resources to
new R&D ventures. Will governments get on board when we canprove the benefits of these operations to society? I believe they will.
At H3D, our research on malaria, tuberculosis, and antimicrobial
resistance has seen us develop clinical candidates, create jobs, andwork with leading figures from big pharma – and it has made theSouth African government one of our greatest supporters.
Though it is risky, I advise others to take the chance andlaunch their own R&D facilities. Doing so will force our leaders’attitudes to change and could help build a robust innovative
pharmaceutical ecosystem across the continent. We have thepower to influence change, but we must take opportunities to
do so as they arise. We owe it to future generations of scientists.

F o r a b e t t e r
t o m o r r o w
African pharma has a promising future. More than ever, companies
who take risks are establishing themselves as serious partners forinternational organizations. H3D recently partnered with the African

Academy of Sciences, Bill and Melinda Gates Foundation, and the
Medicines for Malaria Venture on “Grand Challenges Africa,” ascheme that encourages innovation to address the continent’s healthand development needs. The project aims to expand the drug discovery
community across Africa by, amongst other things, linking African
academic institutions with partners from big pharma – crucially
important for the future of our industry. The more R&D centers wehave with advanced capabilities and robust infrastructure, the greater
our impact. It won’t be easy to achieve, but it is within our reach.
I am also excited by the possibilities that regulatory harmonization
will bring to the community. At the regional level, regulatory bodies
are improving access to much-needed medicines. In southern
Africa, for example, ZAZIBONA brings together regulators from
Botswana, Namibia, Zambia, and Zimbabwe. The benefit of thistransnational collaboration is that, once a drug has been approved in
one country, it is deemed fit for the rest. This ensures uniformity of
dosing and pricing and ultimately helps improve the perception of ourpharmaceutical industry among patients and external stakeholders.
At the moment, a continent-wide regulatory authority is
not a reality. But, as an industry, we are getting closer to thepoint where we can speak with a unified voice. Though we still
face challenges, we are proving ourselves willing and capableof managing them. I can only hope that these positive steps
forward will give some of Africa’s best and brightest pause forthought when making decisions about their professional futures.
Kelly Chibale is the Neville Isdell Chair in African-centric Drug
Discovery & Development and South Africa Research Chair in
Drug Discovery
Reference1.

African Union, “Pharmaceutical manufacturing plan for Africa businessplan” (2012). Available at: https://bit.ly/32Ughx3.

www.themedicinemaker.com

22

Featuret h e

H O U R H A S
A R R I V E D
C a n t he A f r ic a n Me d ic i ne s A genc ymobi l ize q u ic k ly enough t o r e sp ond t o
g r ow i ng he a lt hc a r e is sue s ?
By Sarah Adam and Cyntia Genolet
With SARS-CoV-2 infections on the rise, health systems across
Africa are facing increasing pressure. Though researchers areworking around the clock to unlock the science to help treat thedisease, regulators must play a key role in ensuring the rapid – yetsafe - development of treatments and vaccines. But Africa faces asignificant stumbling block in its ability to address the pandemic:varying regulatory systems across the continent make it difficult tomount appropriate responses. Efforts for regulatory harmonization
have been underway for the past decade, and this work has neverbeen more important. Parliaments are now calling for approval toestablish the African Medicines Agency (AMA) (1) – a proposed
regulatory authority that would oversee the harmonization andconvergence of medical and pharmaceutical regulation for African
Union (AU) member states. Recently, Margaret Agama-Anyetei,
Head of Health, Nutrition, and Population at the African Union
Commission, urged the AU to ratify the treaty for the formation of
the AMA before its next assembly in February 2021. The benefit, she
explained, was that “instead of talking to eight regional economic
communities or 55 countries, there would be one organization
speaking on behalf of the continent (2).”The AMA is expected to be essential in enabling patients toaccess safe, effective, high-quality, and affordable drugs, treatments,and vaccines. The main purpose of the agency will be to coordinate
ongoing regulatory systems, provide guidance, and to foster relianceand regulatory harmonization across the continent. These aims are
crucial to responding to public health threats, such as COVID-19.
They will also help thwart the dangerously large and thriving
market for falsified medicines. The unregulated sale of fake drugs
is responsible for tens of thousands of premature and unnecessary
deaths among African patients who unwittingly fall prey tocounterfeiters. The WHO stated that the continent accounted for
42 percent of all counterfeit drug reports between 2013 and 2017 (3).
With the need to manage such significant issues, most people
are in agreement that a continent-wide body will coordinate
the work already being done by national regulatory authorities(NRAs) and allow the pharmaceutical industry to make goodon its promise to leave no-one behind. But with the disruption
caused by the pandemic, how near are African governments torealizing their goal?

I n i t i a t i v e s

n o w

The pandemic has slowed down the process of ratifying the AMA
in some countries because it has become the sole major issue
confronting and preoccupying national authorities. However,“We are making good progress,” said Margareth NdomondoSigonda, AUDA-NEPAD’s Head of Health Programmes.
She explained that the results already achieved by the African
Medicines Regulation Harmonization initiative (AMRH) have
proven “key in building robust regulatory systems in Africa,
including the establishment of the AMA (4).”Africa’s national regulatory authorities (NRAs) have already
faced many challenges that come with infectious diseases – theHIV-AIDs crisis, Ebola and malaria have all tested capabilities.
However, with COVID-19, NRAs can now benefit from virtual
working methods that the pandemic has, in a matter of months,
made the new norm for many. Using modern digital infrastructure,
we hope to accelerate the implementation of good and efficientregulatory policies and practices and make the AMA one of themost efficient and modern regulatory systems in the world.
Africa still has some ground to cover in closing the regulatory
gap. With this being said, the AMA should be empowered tofoster unprecedented coordination, partnership, and sharing thatwe’ve all witnessed during this pandemic, and enjoy the benefitsof shared regulatory experience. There is scope for expanding thecurrent expedited processes to facilitate regulatory applications
for new drugs, variations, and clinical trials used for COVID-19
treatments and vaccines – without, of course, cutting any corners.
We’re talking about priority and fast-track reviews, as well as
temporary authorizations.
Similarly, the pandemic has underlined the vital need to ensure thecontinuous supply of existing medicines that patients urgently require.
There are a range of ways that regulators like AMA can facilitate theprocess, including expediting procurement, helping with the securityof the supply chain, and fighting falsified medicines.
Elsewhere, the pandemic has, fortunately, prompted a growing
awareness of the need for coordinated regulation; 17 countries
out of the 55 have now signed the AMA treaty, demonstratingthat they see the agency’s work as vital. Ghana and the Seychelles
ratified the AMA last month; just after three other countries –Burkina Faso, Mali, and Rwanda – did the same.
Today, there are various coordinated national efforts to combat
and mitigate the effects of COVID-19 led by the Africa Centres
for Disease Control and Prevention (Africa CDC) Africa Task
Force for Novel Coronavirus (AFCOR) and WHO Afro, inSarah Adam is Headof Regulatory Science
Policy, Africa

Cyntia Genolet is
Head of Health
Systems andAfrica Policy

collaboration in particular with the African Vaccine Regulatory
Forum (AVAREF) and the Africa Medical Devices Forum(AMDF). In addition, the AU launched a new multi-stakeholder
initiative via the Africa CDC: The Consortium for COVID-19
Vaccine Clinical Trial (CONVACT). It aims to get more than
10 late-stage vaccine clinical trials up and running as early as
possible on the continent by bringing together global vaccine
developers and funders, as well as African organizations that canfacilitate clinical trials.

S of a r ,

s o . . .

Though the AMA is not yet a reality, other pharmaceuticalbodies are working to address current health threats. AVAREF
and other stakeholders have been successfully working together,often sharing data and collaborating on new initiatives –examples of this are the clinical trial authorizations (CTAs) forhydroxychloroquine and ritonavir involving 14 countries in an
unprecedented joint review. If expedited, CTA could be deliveredin just over 30 days and, in an emergency, 10-15 days comparedwith the conventional 6-12 months if national regulators go italone. But this approach is just one piece in the complex jigsaw toremove potential inefficiencies and delays resulting from repeatedsteps and duplication of work.
Thankfully, progress in information sharing and implementation
is being made. Our industry’s commitment to “define the best
science-based regulatory strategies for ensuring the availabilityof COVID-19 medicines and vaccines” is being realized andwhether or not the AMA is approved before the AU Assembly
meets again, pharma is dedicated to supporting those most in
need. Leaning on decades of innovation and experience, theinternational community will be able to contain and find real
solutions to the COVID-19 pandemic together.

Sarah Adam is Head of Regulatory Science Policy, Africa, andCyntia Genolet is Head of Health Systems and Africa Policy,
both at IFPMA
References1.

African Union, “Treaty for the Establishment of the African Medicines
Agency” (2019). Available at https://bit.ly/3jkbFHf.

2. S Jerving, “African Union needs more country support to launch the African
3.

Medicines Agency” (2020). Available at https://bit.ly/3cMN77l.

Abi Millar, “The rise of fake medicines in Africa” (2020). Available athttps://bit.ly/3cJzDcI.

