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Volume 42 Number 1
PHARMACEUTICAL TECHNOLOGY

HUMAN DATA SCIENCE

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JANUARY 2018

Research & Development | Real-World Value & Outcomes | Commercialization | Technologies

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 Data Integrity Process Elemental JANUARY 2018 Volume 42 Number 1
PLUS: Requirements Validation Impurities

Advancing Development & Manufacturing

PharmTech.com

Finding the Right Mix

for 2018 Bio/Pharma Success

PEER-REVIEWED
Removing Subjectivity from the Assessment
of Critical Process Parameters and Their Impact
FORMULATION FLUID HANDLING PACKAGING
Opioid Abuse-Deterrents Peristaltic Pump Tubing Container Closures
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 “Researchers at
the Population
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working to
protect
women’s lives.”
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Desmond Allen,
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Ross Employee Owner

Scan to learn more.

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4 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

 
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 January 2018 Volume 42 Number 1

Pharmaceutical Technology is the authoritative source of peer-reviewed research

and expert analyses for scientists, engineers, and managers engaged in process
development, manufacturing, formulation and drug delivery, API synthesis, analytical
technology
techno
tec hnolog
logg y and
and testing,
testin
tes g, packaging,
ting, p kag
pac ging, IT, outsourcing, and regulatory compliance in the
pharmaceutical
pha
harma
rmaceu
rma ceutic
ceu tical
tic al and biotechnology
biote
bi otechn
ote chnolo
chn o ogy
olo g y industries.
ind
t e cover

COVER
CO STORY
co e

4 Finding
14
1 the Right Mix for
2018
20 Bio/Pharma Success
n the

Will
W ill b
business decisions and drug pricing policies help or
hinder
h in
nde science and drug approval advances in 2018?

Cover
C over Design by Dan Ward
On

IImages:
Im
mage Iraidka/Shutterstock.com
O

FEATURES
F E ATURES
2018 BIO/PHARMA OUTLOOK API SYNTHESIS & MANUFACTURING FLUID HANDLING

20 Drug Pricing 24 FDA Ramped up 38 Selecting and Installing

and Quality Are
Top Issues for 2018
Policy makers look to boost
generic drugs, curb opioid abuse,
and maintain incentives for innovation.
22 What to
Watch for in 2018
The industry will see an
impact from financing, M&As,
advanced therapies, generic
drugs, and the retail market in 2018.
Approval Rate in 2017
FDA looks to achieve near-record
level of new drug approvals
following slowdown in 2016.
FORMULATION
34 Tackling the
Opioid Crisis with Abuse-
Deterrent Formulations
Abuse-deterrent opioid formulations
generally fall into two categories: the first
is based on a physiochemical abuse-
deterrent approach and the second
combines the opioid with an antagonist.
Peristaltic Pump Tubing
Proper selection and installation
optimizes fluid system performance.
INTERNET OF THINGS
40 Pharma
Equipment Gets Smart
The Industrial Internet of Things
can be used to monitor equipment
health and optimize processes.
QUALITY
56 Process Validation
in Biologics Development
Process validation is an extension
of biologics development processes.

Continued on page 8

PEER-REVIEWED RESEARCH
PEER-REVIEWED

46 Removing Subjectivity from the Assessment

of Critical Process Parameters and Their Impact
A new algorithm uses a statistical approach to critical process
parameter assessment, allowing for faster, more consistent, and less
subjective critical process parameter quantification, visualization, and documentation.

PharmTech.com
Continued from page 6
FEATURES continued
ELEMENTAL IMPURITIES
58 Determination
of Dermal PDE for
Pharmaceutical Products
The authors offer recommendations
for permissible daily exposures and
concentration limits of elemental
impurities for dermal drug products.
PACKAGING
62 Boosting Functionality
of Container Closures
Advanced closures and capping equipment
have new product-protecting features.   according to Siegfried Schmitt, PhD,
PHARMACEUTICAL SERIALIZATION
64 Pharma Serialization
Nears a Tipping Point
Everyone may not be ready for the
deadline, but open standards based on
GAMP and GS1 will soon be released;
more companies are also leveraging
what they’ve learned from serialization
to improve overall efficiency.
Pharmaceutical Technology is selectively abstracted or indexed in:
» Biological Sciences Database
(Cambridge Scientific Abstracts)
» Biotechnology and Bioengineering Database
(Cambridge Scientific Abstracts)
» Business and Management Practices (RDSI)
» Chemical Abstracts (CAS)
» Current Packaging Abstracts
» DECHEMA
» Derwent Biotechnology Abstracts
(Derwent Information, Ltd.)
» Excerpta Medica (Elsevier)
» International Pharmaceutical Abstracts (ASHP)
» Science Citation Index (Thomson)
Pharmaceutical Technology is proud to be a member of IPEC and PDA.
NEWS & ANALYSIS DEPARTMENTS/
FROM THE EDITOR
PRODUCTS
10 New Year, 12 Product Spotlight
New Questions 68 Pharma Capsules
Bio/pharma
professionals manage expectations
69 Showcase/Marketplace
amid industry uncertainty. 69 Ad Index
ASK THE EXPERT
70 Meeting Data
Integrity Requirements
Enterprise-wide processes,
procedures, and systems are the keys
to data integrity and peace of mind,
principal consultant at PAREXEL.
PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-
2521, Digital ISSN: 2150-7376) is published monthly,
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PharmTech.com
from the editor

New Year,
New Questions
Rita Peters

Bio/pharma professionals manage

expectations amid industry uncertainty.

I
n the first year of the Trump ad-
ministration, people have learned
to expect the unexpected. Executive
orders and policy statements issued
by the administration in the first few
months of 2017 were at times con-
tradictory and conflicted with bio/
pharma operations.
President Tr u mp promised to
streamline FDA approvals, promote
market-based reforms to create com-
petition and lower drug prices, and
cut regulations. A temporary hiring
freeze, however, delayed FDA from
filling hundreds of positions needed to
fulfill agency goals. The administra-
tion’s agenda to move drug manufac-
turing back to the United States from
cheaper offshore locations ran counter
to the goal of reducing drug prices (1).
A directive to curb immigration from
certain regions spurred worry about
restrictions on foreign-born research-
ers working in the US (2).
The confirmation of Scott Gottlieb
as FDA commissioner provided some
stability for the agency, as did renewal
of the user fee programs. The slashing
of corporate taxes at the end of 2017
promised more financial options for
bio/pharma companies.
Uncertainties surrounding the
healthcare reform and funding for
Medicaid and children’s health pro- predicting business would decline in
grams lingered as 2018 began. The the next year (14%) was slightly higher
threat of drug shortages continued as than the previous year.
Puerto Rico, a major pharma manu-
facturing region, struggled to recover Prognosis for the industry
The one-year outlook for the bio/phar-
from the effects of Hurricane Maria (3).
While such macro events may be be- maceutical industry as a whole was a
yond the control of most bio/pharma bit more positive after sliding in re-
professionals, see daily business opera-
cent years. More than half (54.2%) of
tions up close and form opinions about respondents said business would im-
the outlook for 2018. prove for 2015; however, only 47.8% ex-
pected improvement in 2016 and 45.6%
Outlook from the front line in 2017. For 2018, 47.6% expressed a
Pharmaceutical Technology sampled positive one-year outlook.
opinions of more than 480 bio/pharma For the longer term (five years), re-
professionals from around the world (4) spondents were less optimistic than
about job security, trends in the in- the previous year. Fewer respondents
dustry, how changes impact their daily said business would improve (59.3%
work, and future business prospects. in 2017 compared with 63.3% in 2016).
The survey was conducted in Septem- However, fewer respondents antici-
ber and October 2017. pated declines in business and more
Fewer respondents (39%) said busi- expected business stability in the lon-
ness at their company increased in ger term.
2017 compared with 2016 (44%) (5);
however, fewer (14.9%) respondents References
also said business decreased in 2017 1. J. Wechsler, “Does Pharma Really Want
compared with 2016 (19.3%). The to Overhaul FDA?” www.PharmTech.
com, Feb. 1, 2017, pharmtech.com/does-
number of respondents reporting a pharma-really-want-overhaul-fda.
downsizing was up slightly (17.9% in 2. C. Hroncich, “Biotech Executives Ex-
2017 vs. 16.9% in 2016). The percent- press Concern Over Immigration Order,”
age of workers reporting work mov- PharmTech.com, Feb. 10, 2017, www.
ing to contract service providers was pharmtech.com/biotech-executives-
express-concern-over-immigration-
up slightly (12.5% in 2017 vs. 10.5%
PATPITCHAYA/SHUTTERSTOCK.COM

Rita Peters is editorial
director of Pharmaceutical
Technology. Send your
thoughts and story ideas to
rita.peters@ubm.com.
in 2016).
Respondents were slightly less up-
beat about the prospects of business
improvements at their companies;
54.2% predicted that their compa-
ny’s business would improve in 2018, 5. 2016 Pharmaceutical Technology/Phar-
compared to 59.1% predicting im-
provements for 2017. The percentage
order-0
3. “FDA Commissioner Gottlieb Gives Up-
date on Saline and Amino Acid Short-
ages,” PharmTech.com, Jan. 5, 2018.
4. 2017 Pharmaceutical Technology/Phar-
maceutical Technology Europe Annual
Employment Survey.
maceutical Technology Europe Annual
Employment Survey. PT

10 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

Flexible by Design
Comprehensive options for changing needs
The BioFlo® 320 offers a wide range
of options to meet your ever changing
needs. It controls both single-use and
autoclavable vessels. Its universal
gas control strategy allows for both
microbial and cell culture applications.
The BioFlo 320 can do it all.
www.eppendorf.com • 800-645-3050
131.A1.0137.A © 2017 Eppendorf AG.
> Compatible with the BioBLU®
Single-use Vessel portfolio
> Extensive working volume range
of 250 mL–40 L on a single bench-
scale control platform
> Multi-unit control of up to eight
systems from a single interface
improves efficiency
PRODUCT SPOTLIGHT

Planetary Mixer for Additional Size

Mixing and Dispersion
The four-gallon model PDDM-4
planetary dual disperser from
Ross, Charles & Son is equipped
with two high-viscosity blades
and two high-speed dispersers.
All four agitators rotate on their
own axes while orbiting the
vessel, ensuring rapid powder
wet-out and deagglomeration.
The mixer is suited for vacuum
operation, mixing thick slur-
ries and highly-filled pastes,
and includes a jacketed mix
vessel. According to the com-
pany, the mixer delivers improved dispersion and uniformity
throughout a viscosity range up to around 2 million centipoise.
Ross, Charles & Son
www.mixers.com
for Quaternary
Diaphragm Pumps
PSG, a Dover company, has
expanded its Quattroflow line of
quaternary, four-piston diaphragm
pumps to include the QF10k
size pump. The pump has been
designed to fill the gap between
the existing QF4400/5050 and
QF20k pump sizes and provides a
maximum flow rate of 10,000 lph.
Product features include a
stainless-steel pump chamber design, a maximum pressure of 6
bar (87 psi), 20:1 turn-down ratio, linear flow performance, and
high-flow stability even at low flow rates. Additionally, the pump
offers clean-in-place/steaming-in-place and autoclave capabilities.
Available accessories include control box, power box, diaphragm
sensor, and proportional–integral–derivative controller. Typical
applications include chromatography and cross-flow filter systems.

Wilden
www.psgdover.com/en/wilden

Cartridge Filters for Space-

Restricted Applications
Amazon Filters has developed 2.5-
and 5-in. SupaPore Junior cartridge
filters for processes requiring a
compact filter system. These filter
sizes are suited for low flow, up
to 2m3/Hr of fluids and 100Nm3/
Single-Use Filling Hr of gas processes, including a
range of pharmaceutical applica-
Assemblies for Aseptic tions where space is limited.

Fill/Finish Applications The products come in a

AdvantaPure’s sterile-molded filling assemblies are suited for
single-use vial and syringe filling. The products are made from
AdvantaSil silicone tubing and molded components, or weld-
able and sealable AdvantaFlex biopharmaceutical tubing and
components. The assemblies are completed with bags, filters,
sterile connectors, filling needles, and other accessories.
The assemblies also are supplied sterilized and ready to use,
and feature smooth, molded junctions for continuous flow and to
reduce leak and entrapment issues associated with barbed fit-
tings. The multiport tri-clamp design helps reduce potential leak
points and minimizes holdup volume, according to the company.
AdvantaPure
www.advantapure.com
range of different pleated
depth media, including pre-
filters and sterilizing grade
membranes. Additionally, the filters are available with a range
of different end fittings to enable use with existing equipment.
The cartridge filter range is fully compatible with the company’s
industrial housings (51A Series) and sanitary housing options
(70 Series). All housings are Pressure Equipment Directive-
compliant and can be used in temperatures from -10 to 150 °C.
Company housings are CE-marked for European conformity
and are available in both 316L stainless steel and alloy 22.
Amazon Filters
www.amazonfilters.com

12 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

 Bio/Pharma Outlook
Finding the
Right Mix for 2018
Bio/Pharma Success
Rita Peters
Will business decisions and drug pricing policies
help or hinder science and drug approval advances in 2018?
U
ncertainty was the theme for the
bio/pharma companies at the start
of 2017 as the industry waited to
see how the political agenda of the in-
coming Trump administration would
affect healthcare reform, drug pricing,
R&D investment, and regulations.
In the ensuing 12 months, the in-
dustry witnessed a record number of
drug approvals including the first gene
therapies and a digital pill, a new com-
missioner at FDA, a major overhaul to
US corporate tax structure, and the an-
nounced move of the European Medi-
cines Agency to Amsterdam. Unfin-
ished business—open questions about
the fate of the US healthcare system, an
unresolved federal budget, and ongoing
debate over drug pricing—have extended
the air of unpredictability into 2018.
Despite bio/pharma’s strong empha-
sis and success in science and technol-
14 Pharmaceutical Technology JANUARY 2018
ogy, financial and policy questions
may be the dominant factors in the
outlook for 2018.
Politics, taxes, and drug prices
Efforts to replace the Affordable Care
Act (ACA) failed in 2017; only one com-
ponentthe individual mandatewas
repealed as part of the Tax Cuts and
Jobs Act (TCJA) of 2017. The future
funding for Medicaid and children’s
health programs remained uncertain
at the beginning of 2018.
A reduction in the number of in-
sured patients could translate into a
drop in drug sales. The Congressional
Budget Office estimated that by 2027,
13 million fewer people would have in-
surance coverage if the mandate were
repealed, potentially reducing the
number of patients seeking prescrip-
tion or generic drugs (1).
P h a r mTe c h . c o m
Thanks to the overhaul of the tax
system enacted in late December 2017,
US-based bio/pharma companies
started 2018 with a sharp reduction in
the corporate tax rate, lower taxes on
income earned abroad, and simplified
rules for expensing new investment
purchases. On the negative side, the
orphan drug tax credit was reduced
from 50% to 25% of qualified research
and clinical testing activities.
While lower tax bills may help fill
bio/pharma company coffers, the
debate over the high cost of drugs
remains a threat to profitability. A
IRAIDKA/SHUTTERSTOCK.COM
2017 sur vey by PwC’s Health Re-
search Institute (2) found that, in
general, bio/pharma executives rec-
ognize that the industry has a drug
pricing problem. Executives are split,
however, as to how—or if—the prob-
lem should be addressed.
 ®
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tive
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 Bio/Pharma Outlook
The survey assessed opinions of ex-
ecutives from pharma and insurance
companies on drug prices and value-
based payment models; 45% of the re-
spondents expect the Trump adminis-
tration to accelerate downward pressure
on drug prices. More than half of the
respondents (54%) thought new federal
or state drug pricing laws were very or
somewhat likely to be enacted.
Respondents were equally split (44%
responding “yes,” 44% responding “no”)
on the question: Do you think the in-
dustry should consider limiting the
growth of drug prices during the next
fiscal year? However, more than half
(53%) said their organization was not
considering limiting the growth of drug
prices during the next fiscal year; only
23% said their organization was consid-
ering limits to growth of drug prices.
The PwC report explored the poten-
tial of value-based contracts: a drug’s
price is set based on how it performs in
real-world settings versus the current
approach of basing pricing on data col-
lected during controlled clinical trials.
Successful therapies would create re-
wards; drugs that did not perform may
result in reimbursements to patients.
Pharma and health industry execu-
tives surveyed expressed enthusiasm
for value-based contracts; however,
participation is limited. Only one-
quar ter of t he sur veyed pharma
executives reported that their or-
ganizations had participated in a
value-based program; however, 80%
of those that participated said the
contracts were successful. More than
one-third (38%) said the potential re-
wards of a value-based contract were
worth the risks.
Value-based pricing models face a
number of operational hurdles, in-
cluding the lack of measurable out-
comes regulatory questions, data
sharing, and establishing agreement
on performance metrics. The value for
the patient must also be assessed.
Cost of innovation
Although promising platforms such
as gene therapies are emerging, the
challenge for bio/pharma is to develop
these platforms in an efficient way to
create “near-term value for all stake-
holders,” according to the authors of
Deloitte’s annual study on industry
return on investment (3).
The report—based on analysis of
estimated return on investment from
late-stage pipelines of 12 large-cap
biopharma companies—noted that
projected R&D returns continued to
decline from 10.1% in 2010 to 3.7% in
2016 and 3.2% in 2017. The average cost
to bring a drug to market continued to
increase from $1.188 billion in 2010 to
$1.992 billion in 2017.
Innovation appears to be on the
upswing, however, particularly in the
biologics drug arena. FDA’s approval of
the first gene-therapy drugs and the re-
bound in the number of new molecular
entities approved (46 in 2017 compared
with 22 in 2016) are signs of payoffs for
research efforts.
Analysts at Evaluate Pharma (4) note
that such scientific breakthroughs im-
prove the lives of patients, and can richly
reward the drug’s creators. They also
credit FDA’s efforts to speed approvals
of new therapies and generic drugs.
Recent successes and the implemen-
tation of the US tax cuts may spur re-
newed investment and acquisitions in
2018. The successes need to continue,
however, to keep investors interested
in the market. The bar for success is
set high with rapid progress during
the past few years, Evaluate Pharma
reports, and disappointments would
remind investors that in biopharma,
“failure is a fact of life.”
References
1. Congressional Budget Office, “The Bi-
partisan Health Care Stabilization Act
of 2017 and the Individual Mandate,”
(Nov. 29, 2017), www.cbo.gov/publica-
tion/53352.
2. PwC, Launching to Value: Pharma’s
Quest to Align Drug Prices with Out-
comes, September 2017.
3. C. Terry and N. Lesser, A New Future for
R&D?, Deloitte, 2017.
4. A. Brown, E. Elmhirst, J. Gardner, EP
Vantage 2018 Preview, Evaluate Pharma,
December 2017. PT

Gottlieb outlines FDA 2018 policy goals

Reducing the number of regulations was a key component of the Trump ad-
ministration’s 2017 agenda. FDA Commissioner Scott Gottlieb (1) noted the
agency must recognize “when scientific innovations warrant new, more flex-
ible regulatory approaches in order to make sure advances in care can reach
patients.” To accomplish this, he wrote, the agency must “continually adapt
our regulations to enhance efficiency, improve our effectiveness, and update
old and out-of-date requirements.”
Planned 2018 regulations for drug compounding facilities would clarify
which drugs may be compounded and promote more efficient, streamlined
manufacturing standards, while ensuring safety and quality measures.
Another proposed rule would establish national standards for the licensing of
prescription drug wholesale distributors and third-party logistics providers, as
part of track-and-trace requirements.
Clearly defined standards must not place unnecessary burdens on regulated
companies, Gottlieb wrote, and should reflect the latest science. Outdated
rules will be removed, he noted, singling out “an outdated inspection provision
for biologics and outdated drug sterilization requirements to remove barriers
to the use of certain sterilization techniques.”
The agency also faces 2018 deadlines associated with the 21st Century
Cures Act including drafting guidance documents for patient-focused drug
development; reporting to Congress on standards for advanced regenerative
therapies, compliance activities, and hiring authority or scientific, technical,
and professional personnel; and holding public meetings on the qualification
of drug development tools.
A key deadlineNov. 26, 2018looms for bio/pharma companies
to comply with requirements for product identifiers and verification in
accordance with the US Drug Supply Chain Security Act.
Reference
1. S. Gottlieb, “Looking Ahead: Some of FDA’s Major Policy Goals for
2018” FDA Voice, Dec. 14, 2017, https://blogs.fda.gov/fdavoice/index.
php/2017/12/looking-ahead-some-of-fdas-major-policy-goals-for-2018/.

16 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

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Commercialization | Technologies
 Bio/Pharma Outlook
Drug Pricing and Quality
Are Top Issues for 2018
Jill Wechsler
Policy makers look to boost generic drugs,
curb opioid abuse, and maintain incentives for innovation.
C
oncerns that high and rising drug
prices hinder patient treatment will
continue to shape pharmaceutical
markets in what promises to be a tumul-
tuous year in Washington. Policy mak-
ers will weigh access to medicines with
the desire to encourage biopharmaceu-
tical R&D, which relies on regulatory
efforts to streamline clinical research,
ensure product quality, and achieve
more efficient oversight. The Novem-
ber mid-term Congressional elections
already are heating up, as Republicans
seek to maintain control of the House
and Senate amidst continuing debate
over government funding and health-
care policies. These developments will
affect resources and initiatives for FDA,
the National Institutes of Health, and
federal and state health programs.
Global regulatory issues will be im-
portant, as drug sourcing and produc-
tion expands overseas and disease out-
breaks threaten public health around
the world. International harmonization
of regulatory standards and mutual
recognition agreements will advance
as authorities look for efficiencies in
ensuring drug quality, in managing
product lifecycles, and in blocking il-
legal trafficking of counterfeit drugs.
Drugmakers also face extensive changes
under Brexit, including relocation of the
Jill Wechsler
is Pharmaceutical
Technology’s Washington
editor, 7715 Rocton Ave.,
Chevy Chase, MD 20815,
jillwechsler7@gmail.com.
20 Pharmaceutical Technology JANUARY 2018
European Medicines Agency to Amster- important one-time therapies. Manu-
dam and the need to ensure appropriate facturers will need strong data to jus-
marketing authorizations in Europe. tify launch prices, especially for targeted
therapies. And payers will look more to
Coverage and controls reports from the Institute for Clini-
The heated, ongoing debate over revis- cal and Economic Review (ICER) and
ing the Affordable Care Act (ACA) and other third-party analysts on whether
state Medicaid and children’s health benefits of a new medicine justify costs.
programs will remain in the spotlight
as manufacturers evaluate how policy Encouraging innovation
changes may limit drug coverage and A main concern for the biomedical re-
reimbursement. Pharma companies search community is that any form of
backed the ACA and agreed to pay price controls would discourage private
millions in additional taxes to expand investment in biomedical innovation
pharmacy benefits. Now consumers and limit development of new cures
may face higher out-of-pocket costs that for critical diseases. Even though drug
will squeeze drug utilization and ignite companies enjoy healthy profits, policy
further efforts to rein in pharmaceuti- makers are reluctant to dampen the cur-
cal prices. The Centers for Medicare rent boom in scientific discovery that
and Medicaid Services (CMS) recently has led to new gene and cellular thera-
revised how Medicare Part B pays hos- pies and robust R&D pipelines. FDA ap-
pitals for administering certain drugs proved more than 40 novel medicines
and seeks to facilitate coverage of newly through early December 2017, heading
approved biosimilars and generic drugs. for a record year.
A new proposal calls for Medicare Part US-patent policy and market ex-
D prescription drug plans to share with clusivity provisions are crucial to
patients the rebates and discounts nego- maintaining an inviting climate for
tiated by manufacturers and pharmacy investing in the biotech industry, but
benefit managers (PBMs). This push issues have emerged about innovator
for more transparency in drug prices firms using patents to block competi-
and discounts could erode revenues for tion. The development and marketing
PBMs and further escalate the finger- of new biosimilars face delays from
pointing by manufacturers, insurers, intense patent battles, and a recent ef-
ORHAN CAM/SHUTTERSTOCK.COM
and PBMs over who’s to blame for high- fort to extend protections by transfer-
priced medicines. ring patents to a Native American tribe
These trends will build interest in has generated a strong backlash. These
value-based pricing strategies that link actions fuel questions about over-ex-
drug reimbursement to patient response tended exclusivity periods for newly
to treatment. CMS and insurers also approved drugs and biologics, par-
contemplate arrangements that spread ticularly for orphan drugs and refor-
reimbursement over several years for mulated products. The Supreme Court
P h a r mTe c h . c o m