4. Mail & Guardian, “A decade of the AMRH initiative” (2020). Available
at https://bit.ly/3n89ol6.

www.themedicinemaker.com

24

FeatureC R I S I S
P O I N T
How a r e A f r ic a n c ou nt r ie s h a nd l i ng t he
C OV I D -19 out br e a k ?
Over the last 9 months, COVID-19 has claimed hundreds ofthousands of lives – and thrust the pharmaceutical industry into
the spotlight. The sector is now under pressure to deliver safe andeffective solutions to an unprecedented problem. And though theworld’s eyes may be on the West when it comes to the developmentof new therapeutic options, pharmaceutical industries in other partsof the world must also evolve to manage the fallout from the disease.
African countries have not experienced the huge death tolls ofsome of the world’s most developed economies, but concerns about
their ability to manage the long-term effects of the pandemic
remain. Here, Paul Tanui, Senior Programme Officer – TechnicalSupport at the African Union Development Agency - NEPAD,
and Arthur Minsat, Head of the OECD Development Centre’s
Europe, Middle East, and Africa unit, outline how the pandemic
is affecting the continent’s pharmaceutical industry and consider
opportunities for change.
What is the current state of African pharma?
Paul Tanui: Some estimates indicate that over 70 percent of Africa’s
pharmaceutical needs are met through importation. A number ofAfrican countries rely entirely on imports for their pharmaceuticalsupply – but many are working to change this. In 2007, for example,
the African Union Conference of Health Ministers mandated thedevelopment of the Pharmaceutical Manufacturing Plan for Africa(PMPA) – a roadmap to improved pharmaceutical capacity. As a
direct result, the African Medicines Regulatory Harmonization(AMRH) initiative was established. Since its inception in 2009, it
has helped build a regulatory environment for the development ofa more robust pharmaceutical sector.
Today, there are regional pharmaceutical associations inSouthern, Eastern, and Western Africa, as well as a continentalorganization for regulatory issues: the Federation of African
Pharmaceutical Manufacturers Associations (FAPMA). In
alignment with AMRH, these industry associations and
FAPMA provide a voice to promote Africa’s pharmaceuticalindustry. They interact as a common front with governments,
multilateral institutions, and international procurement agencies
to help push African pharma forward.
Arthur Minsat: The local pharmaceutical sector is burgeoning
in Africa and, as Paul stated, most pharmaceutical goods areimported. Local manufacturers produce about 25-30 percent ofpharmaceuticals and less than 10 percent of medical supplies thatare on the African market. Over the 2016-18 period, only South
Africa, Egypt, Kenya, and Morocco (in order of magnitude)
exported more than $100 million, while importing about $5.8
billion in medicinal and pharmaceutical products. More thanhalf (57 percent) of Africa’s official exports in pharmaceuticalproducts are directed to neighboring African countries. Producing
pharmaceuticals locally on the continent is key to better fight local
diseases, increase resilience, and advance the African Union’s
Agenda on productive transformation. Too few multinational
pharmaceutical enterprises invest locally in Africa. Policies
can continue to improve the incentives for better investment,
and working together regionally is paramount. Here, theimplementation of the African Continental Free Trade Area
(AfCFTA) offers larger economies of scale by tackling the issue offragmented markets for the local production of generic medicines,or by pooling the procurement of medicines.
How is COVID-19 affecting Africa?
Minsat: The crisis is affecting African economies through many
interdependent channels. The African continent is very dependent
on the international economy: commodities earnings slumped,
trade in goods and services became disrupted, and external financial
inflows fell drastically, in particular remittances from Europe,
foreign direct and portfolio investment. Many economies sufferedfrom massive capital outflows. COVID-19 led to postponing theimplementation of the Continental Free Trade Area, thus limiting
the expansion of internal trade. Countries have to run fiscal deficits,by spending more to mitigate the economy, health, and social
impacts, while revenues slumped in many countries. The risk ofa debt crisis becomes more acute in some countries. As a result,
Africa is facing its first recession in 25 years, with various GDP
forecasts ranging from -2.1 percent to -4.9 percent.
Africa’s pharmaceutical value chain is disrupted through threemain channels. First, it suffers from lower access to medicine
supplies owing to the shutdown of manufacturing facilities
globally. African countries import much of their pharmaceuticals
and protective equipment from Europe (51.5 percent of total
imports), India (19.3 percent) and to a lesser extent Switzerland(7.7 percent), China (5.2 percent), the United States (4.3 percent)and the United Kingdom (3.3 percent). Second, heightenedcompetition to access basic goods (e.g. masks) made themless available and more expensive for many African countries.
Globally, about 40 countries implemented bans on the export ofcertain drugs, pharmaceutical ingredients, or medical equipment(so as to be able to tackle domestic demand), leading to shortages
in import-dependent countries. Third, macro-economic channels(in particular currency devaluation and capital outflow) have also
impacted the sector.

Arthur Minsat, Head of the OECD
Development Centre’s
Europe, Middle East, and Africa unit

Paul Tanui, Senior
Programme Officer –Technical Support
at the African
Union Development
Agency - NEPAD

On the bright side, the COVID-19 crisis also gave unprecedented
impetus for developing health and pharmaceutical services online
and locally. Public and private pan-African cooperation basedon new technologies allowed countries to negotiate better prices
for medical supplies with certified global suppliers. The Africa
Centres for Disease Control and Prevention – in collaboration
with Janngo (a pan-African tech startup), Afreximbank, and 20
international partners and foundations – has launched a pooled
digital purchasing platform – the Africa Medical Supplies
Platform – to support African governments ordering diagnostics
and medical equipment on the global market. Afreximbank will
facilitate payments, and logistics partners (including African
national carriers and global freight forwarders) will expedite

delivery. In the longer term, supporting the digital transformationof African economies could foster innovative solutions in thehealth and other sectors, and accelerate the economic recovery.
How well is Africa coping with the pandemic?
Tanui: In my opinion, though there have been difficulties, theNational Regulatory Authorities (NRAs) across Africa have
responded quickly to the pandemic. NRAs have a key role inensuring that approved products meet quality, safety, and efficacy
standards. Throughout this period, they have ensured appropriate
access to diagnostic tests and treatment. They’ve also foundsupport from technical committees, like the African Medical
Devices Forum and the African Vaccine Regulatory Forum, whohave provided guidance on clinical trials.
What about access to essential medicines?
Tanui: In addition to responding to COVID-19, NRAs arecontinuing with their regular activities – ensuring faster approvalof products used in other diseases and contributing to the optimalfunctioning of Africa’s healthcare systems.
Minsat: The informal workforce is the most vulnerable. About
82 percent of African people live without social protection, andthe majority pays out-of-pocket healthcare. Data collected from
more than 45,800 respondents across 34 African countries over
2016-18 highlighted that more than half (53 percent) of Africans
went without needed medicines or medical treatment at least once
during the 12 months preceding the survey. This demonstrates the
www.themedicinemaker.com

26

FeatureA F R ICA

I N

billion is the value
African pharma is
expected to reachin 2022N U M BE R S

of the worldwide
pharmaceuticalmarket is accounted
for by Africancountries

drug makers
across thecontinent
The countries with thestrongest growth between
2011 and 2016 included:
Morocco 6%
South Africa 8%
Algeria 9%
Botswana 12%
Nigeria 13%
Egypt 14%
Kenya 17%COV I D -19

I N

A F R ICAAt thetime ofwritingurgency to expand health and social protection coverage throughthe development of national social protection action plans toachieve universal protection and improve its quality.
What lessons can be learned from other regions’ managementof the crisis?
Minsat: Africa’s epidemiology curve is at an earlier stage thanmany other parts of the world, which means African policymakers have been able to learn many lessons to handle thepandemic better. Most African governments reacted more quickly
to prevent the pandemic from spreading. Many governments
also provided rapid support to the local economy, in the formof macro-economic and monetary interventions, lockdowns,
e-schooling, support to enterprises, entrepreneurs, and cashtransfers. However, we also saw the limits of lockdown and otherpolicies in Africa, notably due to the size of the informal sector.
Since late April, the necessity to keep the economy afloat led
countries like Cameroon, Mauritius, Niger, Rwanda, and South
Africa, to ease containment measures gradually, even though theinfection curve had not yet reached its peak. The scope of thepandemic remains uncertain as cases are likely underreported
and data collection varies across countries. By September 2020,
the number of confirmed COVID-19 cases in Africa had risen
to a million with over 50 percent in South Africa, and caused
about 30,000 deaths.
It’s crucial to recognize the importance of international
cooperation in mounting an appropriate response.
•

countries
are affected

1,175,267
cumulative cases

25,825deaths

Sources1.

2.
3.

WHO, “COVID-19 in the WHO African Region” (2020). Available

at: https://bit.ly/34Z6Yyt.

IQVIA, “Differentiate and win in the African pharmaceutical market”(2019). Available at: https://bit.ly/3jOQJs6.

International Finance Corporation (IFC), “Private Sector

Pharmaceutical Distribution and Retailing in Emerging Markets”(2017). Available at: https://bit.ly/3gTMcm8.

•

In the immediate term, the international community
should provide adequate support to the healthcare sector,
its workers, and social infrastructure. Major producersof medical products should refrain from export bans andother trade policies that fragment production and increase
the costs of essential supplies for import-dependent
countries. Debt cancellation or even restructuring may
also become imperative to enable countries to respond andcontinue to conduct counter-cyclical fiscal policies.
In the medium-term, large domestic and international
resource mobilization should be prioritized and coordinated at the continental level to support healthsystems. Most African Union countries are still far frommeeting the 2001 Abuja declaration target to allocate
at least 15 percent of their annual national budgets on
health. By 2011, only Tanzania had hit the target while
11 countries had cut their health expenditures. If African
nations can develop mechanisms for early, synchronize
economic policy with social and healthcare policy, anddevelop the capacity to monitor and evaluate thesepolicies, it should lead to a quicker response to the virus.