will weigh related issues as it considers
an important case in 2018 that could
revise the current US Patent Office
process for reviewing patent challenges.
While FDA generally avoids involve-
ment in pricing issues, commissioner
Scott Gottlieb looks to enhance con-
sumer access to medicines by promoting
market competition. A main strategy is
to speed the development and approval
of generic drugs, particularly for com-
plex therapies and combination prod-
ucts and in classes dominated by one or
two brands. Gottlieb also wants to pre-
vent brands from blocking generic-drug
makers from obtaining supplies needed
for bioequivalence testing and other tac-
tics that delay market entry.
More efficient and timely FDA re-
view and approval of new medical prod-
ucts also will enhance competition, and
the agency should gain added flexibility
in this area from implementing the 21st
Century Cures Act and reauthorized
user fee programs. Further advances
should emerge in the coming months
as Gottlieb unveils more proposals
for spurring efficient clinical research
methods, particularly to broaden indi-
cations for cancer therapies, and wider
use of digital technology and updated
information systems. Janet Woodcock,
director of the Center for Drug Evalua-
tion and Research (CDER), is working
to further automate and better manage
the new drug development and appli-
cation review system. And Peter Marks,
director of the Center for Biologics Eval-
uation and Research (CBER), is imple-
menting a framework for identifying
and evaluating regenerative medicine
advanced therapies (RMATs), includ-
ing gene therapies.
To meet goals for the timely evalu-
ation of applications for these cutting-
edge medicines, including priority ge-
nerics, FDA wants manufacturers to
update facilities and processes to ensure
more reliable production of high-qual-
ity medicines so that manufacturing is-
sues will not delay the approval of new
breakthrough drugs or biosimilars. To
this end, FDA is requiring applications
for new drugs, biologics, and generics
to list all facilities involved in prod-
 Bio/Pharma Outlook
uct testing and production in order to for addicts and access to opioid overdose
meet accelerated review goals. Ongoing rescue drugs to lower the death rate
shortages in sterile injectibles, biotech from abuse and will look to implement
therapies, and even conventional drugs new strategies more effectively.
spotlight the need for industry to invest FDA has ramped up its direct involve-
in modern facilities and quality opera- ment in tackling opioid abuse by encour-
tions able to detect and prevent distri- aging research on new non-opioid pain
bution of adulterated and contaminated treatments and more effective medicines
medicines. to prevent and treat addiction. A related
goal is to help overcome hurdles in de-
Combating opioids veloping low-cost generic abuse deterrent
The deadly opioid epidemic, which is formulations (ADFs) and overdose treat-
taking thousands of lives and driving ments and to devise more secure pack-
up healthcare costs on every level, pres- aging and distribution strategies for pain
ents serious challenges to pharmaceuti- medications.
cal companies. Health authorities and On the international front, FDA is col-
medical practitioners recognize the laborating with other agencies to combat
need for pain medicines for patients import of falsified/substandard medi-
with genuine need of treatment, while cines, including dangerous pain treat-
also struggling to curb excessive pre- ments from overseas. At home, opioid
scribing and distribution of drugs sub- manufacturers face criminal investiga-
ject to abuse and misuse. Congress and tions and lawsuits for excessive marketing
the White House have rolled out poli- and distribution of these products, and
cies and plans for limiting inappropriate legal challenges are likely to escalate as
opioid use and for expanding treatment overdose rates continue to rise. PT
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Pharmaceutical Technology JANUARY 2018 21
 Bio/Pharma Outlook
What to Watch for in 2018
Jim Miller
The industry will see an impact from financing,
M&As, advanced therapies, generic drugs, and the retail market in 2018.
I
t was a great year for much of the bio/
pharmaceutical contract manufactur-
ing and development (CDMO) in-
dustry in 2017. Research organizations
continued to generate hundreds of new
candidates, while venture capitalists
and private equity investors maintained
a robust flow of new funding to emerg-
ing bio/pharma companies, which are
highly dependent on CDMOs. An active
deal environment provided rich exits for
CDMO founders and investors.
The momentum from 2017 looks
like it will continue into 2018, but one
should never extrapolate today’s trends
inexorably into the future. Here are
five industry themes to watch closely
for their potential impact on the
CDMO industry.
Bio/pharma financing
The demand for CDMO services has
historically been tied to funding cycles
for emerging bio/pharma companies,
and 2017 was the fifth year of the up-
ward slope of the funding cycle that
began in 2013. The capital raised by
emerging bio/pharma in 2017 should
certainly maintain demand for CDMO
services through 2018. Indeed, new
business bookings by clinical contract
research organizations (CROs), a bell-
wether for development activity, re-
mained quite strong through 2017.
CDMO executives should keep a
close eye on the fundraising environ-
Jim Miller is president of
PharmSource Information
Services, Inc., A GlobalData
Company, and publisher
of Bio/Pharmaceutical
Outsourcing Report,
tel. 703.383.4903,
Twitter@JimPharmSource,
info@pharmsource.com,
www.pharmsource.com.
22 Pharmaceutical Technology JANUARY 2018
ment, however, especially the public
equity markets. Availability of capital
can be impacted by factors external to
the industry that change investor psy-
chology, even when underlying industry
fundamentals are unchanged. Those
factors include a general economic slow-
down (which many economists are pre-
dicting for 2019), rising interest rates (a
reality), and political uncertainty (2018
is an election year in the United States).
On average, emerging bio/pharma com-
panies have only 12–15 months of cash
of hand, and they are likely to slow their
spending at the first sign that raising
new capital could be difficult.
Mergers and acquisitions
There were some very large deals in the
CDMO industry in 2017, and a lot of
smaller ones. Private equity firms con-
tinue to be drawn by the high level of
drug development activity and the op-
portunity to roll up small CDMOs into
larger entities. Larger CDMOs continue
to pursue strategic acquisitions that add
technical capabilities and provide entry
into new market segments.
The industry will see more M&A
activity in 2018, but the pace may slow
down. Valuations have gotten quite high,
even for smaller properties that require
investors to fund substantial additional
capital for capacity expansions and up-
grades. Financing will get progressively
more expensive as interest rates rise dur-
ing the year; that could force valuations
down but potential sellers may balk at
taking lower valuations than their com-
petitors got just a few months ago.
One development to watch for is
a very big deal involving an industry
leader, along the lines of Thermo Fish-
er’s acquisition of Patheon and Lonza’s
acquisition of Capsugel in 2017. The
P h a r mTe c h . c o m
largest CDMOs need to do deals to
deliver on promises to investors and to
increase their ability to service global
bio/pharma companies with their bil-
lions in manufacturing and R&D ex-
penditures. It would not be surprising
to see another large private equity firm
or strategic buyer from outside the in-
dustry make a game-changing entry
into the CDMO industry.
Advanced therapies
New treatment modalities such as gene
therapy, cell therapy, and antibody drug
conjugates are becoming a bigger part of
the new drug pipeline. Most of the candi-
dates are early stage, with a high percent-
age still owned by academic institutions,
but some initial clinical successes in ac-
tually curing once-incurable diseases is
stoking investor interest, and established
bio/pharma companies are actively buy-
ing up advanced-therapy companies.
Advanced therapies present a chal-
lenge for CDMOs because their busi-
ness model and technology often don’t
fit the traditional CDMO model. Many
of the candidates are autologous (i.e.,
they involve taking cells from a patient,
processing them with the sponsor’s
technology, and re-injecting them into
the same patient). That is very different
from the CDMO model of producing
multiple units of a single product.
Still, a number of entrepreneurial
CDMOs have positioned themselves
for advanced therapies, and several es-
tablished CDMOs have built positions
LIGHTSPRING/SHUTTERSTOCK.COM
that are expanding with acquisitions
and internal investment. Demand for
these services appears strong, and the
industry can expect to see further M&A
activity in this sector during the year,
as major CDMOs look to add advanced
therapies to their portfolios.
  Bio/Pharma Outlook
Restructuring in The CVS–Aetna announcement The kind of market power that might
generic-drug industry came in the midst of speculation that be accumulated by CVS/Aetna and
Pricing and margins for generic drugs Amazon is preparing to enter the Amazon could create new demands on
continue to spiral downward, and drug distribution business. The on- drug sponsors and manufacturers over
regulators and payers are determined line retailing giant threatens to dis- issues such as price, inventory mainte-
to keep the pressure on. In the US, rupt the way patients get their drugs nance, just-in-time delivery, and pack-
the FDA commissioner has promised today thanks to its large customer aging. CMO executives should probably
new procedures and regulations to base, skill in app-based ordering, devote some time to understanding
speed approval of generic drugs, and warehousing and distribution scale, the implications of those downstream
the nominee to head the Department and willingness to take low profit changes and begin thinking about how
of Health and Human Services has margins. they should respond. PT
promised to focus on bringing drug
prices down. In Europe, the turn from
branded to commodity generics has
undermined the industry’s profitability
as governments use tendering to pur-
So much more
chase pharmaceuticals.
The pressure on generics has signifi-
than a clean surface
cant implications for the bio/pharma
CMO industry. Much of the industry
has been dependent on branded gener-
ics, especially the European CMOs. Lost
volumes and narrowed margins, com-
pounded by overcapacity in solid dose
manufacturing, are forcing CMOs to re-
structure, including facility shutdowns.
The problem could be compounded
by the restructuring efforts of the large
generic-drug companies themselves.
Some, like Teva, are committed to
downsizing their sprawling and ineffi- Rese earch h & Deve elop
op
o pment
cient manufacturing networks. Others, Tecchniccal
c Sp peccialists ts
ts
like Sandoz, are reportedly preparing
to exit the solid dose portion of their Qua ality Buiilt In
business, which is also likely to result in
plant closings. The risk to CMOs is that
Global Presence
some of the closed or divested manufac- Complete Range
turing facilities will end up becoming
CMO operations themselves, worsening Industry Experts
the overcapacity problem. Validation
Retail revolution Innovatio
onn
CMOs will do well to follow develop-
ments in the retail supply chain, be-
Exxperienc
nced
cause they could create new opportuni- Co
Collaborative
ties and challenges. The pharmaceutical
It’s not just about the products. It’s more
industry was rocked at the end of 2017 than just a clean surface. Contec prides
when the retail and mail order phar- itself on its longstanding technical
macy giant CVS announced that it in- expertise, innovation and commitment to
quality. Continued improvements in lean
tended to buy health insurer Aetna. If manufacturing, safety initiatives, vertical
the deal were to go through, it could global integration as well as Research and
drive a lot of changes in the healthcare Development, drive our critical environments
product range forward.
delivery system, concentrating more
market power in the hands of a few For more information, email
www.contecinc.com wipers@contecinc.com or call 864-503-8333.
large integrated providers.
Pharmaceutical Technology JANUARY 2018 23
API Synthesis & Manufacturing
FDA Ramped up
Approval Rate in 2017
Cynthia A. Challener
FDA looks to achieve near-record level of new
drug approvals following slowdown in 2016.
T
he small number of new drug
approvals in 2016only 22 (1)
may have been an anomaly. As of
Nov. 14, 2017, FDA’s Center for Drug
Evaluation and Research (CDER) has
approved 38 new drugs (2) and is on
track to achieve numbers similar to
the 41 approvals in 2014 (3) and 45
approvals in 2015 (4). The approved
drugs include a number of firsts in
terms of both drugs for untreated dis-
eases and new modes of action. Nearly
two-thirds were approved under one
or more accelerated pathways and
just over one-third were designated as
orphan drugs.
Healthy market for APIs
Given the return to record-level FDA
approvals, it is not surprising that
Cynthia A. Challener, PhD, is a
contributing editor to Pharmaceutical Technology.
24 Pharmaceutical Technology JANUARY 2018
most industry analysts predict strong
growth in the market for APIs. Mar-
kets and Markets, for instance, pre-
dicts the global API market, including
chemical and biologic branded and ge-
neric-drug substances, will expand at a
compound annual growth rate of 6.3%
from $157.95 billion in 2016 to $213.97
billion in 2021 (5). Market research
firm Grand View Research predicts
the value of the global API market will
reach $239.8 billion by 2025 (6).
Growth is attributed to the aging of
the world population with a concomi-
tant rise in age-related diseases and an
increase in lifestyle-induced condi-
tions and cancer. Small-molecule APIs
account for the greatest share of the
market (6), which reflects the rate of
approvals for drugs based on chemical
and biologic APIs; in 2017 nearly 75%
of the approved drugs as of November
14 were formulated with small-mole-
P h a r mTe c h . c o m
cule APIs (2). Captive manufacturers
held the greatest market share, but due
to increased outsourcing of API manu-
facturing, contract manufacturers are
expected to expand their share more
rapidly in the coming years. Demand
for generic APIs is also increasing rap-
idly (6).
Many accelerated approvals
Manufacturers continue to lever-
age the four expedited review and
approval programs−Fast Track and
Breakthrough Therapy Designations
and Accelerated Approval and Prior-
ity Review processes−made possible
with passage of the FDA Safety and
Innovation Act (FDASIA) in 2012.
FDA under Commissioner Scott Got-
tlieb is also committed to accelerating
the approval of new drugs (7). Nearly
two-thirds (24 out of 38, 63.2%) of the
drugs approved in 2017 through mid-
November were filed under at least
one of these four programs. Of those
24 drugs, just over one-third qualified
for two programs, and nearly 16% for
three. Of the four programs, 22 drugs
were approved under Priority Review,
14 as Breakthrough Therapies, eight
with the Fast Track designation, and
six with Accelerated Approval.
More orphan drugs
The Orphan Drug Act (ODA) was
passed in January 1983 to encourage
the development of drugs to treat rare
diseases. Drugs intended to prevent,
treat, or diagnose a disease/condition
that occurs in less than 200,000 pa-
tients in the United States may be des-
ignated as an orphan drug. Developers
also can receive tax credits for clinical
research expenses and seven years of
marketing exclusivity upon FDA ap-
proval. In the 10 years prior to passage
CONSTANTINE_PAPP/SHUTTERSTOCK.COM
of the ODA, the pharma industry com-
mercialized only 10 products for rare
diseases; since 1983, more than 450
orphan drug products have been ap-
proved for more than 600 indications
(8). In addition, 60% of the 87 Break-
through Therapies approved from
contin. on page 28
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currency and one invoicing process.

© 2017 Patheon Inc. All rights reserved.

Faster Drug Development

IN
I C A L TR I 112 NDA approvals
in 10 years
We develop 75% More than 2x any other CDMO

CL

AL
of all dosage forms For both large and small molecules, the
For large and small molecules, close collaboration Patheon OneSource™ methodology
with the Drug Substance Molecule Team allows minimizes failures due to foreseeable events

G
the application of right-fit science for formulation, and maximizes your molecule’s chances of
N

N
A
UF I
process development, tech transfer and scale-up ACTU R out-licensing or making it to market.
to ensure a smoother transition to market.
Anil Kane, Ph.D., MBA, joined us in 2000
Executive Director, Global Head of
Technical & Scientific Affairs PRODU
UG CT
DR

Stability and scalability

By collaborating with the Drug Substance Project
Manager, the Drug Product Project Manager ensures your
trial-level drug product is also suitable for scale-up.
Nicky Arvanitis, MBA, joined us in 1997
Director, PDS Project Management

RO R
P

JE C GE
T MA NA AL
PACK
IC A
GI
N

Securely packaged for on-time distribution

CL I

NG

Combining best-in-class robust primary and secondary

clinical packaging and secure on-time distribution to meet
quality standards and patient compliance.
AN

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IO
D

DI T
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CK - UP
BA We always have a back-up plan
To ensure your molecule never goes
off track, every team includes a
Save an average of
14 Weeks
P RO

Back-up Program Manager ready to

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RA step in any time life gets in the way.

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& $44.7M
Something needs to be done about the
high cost of drug development. By
combining drug substance, drug
product, clinical manufacturing and
clinical packaging into a single process,
Patheon OneSource™ accelerates your
Speed through communication molecule like nobody else can.
The Program Manager is the architect
of your drug development program. This
single point of contact both within Patheon,
and with you, simplifies every interaction
and manages your molecule’s critical path to
deliver unmatched time and cost savings. OneSource™
Aaron Williams, PMP, joined us in 2011
Program Manager,
www.patheon.com/onesource
Patheon OneSource™
1. Assessing the Financial Benefits of Faster Development Times: The Case of Single-Source
vs. Multi-Vendor Outsourced Manufacturing, Tufts Center for the Study of Drug Development, 2017
API Synthesis & Manufacturing
contin. from page 24
January 2013 to Sept. 15, 2017 are in-
dicated for rare diseases and accounted
for 25% of the orphan drug approvals.
Nearly 75% of orphan drugs received
Priority Review.
In 2017, 13 of the 38 new drugs ap-
proved through November 14, or 34%,
were classified as orphan drugs.
Cancer treatments lead the way
Of the types of diseases targeted by
the 38 new drugs approved by FDA
in 2017 through November 14, can-
cer accounted for the largest propor-
tion. Drugs were approved for leuke-
mia (9–11), urothelial carcinoma (12),
mantle cell lymphoma (13), and lung
(14), skin (15), breast (16–18), follicular
lymphoma (19), and epithelial ovarian,
fallopian tube, and primary peritoneal
(20) cancers. Seven of these drugs are
kinase inhibitors.
Nerlynx (neratinib maleate) is the
first extended adjuvant therapy, a form
of therapy that is taken after an initial
treatment to further lower the risk of
breast cancer returning. Two of the
drugs were approved for treatment of
acute myeloid leukemia (AML) with
companion diagnostics. Idhifa (ena-
sidenib), which is for treatment of adult
patients with relapsed or refractory
AML who have mutations in the IDH2
gene, was approved for use with the
RealTime IDH2 Assay (9). Rydapt (mi-
dostaurin) from Novartis, a treatment
for adult patients with newly diagnosed
AML that have the FLT3 gene mutation,
was approved for use with the Leu-
koStrat CDx FLT3 Mutation Assay (10).
Bavencia (avelumab), a monoclonal
antibody (mAb), is the first treatment
for metastatic Merkel cell carcinoma
(MCC), a rare aggressive form of skin
cancer (15).
A number of firsts
A number of the new drugs approved
in 2017 through November 14 are firsts
in the treatment of rare diseases. Ben-
znidazole is the first drug approved
in the US for the treatment of Cha-
gas disease, or American trypanoso-
28 Pharmaceutical Technology JANUARY 2018
miasis, a parasitic infection caused by
Trypanosoma cruzi that can lead to
serious heart illnesses and affect swal-
lowing and digestion (21). Radicava
(edaravone) is the first new treatment
approved in the US in many years for
the treatment of myotrophic lateral
sclerosis (ALS), commonly referred to
as Lou Gehrig’s disease (22).
Two drugs received the ninth and
tenth rare pediatric disease priority re-
view vouchers issued by FDA. Emflaza
(deflazacort) is a corticosteroid for the
treatment of Duchenne muscular dys-
trophy (DMD), a rare genetic disorder
that causes progressive muscle dete-
rioration and weakness and the first
treatment approved for a wide range of
patients with DMD (23). Brineura (cer-
liponase alfa), an enzyme replacement
therapy, is the first FDA-approved
treatment to slow loss of walking abil-
ity in symptomatic pediatric patients
three years of age and older with late
infantile neuronal ceroid lipofuscino-
sis type 2 (CLN2), also known as tri-
peptidyl peptidase-1 (TPP1) deficiency
and a form of Batten disease (24).
The mAb Ocrevus (ocrelizumab),
which acts as a direct factor Xa inhibi-
tor, is the first treatment approved for
primary progressive multiple sclerosis
(25). Bevyxxa (betrixaban) is the first
treatment to prevent the development
of deep vein thrombosis and pulmo-
nary embolism blood clots in adults
hospitalized with acute illnesses for
extended periods of time (26). In-
grezza (valbenazine) is the first drug
approved by FDA for the treatment of
tardive dyskinesia a neurological dis-
order characterized by repetitive invol-
untary movements, usually of the jaw,
lips, and tongue that is seen in patients
that have been taking antipsychotic
medications for schizophrenia, bipo-
lar disorder, and depression for long
durations (27).
In many cases, the new drugs ap-
proved in 2017 are the first treatments
commercialized for diseases in 10 or
more years. Tymlos (abaloparatide) is
the first new bone building agent for
postmenopausal women with osteo-
porosis in the US in nearly 15 years
P h a r mTe c h . c o m
(28). Prevymis (letermovir) is the first
new medicine for the prevention of
cytomegalovirus infection and dis-
ease in adults receiving allogeneic
hematopoietic stem cell transplants
to be approved in 15 years (29). Aust-
edo (deutetrabenazine) is the first new
treatment option in nearly a decade
for chorea associated with Hunting-
ton’s disease, a rare and fatal neuro-
degenerative disorder (30). Parsabiv
(etelcalcetide) is the first therapy ap-
proved for the treatment of secondary
hyperparathyroidism in adult patients
with chronic kidney disease on hemo-
dialysis in 12 years and the only calci-
mimetic that can be administered in-
travenously by the dialysis healthcare
team at the end of the hemodialysis
session (31).
Two of the approved drugs operate
by new mechanisms of action. Vyzulta
(latanoprostene bunod ophthalmic
solution, 0.024%) is the first prosta-
glandin analog with nitric oxide as
a metabolite to be approved for the
reduction of intraocular pressure in
patients with open-angle glaucoma
or ocular hypertension (32). Solo-
sec (secnidazole) is a next-generation
5-nitroimidazole antibiotic and the
first and only single-dose oral therapy
for bacterial vaginosis in adult women
(compared to twice-per-day dosing for
seven days) (33).
Two new gene therapies
Although not approved by CDER and
thus not appearing on its list of novel
approved drugs (2), FDA, through the
Center for Biologics Evaluation and
Research, has approved gene therapies
for the first time in 2017.
The first, Kymriah (tisagenlecleu-
cel) from Novartis, was approved in
August and is a chimeric antigen re-
ceptor (CAR) T-cell immunotherapy
for the treatment of patients up to
age 25 years with B-cell precursor
acute lymphoblastic leukemia (34).
Kymriah was approved under Prior-
ity Review with the Breakthrough
Therapy designation.
contin. on page 32
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API Synthesis & Manufacturing

Approaches to USP OTC Monograph Modernization

To facilitate further collaboration among all the stakeholders for the US Phar-
macopeial Convention’s (USP) Over-the-Counter (OTC) Monograph Moderniza-
tion, several options for an efficient, organized approach to development of
these monographs have been proposed and are outlined and discussed in a
paper published on PharmTech.com. The authors hope to facilitate further col-
laboration among all the stakeholders for USP OTC Monograph Modernization
with the goal of identifying a satisfactory approach for USP, FDA, and industry.
FDA’s Over-the-Counter Drug Monograph System allows marketing of drug
products that are “generally recognized as safe and effective” without a drug
application or pre-market approval. This system includes hundreds of APIs that
manufacturers can formulate into specific doses and dosage forms with differ-
ent excipients that can result in thousands of different ingredient combinations.
Products marketed under this system require compliance to the quality-related
specifications in a USP monograph, if one is available, but since most are not, each
manufacturer is responsible for establishing the necessary specifications and
quality assurance controls with current good manufacturing practices. This lack
of standardized quality expectations (“a public standard”) complicates surveil-
lance activities by FDA. Without them, the enforcement arm of FDA must either
develop its own analytical method or contact the product manufacturer to obtain
analytical methods and specifications.
Several approaches for development of these monographs have been proposed
(see Table I); the primary focus is to help organize the content of information within
the USP monographs and chapters. Implementation of some of these options may
require an accompanying pathway of updates to current regulatory guidance or no-
tices that govern the use of a public standard within the FDA OTC Monograph System.
The paper is posted online at: www.pharmtech.com/pt/otc_usp.
— Amy Ellefsen, Catherine Vicente, Donna Seibert, Mike Rankin, Mike Wisser,
Saul Gylys, Alan Potts, and John Punzi

Table I: Proposed definitions for approaches to modernization. USP is US Pharmacopeial Convention.