What can be done to support the continued growth of theAfrican pharmaceutical industry?
Minsat: The pandemic is exposing Africa’s reliance on external
suppliers in meeting its internal demand for medicines. However,African pharmaceutical and manufacturing companies are
stepping up to produce critical supplies amid global shortages,
disrupted supply chains, and export bans. African leaders can
now decide which production capabilities are essential for thecontinent’s health security going forward and provide thoseindustries with the support they need to survive and develop.
•

Countries should use this opportunity to accelerate theimplementation of the Pharmaceutical Manufacturing
Plan for Africa (PMPA) and establishment of the African
Medicine Agency (AMA) by prioritizing investment for
regulatory capacity development; pursuing convergenceand harmonization of medical products regulation inregional economic commissions; and allocating adequate
resources for AMA.
Accelerating progress towards the next phases of the
AfCFTA, particularly the agreements on investment,competition policy, and e-commerce, will create anenvironment conducive to establishing regional value
chains in pharmaceuticals and will be critical to position
the region as an attractive investment destination
as the regional and global economy starts torecover.
I am confident in the bright future of the African
pharmaceutical industry, given the high demand, therenewed political momentum, and the ingenious spirit ofAfrican entrepreneurs.

INSPIRINGSUSTAINABLE
CONNECTIONS

Tanui: The PMPA business plan has identified several incentives
that will support the growth of the pharmaceutical industry.
These include:

World Forum and Leading Showfor the Process Industries

•

•
•
•
•
•

supporting affordable financestrengthening regulatory systems and harmonization
enhancing the quality and efficiency of production
promoting technology transfer initiatives
developing enabling policy and skilled human resources

Young scientists should also be encouraged to pursue careers
in NRAs and the pharmaceutical industry. As they become
experts in QC, GMP, and industry, we will have a wealthof talent to help guide our future trajectory. But seasoned
professionals also have a role to play; their mentorship of
upcoming regulatory professionals will be vital for developing
skills and knowledge.
I can only express my optimism for the future of our industry.

ACHEMA is the global hotspot for industry experts,
decision-makers and solution providers. Experience
unseen technology, collaborate cross-industry andconnect yourself worldwide to make an impact.

#ACHEMA21
14 – 18 June 2021
Frankfurt, Germany
Are you ready?
Join now as speaker or exhibitor!
www.achema.de

28

 S p o ns o r e d F e a tu r e

strand containing typically

What analytical technologies are used for

Understanding the 19 to 23 nucleotides.
the characterization of oligonucleotides?
Each class of oligonucleotide comes with There are several, including (5):Oligonucleotide
its own advantages and limitations. For
example, siRNAs can be more potent • Ion pairing reversed-phase (IPRP)
Landscapethan ASOs for some targets as theychromatography – the mostThough attracting growing interestin drug development circles,
oligonucleotide-based therapeutics
present manufacturers withspecific processing andcharacterization challenges
Oligonucleotide-based
ther apeu tics r epr esent
the changing face of drug
discovery and development.
Designed to prevent or
modulate the translationof a specif ic gene, these
therapies have the potential
to tackle previously undruggabletargets and could set the tone for the
future of personalized medicine. As ofJanuary 2020, the FDA has approved 10
oligonucleotide drugs, but the numberof therapeutics moving into and throughthe development pipeline is blossomingwith six of these oligonucleotide drugs
approved between 2016 and 2019 (1).
Here, Genentech associate scientist
Alexandre Goyon outlines the pros andcons of currently available techniques
for characterization of oligonucleotides– and considers what the technologies
of tomorrow might look like.
What are the main typesof oligonucleotides?
When it comes to pharmaceuticalclinical development, there are two maincategories of oligonucleotides:• Antisense oligonucleotides (ASOs)– single-stranded, typically 10 to 30
nucleotide units• Small interfering RNAs(siRNAs) – double-stranded, eachinvolve different enzymes for the RNA
cleavage mechanism of action, i.e. RNase
H1 for ASOs and Ago2 for siRNAs, but
siRNAs can lack stability and effective
strategies must be employed to ensure
their delivery to target sites. Lipid
nanoparticles can be used as carriers
to transport siRNAs to the targetcell’s cytoplasm and improvesiR NA s tabilit y agains t
ribonucleases. siRNAs canalso be conjugated to aligand called GalNAC fortransportation to the liver.

What’s the regulatory view
on oligonucleotides?
Oligonucleotides are considered small
molecules since they are manufactured bysolid phase synthesis. However, as mentioned
by Mohan Sapru of the FDA, there is no
ICH and FDA regulations that specificallyaddress the quality expectations of thediverse oligonucleotide products (2).
Discussions about legislation are ongoing!
Some of the challenges are addressedin two industr y-led white paper s
produced by a collaborative team from
Ionis Pharmaceuticals, AstraZeneca,
GlaxoSmithKline, Sanofi-Aventis, Janssen
Pharmaceutical, F. Hoffmann-La Roche,
Biogen and Novartis in 2017 and 2020(3,4). In the papers, the authors issue
advice on myriad chemistry challenges
affecting oligonucleotides and encourage
information sharing and chemistry,
manufacturing, and control (CMC)
harmonization strategies between
research groups to reduce the risks thatthese therapies can potentially poseto human health. They have sparked
much discussion about the next steps
regulators could take.

common method for the analysisof oligonucleotide impurities. It
can separate shortmers, longmers,
and phosphodiester (PO)
impurities, among others. It canbe coupled to mass spectrometry
in particular when combining thealkylamine ion-pairing agent withhexafluoroisopropanol (HFIP).
• Anion exchange chromatography– this can also be used to separate
impurities, but the large amounts
of non-volatile salts involved
prevents its direct coupling to mass
spectrometry, which is one reason
why IPRP is more widely used.
• Hydrophilic interaction
chromatography (HILIC) – there
have been surprisingly few publishedreports about the use of HILIC
for oligonucleotides. HILIC has theadvantage of allowing direct coupling
to mass spectrometry without using
ion-pairing agents. There is a great
diversity of stationary phases, which
could provide orthogonal separation
to IPRP and thus be complementary.
• Size exclusion chromatography –this method is used with doublestranded oligonucleotides such as
siRNAs in order to determine thenumber of single strands in the
double-stranded product using
non-denaturing conditions.
How would you like to see analyticaltechnology in this area improve?
The first oligonucleotides were investigatedabout 30 years ago and it is only in recent
years that the industry’s interest in themhas been renewed in part due to theadvances in oligonucleotide chemistryengineering and delivery systems. In my

Oligonucleotides:
Perfecting Purification
By Manuela Sevilla, technicalexpert at Tosoh Bioscience
For the companies
pursuing oligonucleotidebased ther apies, therelative complexity of theirsynthesis can pose purification
challenges. Oligonucleotides areshort DNA or RNA molecules that are“grown” via the addition of nucleotidegroups in a series of solid-phase
synthesis cycles – a failure in this process
can allow impurities to emerge. Somechemical modifications are necessary
to improve their pharmacokinetics andstability. These could result in anothersource of impurities.
Irregularities in the manufacturing
process can lead to the formation of thefollowing common impurities:• Shortmers – oligonucleotides
missing one or more nucleotides,
or N-1• Longmers – oligonucleotides that
include more than the intended
number of nucleotides, or N+1• Lack of protecting groups(derivatives of existing functionalgroups that decrease reactivity andopinion, there are three main areas for
improvement in the field of analyticalche mis t r y. F ir s t l y, i t ’s im por t a ntthat we limit oligonucleotides’ nonspecif ic inte r ac tions w i t h me t alsurfaces and, therefore, the use of
truly biocompatible instruments andcolumns will become crucial. Secondly,
the use of superficially porous particles
may improve the separation of thelarger oligonucleotides being developed
today. Thirdly, the use of volatilemobile phase in cation exchange
chromatography is an important trend
for antibodies. Hopefully, a similar

increase stability)• Phosphodiester impurities (PO) in
phosphorothioate oligonucleotides
A helping hand
Fortunately, when it comesto removing impurities that
occur during oligonucleotide
manufacturing, a rangeof chromatogr aphic
techniques ensure that thehighest levels of purification
can be achieved.
A n i o n e x c h a n g e (A I E X )chromatography is the optimal solution
for addressing variation in strand lengths –shortmers and longmers. AIEX separates
oligonucleotides by the negative chargeof the backbone. Because siRNAs arehighly polar by nature, Tosoh’s highperformance anion-exchange medium,
TSKgel SuperQ-5PW (20), can easily
separate unwanted synthetic strands
from the desired product. Consistingof highly cross-linked hydroxylated
methacrylic polymer beads and with aparticle size of 20 μm, this resin offers
both high resolution and high loading
capacity – essential from a productivity
point of view. And this resin is available
as SkillPak pre-packed columns for fastermethod development!
Analytically minded
Characterization and quality control ofoligonucleotides essentially apply thestrategy could be applied for the anion
exchange analysis of oligonucleotides,
but column development would haveto focus on reducing the amount ofsalt needed to elute oligonucleotides.
Developments in the oligonucleotide
space are happening at a rapid pace, andit’s truly exciting to be a part of this field!
Regulators are paying increasing attention
to these products and the approval of
new therapies will certainly help us push
the boundaries of their potential.

same modes of chromatography as
purification. In AIEX chromatography,
TSKgel (U)HPLC columns based on
non-porous particles are available withthe same surface and ligand chemistries
as the TOYOPEARL and TSKgel
purification media. TSKgel DNA-STAT
or DNA-NPR columns offer fast kinetics
and high-resolution separation.
Size exclusion chromatography (SEC)
can also be applied in combination withlight scattering detection. The TSKgel
UP-SW2000 UHPLC column canseparate oligonucleotides differing by
one base in length. And when coupledwith our new LenS3 multi-angle lightscattering (MALS) detector, a detailed
picture of the oligonucleotide purity canbe achieved.
Options aplenty
At Tosoh Bioscience, we’ve amassed
a wealth of experience in thedevelopment of chromatographic
methods for downstream processes
and characterization – and weare happy to help in any processoptimiz ation . Fr om s mall -sc ale
academic environments to big pharma,
we can support all your growing needs;
we pride ourselves in continuallyadvancing our product offering in linewith industry advances.
Oligonucleotides are the next frontierin biopharma – and we are there foryou in your pursuit of a healthier future.

drug delivery,” Nat Rev Drug Discov (2020).
2.