Option Proposed
Basic definition and concept
number option name
Referee • Unique, well-defined, validated procedure, officially published within a drug substance or drug
I
(traditional) product monograph
• Multiple well-defined, validated procedures officially published within a substance or product
monograph
- First published=first approved by USP Expert Committee and designated as Test 1 or Procedure
II Flexible
1 in the monograph
- Conformance to procedures other than Test 1 or Procedure 1 requires the product label to
indicate the applicable Test or Procedure
• Procedures within a drug substance or drug product monographs, where only performance
characteristics are defined (e.g., base chromatographic conditions, specifications for active
ingredients and their impurities and/or select system suitability criteria)
- Manufacturers are given flexibility to optimize their specific testing parameters as long as
Performance-
III performance characteristics are met and methods (sample preparations and analyses) are
based
appropriate for intended use and are validated to current CGMP and USP expectations.
- Differentiated from alternative methods or procedures in that there is no requirement for
submission to the USP; however, the test method and associated validation may be requested by
FDA for surveillance activities.
• Published as a general method in its own unique chapter that is referenced by multiple drug
product monographs
General
IV - Chapter may incorporate any of the other procedure approaches (i.e., referee, flexible, performance-
Chapter
based, etc.) that can then be applied across multiple product monographs. However, if the General
Chapter contains multiple test methods then labeling of test methods may be required.
• Multiple test methods that are developed to cover a wide design space to maximize separation of
potential impurities. The test methods are not necessarily optimized or practical for routine quality
control use. For example, the Tool Kit methods may include the option of several high-performance
liquid chromatography (HPLC) column chemistries each with a long, shallow gradient and the option
of a few mobile phase solvent systems.
V Tool kit
- Only one of the procedures is required to be suitable to demonstrate product compliance and the
most suitable procedure is to be determined by the product manufacturer.
- Surveillance activities may include analysis of the product against all Tool Kit procedures.
- Labeling is not required.
- This has the potential to be used within a product monograph or General Chapter.
• Individual product monographs or General Chapter that includes only the required specifications
- Manufacturers develop tests and procedures, supported with an appropriate validation, that are
Specification- optimized for their product and product matrices.
VI
only - No labeling is required if the product complies with the specification limits.
- Manufacturers must provide testing procedures and supporting validation documents as
requested by the regulatory authority.

30 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

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API Synthesis & Manufacturing
contin. from page 28 In addition, as of Nov. 28, 2017, FDA 10. FDA, “FDA Approves New Combination
had approved 65 first generics (38)— Treatment for Acute Myeloid Leukemia,”
At the same time, FDA expanded or products that are the first generic Press Release (Silver Spring, MD, April
28, 2017).
the approval of Actemra (tocilizumab) competitors to their branded coun-
11. FDA, “FDA Approves New Treatment
from Genentech for the treatment of terparts—and looks to be on track to
for Adults with Relapsed Or Refractory
patients two years of age or older with meet or exceed last year’s figure of 73.
Acute Lymphoblastic Leukemia,” Press
cytokine release syndrome that occurs The increased rate of approvals is at- Release (Silver Spring, MD, Aug. 17,
with CAR T-cell therapy. Because of tributed to an increase in FDA person- 2017).
the risk cytokine release syndrome nel by nearly 1000 as a result of funds 12. FDA, “Durvalumab (Imfinzi),” www.
(CRS) and neurological events, Kym- collected through the Generic Drug fda.gov/Drugs/InformationOnDrugs/
riah is being approved with a risk eval- User Fee Amendments. FDA has also ApprovedDrugs/ucm555930.htm.
uation and mitigation strategy (REMS), prioritized the approval of generics to 13. FDA, “FDA Approves New Treatment
which includes elements to assure safe help reduce drug costs. for Adults with Mantle Cell Lymphoma,”
use (ETASU). FDA is requiring that Press Release (Silver Spring, MD, Oct. 31,
hospitals and their associated clinics References 2017).
that dispense Kymriah be specially 1. FDA, “Novel Drug Approvals for 2016,” 14. Ta keda Pha rmaceut ica l Compa ny,
certified and trained to recognize and w w w.fd a .gov/ D r u gs/ De velopmen- “Takeda Announces FDA Accelerated
tApprovalProcess/DrugInnovation/ Approval of ALUNBRIG (brigatinib),”
manage CRS and neurological events. ucm483775.htm. Press Release (Cambridge, MA, April
The second, Yescarta (axicabtagene 2. FDA, “Novel Drug Approvals for 2017,” 28, 2017).
ciloleucel), is also a CAR T-cell therapy, w w w.fd a .gov/ D r u gs/ De velopmen- 15. FDA, “FDA Approves First Treatment for
but for the treatment of adult patients tApprovalProcess/DrugInnovation/
Rare Form of Skin Cancer,” Press Release
with certain types of large B-cell lym- ucm537040.htm.
3. J. Jenkins, “CDER Approved Many In- (Silver Spring, MD, March 23, 2017).
phoma who have not responded to or 16. Novartis, “Novartis Kisqali (ribociclib,
novative Drugs in 2014,” FDA Voice, Jan.
who have relapsed after at least two 14, 2015. https://blogs.fda.gov/fdavoice/ LEE011) Receives FDA Approval as First-
other kinds of treatment (35). Yescarta index.php/2015/01/cder-approved-many- Line Treatment for HR+/HER2- Meta-
was approved under Priority Review innovative-drugs-in-2014/. static Breast Cancer in Combination
and had both Breakthrough Therapy 4. FDA, “Novel Drug Approvals for 2015,” with Any Aromatase Inhibitor,” Press
and Orphan Drug designations. Yecarta w w w.fd a .gov/ D r u gs/ De velopmen- Release (March 13, 2017).
tApprovalProcess/DrugInnovation/ 17. FDA, “FDA Approves New Treatment for
was approved with a similar REMS.
ucm430302.htm. Certain Advanced Or Metastatic Breast
5. Markets and Markets, Active Pharma-
Numerous other treatments Cancers,” Press Release (Silver Spring,
ceutical Ingredients/API Market by Type
Other diseases targeted by novel drugs MD, Sept. 28, 2017).
(Innovative, Generic), Manufacturer
(Captive, Merchant), Synthesis (Synthetic, 18. FDA, “FDA Approves New Treatment
approved by FDA in 2017 include
Biotech), Product (mAb, Hormone) Drug to Reduce the Risk of Breast Cancer Re-
chronic hepatitis C virus (two different
(OTC, Rx), Therapy (Diabetes, Oncology, turning,” Press Release (Silver Spring,
products), complicated urinary tract in- MD, July 17, 2017).
CNS, CVD) - Global Forecast to 2021,
fections, acute bacterial skin and skin January 2017. 19. FDA, “FDA Approves New Treatment
structure infections caused by gram- 6. Grand View Research, “API Market Size for Adults with Relapsed Follicular
positive and gram-negative pathogens, Worth USD 239.8 Billion By 2025,” Press Lymphoma,” Press Release (Silver Spring,
eczema, plaque psoriasis (two prod- Release, January 2017. MD, Sept. 14, 2017).
ucts), Parkinson’s disease, carcinoid 7. B. Norman, S. Karlin-Smith, and B.
20. FDA, “FDA Approves Maintenance
Griffiths, “Gottlieb Signals Priorities
syndrome diarrhea, chronic idiopathic for FDA, Including Drug Pricing,” Po-
Treatment for Recurrent Epithelial
constipation, opioid-induced constipa- litico, May 30, 2017, www.politico.com/ Ovarian, Fallopian Tube or Primary
tion, rheumatoid arthritis, and asthma. tipsheets/prescription-pulse/2017/05/30/ Peritoneal Cancers,” Press Release (Silver
gottlieb-signals-priorities-for-fda-in- Spring, MD, March 27, 2017).
Lots of generic approvals too cluding-drug-pricing-220567. 21. FDA, “FDA Approves First US Treatment
8. M. Lanthier, “Insights into Rare Disease for Chagas Disease,” Press Release (Silver
FDA approved a record number of
Drug Approval: Trends and Recent De- Spring, MD, Aug. 29, 2017).
abbreviated new drug applications velopments,” presented at the NORD 22. FDA, “FDA Approves Drug to Treat ALS,”
(ANDAs)—763 approvals and 174 ten- Rare Diseases & Orphan Products Break- Press Release (Silver Spring, MD, May 5,
tative approvals—in fiscal year 2017 through Summit, Oct. 17, 2017, www.fda.
2017).
(36), compared with 639 ANDA ap- gov/downloads/ForIndustry/Develop-
23. FDA, “FDA Approves Drug to Treat
provals and 183 tentative approvals ingProductsforRareDiseasesConditions/
UCM581335.pdf. Duchenne Muscular Dystrophy,” Press
in fiscal year 2016 (37). Not only were Release (Silver Spring, MD, Feb. 9, 2017).
9. FDA, “FDA Approves New Targeted
more ANDAs approved in 2017 com- Treatment for Relapsed or Refractory 24. FDA, “FDA Approves First Treatment for
pared to 2016, a much higher number Acute Myeloid Leukemia,” Press Release a Form of Batten Disease,” Press Release
of ANDAs was received as well. (Silver Spring, MD, Aug. 1, 2017). (Silver Spring, MD, April 27, 2017).

32 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

25. FDA, “FDA Approves New Drug to Treat
Multiple Sclerosis,” Press Release (Silver
Spring, MD, March 29, 2017).
26. Portola Pharmaceuticals, “US FDA Ap-
proves Bevyxxa (betrixaban) First and
Only Anticoagulant for Hospital and Ex-
tended Duration Prevention of Venous
Thromboembolism (VTE) in Acutely Ill
Medical Patients,” Press Release (South
San Francisco, June 23, 2017).
27. FDA, “FDA Approves First Drug to Treat
Tardive Dyskinesia,” Press Release (Silver
Spring, MD, April 11, 2017).
28. Radius Health, “FDA Approves Radius
Health’s TYMLOS (abaloparatide), a
Bone Building Agent for the Treatment
of Postmenopausal Women with Osteo-
porosis at High Risk for Fracture,” Press
Release (Waltham, MA, April 28, 2017).
29. Merck & Co., “Merck Receives FDA Ap-
proval of PREVYMIS (letermovir) for
Prevention of Cytomegalovirus (CMV)
Infection and Disease in Adult Allo-
geneic Stem Cell Transplant Patients,”
Press Release (Kenilworth, NJ, Nov. 9,
2017).
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30. Teva Pharmaceuticals, “Teva Announces
FDA Approval of AUSTEDO (deutetra-
benazine) Tablets for the Treatment of
Chorea Associated with Huntington’s
Disease,” Press Release (Jerusalem, Israel,
April 3, 2017).
31. Amgen, “FDA Approves Amgen’s Pars-
abiv (Etelcalcetide), First New Treatment
in More Than a Decade for Secondary
Hyperparathyroidism in Adult Patients
on Hemodialysis,” Press Release, Feb. 7,
2017.
32. Valenat Pharmaceuticals, “Bausch + Lomb
and Nicox Announce FDA Approval of
VYZULTA (Latanoprostene Bunod Oph-
thalmic Solution), 0.024%,” Press Release
(Thousand Oaks, CA, Nov. 2, 2017).
33. Symbiomix Therapeutics, “FDA Ap-
proves Symbiomix Therapeutics’ So-
lose (secnidazole) Oral Granules for
the Treatment of Bacterial Vaginosis in
Adult Women,” Press Release (Newark,
NJ, Sept. 18, 2017.
34. FDA, “FDA Approves tisagenlecleucel
for B-cell ALL and Tocilizumab for Cy-
tokine Release Syndrome,” Press Release
(Silver Spring, MD, Aug. 30 2017).
35. FDA, “FDA Approves CAR-T Cell Ther-
apy to Treat Adults with Certain Types
of Large B-cell lymphoma,” Press Release
(Silver Spring, MD, Oct. 18, 2017). www.
fda.gov/NewsEvents/Newsroom/Pres-
sAnnouncements/ucm581216.htm
36. FDA, “Activities Report of the Generic
Drug Program (FY 2017),” www.fda.gov/
Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/
ApprovalApplications/Abbreviated-
NewDrugApplicationANDAGenerics/
ucm584749.htm.
37. FDA Office of Generic Drugs, 2016 OGD
Annual Report, www.fda.gov/downloads/
Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/
ApprovalApplications/Abbreviated-
NewDrugApplicationANDAGenerics/
UCM542929.pdf.
38. FDA, “First Generic Drug Approvals,”
w w w.fda.gov/drugs/developmentap-
provalprocess/howdrugsaredeveloped-
andapproved/drugandbiologicapprov-
alreports/andagenericdrugapprovals/
default.htm PT
Pharmaceutical Technology JANUARY 2018 33
Formulation
Tackling the Opioid Crisis
with Abuse-Deterrent
Formulations
Adeline Siew, PhD
Abuse-deterrent opioid formulations generally
fall into two categories: the first is based on a
physiochemical abuse-deterrent approach and the
second combines the opioid with an antagonist.
T
he United States is facing an
opioid crisis. FDA has expressed
concern about the growing epi-
demic of opioid abuse, dependence,
and overdose, and part of its action
plan includes a call to pharmaceuti-
cal manufacturers to develop opioid
formulations with abuse-deterrent
properties (1). As a result, there is
increasing interest in the development
of abuse-deterrent formulations as the
technologies to prevent abuse among
patients and recreational abusers con-
tinue to advance rapidly.
“Generally speaking, abuse-deter-
rent formulations should prevent drug
abuse, but maintain clinical benefit
and patient compliance,” says Michael
DeHart, associate director, Phar-
34 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
Abuse-deterrent approaches
Alcami. One is based on a physio-
“Grunenthal’s abuse-deterrent Intac
maceutical Development, Metrics
Contract Services. “In other words,
incorporating excipients to prevent
drug abuse should not alter the bio-
availability of the API or increase the
tablet/capsule size dramatically.”
According to DeHart, one of the
biggest challenges in developing an
abuse-deterrent opioid formulation
is that formulators are sometimes
formu lating from a reactive per-
spective. “A similar comparison can
be made to how antivirus software
developers must sometimes react to,
or address, hackers who have already
released a virus,” he says. “Drug
abusers are highly resourceful and
can generally ‘hack’ a formulation to
get what they want.”
Current products on t he market
that contain abuse-deterrent label-
ing approved by FDA fall into two
categories, highlights Angela Moore,
scientist, Analytical Development,
chemical abuse-deterrent approach
and the other combines the opioid
with an antagonist. “Physiochemical
abuse-deterrent properties include
products that are formulated to resist
crushing, chewing, and physical ma-
nipulation. They contain excipients
that will gel upon contact with sol-
vents to make them difficult to inject
intravenously,” she explains.
One of the more common excipients
used to impart abuse-deterrent prop-
erties is polyethylene oxide (PEO), ob-
serves DeHart. “PEO can be cured or
processed through hot-melt extrusion
so that it cannot be crushed,” he says.
Technology is based on this approach.”
Tablets produced using Intac Technol-
ogy have higher mechanical strength
and are, therefore, resistant to crush-
ing (2). An additional advantage is the
low extractability of the active drug
from the tablet in a wide range of sol-
vents (2). “This low extractability is
because PEO swells when exposed to
various solvents,” DeHart says. The
gelling of the polymer creates a vis-
cous mass that is difficult to draw into
a syringe, hence, raising the hurdles to
drug abuse. DeHart notes that Purdue
Pharma uses PEO in their reformu-
lated OxyContin tablets.
“Opioid/antagonist products, on
the other hand, contain the active
opioid intended for therapeutic use
as well as a sequestered antagonist,
so that if the product is manipulated
intentionally, it will release a chemi-
cal that will prevent the user from
MAJO1122331/SHUTTERSTOCK.COM
feeling the euphoric effects of the
opioid,” Moore points out.
DeHart cites Pfizer’s Embeda as an
example of an opioid formulation con-
taining an antagonist. “In the case of
Embeda, inactive naltrexone (i.e., the
antagonist) is formulated with mor-
phine sulfate in the capsules. If the
 pda.org/2018Annual

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Formulation
capsules have been adulterated for
potential abuse, the antagonist would
become bioavailable and prevent
any kind of abuse,” he says. “Opioid
formulations may also include ex-
cipients such as sodium lauryl sul-
fate that can cause irritation when
crushed and snorted.”
According to Moore, there are
many considerations for manufac-
turers developing abuse-deterrent
opioid formulations. “Most impor-
tantly, the product must be considered
safe and effective, and it must adhere
to all FDA manufacturing and test-
ing guidelines,” she stresses. “From
a chemistry and biologic perspective,
the product must resist dose dumping
and abuse, but still release the active
ingredient when ingested as intended.
From a commercial viewpoint, one of
the key considerations is to develop a
product that has a competitive advan-
tage over those already on the market.”
She explains that a company must
differentiate its product in such a way
that doctors will want to prescribe
the new product over other available
alternatives. She adds that insurance
companies must also be convinced
that the new product is worth paying
more money for compared to cheaper
products that do not contain abuse-
deterrent formulation properties.
Evaluating the effectiveness
of abuse-deterrent formulations
The current FDA guidelines (3) for de-
termining the effectiveness of abuse-
deterrence of a drug product involve
four main studies, termed Category
1, 2, 3, and 4. “Category 1 testing in-
volves laboratory manipulation and
extraction studies,” says Moore. “In
these studies, the product is evaluated
and compared to currently marketed
formulation(s) for the ability to defeat
or compromise the abuse-deterrent
properties. This testing is done in vitro
and provides the physical characteris-
tics of the product and its ability to re-
sist crushing, grinding, melting, and to
resist nasal abuse. Extraction studies
provide information on the product’s
ability to isolate the antagonist, or
36 Pharmaceutical Technology JANUARY 2018
resist abuse by injection, or, in larger
volumes, resist abuse by ingestion,” she
explains.
There is increasing
interest in the
development of
abuse-deterrent
formulations as
the technologies
to prevent opioid
abuse.
“Category 2 testing involves pharma-
cokinetic studies in healthy humans.
The product’s in-vivo properties are
evaluated by comparing an intact for-
mulation against the manipulated for-
mulation through one or more routes
of administration. Comparator prod-
ucts are also evaluated for compari-
son,” says Moore. She adds that Cat-
egory 3 testing evaluates the clinical
abuse potential of the product. “These
are large, complicated in-vivo stud-
ies that are generally conducted with
recreational drug users as test subjects.
These test subjects are screened prior
to the study to ensure that they are
able to distinguish between the active
drug and a placebo in a drug abuse set-
ting. In these studies, the test subjects
are provided the drug product being
developed and suitable comparators.
The drugs are administered through
the route of abuse that is being stud-
ied (i.e., oral or intranasal) and the
patients provide not only pharmaco-
kinetic data, but also subjective data
on the drug liking (how high they are)
and if they would take the drug again,”
she explains.
Moore highlights that Category 4 as-
sessment is a post-approval study that
determines if the product has resulted
in meaningful reductions in abuse,
misuse, or adverse clinical outcomes
(addiction, overdose, and death).
P h a r mTe c h . c o m
“These evaluations are conducted
by the product manufacturer,” she
says, pointing out that currently,
there are no products on the market
that qualify for the Category 4 label
for abuse-deterrence.
“Recently, one of the more com-
mon tests that we have seen being
used to evaluate the effectiveness of
abuse-deterrent formulations is its
syringeability,” DeHart notes. “Sy-
ringeability looks at how much opi-
oid can be extracted from a tablet
using heat, agitation, and in small
volumes of water to see if it can be
pulled through a syringe.”
According to DeHart, drug prod-
ucts that are susceptible to snorting
should be evaluated for crushability
and particle size distribution. He
adds that tablets should also be eval-
uated to determine if dose dumping
can be prevented.
“Dose dumping typically occurs
when painkillers are consumed with al-
cohol,” he explains. “It is, therefore, im-
portant to evaluate opioid release from
drug products in dissolution media
with various concentration of ethanol.”
While the pharmaceutical indus-
try has a crucial role to play in de-
veloping opioid formulations that
are more resistant to abuse and ma-
nipulation, the opioid crisis can only
be tackled effectively if FDA, govern-
ments, policymakers, healthcare pro-
viders, patients, and their families to
work together, as pointed out by FDA
Commissioner, Scott Gottlieb (4).
References
1. FDA, “FDA Opioids Action Plan,” www.
fda.gov/drugs/d r ugsa fet y/informa-
tionbydrugclass/ucm484714.htm, ac-
cessed Dec. 13, 2017.
2. Grunenthal, Intac, www.intac.com, ac-
cessed Dec. 13, 2017.
3. FDA, Guidance for Industry: Abuse-
Deterrent Opioids—Evaluation and
Labeling (Rockville, MD, April 2015).
4. FDA, “Statement from FDA commis-
sioner Scot t Got t lieb, MD, on t he
Trump Administration’s Important
Efforts to Address the Opioid Crisis,”
Oct. 26, 2017. PT

April 24-26 2018
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Fluid Handling
charge side of the pump when starting
up, which can cause early failure and
decrease accuracy of the pump system.
Do not overstretch the tubing, which
will change its dimensions and thus af-
fect flow rates.
Center the tubing. When loading tubing,
make sure it is in the center of the roller
and occlusion bed. If installed off center,
or with a twist, it can be driven into the
rotor plate, causing damage to the tubing.
Following these simple loading steps
can ensure consistent tube loading and
serve as a standardized process.

Tubing selection

Selecting Proper tubing selection, which is detailed

in the following section, will ensure that
the tubing matches the requirements for

and Installing the fluid system design. When choosing

the right tubing for an application, there

Peristaltic Pump Tubing are many factors to consider. To make the

process simple, use the acronym STAMP—
size, temperature, application, media, and
Gregg Johnson pressure—to help remember each factor.
Size. The ID, OD, and wall thickness of
the tube are significant factors in pressure
and vacuum ratings and must be consid-
Proper selection and installation ered in the decision. The tolerances are
optimizes fluid system performance. also a concern for optimal operation in
peristaltic pumps. The typical tolerance

T
he heart of any peristatic pump is the wall thickness—to operate correctly. of off-the-shelf nominal tubing can be
the tubing. It is the primary fluid- Using the wrong size in a pump can lead greater than +/-5%. If this non-precision
contacting part and is occluded by to improper function of the retaining tubing is used, it can cause problems with
the pump rotor and housing, thus provid- mechanism, no pumping action, and volumetric accuracy, suction lift, or pres-
ing the pumping action. With some atten- even premature failure of the tubing. sure; poor tubing life can also be a result.
tion when installing or changing tubing Use of precision peristaltic pump tubing Temperature. Operating temperature is
and proper tubing material selection, the in the right size can ensure that the pump most often considered due to its impor-
pumping system can be optimized. system will operate correctly. tance, but cleaning temperature, ambient
Follow the natural curvature. During man- temperature, and the overall temperature
Tubing installation ufacturing of the tubing, it is laid up in a fluctuation must also be considered. Sud-
Proper tube loading can improve the coil, which imparts a natural curvature to den changes or extreme temperatures can
tubing life and overall pumping perfor- the tubing. When loading the tubing into negatively affect performance and cause
mance and accuracy. It can also provide a pump, allowing it to follow its natural premature failures. A higher cost mate-
consistency between tubing changes by curvature with the curvature of the oc- rial has traditionally been the only op-
implementing a standardized process for clusion bed will improve tubing perfor- tion to improve performance in extreme
tubing installation. mance. If the tubing is twisted, it can roll temperatures. With advances in manu-
Match the pump to the tubing size. Peri- to one side of the rotor and may strike facturing capabilities, however, multilayer
ARLEKSEY/SHUTTERSTOCK.COM

staltic pumps require specific tubing the rotor place, thus damaging the tubing. products are available that can help ease
sizes—determined by the inside diam- Stretch the tubing. As the tubing is this cost while still meeting the perfor-
eter (ID), the outside diameter (OD), and being loaded, giving it a slight stretch mance expectations.
by pulling it gently by hand, as shown Application. Understanding the full scope
in Figure 1, will improve performance. of the application is the most complex
Gregg Johnson is global senior product
manager for Masterflex and Ismatec Product
Stretching eliminates the potential for portion of the selection process and most
Lines, Cole-Parmer. excess bunching of tubing at the dis- often overlooked. Regulatory concerns are
38 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
 always at the top of the list. Understanding what documentation sterilization cycles Figure 1. Stretch tubing slightly while
is needed and what special regulations must be complied with are can create the most loading it into the peristaltic pump, and
important; different compliance concerns may call for different extreme pressure make sure it is in the center of the roller
material selection. Tubing materials and formulas can be tested cond it ions a nd and occlusion bed.
to ensure they comply with the appropriate criteria. must be consid-
Knowing the dynamics (e.g., flow rate, pressure, or viscosity) ered during the
of the application will assist with material selection for clarity, selection.
durometer (relative hardness), flexural fatigue, abrasion resis-
tance, spallation (the tendency of materials to release particu- Summary
lates due to impact or stress), and particulates (pyrogens). There T he p er i s t a lt ic
are materials available to combat each of these concerns indi- pump system can
vidually and multi-layer options to solve a mix of these factors. be optimized with
Media. Knowing the media or fluid being transported and proper tubing in-
its characteristics, such as extractables level, the tendency for stallation material
adsorption or absorption of fluid into the tubing material, and selection that takes
the tendency of media to entrap particulates, is necessary to into account the
assure high purity. Different chemicals attack various materi- size of the tubing
als at different rates, so understanding all the chemicals that and the tempera-
might be used in the tubing will help with proper selection. ture, application, media, and pressure of the system. When
Cleaning agents are often the most aggressive fluids used; be selecting a tubing product, quality is of the utmost importance.
aware of any chemical reactions which might be caused by Do not shy away from asking the manufacturer about their
cleaning or sterilizing agents. Often overlooked are the ambi- quality process, and take a plant tour to see how a product is
ent chemicals (e.g., solvents) present in the atmosphere, either designed and produced. Should something ever go wrong in
present in the air surrounding the tubing product or drip- the field, a manufacturer should have the supporting quality
ping by way of leaks or condensation creation. The effect of documentation. PT
these chemicals on the tubing should also be considered. If the
fluid is very aggressive, a more resistant material can be used,
or multilayer tubing can be selected that assists with barrier
protection but is not as costly as tubing made completely from
a more resistant material.
Some tubing materials can be produced at tighter tolerances
for tighter fitting connections to avoid leak points. Others can
be produced with a smoother inner surface for better flushing.
Understanding the fluid being conveyed can help maximize
the efficiency of your project to assist with easier flushing and
avoidance of costly leaks.
Safety also plays a role with material choice. Some require-
ments mandate viewing the fluid being conveyed. This means
the material must have a sufficient level of clarity to see the fluid
path and distinguish if any particulates are present. Other op-
tions require identifying marks for various chemicals through
the use of colored tubing products or specific marking text. Use
of these marks is a growing trend in efforts to further company’s
safety improvements.
Pressure. Vacuum and positive pressure create stress on any
tubing product. Ignoring these factors can create hazardous
FIGURE IS COURTESY OF THE AUTHOR.