M Sapru, “CMC Regulatory Considerations for
Oligonucleotide Drug Products: FDA Perspective,”(2017). Available at: https://bit.ly/3iICvZA

3.

D Capaldi et al., “Impurities in Oligonucleotide
Drug Substances and Drug Products,” Nucleic
Acid Therapeutics, 27, 309 (2017).

4.

D Capaldi et al., “Strategies for Identity Testingof Therapeutic Oligonucleotide Drug
Substances and Drug Products,” Nucleic Acid
Therapeutics (2020).

5.

A Goyon et al., “Characterization oftherapeutic oligonucleotides by liquid

References

chromatography,” Journal of Pharmaceutical1.

and Biomedical Analysis, 182, 113105 (2020).

TC Roberts et al., “Advances in oligonucleotide

www.tosoh.com

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NextGenR&D pipeline
New technology
Future trends

32-34
A Living Elixir?
Microorganisms isolated from thehuman gut have the potential totreat disease without much riskof adverse effects. Duncan Peyton
explains why he’s so excited about
the fourth class of therapeutics: live
biotherapeutics.

32

N ex t G e n

A Living Elixir?
Live biotherapeutics aremicroorganisms isolated
from the human gut with thepotential to treat diseases
such as Crohn’s, cancer andeven Alzheimer’s. Duncan
Peyton, Chief Executive
Officer at 4D pharma, walks
us through its pipeline,
including oncology, and why
the inherent safety profile ofthis new class of medicines
makes them so exciting fordevelopers – and patients.
By James Strachan
What led you to the live
biotherapeutic field?
My background is in genetics. Interestingly,
I started off in microbial genetics at a small
biotech in the early 1990s. In addition to apassion for the science, I was also interested
in the business side of things, so I decided
to go back to university to study law. There,
I learned more about corporate finance andstarted working for a private equity andventure capital firm. They wanted to get
into healthcare and biotech, so I was able
to become an investment manager.
And that led me to set up my own fundwith my business partner, Alex Stevenson,
mainly focusing on small biotech
businesses. We had a lot of success, but wealways felt under pressure from investors todeliver quickly – which can be difficult in afield with a high rate of clinical failure – so
we started looking for something reliable
that could succeed over the longer term.
Once we heard about the microbiome, we
felt we had our answer.
How did you find out about
the microbiome?
In 2011, our fund was looking at around
300 early stage research projects a year

to invest in. One of those companies
was a shark antibody business, basedout of Aberdeen University, which Pfizer
inherited from Wyeth. We travelled up
to have a look at the technology andwhile we were there asked if we could
take a look at some of the other stuff
they had too.
There was a group that had identified
two bacteria that could dampen down
the immune system. They were actuallyplanning on using the bacteria in
pig feeds to prevent disease in piglets
when they’re being weaned. But welooked at the data – which included
mechanistic details – and thought“there’s a therapeutic here.” We decided
to invest in a research project withinthat group and after realizing that there
are many other bacteria with different
mechanisms of action – all of whichshould be inherently safe and free fromside effects – we began to appreciate
the potential of the microbiome as anuntapped resource for pharmaceuticaldevelopment. With this in mind, we
founded 4D pharma.
Why are live biotherapeutics
inherently safe and what does thatmean for drug development?
Microbes already exist inside the human
body, which makes them inherently
tolerable and unlikely to produceside effects. This is huge from a drug
development perspective. Pharmacompanies lose around 30 percent of
products at each clinical stage. Why?
More often than not due to safety andtoxicology. Often you’ll see this cited
as a reason for high drug prices too –companies have to charge high prices
for their successful drugs to recuperate
the funds they lost for the unsuccessful
ones. What if clinical trials were tests ofefficacy alone because the products are
inherently safe and tolerable? The hugedevelopment risk would be slashed.
And from the patient perspective,

I’m sure everyone reading this has been
touched by cancer in some way, and many
will have seen how ill people feel whenthey’re taking some of the commonlyprescribed chemotherapies. It’s notuncommon for someone to opt against
an effective treatment because of thepotential side effects. Another example
is Crohn’s disease, which can severely
impact a patient’s life – even in terms of

growth and puberty. Patients (or theirparents) often have to decide whether
or not to take an immunosuppressantwith some very serious side effects.
With live biotherapeutics, you candevelop a treatment that is likely to
be safe and easily delivered by an oral
capsule – as opposed to expensive,
immunosuppressive injections.

Which projects are you most
excited about?
I’m most excited about our oncology
program and our prime candidate
MRx0518. We are currently working
on a clinical trial with Merck & Co. andtheir checkpoint inhibitor, Keytruda.
Keytruda is, of course, a successful drugthat is generating close to $4 billion insales in a single quarter. But there aresome major limitations. Firstly, it only
works in three-out-of-ten patients;
secondly, some patients, such as thosewith non-small cell lung cancer carrying
certain mutations, don’t respond.
Naturally, Merck is interested in finding
ways to expand the number of patientsthat Keytruda can treat.
Our preclinical research showed that
MRx0518 can reduce tumor volumes andwww.themedicinemaker.com

34

N ex t G e n“When welaunched thecompany in 2011,
the FDA hadn’t
even defined a live
biotherapeutic.”
tumor size as a monotherapy. And when
you dose MRx0518 with a checkpoint
inhibitor, you see a synergistic effect.
So we’re trying to find out whether
MRx0518 is effective in checkpoint
inhibitor refractory patient populations– patients who have stopped responding
to drugs like Keytruda. The question is:
can we re-stimulate the immune system?
Usually when you re-treat a patient
who has already stopped responding toa checkpoint inhibitor you would expect
something like a five percent response rate
– so we set the bar in our combination trialat 10 percent. In our initial population of
12 patients with growing tumors, someof whom had received seven or eight
different prior treatments, five had durable
responses to MRx0518 in combination
with Keytruda. That was a fantastic
result and we’re excited to conduct laterstage trials, with an approval next year
potentially on the cards.
Do you understand the mechanism
behind the effect?
To successfully develop a live biotherapeutic,
we believe it’s vital to distill down theessential components of the microorganism
and understand how it works at themolecular level – we try to treat theseproducts like any other pharmaceutical.
Taking this approach, we’ve discovered thata specific region on MRx0518’s flagellum

acts as an agonist for TLR5 on the cellsurface, which triggers a signaling cascade
leading to immune stimulation. We’ve
carried out studies with flagellin knockout
MRx0518 and found little to no TLR5
activation or immunostimulatory effects.
Are there many manufacturing
challenges associated with live
biotherapeutics?
For live biotherapeutics broadly, there isa potential for change to occur between
batches and over time if not properly
controlled because of the complexity ofthe product. This problem is multiplied
exponentially if the product contains
multiple organisms. We’re only dealing
with single-strains, which allows us tomore easily control the identity, purity,
potency, and stability of our products.
Another challenge is that there
aren’t many CDMOs out there withthe experience of manufacturing live
biotherapeutics, so we decided to
manufacture in house. The main challenge
for us was ensuring that our bacteria are
not exposed to oxygen during the process(they are anaerobic). To do this, we had
to develop some novel manufacturing
techniques. For example, we use a“Quality by Design” approach to efficiently
and effectively optimize fermentationand lyophilization conditions, as well as
developing in-house some of our own
hardware used in the production process.
So there are challenges, but they
aren’t insurmountable. We have an
cGMP-certified live biotherapeutic
manufacturing facility in Spain and
we’ve put nine programs through ourmanufacturing process – with someproducts having a stable shelf life of two
years and counting.
Interestingly, we’ve also found thatscaling up into larger tanks has actually
improved titers – our productionengineer tells me it has to do with fluid
dynamics favorably altering the flow ofnutrients in the bigger vessels.

Given the novelty of the field, what are
the regulatory hurdles?
When we launched the company in2011, the FDA hadn’t even defined a live
biotherapeutic. The first definition came in2012. That said, we’ve found the regulators
to be very easy to work with. Their mainconcern is, of course, safety. But they arealso scientists. If you can present a logicalargument – supported by a solid dataset –they tend to be receptive. In fact, Alex was
asked, on behalf of the MHRA, to work on
the European Pharmacopeia chapters on
quality standards for live biotherapeutics,
so we’ve had a role in setting the regulations
for live biotherapeutics. And, as I’ve said,
live biotherapeutics are microorganismsthat exist in the human body, which makes
them inherently safe – and that really helps
allay the concerns of the regulators.
How would you summarize thepotential of the field?
In more recent years, the microbiome hasgarnered a lot of attention. But back in 2011,
if you were to tell someone that your plan
was to isolate bacteria from someone’s fecal
sample, put it in a capsule, and feed it to apatient to cure Crohn’s disease, they would
have thought you were mad. Fast forward
to 2020 and it’s looking like we might beable to address neurological conditions, suchas Alzheimer’s and Parkinson’s with themicrobiome – two of the biggest problems
we face as an aging society. If you’d have told
me this three years ago, I might have thought
you were mad! But that’s where we are today.
From our perspective, we’re closing inon bringing a live biotherapeutic drug tomarket. But we’re talking about a single
strain of a single microorganism. The humanmicrobiota consists of something like 1000
different species of microorganisms, so it’sfair to say we haven’t even begun to scratch
the surface of what might be possible interms of pharmaceutical development.
We’re talking about an entirely new class of
medicines with the potential to transform
how we treat many diseases.