conditions during product use. Use temperature also has a sig-

nificant effect on the pressure rating for materials, and proper
measures must be taken. Changing the wall thickness can help
increase pressure rating, as can reducing the overall OD and
ID. If these measures are not an option, multilayer products of
various materials can help handle the desired pressure as well
as maintain the proper condition in the fluid path.
Pressures created during normal operation are not the
only factor when selecting the proper tubing. Cleaning or
Pharmaceutical Technology JANUARY 2018 39
Internet of Things
Pharma Equipment
Gets Smart
Jennifer Markarian
The Industrial Internet of Things can be used to
monitor equipment health and optimize processes.
T
he Industrial Internet of Things
(IIoT) involves connecting “things”
(i.e., equipment) through the Inter-
net. “Smart” equipment uses sensors to
provide data for improving a process
or monitoring equipment health, for
example.
“The IIoT brings new options to the
table for collecting data from the pro-
cess and sending it to manufacturing
execution systems and distributed
control systems (DCS),” explains Greg
Newman, vice-president of Marketing
at Parsec Automation Corp. “IIoT de-
vices on the plant floor are being used
to reduce the investment in infrastruc-
ture and setup time for simple data
collection tasks, such as production
counters, temperature measurement,
and equipment state. IIoT devices can
also more easily enable sending these
data off-site to remote data-capture
software.”
40 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
Predictive maintenance
Manufacturing companies from differ-
ent industries are relying on data ana-
lytics, with data collected by the IIoT,
to solve problems related to unsched-
uled downtime, a survey conducted in
2016 by Honeywell found (1). Although
pharma manufacturing is different
from other manufacturing sectors in
its focus on regulatory compliance and
in the types of equipment being used,
the ultimate aim to prevent downtime
and improve reliability still applies.
“Manufacturers want to produce high
quality products, and they don’t want
to lose batches. Monitoring equipment
and process data is crucial to achieve
this goal,” notes Matthias Maaz, direc-
tor of Pharma and Specialty Chemicals,
Honeywell Process Solution.
“Predictive maintenance might be
the killer app for IIoT,” says Petter
Mörée, industry principal for Life Sci-
ence, Food and Beverage, Chemical at
software supplier OSIsoft. Mörée re-
ports that one pharma company using
remote monitoring of real-time data
had reduced unplanned downtime at
a facility because it could more closely
monitor conditions such as tempera-
ture and humidity, and calibrate sys-
tems more accurately.
“Continuously collecting real-time
data from the operating equipment
and machines, and then analyzing these
data to harness and deliver actionable
insights related to asset utilization will
help with failure prediction and can
improve uptime in all the machines
across the plant,” says Billy Sisk, Life
Sciences Industry manager for EMEA
at Rockwell Automation. He says that
although predictive maintenance isn’t
a new concept, more data can now be
captured, and the cost of computing
and data storage is now lower. “One
of the key values of scalable analytics
is the ability to leverage all the data
gathered from the shop-floor equip-
ment and analyze it to improve plant
and asset performance. For instance,
pharmaceutical producers can monitor
performance at an equipment or system
level, and track what assets are failing
more frequently or are degrading. This
information can be used to develop a
comprehensive maintenance and pre-
dictive asset-management program.”
Troubleshooting is also enhanced.
For example, reports Sisk, a biophar-
maceutical company that was upgrad-
ing to new purification skids added
monitoring of the skids’ variable fre-
quency drives (VFDs). “The VFD fault
codes are reported to the programma-
ble logic controller (PLC) and collected
in a data historian. The company said
using such monitoring saved a day’s
worth of troubleshooting in just the
first week. The new skids also support
AFRICA STUDIO/SHUTTERSTOCK.COM
workers who want remote access from
the office or another location, which
provides the ability to begin trouble-
shooting in mere minutes.”
Another example of an IIoT-enabled
device is the i-ALERT2 Bluetooth Smart
monitor from ITT. The monitor tracks
pump vibration, temperature, and run-
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Internet of Things
time hours, and the data are sent wire-
lessly to cloud storage for analysis of
equipment health. Guidance can then
be sent to the operators to schedule reg-
ular maintenance, and the system can
alert operators of problems so they can
take action to prevent equipment failure.
Process optimization
Equipment performance is directly af-
fected by process performance, and
overall production reliability is inter-
twined with overall equipment effective-
ness (OEE), says Edwin van Dijk, vice-
president of Marketing at TrendMiner, a
company offering self-service industrial
analytics software. He says that “contex-
tualizing asset performance with process
data” is crucial, and that a better under-
standing of the connection of the equip-
ment and process will enable improved
reliability and control of product quality
and efficiency.
Manufacturing process data tied to
the process (i.e., time-series data) are
valuable when presented graphically to
subject-matter experts, says van Dijk.
He explains that process engineers can
use the advanced analytics software to
search the historian for similar behavior
in the past and graphically overlay the
performance patterns. “In correlation
with behavior of other tags, these com-
parisons may indicate root causes for
anomalies,” says van Dijk. “On the other
hand, in case of good behavior, the pat-
terns of multiple periods of preferred
behavior can be combined into golden
fingerprints for batch or continuous
production. Actual production can then
be monitored against the golden finger-
print, even remotely.”
Smaller batches, such as those used in
personalized medicine, can be more diffi-
cult to optimize for process efficiency and
reliability. Analyzing the data collected
through the IIoT, however, enables opti-
mization. “Data analytics by subject mat-
ter experts thus becomes more important,
and they need tools to quickly analyze,
monitor, and predict process and asset
performance,” says van Dijk.
The IIoT allows producers to more
accurately monitor production, which
enables personalized batches, adds
42 Pharmaceutical Technology JANUARY 2018
Mörée. Consistency and reliability are
crucial for reducing product losses no
matter what the batch size is. Using data
analysis to catch problems early, or even
prevent them, will be one of the major
trends over the next several years, says
Mörée. He reports that one of OSIsoft’s
biopharma users is using IIoT technol-
ogy to monitor and correct deviations
in a fermentation process to reduce the
inherent variability in the process. “In
a traditional production environment,
you may not be aware of deviations until
two days into the process. This manu-
facturer expects to triple its yields by
better monitoring,” reports Mörée.
Enabling modular pharma facilities
Modular, “plug-and-play” equipment
is increasingly being used, and bio/
pharma manufacturing that uses skid-
mounted, moveable, and modular
equipment can particularly benefit from
IIoT solutions, adds Chris Morse, tech-
nical solution consultant at Honeywell
Process Solutions. “With the IIoT, you
can connect a piece of mobile equip-
ment and the system automatically
identifies the equipment and knows in-
formation such as its cleanliness status.
The IIoT simplifies configuration and
prevents connection errors.”
The IIoT can optimize manufactur-
ing processes that use single-use equip-
ment, which require equipment track-
ing, flow-path verification, material
tracking, and hygienic status tracking,
says Sisk. In the facility of the future,
he envisions that “workers will move
assets such as mobile mixing tanks and
smart totes into and out of production
areas. A modern DCS can coordinate
this movement, including verifying
the right asset is in the right place, ex-
ecuting production processes, releas-
ing equipment modules, and disabling
display information after a process is
complete. Mobile tablets or screens on
wheels will be able to go with operators
as they follow production from one
process area to another.”
Remote monitoring
The IIoT is built around sending data
from the plant f loor to “remote” lo-
P h a r mTe c h . c o m
cations, whether these locations are
a few feet away in the facility control
room or many miles away at a location
where specialists can analyze the data.
Pharma manufacturers are typically
leery of the concept of remote moni-
toring, says Maaz, because they don’t
want equipment manufacturers to have
direct access to their DCS and to sen-
sitive data. “Remote,” however, could
also mean that a pharma manufac-
turer’s engineers have a secured line of
information from the process at their
desktop or mobile device, or that the
maintenance person outside of the
cleanroom can have access to data at
the same time as the operator inside
of the cleanroom, explains Maaz. “The
‘mobile operator’ can be in the area but
not directly at the equipment monitor.
They can carry a mobile human-ma-
chine interface (HMI) that can alert
them when a disturbance may have
occurred,” he adds.
“Decision making in pharma manu-
facturing is not just by the operator,”
says Maaz. “The operator, quality as-
surance personnel, management, and
regulatory compliance personnel also
want access to data. An IIoT platform
is flexible and enables everyone to be
involved in complex decisions.” In ad-
dition to data access, data configura-
tion is important. For the operators, for
example, the HMI should present in-
formation “in a way that they can use it,
so they can react to a disturbance, for
example, or be reminded what process
step is coming up next so they can pre-
pare for it,” explains Maaz.
It can also be valuable for remote
access to be given to an equipment
manufacturer to look at a specific
issue. This access, which could be en-
abled and then disabled again, would
be limited to specific instances under
high security, adds Morse.
Another potential use of remote
monitoring is that pharma companies
may be able to use IIoT technology to
remotely monitor and track produc-
tion at a contract manufacturing orga-
nization, enabling them to ensure data
integrity and optimize production at
different sites, says Mörée.
Security challenges
Securing IIoT devices is a significant
concern. “There are many facets, in-
cluding isolating the interference that
a rough data collection device could
cause, to the overall network exposure
as the devices are opened up to the pub-
lic internet,” notes Newman. Although
the ability for remotely located software
solutions, either in the cloud or in cen-
tral private data centers, is a significant
potential benefit for pharma manufac-
turing, the biggest barriers to using
such solutions, Newman says, are “re-
liable remote connections and network
infrastructure, as well as organizational
maturity in setting up risk-acceptable
security around the implementations.”
Additional connections can cre-
ate more potential entrance points for
threats, adds Sisk. “Pharma producers
should adopt a defense-in-depth secu-
rity approach, which deploys multiple
layers of protection, assuming that any
one protection point can and likely will
be defeated. Some security measures
that pharma producers should use as
part of a defense-in-depth strategy in-
clude anomaly-detection software, AAA
[authentication, authorization, and ac-
counting] software, and an industrial
‘demilitarized zone’.”
A survey sponsored by Honeywell
found that industrial companies, in
general, are lacking in their adoption
of cyber-security measures. “To take
advantage of the tremendous benefits
of industrial digital transformation and
IIoT, companies must improve their cy-
ber-security defenses and adapt to the
heightened threat landscape now,” said
Jeff Zindel, vice-president and general
manager, Honeywell Industrial Cyber
Security, in a press release (2).
References
1. Honeywell, “Survey Finds Manufactur-
ing Executives Will Prioritize Big Data
Investments to Solve Problems,” Press
Release, Sept. 13, 2016.
2. Honeywell, “Honeywell Survey Shows Low
Adoption of Industrial Cyber Security Mea-
sures,” Press Release, Dec. 6, 2017. PT
ADDITIONAL READING
Visit PharmTech.com to read the following:
• Using the Internet of Things to
Manage Manufacturing Equipment
www.PharmTech.com/using-internet-
things-manage-manufacturing-equipment
• Real-Time Logistics
www.PharmTech.com/real-time-logistics-0
• The Internet of Things for
Pharmaceutical Manufacturing
www.PharmTech.com/internet-things-
pharmaceutical-manufacturing
• Integrating Industrial Internet
of Things and Pharmaceutical
Manufacturing Processes
www.PharmTech.com/integrating-
industrial-internet-things-and-
pharmaceutical-manufacturing-processes

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Pharmaceutical Technology JANUARY 2018 43

 Accelerating Biological Assay
Method Transfer Through
A Q&A Effective Automation

Automating bioassays improves success

rates and reduces manual steps.
ioassay automation offers ergonomic relief for scientists, consistent method execu-

Michael Merges
Director of
Strategic Growth
B tion, increased throughput, and reduced full-time equivalent expenditure. Importantly,
successful automation programs allow unparalleled efficiency in method transfer to
receiving laboratories. Pharmaceutical Technology recently spoke with Michael Merges,
Catalent Biologics director of strategic growth at Catalent Biologics, about which factors are critical to achieving
consistent methods transfer.

Pharmaceutical Technology: Why did Catalent invest in automation for biological

assays at its facilities?

Merges: We wanted to enhance the safety of our scientists by reducing the potential for
ergonomic hand injuries caused by manual pipetting. We also wanted to increase our
efficiency and lower operational costs for our partners. Finally, automation increases the
accuracy and precision of our bioassay results.

Pharmaceutical Technology: What benefits have you experienced?

Merges: Our bioassays have especially high time demands on our scientists because
they are long and laborious procedures. Automation has reduced our risk for work-related
injuries due to repetitive motion for manual pipetting.
Automation of our bioassays makes our scientists more efficient; they also prefer to
spend their time performing tasks associated with creative scientific thinking. Our scientists
can multitask by reducing the time devoted to performing a single assay. Instead, they can
focus on assay development and data analysis.
Automation has also made our scientific workforce more competitive by significantly
reducing hands-on time with fully automated tests. We can more freely balance our scientific

SPONSORED BY
 ACCELERATING BIOLOGICAL ASSAY METHOD TRANSFER THROUGH EFFECTIVE AUTOMATION

te am amongst methods. recruit these expert scien-

We can also batch samples “We went from manually running a tists upfront.
and process them once M u t u a l l y, w e w a n t to
a week. A single scientist maximum of 100 samples per week understand and agree upon
can per form that testing a bioassay method specific
for one or multiple tests. with two analysts, to potentially running transfer protocol. We also
Finally, the variability is also want to have realistic time-
reduced or eliminated from more than 1,000 samples in a week lines including time for water
the bioassay results, so runs, troubleshooting, opti-
costly investigation time is with one scientist.” mization, and contingencies.
reduced. One other thing that
Catalent has learned from our partnerships is to focus on
Pharmaceutical Technology: How does automation fit the data that is outputted by the bioassay, not necessarily
into a biological method transfer strategy? the automation itself.

Merges: Catalent can now transfer bioassays from a manual
to an automated format or from an automated to automated
format. Both strategies support any or all of the three tac-
tical reasons for utilizing automation: the scientists’ safety,
the lowered operational costs, and variability reduction.
Pharmaceutical Technology: What is important to the
process of transferring an assay to automation?
Merges: Catalent has standard operating procedures in place,
and we have candid and transparent communication with
our partners to understand the pain points of their manual
methods. Transfers are not always like-for-like processes.
Sometimes, we also need to understand the automation
pain points.
Upfront training is essential. We might even split training
between our site and our partner site. We have learned it is
really important to have a dedicated automation staff with
expertise across common platforms and it is important to
Pharmaceutical Technology: Do you have any examples
of successful transfers to automated platforms?
Merges: The first one was a high-throughput assay designed
for screening donor samples. It was a manual, very tedious
assay. The foundation of the assay is quite old and we
were able to automate it. We went from manually running
a maximum of 100 samples per week with two analysts,
to potentially running more than 1,000 samples in a week
with one scientist. We reduced the number of steps from
eight to five, and we condensed the liquid handling steps
involved in that bioassay. We consider that improvement a
big success for an important bioassay used to screen donor
plasma samples.
The second example is where we are using a bioassay to
release a commercial product under good manufacturing
practices. We took a manual assay that we inherited that
was running with a 30% failure rate to more than a 98%
success rate once we automated that bioassay.

Catalent is a leading global provider of advanced delivery technologies and development solutions for drugs, biolog-
ics, and consumer health products. Catalent employs approximately 10,000 people, including over 1,400 scientists, at
more than 30 facilities across five continents, and in fiscal 2016 generated $1.85 billion in annual revenue. For more
information, please visit www.catalentbiologics.com
g .
 Peer-Reviewed
Removing Subjectivity from
the Assessment of Critical
Process Parameters
and Their Impact
Fasheng Li, Brad Evans, Fangfang Liu, Jingnan Zhang, Ke Wang, and Aili Cheng
A new algorithm uses a statistical approach to
critical process parameter assessment, allowing
for faster, more consistent, and less subjective
critical process parameter quantification,
visualization, and documentation.
Submitted: July 31, 2017.
Accepted: August 11, 2017.
46 Pharmaceutical Technology JANUARY 2018
D
etermining critical process parameters (CPPs) is vital
to defining the control strategy for drug substance
and drug product manufacturing processes (1). De-
ciding the criticality of a process parameter, however,
can often become a subjective exercise, resulting in long
discussions within product development teams as well as
back-and-forth communication with government regulators
during new drug application review.
A data-driven statistical approach was developed (2) to
help reduce subjectivity and debate in determining the
criticality of process parameters in the manufacturing of
drug substance and drug product. The approach uses the
distance of a critical quality attribute (CQA) from its quality
limit, together with the estimated parameter effect size, to
designate the criticality of a process parameter.
The method relies on straightforward calculations. How-
ever, performing these calculations manually can be time-
consuming and error-prone when the statistical model in-
volves multi-factor interactions and higher order parameter
effects. To incorporate this systematic approach into daily
practice, statisticians have developed a web-based compu-
tational tool that uses this method.
This article examines how the algorithm was developed,
focusing on the calculation of process parameter effect size
on a CQA. It also discusses how analytical and numerical
solutions of parameter effect size resulted from conventional
linear models.
Using grid search to develop a numerical approach makes
the algorithm flexible and simple enough to cope with all
PROSTOCKSTUDIO/SHUTTERSTOCK.COM
types of linear models that could have main effects, as well
as higher order interaction and parameter effects. In ad-
dition, the resulting tool supports the linear model with
transformation and provides a bias correction for model-
ing responses in the transformed scale.
A statistical approach to identifying CPPs
The assessment of CQAs and the control of the CPPs that
impact these attributes are crucial to the overall control
strategy for biopharmaceutical product manufacturing (2).
P h a r mTe c h . c o m
 Figure 1: Use of the Z score in CPP assessment.

Target limit >70% Target limit >90% Target limit < 3%

85 98 3
84 2.8
83 97 2.6
82 2.4
81 96 2.2
80 2
95
79 1.8
78
“close” to limit so
94
far from limit, so no 1.6
77
every parameter in
CPPs for this step 1.4
76 1.2
the model is a CPP
93
75 1
Z>6
74 92 0.8 Z<2
20% rule used to
73 0.6
72
determine CPP
91 0.4
71
2<Z<6
0.2
70 90 0

The International Council for Harmonization ICH Q8(R2)
(3) describes a CPP as “a process parameter whose variability
has an impact on a CQA and therefore should be monitored
or controlled to ensure that the process produces the desired
[level of] quality.”
There are many different approaches for assessing process
parameter criticality. Statistics, typically using data from
a designed experiment, plays an important role in these
evaluations. However, assessing the impact based solely on
statistical significance (e.g., p-value) is inadequate, because
it does not take into account the strength of the relationship
between variables and the process risk.
The new statistical approach (1) helps determine when a
statistically significant relationship between a process pa-
rameter and a critical quality attribute imposes a practical
concern, based on how close the data are to the target limit.
Figure 1 illustrates the approach, highlighting its three
main components: a statistically significant relationship, a
Z score, and use of the 20% rule. The Z score for a CQA
(y) with a one-sided quality target limit (L), is calculated as
shown in Equation 1.
ALL FIGURES ARE COURTESY OF THE AUTHORS
set of collected data is far from the lower quality target
limit, the process is at low risk of producing out-of-limit
(OOL) results.
The right-hand plot in Figure 1, however, shows data with
a low Z score. This shows that this set of data is close to the
targeted limit, and, thus, that the process is at higher risk of
producing OOL results.
In established practice, Z scores of two and six are used
as cutoff values in determining the criticality of process pa-
rameters. For example, if the data have a Z score greater than
six, no CPP will be assigned to the CQA because the process
is at low risk. Moving any parameter over its proven accept-
able range will not compromise product quality.
If the data of a CQA are close to its target limit, however,
and their Z score is less than two, it is generally appropriate
to assume that all statistically significant parameters are
CPPs. If the data of a CQA have a Z score between two and
six, all statistically significant effects are potential CPPs and
the data will be subject to the 20% rule (i.e., if the param-
eter’s impact is greater than 20% of the quality target range
[QTR], that process parameter will be considered a CPP).

The QTR is the window where we expect or need the quality

[Eq. 1]
where s is the estimated standard deviation of y.
The Z Scores can be applied to any CQA with either a
one-sided or a two-sided target limit. For a two-sided limit,
the Z score is determined by the limit closest to the mean.
The value of Z indicates how far, in standard deviation
units, the data are from the quality limits. A large Z score
is shown in the middle plot in Figure 1. Because the whole
attribute to land at that step in the process. The CTR can
be defined as |upper limit – min(y)| or |max(y)-lower limit|
for one-sided target limit, and |upper limit – lower limit| for
two-sided target limits.
If the parameter is determined not to have a statistically
significant relationship to a CQA, or its effect size is less
than 20% of QTR, subject matter experts should review the
established science related to this process parameter in the
context of the entire control strategy before designating this
parameter as non-critical.
Pharmaceutical Technology JANUARY 2018 47
Peer-Reviewed
Table I: Estimated effect size for parameter xi under different scenarios assuming the regression model (1).
Scenario
Only linear effect but no interaction with other parameters
Linear effect and interaction with some parameters
Quadratic effect and no interaction with other parameters
Quadratic effect and an interaction with other parameters
Following a holistic review of control strategy, most
parameters that are found to be insignificant will be de-
fined as non-critical process parameters. Exceptions would
only be made for parameters where significant scientific
evidence suggests that they will have an impact on a CQA
and where designating them as critical would improve the
overall control strategy. However, such cases would be rela-
tively rare.
Parameter effect size
The effect size of a process parameter provides an estimate
of the maximum change in a product quality attribute that
is contributed by that process parameter. Parameter effect
size calculation is carried out through the established func-
tional relationships between process parameters and quality
attributes. This paper focuses on the functional relationship
(i.e., the statistical model). A conventional statistical linear
model can provide an analytical solution of the parameter
effect size. When the model has higher-order terms, how-
ever, the analytical solutions are in more complex forms,
and a practical computational algorithm would be needed
to be able to perform such evaluations routinely.
A second-order linear model is commonly used in statisti-
cal design of experiments to reveal the functional relation-
ship between process parameters and a quality attribute.
The general form can be expressed as shown in Equation 2:
y resulting in a max change of 9. It is necessary to find a single
[Eq. 2]
where x i (1≤i≤n) represents the ith process parameters on
[-1, 1] with center point 0, y represents the quality attribute,
ε follows from the normal distribution N(0,σ2 ), βi (1≤i≤n)
is the regression coefficient corresponding to the first order
48 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
Estimated effect size for parameter xi
Same as above but evaluated at all combinations of +/- 1 for all parameters
involved in an interaction with xi
term x i, and βij (1≤i≤j≤n) is the regression coefficient cor-
responding to the second order term x i xj.
Without loss of generality, let us consider how to estimate
the effect sizes of x i under four different scenarios. In the
first three cases, the effect sizes have explicit analytical solu-
tions, and the corresponding expressions are summarized
in Table I. The effect sizes of other process parameters can
be estimated similarly.
Figure 2(i) shows a contour plot of predicted values for the
fitted model ŷ = 8 + 5x1-2x 2. The maximum change of y
due to x1 is 10 (regardless of x 2) and the change due to x 2 is
4 (regardless of x1).
Figure 2(ii) shows a contour plot of predicted values for the
fitted model ŷ = 8 + 5x1-2x 2 +4x1 x 2. The maximum change
of y due to x1 is 2 given x 2 fixed at -1 (bottom edge); whereas
the maximum change is 18 when x 2 is +1. Taking the larger
value, the effect size of x1 is estimated to be 18. Visually,
these are simply the changes along the top and left edges,
respectively. For the change due to x 2, the left edge shows
a change of 11 while the right edge shows a change of 4.
Therefore, the effect size for x 2 is 11.
Figure 2(iii) shows a contour plot of predicted values
for the fitted model ŷ =80-5x1+4x 2+4x 22 . The maximum
change of y along x 2,given x1= -1, is the difference between
the largest predicted value of 93 at x 2= 1 and the small-
est predicted value of 84 at the inflection point -0.5. The
maximum change is 9.
When x1=1, the corresponding values are 83 and 74, still
inflection point. Switching to x1, the maximum change is
10 (regardless of the value of x 2).
Figure 2(iv) is similar to Figure 2(iii), but now includes an
interaction along with a quadratic effect. This fitted model
is ŷ=80-5x1+3x 2+3x1 x 2+4x 22. Due to the interaction, the in-
flection points must be found along the both left edge and
the right edge.
 PLUS: Automati
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Peer-Reviewed
Figure 2: Contour plots of predictions for four examples:
(i) with only linear effects of two parameters on the quality attribute
(ii) with interaction effect of two parameters on the quality attribute
(iii) with quadratic effect of parameter x1 on the quality attribute
(iv) quadratic with two factor interaction
(v-vi) For model log10(y)=2+0.5x1+x2
(v): the prediction of log10(y) across the design space

1 1
74 72 86
74
0.5 0.5 76
76
84
78
78 80 82
0 0 82
84 80

-0.5 -0.5
86

-1 -1
-1 -0.5 0 0.5 1 -1 -0.5 0 0.5 1
2(i) 2(ii)

1 1
90 88 87
86
0.5 0.5 85
84 83
82
80 81
79
0 78 0
77
76
75
-0.5 -0.5
87
-1 -1
-1 -0.5 0 0.5 1 -1 -0.5 0 0.5 1
2(iii) 2(iv)

1 1
3
450 650 850 1050
2.5 0.5
0.5 250

2 0
0
50
1.5 -0.5
-0.5
1

-1 -1
-1 -0.5 0 0.5 1 -1 -0.5 0 0.5 1
2(v) 2(vi)

Along the left edge, the maximum change is 4, with 89 tions. In the transformed scale, the effect size of a process
being the prediction at both the lower left and lower right parameter for an attribute can be obtained formally by ap-
and 85 being the minimum, at the inflection point of 0.5. plying the formulas previously introduced. If the situation
Along the right edge, the inflection point occurs at x 2=- calls for examining the change of a quality attribute in its
0.75 and the change of 12.25 occurring along the right edge, original scale, the effect size must be evaluated on a case-
based on a minimum of 72.75 at the inflection point and a by-case basis, depending on the transformation.
maximum of 85 when x1=1. Assume that the model is constructed based on a mono-
tone-transformed response, denoted as g(y), where g(•) is
Effect size with transformed quality attribute the transformation function. The second-order linear model
Transformation of a quality attribute is often used to im- with transformation can be written as shown in the follow-
prove the model fit or to correct violations of model assump- ing expression, labeled Equation 3.
50 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
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Peer-Reviewed
Table II: Estimated mean of response with and without bias correction.*
*Note that μ is the prediction of transformed response g(y), and σ is the standard deviation of error. φ(·) is the
probability density function of the normal distribution with mean μ and standard deviation σ.
Transformation Estimated mean E(Y) without bias correction
[Eq. 3]
where ε~N(0,σ2).
Without loss of generality, consider only the calculation
of the x1 effect size. By definition, the effect size of param-
eter x1 is the maximum change in predicted response due
to parameter x1 when the other (n-1) dimensional vector
(x 2,…,x n) is fixed at any point in the parameter space [-1,1]
n-1
. Thus, the effect size due to parameter x1 may be found
by solving the following optimization problem, defined in
the following expression (Equation 4):
[Eq. 4]
where f(x1,…,x n ) denotes the prediction of response at a
given design point {x1,…,x n}. Manually solving this optimi-
zation problem is complicated. Due to transformation, the
parameters x 2,…,x n can have an influence on effect size re-
gardless of the model form. To illustrate this point, consider
a simple linear model with logarithm transformation of y as
expressed in Equation 5.
[Eq. 5]
52 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
Estimated mean E(Y) with bias correction
where x1 and x 2 are the parameters, and ε~N(0,σ2 ). The
prediction of y given x1 and x 2 is expressed in Equation 6.
[Eq. 6]
Note that a bias correction for prediction is employed
in Equation 6. Comparing this approach to inversely trans-
forming the prediction of log (y), the bias correction pro-
vides unbiased, or, at least, less biased predictions for the
response.
Discussion of this topic can be found in the literature (4,
5). Table II provides the bias-corrected prediction formulas
for some commonly used transformation functions.
Also notice that, in Equation 6, the change of predictions
contributed by x1 relates to the value of x 2. The analytical
formula of effect size is expressed in Equation 7.
[Eq. 7]
In this case, unlike the situation found in the “main ef-
fects” model without transformation, x 2 has an impact on
the effect size of x1.
To illustrate this, Figures 2(v) and 2(vi) display contour plots
from the model log10(y)=2+0.5x1+x2 in both transformed and
original scales, respectively.
Note that, in the plot of transformed scale, the impact
due to x1 does not depend on x 2, and the same holds for the
impact of x 2.
However, in the original scale, the maximum changes
clearly occur along the top edge (i.e., the impact of x1 when
x 2=1) and the right edge (i.e., the impact of x 2 when x1=1).
 This example shows that, even under the simplest case of Figure 3: Illustration of the grid-search algorithm for
linear model with transformation, the effect size of param- calculating factor effective sizes (5 x 5 grid)
eter must be evaluated across the entire design space.
When the model or transformation function is compli- Effect Size of X2: max(Delta) = 12

cated, it would not be feasible to evaluate the effect size Delta: 4 5.5 7.5 9.75 12
4
1
manually.

Using an algorithm to calculate parameter effect size

As described in the previous session, the effect size of a pa- 0.5 7

Effect Size of X1: max(Delta) = 16

rameter can be calculated analytically and programmed
with any computational language.
However, when more process parameters are included in
models, especially with higher order terms, it becomes more

X2
0 10

complex to derive the analytical solutions. A generalized,

practical computational tool is needed.
A grid-search algorithm was developed to calculate the
parameter effect sizes for any parameters in all types of lin- -0.5 13

ear models. Using this approach, the number of grid levels is

set based on the complexity of the model that is being used.
If the process parameters involved interact in linear fash-
-1 16
ion with other terms, the number of grid levels can be simply

-0.5

0.5

1
-1

Delta:
X1
set to two at the boundary of the parameter range.
However, if the parameters are involved in higher order
curvature terms, the number of grid levels must be set to
much larger than 2 in order to accurately locate the global eter by finding the maximum change of the predicted CQA
optimum point. caused by the process parameter change when other factors
The pseudo code used for the grid-search algorithm is are fixed at their possible levels:
shown below. Note that, when transformation of a CQA is
involved, the effect sizes are calculated based on the predic-
tions in original scale with bias corrections.

A grid-search algorithm for effect sizes

Step 1: List all process parameters in the model: x1, x 2, …, x k

Step 2: Set levels of grid for each of the parameters

For i in 1 to k
If x i has only linear effects in the model, the number of
grids is set to ni=2;
Else if x ihas curvature effects, the number of grid levels
can be set to ni=104/k, where k is the number of parameter
having higher order effect (e.g., if k=2, n i=100). The grid
points are selected over the ranges of parameters.
Figure 3 graphically shows how the grid-search algorithm
finds the maximum changes in a CQA over the ranges of
two process parameters. This CQA has an interaction/qua-
dratic model y=b 0+b1 x1 + b2 x 2 + b12 x1 x 2 + b 22 x 22. Notice
that, for illustration purposes, the grid levels were set to 5
for each of the two process parameters.

Step 3: Generate a matrix with combinations of grid levels
of parameters (1, 2, …, k) as shown below:
Step 4: Predict CQA (i.e., y) from its model fit, y=f(x)+ ε
Step 5: Determine the effect size (Δ) for each process param- tributes, with a target limit of not more than 0.6.
An example with algorithm output
For a moisture-sensitive product, aluminum foil and/or foil
packaging plus tablet water-activity controls are needed to
ensure that the drug product quality is maintained through-
out the desired shelf life.
A two-level full factorial design of experiment (DoE) was
performed to evaluate the impacts of three film coating pro-
cess parameters—spray rate, air-flow and exhaust tempera-
ture—on tablet water activity through the coating process.
Tablet water activity at the end of coating and water activity
at the end of cooling are identified as the critical quality at-
Pharmaceutical Technology JANUARY 2018 53
Peer-Reviewed
Figure 4: Using Z score and effect-size plots to evaluate the parameter criticality. CPP is critical process parameter.
The plot on the left shows the Z scores, with reference lines at 2 and 6. On the right, the absolute effect size is shown on the left axis
while the percentage of the quality target range (QTR) is shown on the right axis, with a reference line at 20% of QTR.