S p o ns o r e d F e a tu r e

io n

How does GenScript ProBio serve its
GCT customers?
We are a one-stop-shop provider for

Could you speak to the importance ofplasmids and viral vectors supply?
Viral vectors are crucial for introducing
genetic material into cells – there areover 2,600 ongoing gene therapy clinical
trials that rely on them. Developers
need a steady supply of lentiviruses
and adeno-associated viruses (AAVs),and other viral vectors such as vaccinia,
retro, adeno and herpes can beproduced with protocol transfer from
customer. Stable supply might not be a
problem in early clinical trials, but it canbecome an issue when mass production
is needed to address larger trial cohorts.
And I believe this could be the biggest
bottleneck for the field.
Another challenge companies face isthat, though lentiviruses and AAVs areshowing promise in the clinic, there areconcerns around the potential for side
effects. Companies simply must selectvectors with ensured safety and purity for
their GCT products.

ra t

How did GenScript ProBio get started in
the GCT sector?
We live in a world where 4 million people
are diagnosed with cancer each year;
ultimately, our goal is to see as manysuccessful GCT products reach patientsas possible. It’s an area with an upward
trajectory. Though GCTs were firstdeveloped in the USA, there is a massive
opportunity for companies around theworld to get involved with the progressionof the field. China, for example, was quick
to adopt the concept and now runs nearly
as many CAR T trials as the USA. The
problem the market now faces is that,
despite the huge network of talented
companies, the number of CDMOs that areable to help in GCT product development
are few and far between. We can help
companies achieve their goals through our
expedited services. GenScript has supplied
R&D grade plasmids to GCT companies
since 2004, and continues to serve thesecompanies with process development and
GMP manufacturing.

io n t hr o ug h colla b oGene and cell therapies (GCTs) are
capturing the attention of players fromacross the pharmaceutical industry. And
with rapid growth comes the need forsupport from specialized CDMOs. Here,
Brian Min, CEO of GenScript ProBio,
explains how the company is gearing up
to help the global GCT community deliveron the promise of these exciting therapies.

What’s yourbest advice foraccelerating GCTdevelopment?
The manufactureof viral vectors is
likely to be one of
the biggest constraints
that developers will faceas they shift from clinical trials
to commercialization. Avoiding thisparticular bottleneck is directly linked toaccelerated development. Many CDMOs
have longer wait and lead times to
conduct the GCT product development
and manufacturing, and we are able tosubstantially shorten these time frames.
Though some companies may have inhouse facilities, choosing an experienced
CDMO partner is also important for
ensuring regulatory and clinical successwhile minimizing the burdens of capital
investment and running costs.
ov a t

The gene and cell therapy market
is growing, but does it have the
CDMO support needed to maintainits upward trajectory?

plasmid and viral
vectors, with products
ranging from R&D to
GMP grade. Our total
GCT solutions coverchemistry, manufacturing
and control of plasmidand virus for IND filings, aswell as clinical and commercial
manufacturing. We also ensure
phase appropriate compliance, data
integrity, and traceability with robust quality
management systems.
We currently offer R&D to GMP grade
plasmid and viral vectors to support preclinical and clinical studies, and in 2022–
2023 our GMP commercial center will begin
supporting commercial-scale productions
for our increasing pool of customers
and projects. These facilities will help us
meet customer needs, and signpost ourcommitment to shortening development
timelines – significantly lowering R&D costs
and building a healthier future.

Inn

Servinga Rising Power

 35

How is COVID-19 affecting the
GCT community?
In the first half of 2020, the numberof companies working on regenerative
medicine therapies globally passed the
1,000 mark for the first time, with 415
companies entering clinical development.
Of these, 515 are developing genetherapies and 632 are developing
cell therapies. But the pandemic has
affected the progress of many clinical
trials, causing delays to regulatory
applications and approvals. Even withthese challenges, the market is expected
to pick up in the second half of the year.
At GenScript ProBio, our customers
benefit from reliable and uninterrupted
GCT manufacturing thanks to ourmanufacturing capacity located acrossthe globe including the US and China,
and we will be there to support ourcustomers through it all.
For more information, contact
cdmo@genscript.com
www.genscriptprobio.com

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Business
Economic drivers
Emerging trends
Business strategies

38-43
The Battle for the Future ofAmerican Healthcare
Both candidates for the US
presidency are advocating policies
that would create a new pricing
environment for pharma companies– but we’ve been here before. With
regard to the Affordable Care Act,however, the election could prove areal turning point.
44-48
Pacesetting Leadership
At 25 years old, Kiran MazumdarShaw – despite being unable tosecure a bank loan – set up her own
company, working out of her garage.
Today, that company is the largest
biopharma in India. Here, she shares
her lessons learned along the way.

38
 B usin e s s

The Battle for
the Futureof American
Healthcare
Did the forecasted drug pricing
storm come to pass following
the 2016 US election? And whatmight the 2020 elections meanfor pharma and the Affordable
Healthcare Act?
By James Strachan
Four years ago, The Medicine Maker
made a bold prediction: regardless of who
ended up in the White House, the pharma
industry would have to weather change– with particular regard to drug pricing(1). Hillary Clinton had a long history of
opposing rising drug prices, but Donald
Trump was also making noises in favor of
Medicare price negotiations and “repealing
and replacing Obamacare.” In fact, one of
Trump’s campaign promises was to allow
American consumers to purchase drugs
from abroad. Chris Dale, Director of
Public Relations and Communications
for Turchette, said that Medicare pricenegotiations and drug importation would
become immediately politically untenable
after a Clinton victory (due to the balanceof power in the House of Representatives),
and would only be possible if Trump won.
Thus, we envisaged a strange situation
whereby the USA would only see someof Clinton’s pharma-related policies if
Trump became president. In the wordsof then Novartis CEO, Joe Jimenez, “We
believe that, no matter which candidate
wins, we will see a more difficult pricing
environment in the US.” So did we?
Trump seemed anything but the“business as usual” candidate – an image
he’s deliberately cultivated in interviews

and on social media via more than 17,000
Tweets since he officially declared his
presidential candidacy in July 2015 (seeour sidebar: Talking the Talk). But, as
far as pharma and drug pricing goes, wehaven’t yet seen radical changes. “This issomething I was clearly wrong about,” says
Dean Baker, co-founder of the Center
for Economic Policy and Research. “I
expected Clinton to win, but even if she

didn’t, I thought Trump would feel somepressure to rein in the drug companies.
As it turned out, spending on drugs rose
more rapidly under Trump than during
the Obama years.”
According to Baker, spending onprescription drugs rose by 6.3 percent
annually under Trump compared to a 5.5
percent rate under Obama-Biden. “Thegeneral direction in the Trump years hasbeen upward, with a peak of 9.7 percent
in the first quarter of 2020, then a drop
to 4.4 percent in the second quarter,” said
Baker in a recent blog post (2). “This falloff
is a direct result of the pandemic, as many
people put off doctors’ visits, which meantthat they would be prescribed fewer drugs.
So, before the pandemic, drug spending
was rising at a rapid and accelerating pace.”
In March 2018, Trump promised,“You’ll be seeing drug prices fallingvery substantially in the not-too-distantfuture, and it’s going to be beautiful.”
Then in May, 2019, he said “Drug prices
are coming down; first time in 51 years
because of my administration.” But,
according to the consumer price index,
prescription drug prices in the USA
rose during the Trump presidency by 5.9
percent from December 2016 to December
2019. Though this represents a moderate
reduction in the rate of the increase, it isin line with the upward trend seen in the
USA over the past couple of decades (3).
Why haven’t we seen the kind ofradical shift in drug prices? President
Trump decided in early 2017 – apparently
following a meeting with pharmaceuticalindustry lobbyists and executives – that
he would not seek to allow Medicare tonegotiate directly with pharmaceuticalcompanies. Since then, the President
launched a number of policies aimed at
reducing drug prices (see our sidebar: Trump’s
Pricing Policies on page 42).). But according
to Monique Dabbous and her colleagues at
Aix-Marseille Université, France, Trump’s
primary focus has been on repealing the
Affordable Care Act (ACA) (4).
On his first day in office, President
Trump signed an executive orderinstructing administration officials “towaive, defer, grant exemptions from, ordelay” implementing parts of the ACA.
But, a few months down the line, Trump’splan to repeal and replace “Obamacare”
failed – largely due to the late Republican
senator, John McCain, voting against the
new plan. And though President Trump
has been unable to repeal the ACA, he has
been able to weaken it, mainly by dissolving
the “individual mandate” penalty, whichanyone without coverage had to pay.
However, the result was a 32 percent
increase in average premiums, according to
the Kaiser Family Foundation (5) (althoughmost received subsidies to offset thosepremium hikes) – likely because, without
the financial penalty incentivising peopleONE
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40 B usin e s s

to take out healthcare insurance, insurance
firms anticipated lost revenues.
Further reforms made to the ACA
include: i) allowing states to add “workrequirements” to Medicaid, ii) ending
payments made from the federal
government to insurers to motivate themto stay in the ACA insurance
exchanges, iii) expanding
access to short-term“skinny” plans(allowing them tolast for up to one year
and be renewable
for three years),and iv) slashingfunds to facilitate
HealthCare.gov signups (5). Taken together,
George Sillup, Associate
Professor of Pharmaceutical& Healthcare Marketing at Saint
Joseph ’s University, USA, says that
Trump’s efforts to dismantle the ACA has
made it “more challenging for those who
are underinsured (no drug coverage) to getaffordable coverage”.
A change of priorities?
In 2016, the affordability of prescription
drugs was one of the most important issues
in American politics. According to a poll
conducted the week following the last US
election, healthcare was rated as the third
most important factor in peoples’ vote forpresident – above foreign policy, terrorism,
immigration and either candidate’s personal
characteristics (6). And when thinking
about healthcare priorities, dealing with thehigh price of prescription drugs topped the
public’s list (7).
Today, in the midst of an international
pandemic, and following protests andriots against racism and police violence,drug pricing may be lower on the public’s
priority list this time round. Fiona M.
Scott Morton, Theodore Nierenberg
Professor of Economics at the Yale
University School of Management,

agrees: “We have such important issues of
democracy, corruption, and racial injustice
to worry about.”
Baker thinks the Democrats arefocusing on the pandemic and Trump’s
lack of respect for norms – most recently
his alleged disrespect for people in the
military. On the other hand,
Trump is focusing moreon painting a pictureof the Democrats as
dangerous radicals.
“In neither case is
there much room
for talking about
healthcare,” he says.
“That may change,
and my expectationi s t h at a s h i f t to
healthcare would benefit
the Democrats more than the
Republicans (coverage has fallen andcosts have risen sharply under Trump), but
I know better than to try to predict thecourse of this campaign...”Sillup also hasn’t seen healthcare
discussed much in the media, but thatmight be about to change. “A recent ad byBiden addressed the issue and I anticipate
that will increase as we ramp up for thepresidential election,” he says.
In fact, the COVID-19 pandemic
may have led to an improvement in
the reputation of pharma companies.
Researchers from The Harris Poll foundthat 81 percent of Americans polled
recalled seeing or hearing something about
the industry during the pandemic, with 40
percent believing that pharma’s reputation
had improved since the beginning of the
COVID-19 outbreak. Rob Jekielek,
managing director at Harris, said theindustry was at its highest ever point interms of its reputation and relevance (8).
Interestingly, before the last election
Baker advocated expanding the role ofpublic open research as a means of reducing
drug prices. This has, in a way, taken place
during the development of drugs and“Instead ofprocuring drugs ina cost-effective andrational manner,
we will be forcing
our bad system on
to others.”
vaccines related to the coronavirus. But
the government has not taken ownershipof the research – potentially feeding into
the good press surrounding the pharma
industry at present. “Moderna, which is
generally thought to be the leading US
contender to develop a vaccine, had prettymuch all its research costs paid by thegovernment,” says Baker. “Nonetheless, itwill get a patent monopoly on the vaccine
and will be able to charge what it wants.”
In any case, Baker believes that this could
provide an example of where direct funding
to develop a vaccine leads to a usefuloutcome. “It should be possible to point tothis example as a reason to have more direct
funding in the future, but with the patents
going into the public domain so that a new
drug/vaccine can be produced as a genericfrom the day it is approved,” he says.
The new landscape
What then, given the new landscape,should pharma companies expect
following the outcome of the 2020 US
presidential elections? In July, President
Trump announced four executive orders
to reduce drug prices (see Trump’s Pricing
Policies on page 42).
So far, only the policy to ensure the USA
pays the lowest price for Medicare Part B
drugs compared with other economicallysimilar countries has been officially signed
as an executive order – and actually goes
further by also including Part D drugs.
The move represents a deviation fromthe International Pricing Index modeland instead anchors to the lowest pricefor a product sold across OECD member
countries, with a comparable per-capita
GDP, after adjusting for volume anddifferences in GDP.
Pharma wasn’t best pleased with theproposal. “This reckless scheme will
eliminate hope for vulnerable seniors andother patients waiting for new treatments bydrastically reducing investment in cuttingedge scientific research and development,”
said Michelle McMurry-Heath, CEO of the
Biotechnology Innovation Organization (9).
“That is why we will use every tool available– including legal action if necessary – to fight
this risky foreign price control scheme.”
PhRMA CEO Stephen Ubl agreed,arguing that the administration “hasdoubled down on a reckless attack on thevery companies working around the clock
to beat COVID-19,” and that the order is
an “irresponsible and unworkable policythat will give foreign governments a say in
how America provides access to treatments
and cures for seniors and people struggling
with devastating diseases” (10).
Scott Morton argues that the resultof the policy would be high US prices
exported to its allies. “This is particularly
egregious and poorly thought out,” shesays. “Instead of procuring drugs in a costeffective and rational manner, we will be
forcing our bad system on to others.”
Scott Morton would rather see the nextpresident tackle barriers to entry: “Getting
generics into the market by eliminating
pay for delay, REMS abuse, restriction ofsamples, and price fixing to name a few,”
she says. “Also, biosimilars must have thesame scientific name as the innovator, notface undue approval hurdles at the FDA orloyalty rebates and other contracts that act
as a barrier to entry. Finally, government

purchasing (Medicare, Medicaid, and soon) should incentivize a physician (in PartB, or on the medical side of commercial
plans) to buy a lower cost drug.”
Sue Peschin, President and CEO of the
Alliance for Aging Research, concurredin an article for Stat News. She pointed
out that an Avalere study found thatfewer than one percent of older adults in
Medicare Part B would see a reductionin out-of-pocket costs as a result of theinternational pricing index model (11) –though it is not clear how the inclusion ofPart D might affect the analysis. She also
criticized the policy for endorsing the costeffectiveness standards often used by othergovernments, such as the UK, which she
described as “discriminatory.”
According to a more recent Avalere
analysis, any potential savings will dependon how the system identifies the range of percapita GDPs considered “comparable,” whatdrugs volumes are used for adjustment, andwhat pricing sources are used for calculating
MFN (12).
Either way, as Rachel Sachs, a law
professor at Washington University in
St. Louis and an expert on drug policy,
pointed out on Twitter (13), it seems
unlikely that the Trump administration
would be able to finalize the necessary
regulations before the November election.
“In the best case scenario, it would stilltake quite some time to implement themodel,” she says.
Interestingly, the Democratic-controlled
House also passed a bill in December of2019 that would have allowed the US
Department of Health and Human
Services to negotiate prescription drug
prices using other countries’ prices
in a similar way to Trump’s proposal(Republicans opposed the bill and Trump
threatened to veto it). We may, therefore,
see some sort of proposal implemented
regardless of which candidate wins theelection – though we’ve made similar
predictions before...

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in market preference and are ideal
for new drug development.

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42
 B usin e s sTrump’s Pricing
Policies
May, 2018
Trump’s American Patients First
blueprint to lower drug prices and reduce
out-of-pocket costs by focusing reforms
on the opaque world of pharma rebatesand discounts.
June, 2018
President Trump jawboned pharmaceuticalCEOs to limit and/or delay their company
price increases, with Pfizer reporting
pricing pressures from many sources,
including those from the administration.
July 2018
The Biosimilar Action Plan was rolled
out to lower drug prices by promoting
greater competition through increased
availability of biosimilars in the US.

paying cash rather than thenegotiated contract price on
their drug plan.
President Trump alsoannounced a f ive-year
e x p e r i m e nt to l o w e r
Medicare Part B drug
prices. Administered by
the Centers for Medicare& Me d ic a i d S e r v ic e s(CMS), US prices will belinked to what countries withsimilar economic conditions
pay for drugs by creating an
International Price Index (IPI)
Model (10).

October 2018
President Trump signed t wo bills
that passed virtually unanimously by
Congress to ban “gag orders” in contracts
between pharmacies and insurancecompanies/pharmacy benefit managers(PBMs) to tell consumers that they
could get drugs at a cheaper price by

July 2020
President Trump announced four
executive orders to reduce dr ug
prices: passing discounts obtained byhealth centers from drug companies
on epinephrine and insulin to people
with low incomes, allowing for safe
importation of certain dr ugs bystates, prohibiting deals bet ween
pharmacy benefit managers and drug
manufacturers, and ensuring the US
pays the lowest price for Medicare
Part B drugs compared with otherdeveloped nations.

Obamacare in the balance
Thus far, we’ve paid very little attention
to the man who is, at the time of writing,leading the national presidential polls:
former Vice President Joe Biden. He too
has promised to put a stop to “runaway
drug prices” and the “profiteering of the
drug industry.” In fact, Biden advocates two
policies that Trump touted four years ago:
allowing people to buy prescription drugs
from other countries and repealing lawsthat prevent Medicare from negotiating

lower drug prices with drug companies.
“These are both good measures to lower
prices,” says Baker. “If he gets in, the extent
to which he follows through will dependon the political pressure from both sides.”The major differences between the twocandidates may, therefore, be found notin their approach to reducing the cost ofprescription drugs, but rather in their views
on healthcare – specifically the Affordable
Care Act. “If Biden wins, the ACA willbe the foundational building block of an

September 2020
President Trump signed an executive
order to expand the drugs covered by the
proposed “most favored nations” pricing
scheme to include both Medicare parts B
and D so that Medicare would refuse to
pay more for drugs than the lower prices
paid by other developed nations.
For sources and further elaboration, see:https://themedicinemaker.com/businessregulation/pharma-in-the-firing-line

improved healthcare delivery system – onethat retains cover for pre-existing conditions,”
says Sillup. “If it’s Trump, then he’ll try todismantle it. But, as with his first term, he’ll
need an alternative before he does that.”
Baker agrees: “The Trump administration
has done everything it could to sabotage the
ACA. That would surely continue if he werere-elected.” Baker points to Biden’s promise
to make the subsidies more generous, which
he expects him to follow through with.
But he’s most excited about his proposal to“The majordifferences between
the two candidates
may, therefore, befound not in theirapproach to
reducing the cost ofprescription drugs,
but rather in theirviews onhealthcare.”lower the Medicare age to 60. “That would
be huge, as the older pre-Medicare age
population has the greatest need for healthcare,” he says. “I don’t know if he will beable to do five years at once, but even one or
two years would be a huge foot in the door
towards a universal Medicare program.”
The Affordable Care Act also faces
another existential threat. Following therecent death of Supreme Court Judge
Ruth Bader Ginsburg, President Trump
may appoint (with the approval of the
Republican-controlled senate) a conservative
justice before the election takes place. Thismight give the Supreme Court enoughconservative votes to declare the Affordable
Care Act unconstitutional – causing 20
million Americans to immediately lose
health coverage. Nicholas Bagley, a law
professor at the University of Michigan who
specializes in health issues, tweeted, “Amongother things, the Affordable Care Act now
dangles from a thread” (14).
Lawyers have argued that the Republican-

backed tax-cut law of December 2017
rendered the ACA unconstitutional by
reducing the ACA’s penalty for not having
insurance to zero. This means if Biden
were to win the election, he – along witha Democratic Congress – could in theory
make the entire issue go away by reinstating
the penalty for failure to have insurance (15).
For now, all we can say is that bothcandidates are advocating policies thatwould create a new pricing environment
for pharma companies. And with regards
to healthcare, the outcome of the election
may be a crucial turning point: will
America build upon the foundations of
the ACA? And if not, then what?
References
1.

James Strachan (2016). Available at:ONE
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Qualicaps® delivers
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together with a comprehensive service
along the drug product life cycle
through our global team of commercial,scientific and technical services.
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drug delivery.

https://bit.ly/3mMJcMp

2. CEPR (2020). Available at:3.

https://bit.ly/2RR8aMF

Statista (2020). Available at:https://bit.ly/2HISHwi

4. M Dabbous et al. (2019). Available at:5.

https://bit.ly/3cq5rDc

NPR (2019). Available at:https://n.pr/3i0ji4r

6. KFF (2016). Available at:https://bit.ly/3hUvlQx

7.

KFF (2016). Available:8.

MMM (2020). Available at:9.

https://bit.ly/32XQ fu1

https://bit.ly/301W1bW

BIO (2020). Available at:https://bit.ly/3hYhGrT

10. PhRMA (2020). Available at:https://onphr.ma/306jbxZ

11. Stat News (2020). Available at:https://bit.ly/3kKnGpO

12. Avalere (2020). Available athttps://bit.ly/2RSA36K

13. Rachel Sachs (2020). Available at:https://bit.ly/303hlOt

14. Nicholas Bagley (2020). Available at:https://bit.ly/3jcCjSJ

15. NPR (2020). Available at:https://n.pr/2ZZpdAz

www.themedicinemaker.com

44
 B usin e s sPacesetting
Leadership
Lessons Learned with Kiran
Mazumdar-Shaw
As the founder of India’s largest
biopharma company, Biocon, Kiran
Mazumdar-Shaw’s influence is farreaching – but her professional life
has taken a few surprising turns. Fromlaunching a biotech company with
two retired tractor mechanics as her
first employees to creating a global
brand, serendipitous events and an
entrepreneurial spirit have guided heralong an unusual career path. Here, sheshares the experiences that have shaped
her 40-year career – and the lessons she
has learned along the way.
Career setbacks can fuel future success
I never intended to pursue a career inbiopharma. As a trained brewmaster, I
wanted to earn my stripes in my chosenindustry, but the professional culture at
the time held me back. Women weren’t
particularly visible in the sector andactively choosing to pursue a careerin it was unusual. Though I had thecredentials to make it, no one waswilling to give me the chance to prove it.
Despite my disappointment, I
sought out new opportunities. When abiochemical company in Ireland hired
me as a trainee manager, I jumped at the
chance to develop my knowledge in a new
industry – and the experience inspired
me to set up my own company at homein India. Using enzyme technology, I
planned to develop products needed
for alcohol production. My colleagues
in Ireland supported the idea and webecame business partners. But trying
to create a brand-new service, product,
or experience is an inherently risky
process. I realized this when I first began

looking for funding. Bankers would
stare at me with blank expressions as I
tried to explain the potential of enzyme
technologies for the brewing sector.
Unconvinced, they turned me away
empty-handed. My lack of businessexperience and scant personal savings
didn’t help either…
The rejection was difficult to handle,
but it didn’t dent my determination.
Without a loan, I had to scrape together
the little money I had to set up my first
office (which was conveniently locatedin my garage.) I also rented a shed tohouse the machinery I’d purchased,
and Biocon was born. Now, I needed
employees… But who would want towork for a 25-year-old with nothing but
an idea to her name?
The only people brave enough to takeon the challenge were two retired tractor
mechanics who operated the machineryand helped get the ball rolling. To beviewed as a reputable business, though,I needed scientists and engineers who
could take our operations to the nextlevel. I made connections with academic
institutions and found like-minded
individuals who, excited by the prospectof this unconventional business, took thebold step to join us.
We quickly matured and began thedaunting journey from lab to market.
My partners in Ireland were willing to
manufacture everything we developedin India so, within five years, we had
developed a credible homegrowntechnology. Brewing companies were
now approaching us to learn about our
products. Knowing that my company
was of value to the industry gave mea sense of satisfaction – even after myinitial rejection, brewing was still an
integral part of my professional life.
When we were ready to scale up ouroperations, I returned to the banks,
hoping that Biocon’s years of effort
would inspire their generosity – but theirskepticism remained. “We don’t invest in

homegrown technologies,” they said. “Ifyou want to license a technology, we canmake the funds available, but loaning
you money for your own technology isout of the question.” This second roundof rejections hit me hard. At the time, I
hadn’t considered any alternative formsof funding, and we couldn’t reach ourfull potential without money.
But serendipity answered. Shortly
after these disappointing encounters,
I met a banker who had just started
a venture fund. Our technology andethos appealed to him and he became
our first-ever investor. At the same time,
Unilever acquired our Irish partners’
business and went on to teach me a lot
about intellectual property and what
it takes to be a player on the global
stage. With this newfound support,
I started thinking strategically about
where I wanted Biocon to go next. It
occurred to me that we could expand
our horizons – so we spent the next 20
years developing and diversifying our
enzyme technologies to serve a range ofindustries before ultimately ending up
in biopharma.

“We spent the next
20 years developing
and diversifying
our enzyme
technologies to servea range ofindustries before
ultimately ending
up in biopharma.”B usin e s sAddress the problems that matter
I’ve always been socially conscious and,as a young entrepreneur, it concernedme that many of the environmental
issues affecting our society were being
ignored. But I realized that our growing
company could be a platform for change.
Our portfolio was expanding and manyof our clients belonged to industries
notorious for their polluting protocols.
Some used acid hydrolysis to convert
complex carbohydrates down to simple
sugars – an efficient process, but one
whose long-term consequences received
little consideration.
My colleagues and I became strong
advocates for enzyme hydrolysis as analternative. By this stage, Biocon had
gained enough credibility to bringdifficult conversations to the table,

and we were determined to makesustainable practices part of our clients’culture. Some were hesitant – enzymes
were much more expensive than thechemicals they were accustomed to –but they were willing to give the ideaa chance. The long-term cost savings
from using environment-friendly
enzyme technology convinced themto make the switch. Over the years,
many of these companies have put ecofriendly practices at the heart of theirsocial responsibility strategies. But thework is never finished; we continue tobring attention to ecological issues andexplore ways to help. As a company
that has worked on cleaner and greener
biotechnologies based on enzymes, wehave taken a novel approach to revivesome of Bangalore’s polluted lakes.

 45



We have implemented a three-stepbioremediation process using technology
which is unique and cost effective incomparison to conventional draining
and cleaning processes and havesucceeded in restoring the ecosystemof the dying 35-acre Hebbagodi Lake,located in the outskirts of Bengaluru.
This project has won several awards
including a place in the Limca Book
of Records for introducing the largest
artificial floating wetlands in India.
Having successfully revived the dying
Hebbagodi lake, we are leveraging theexperience to rejuvenate the polluted
Yarandahalli lake.
Our move into the biopharmaceuticalsector put a new perspective on the
problem. India is the diabetes capital of
the world and, at the time, most patients
www.themedicinemaker.com

46 B usin e s sBiocon Today
Biocon may have initially started out ina garage, but today it’s a very different
stor y. Biocon employs over 12000
employees and brings in annual revenues
over US$870 million. The company’s
portfolio includes small molecules, novel
biologics, and biosimilars. Biocon was thefirst Indian company to have a biosimilar
approved in the USA and in Japan, andis one of the largest producers in theworld of statin and immunosuppressantAPIs. It is considered to have thelargest biomanufacturing capacity in allof India.
Biocon has repurposed its “first-inclass,” humanized IgG1 monoclonal
antibody Itolizumab that selectively
targets CD6 cells, to help treat acuterespiratory distress syndrome (ARDS)
in COVID-19 patients. The Indian
health regulator has approved this novel
biologic therapy for restricted emergency
use in India to treat moderate to severe
AR DS patients hospitalized with
COVID-19.
Over the years, the company has won
numerous awards. Achievements in2019 included:
•

•

•

•

Biocon was ranked 6th on theprestigious Global Biotech
Employers rankings 2019 by USbased Science Careers magazine
Best Biotech Patents Award
2018-19 from the Indian Drug
Manufacturing Association’s 58th
Annual Day celebration
Awards in four categories, Women
L&D Programs, Diversity Policies,
Large Enterprise and Diversity
Programs, for the Bowin HR teamState Level Award in
Implementation of Best Safety•

Practices from the Department
of Factories, Government of
Karnataka
Annual Greentech Environment
Award for Outstanding
Achievements in Environment
Management in the
Pharmaceutical Sector for theHyderabad API facility

Kiran Mazumdar-Shaw has also
received many personal awards andhonors. She recently won the EY World
Entrepreneur of the Year Award 2020.
She was conferred with the Order ofAustralia, Australia’s highest civilian
honor in 2020 and recognized with
the Knight of the National Order of
the French Legion of Honour, France’s
highest civilian honor, in 2016. For

her outstanding contributions to theprogress of science and technology, she
got the AWSM Award for Excellencein 2017, the Othmer Gold Medal in2014 and the Global Economy Prize for
Business the same year. She has been
conferred with the Honorary Doctorate
by Deakin University, a leading Global
University based in Victoria, Australia,
and was elected as a member of the US
National Academy of Engineering forher contributions in the developmentof affordable biopharmaceuticals andIndia’s biotechnology industry. She isalso a full-term member of the MIT
Corporation, the board of trustees ofthe MIT. The Indian government hasrecognized her achievements throughtwo of its top civilian awards, the Padma
Shri and the Padma Bhushan.

used disposable pens to administer insulin. Though convenient,
their daily use generated significant amounts of medical waste.
We decided to introduce reusable pen technology to the Indian
market – not only addressing the environmental problem, butalso giving patients across the country access to affordable
recombinant human insulin.
Prior to our transition into biopharma, many diabetic patients
relied on highly immunogenic animal-derived insulin because
they couldn’t afford alternatives. I’ve always believed in theimportance of medical access, particularly in the developingworld. Biocon has become synonymous with the developmentof treatments for these areas of unmet need because of ourdesire to level the playing field. Although widespread poverty
is a reality, it shouldn’t dictate a person’s quality of healthcare.
As long as income-based inequality exists, my colleagues andI will fight for change.
Be ready to find inspiration in unexpected places
By the early 1990s, India’s pharmaceutical sector was booming.
Where previously only a handful of homegrown companies
had existed, many had now cemented themselves in thepharmaceutical landscape. It was encouraging to witness
pharma’s rapid growth, but I found inspiration elsewhere...
The world’s eyes were on India in the 1990s because of
its IT capabilities. The efficiency of the country’s software
services attracted an international client base. And thatpushed me to investigate their development model and createa platform specifically for pharma. My many years in theindustry had taught me the need to accelerate early-stage
research and I believed that a research support service would
help. I launched Syngene in 1993 and, since then, it has
grown from strength to strength, supporting many R&D
programs from start to fruition.
Biocon commenced its pharma journey in 1999 by leveraging
its capabilities in fermentation technologies derived fromits long experience in manufacturing enzymes; this was
unlike other companies in India which were largely focusedon generics made by chemical synthesis. Furthermore, wewere amongst the early movers in developing a portfolioof fermentation-derived statins which gave us a leadership
position in this segment. We simultaneously chose to expand
our strategic options from small molecules like statins torecombinant proteins like insulin to address the growing
healthcare challenges associated with diabetes.
Our product portfolio was not limited to generics orbiosimilars; we sought opportunities to address unmet needs inthese therapeutic segments through novel biologics and novel
targets. These were marked by high entry barriers wherein wewere required to make significant investments in a full range ofComprehensive
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Answers that work

48


 B usin e s s
“My many years in
the industry had
taught me the needto accelerate earlystage research and I
believed that a
research support
service would help.”
R&D capabilities, spanning process andanalytical development to pre-clinicaland clinical research.
These investments have helped Biocon
in its journey of building the science, scaleand expertise needed to enhance access toessential drugs for patients on the lowest
rung of the economic ladder. Through its“Mission 10 cents,” Biocon is today offering
recombinant human Insulin at less than

10 US cents/day for direct procurement bygovernments in low- and middle-income
countries, where millions of people cannot
access insulin as it is unaffordable.
Biocon today has one of the largest
global biosimilars portfolios spanningi n s u l i n s , mono c lon a l a nt ib o d ie sand other recombinant proteins fordiabetes, cancer, immunology and othertherapeutic areas and is well positioned
to offer lower costs and increased accessto this highly innovative class of drugs.
Master the art of accepting advice
My late father was one of the mostinfluential figures in my life. He believedthat good leadership was built on giving
people the freedom to discover their own
capabilities. His thoughts on the subject
have always resonated with me, and I’ve
tried my best to apply them to my own
companies – giving my employees thespace to tackle issues using their own
initiative. Though I was always there to
guide them, I wanted my team to feel
confident in their own decision-making
skills. I’m as passionate about theircontinued growth, as I am about myown, and it’s a privilege to watch thembuild the strength of character to makehard decisions when necessary.
Another important lesson my father
taught me was to always give back. He
always said, “Money is not a currency
to buy favors, but a means to make adifference.” As my companies grew, I
became able to extend a hand where there
is a need. From the arts to healthcareorganizations to R&D, both at home
and abroad, I seek out opportunities
to help. One example that I’m proud
to be involved with is the grassroots
effort expanding access to primary careacross India. Over the years, I havehelped develop new healthcare centers
nationwide and we now have an army ofhealth workers ready to treat and support
patients across the country.
But charity is not about the size ofthe donation given or personal gain;
it’s about the sincerity of the action andthe attention that can be brought toa meaningful cause. I’m glad that myfather instilled this idea in me because
it has brought, and still brings, much
purpose to my life.

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www.themedicinemaker.com

A Wealth ofExperience
Sitting Down With… Richard M. Johnson,
President, and Chief Executive Officer,
Parenteral Drug Association

Si t t in g D ow n W i t h

How has international experience
shaped your career?
I’ve always been interested in travel.
And throughout my career, I’ve
had opportunities to pursue foreign
assignments and learn from people
with different cultural backgrounds.
Their unique perspectives have helped
enrich my own. In a previous role, I was
lucky enough to be based in Switzerlandfor 18 months, where I worked on thedevelopment of an API site – a difficult
task! In the early years of my career,
the European Union didn’t exist, so
regulation across Europe was varied. The
differences between the US regulatoryenvironment and that of our Swiss
partners meant that we had to explain
our ideas on manufacturing to themwithout dictating what they should do.
The experience forced me to develop
better communication skills. I couldn’t
just regurgitate regulatory directives;
I had to find ways of thoughtfully
explaining the aspects that mattered.
In the years since, regulation acrossEurope has harmonized and there arevery few notable differences between US
and European pharmaceutical guidelines.
However, in other regions of the world,
there’s still work to be done – and,through the Parenteral Drug Association(PDA), my colleagues and I are helping
manufacturers understand the benefitsof regulatory convergence, as well as theways cGMP practices can improve their
manufacturing capabilities. I’ve certainly
found a great deal of satisfaction in theseprojects and they continue to affect myprofessional life.
What are the biggest changes you’ve
witnessed?
When I went on my first international
assignment, emails didn’t exist. Neither
did cell phones. To communicate with mycolleagues abroad, I had to wait for theirtelexes to be sent through to the hotel
where I was staying. Now, things arevery different, and the world is connectedin ways I never would have anticipatedback then. This interconnectedness ismirrored in the way manufacturing
has progressed over time. During myfirst working trip to Europe, companies
had many manufacturing plants spread
across different countries. Today, many
companies have consolidated theirproduction processes – often, though
not always, through outsourcing.
Another major change is the riseof biologics. They dominate thepharmaceutical market today, whereasa decade ago, most blockbusters were
small molecule solid dosage forms. This
shift has had an impact on delivery
systems, too. Autoinjectors, for example,
have become commonplace. And I
suspect that the current pandemic will
spark new changes that will shake up theindustry yet again.
What are the goals of PDA?
PDA is a not-for-profit organization. We
are made up of individual members rather
than companies. Though we all havedifferent backgrounds, we are united
by a common goal: the advancement ofpharmaceutical and biopharmaceuticalmanufacturing. We, for example, started
working on biologics in the 1980s – wellbefore they became prevalent in wider
pharmaceutical circles.
Our tagline is “Connecting People,
Science, and Regulation.” It is certainly
a great descriptor of what we do – andone that predates even my membership!
Our organization holds a variety ofvolunteer-led activities and develops
consensus statements on manufacturing
topics. Training our members is also
important to us. We own a facility – aminiature manufacturing plant – where
we host more than 150 classes eachyear, allowing our members and otherindustry professionals to gain hands-on
experience. And, of course, we are heavily
engaged in interaction with regulatory

 51


bodies around the world – and manyof our members are, in fact, regulators.
Importantly, everyone at PDA has anequal role to play. Our members are also
consultants and critical suppliers to theindustry. All voices help inform the way
the organization operates.
What do you predict for pharma’s future?
Cell and gene therapies are fast becoming
an integral part of the pharmaceuticallandscape. They aren’t just treatments;
they’re cures! PDA holds several
meetings each year where we invite
people whose lives are directly affectedby these products to share their stories.
It’s amazing to see first-hand how alifetime of ill health can be transformed
using a cell or gene therapy.
Although these advanced medicines
are exciting, we must not forget theimportance of other types of treatment.
Take COVID-19 as an example; there is apressing need for a vaccine for us all – but,for patients affected by the virus, othertypes of medicine are also necessary.
Striking a balance between old and newtreatments is crucial to the future successof the industry and its ability to manage
emerging healthcare needs.
What advice would you give someone
just starting out in the industry?
First, don’t be afraid to try new things. It’s
easy to get stuck in a rut, but being open
to new opportunities can remedy that.
Some of the most exciting and memorable
moments of my career have been shapedby unexpected offers to participate inexperiences outside my comfort zone.
Second, recognize that mistakes areultimately learning opportunities.
Missteps in the drug manufacturing
process are obviously out of the question– but anyone with experience will tell
you that those times when things don’t
go your way can be some of your best.
Don’t wallow in self-pity; pick yourself
up and do better next time.
www.themedicinemaker.com

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