Attribute: End.of.Coating

0.08
8

Non-CPP

16.6% 20%
0.077

0.06
6.38 0.068
6

of Target Limit
20% Rule
Needed

Effect Size
Z Score

4.80

11%
0.04
4

5.5%
0.027

0.02
2

CPP

0.00
0

0%
ng

ng
ati

oli

ate

ow

p
Co

Co

Tem
. Fl
.R
of.

of.

ray

Air

st.
d.

d.

au
Sp
En

En

The statistical models of the attributes are given below:
End of Coating = 0.324 + 0.0388 * Spray Rate - 0.0138 *
Air Flow - 0.0338 * Exhaust Temp, R 2 = 0.9763
End of Cooling = 0.28 + 0.0225 * Spray Rate - 0.0150 * Air
Flow - 0.0375 * Exhaust Temp, R 2 = 0.9716
Process parameter criticality was assessed based on Z
scores of water activities and parameter effect sizes. Given
the calculated average (0.32), the standard deviation (0.058)
and the target limit of NMT 0.6, the Z score for water activ-
ity at the end of cooling process is 6.38. Because the Z score
is greater than 6, all three parameters are considered to be
non-critical.
Given the calculated average (0.28), the standard devia-
tion (0.05), and the target limit of NMT 0.6, the Z score for
water activity at the end of coating process is 4.80. Because
this Z score is in between 2 and 6, additional assessment is
required via the 20% rule to quantify individual parameter
effect sizes. Figure 4 displays the calculated z-score and the
effect sizes by grid search. Because the effect size of spray
rate is greater than 20% of QTR, spray rate is designated
as a CPP.
Exh
The algorithm of effect size calculation presented in
this paper offers a straightforward and universal solu-
tion, regardless of model complexity and the numbers of
process parameters and CQAs. It is generic enough to be
implemented in any commercial coding software package
(e.g., R and SAS). In addition, prediction biases caused
by certain transformations can be found and corrected,
as shown.
References
1. ICH, Q11 Development and Manufacture of Drug Substances (ICH,
2012).
2. K. Wang et al., Pharmaceutical Technology, 40 (3) 36-44 (2016).
3. ICH, Q8(R2) Pharmaceutical Development (2009).
4. J.Neyman and E.Scott, The Annals of Mathematical Statis-
tics,31(3), 643-655 (1960).
5. M. Newman, Environmental Toxicology and Chemistry, Vol 12,
1129-1133 (1993). PT

Summary
Fasheng Li, PhD, is director; Brad Evans, PhD, is associate
The determination of CPPs is a critical part of process and
director; Fangfang Liu, PhD, is manager; Jingnan
product understanding. A recent statistical approach (1) Zhang,PhD, is manager; Ke Wang*, PhD (ke.wang2@
provides an objective and consistent way to determine the pfizer.com),is director, and Aili Cheng, PhD, is director, all
CPPs based on the statistical analyses of experimental data. within Pfizer’s department of pharmaceutical science and
However, the calculations can be cumbersome, especially manufacturing statistics. Ms. Wang can be reached at 860-
686-2888.
when the predictive models are complicated and multiple
*To whom correspondence should be addressed.
CQAs need to be considered.
54 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
ADVANCING DEVELOPMENT AND MANUFACTURING

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Quality
Process Validation in
Biologics Development
Susan Haigney
Process validation is an extension
of biologics development processes.
W
hen it comes to outsourcing
process validation of biologics,
Abel Hastings, director of pro-
cess sciences at FUJIFILM Diosynth
Biotechnologies, says that the relation-
ship between a contract development and
manufacturing organization (CDMO)
and sponsor is key in ensuring success-
ful process validation. “Customers that
are open about their strategy, their data
(good and bad), and their own strengths
and weaknesses are most successful.”
Pharmaceutical Technology spoke
with Hastings about the specific chal-
lenges that arise in the process validation
of biologics.
Challenges specific to biologics
PharmTech: What are the challenges of
performing process validation during
Phase III of biologics development?
Hastings: A primary challenge we see
is viewing validation as phase-specific.
56 Pharmaceutical Technology JANUARY 2018
Ideally, process validation should be an
extension of the development and refine-
ment processes. To support this, develop
a long-term strategy for implementing
some of the validation-readiness tools
in simple versions early in development
so that a transition toward validation is
less a change in course and more an ac-
celeration of the project.
PharmTech: What aspects of process
validation should companies focus on
when preparing to submit a biologics
license application to FDA?
Hastings: As a CDMO, FUJIFILM
Diosynth Biotechnologies has seen
quite a variety of validation strategies.
Some strategies are influenced by indi-
cation, regulatory designation, or client
platform. Some common themes have
shown themselves to aid in success of
many of these projects. These themes in-
clude building clear attribute‒parameter
linkages, taking a systematic approach
P h a r mTe c h . c o m
to validation, and leveraging data-driven
risk management.
“We also
recommend
building an
iterative and logical
risk-management
program that is
based on data-
driven decisions.”
—Hastings,
FUJIFILM Diosynth
Biotechnologies
Clear attribute‒parameter linkage be-
gins with a fundamental understanding
of the molecule attributes, the measure-
ment systems, and the potential points
of variation and ambiguity therein. This
knowledge of the measurement can then
be applied to the process control strategy
including any ambiguity and interaction
with other attributes. A team’s focus on
required control becomes increasingly
clear by applying a logically mapped
linkage from attribute to the controlling
parameters.
A systematic approach to validation
that is based on consensus on both
definitions and readiness criteria and
is aimed at long-term commercial ex-
ecution is recommended. We have re-
fined our validation-readiness process
to achieve a balance between lean ef-
ficiency and sustainability. This devel-
opment required careful attention to
details such as definition subtleties, sys-
KUNST BILDER/SHUTTERSTOCK.COM
tematic documentation linkage, quanti-
tative assessment including leveraging
previous data, and systematic manufac-
turing execution standards. This focus
on mechanistically applying pre-built
tools has proven to be successful with
numerous clients efficiently driving
their projects to success.
 We also recommend building an iterative and logical risk-
management program that is based on data-driven decisions.
“Process validation should
As progress continues toward validation, teams can often be
influenced by process history (both recent and past), which can
be designed to demonstrate
lead to decision making with unintended consequences. We the capability of the process
push teams to iteratively refine risk-management documents
when new data come available thereby allowing them to make to support commercial
decisions based on data, even in the ‘heat of the moment.’ To
guide teams, we have built a series of risk-management tools manufacturing.”
that range from simple and focused on one problem to large
and involved FMEA [failure mode and effects analysis]. This —Hastings, FUJIFILM Diosynth
focus on regularly reviewing and documenting risk and data
evolution has expedited project execution in a reliable manner.
Biotechnologies
PharmTech: What protocols or tools are used in process vali-
dation of biologics compared with solid-dosage drugs? The quantitative pre-validation statistical guidelines and
Hastings: Biologics, when compared with solid-dosage prod- systematic tool-sets we use for validation-readiness have been
uct, can be a sea of parameters and attributes, many with a high developed and built around the expectations that projects
degree of variability. We have a systematic approach to process must have data to support sustainable commercial success.
validation that draws on experience from more than 300 mol- Approaching statistical risk management with more pre-val-
ecules; this allows us to focus attention on what matters most. idation runs is a common practice for many companies, but
We first begin with high-level process mapping intended to our [process validation] philosophy extends beyond that to
focus attention on parameter-attribute pairings. The next step, leverage a large body of pre-existing data and rigorous pro-
which includes smart use of a proprietary FMEA-like software cess-agnostic testing to augment process-specific data. To our
tool, can help focus characterization and equipment adjust- clients, this means improved knowledge of their supply chain
ments to help improve process reliability. Finally, our platform expectations prior to process validation. PT
quantitative assessment tool for parameter-attribute pairs con-
firms readiness for process validation. Taking this systematic
approach, we have been successful in cutting through a large
number of variables to reduce variation and ensure right-first-
time success for validation campaigns with tight timelines. PharmSource
Utilizing process validation data Lead Sheet
PharmTech: How can the data obtained during process validation
dŚĞĚĞĮŶŝƟǀĞƐŽƵƌĐĞĨŽƌ
be used elsewhere in the production cycle?
Hastings: Process validation should be designed to dem- ƚĂƌŐĞƚĞĚŶĞǁďƵƐŝŶĞƐƐ
onstrate the capability of the process to support commercial ŽƉƉŽƌƚƵŶŝƟĞƐŝŶ
manufacturing. To this end, the data generated during process ďŝŽƉŚĂƌŵĂĐĞƵƟĐĂů
validation should be the forerunner to the commercial control ĐŽŵƉĂŶŝĞƐ
charts. A primary question when reviewing an initial set of
commercial data should be: how do these data compare with the
X “A superb direct source to Used and respected
expected variation from my validation-preparation activities? current, well-suited leads so we can by the top CMOs,
Ideally, we expect commercial manufacturing to flow seamlessly ŽƉƟŵŝnjĞŽƵƌĐůŝĞŶƚďĂƐĞ” CDMOs and CROs
from validation, but due to the artificial-perfection that can ac- –Head of Sales, NA around the world.
company validation, some changes are expected. Recognizing X /ƚƐĂƉŚĞŶŽŵĞŶĂůůĞĂĚ
these subtle changes, and mitigating them as early as possible, ŐĞŶĞƌĂƚŽƌ/ǁŽƵůĚƐĂLJŝƚŚĂƐ Focused.
can substantially improve long-term manufacturing reliability. ĚŽƵďůĞĚŽƵƌŽƉƉŽƌƚƵŶŝƟĞƐ
–Dir., Global BD
Timely.
Supply chain considerations X dŚŝƐŚĂƐůĞĚƚŽŵĂŶLJŝŵƉŽƌƚĂŶƚ Accurate.
PharmTech: How can process validation help companies ensure ŵĞĞƟŶŐƐĂŶĚŽƉƉŽƌƚƵŶŝƟĞƐ
their biologic’s supply chain is reliable? –VP of Business Development,
Global CMO
Hastings: Process validation is not just about three batches
in a row. It is about launching a reliable commercial process. нϭϳϬϯϯဒϯϰဓϬϯDirect
This is why we design process validation campaigns around ϭဒဒဒϳϳϳဓဓϰϬToll-free in USA
an expectation that sustained commercial supply must be info@pharmsource.com | www.pharmsource.com A GlobalData company

planned for.
Pharmaceutical Technology JANUARY 2018 57
Elemental Impurities
Determination of
Dermal PDE for
Pharmaceutical
Products
Guy Bouvier, Amandine Gras, Jean-Guy Boiteau,
Anne-Pascale Luzy, and Jean-Pierre Etchegaray
The authors offer recommendations
for permissible daily exposures and
concentration limits of elemental
impurities for dermal drug products.
T
he International Council for Har-
monization Guideline for Elemental
Impurities (ICH Q3D) establishes
permissible daily exposures (PDE) in
μg/day to evaluate elemental impurities
(EI) in pharmaceutical drug products
(DP) administered by oral, inhalation,
Guy Bouvier,* guybouvier06FR@gmail.com,
is nonclinical coordination and evaluation
manager; Amandine Gras is product
development coordinator and CMC expert;
Jean-Guy Boiteau is head of process
research and development; Anne-Pascale
Luzy is head of in vitro toxicology; and Jean-
Pierre Etchegaray is pharmaceutical
development expert, all at Nestle Skin Health.
The financial support for this work was provided
by Nestlé Skin Health.
*To whom all correspondence should be
addressed.
58 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
or parenteral routes. The guidance
document provides the option to re-
evaluate PDEs for alternative admin-
istration routes when supported by
data, taking into consideration specific
toxic endpoints by other routes and
differences in absorption. Differences
in absorption between the dermal and
oral routes are known for several com-
pounds (1); thus, dermal absorption
data may allow re-evaluations (increase
or decrease) of some oral PDEs.
On the other hand, as the skin is
the primary organ in contact with DP,
specific toxic endpoints may appear for
some EIs and require a specific dermal
PDE (dPDE). Among skin-specific toxic
end points, sensitization has been iden-
tified for few EIs after dermal contact
from occupational exposure or from
cosmetic and house-hold product uses
(2–4). Such exposure represents an ad-
ditional safety issue to consider in the
evaluation of EIs in dermal DP.
The authors conducted an analysis of
all EIs for which an oral PDE was as-
signed in ICH Q3D to identify differ-
ences between oral and dermal bioavail-
abilities, following the work previously
published by Tesdale et al. (5). When
possible, the oral PDE was corrected
by the difference between the oral and
dermal absorptions to propose a specific
dPDE for topical DP. In addition, skin
sensitization was investigated to propose
minimal dermal concentration limits
(μg/g) for few EIs in DP.
Sufficient data to correct the oral
PDE were available for a few EIs only,
but establishing a dPDE may increase
the safety of dermatological products.
Skin sensitization has been identified as
a cause of potential safety issue for a few
EIs. The consideration of concentration
limits, in addition to PDEs, may increase
the safety of EIs for their overall dermal
safety evaluation.
Study methods
Safety evaluation. For each EI, a litera-
ture search for toxicity endpoints was
performed covering the time period
since the establishment of the oral PDE
for the EI. New information related to
carcinogenicity, genotoxicity, repro-
duction toxicity, and dermal toxicity—
including sensitization—were particu-
larly scrutinized.
Determination of oral and dermal absorp-
tions. The literature search explored the
oral absorption value for each EI when
administered under its specific ionic
salt form corresponding to the no ob-
servable adverse effect level (NOAEL)
in animal studies, or to the maximal
residual limit (MLR) in humans; this
information was used to calculate its
oral PDE. When ranges of values were
SISACORN/SHUTTERSTOCK.COM
reported without a definitive conclusion,
the lowest reported value—the most
conservative approach—was used for
the oral bioavailability.
The literature search also explored
the human dermal bioavailability for
each EI. If no human data were avail-
 Table I: Summary table of oral permissible daily exposures (PDEs), dermal PDEs, and dermal concentration limits.
Element Oral PDE μg/day Dermal PDE μg/day* (a) Concentration limits μg/g (a)

Class 1
Cadmium (Cd) 5 5 NA
Lead (Pb) 5 5 NA
Arsenic (As) 15 15 NA
Mercury (Hg) 30 30 10 μg/g
Class 2A
Cobalt (Co) 50 50 10 μg/g
Vanadium (V) 100 100 NA
Nickel (Ni) 200 110 5 μg/g
Class 2B
Tallium (Tl) 8 8 NA
Gold (Au) 100 100 NA
Palladium (Pd) 100 100 NA
Iridium (Ir) 100 100 NA
Osmium (Os) 100 100 NA
Rhodium (Rh) 100 100 NA
Ruthenium (Ru) 100 100 NA
Selenium (Se) 150 150 NA
Silver (Ag) 150 150 NA
Platinum (Pt) 100 50 NA
Class 3
Lithium (Li) 550 47,600 NA
Antimony (Sb) 1200 1200 NA
Barium (Ba) 1400 1400 NA
Molybdenum (Mo) 3000 3000 NA
Copper (Cu) 3000 3000 NA
Tin (Sn) 6000 6000 NA
Chromium (Cr) 11000 11000 100 μg/g
* Dermal PDE values were calculated based on oral PDE values before rounding as reported in the appendix of Guideline for Elemental Impurities (ICH Q3D)
(a) Concentration limit for dermatological product, expressed in μg per g of drug product (DP).
NA: Not applicable. As no specific limit related to skin toxicity was identified, the dermal PDE must be used.

able, in-vitro human skin penetration
studies were considered and, lastly, ani-
mal data. All ionic forms were generally
considered and the most reasonable
penetration value was retained exclud-
ing maximizing procedures (e.g., occlu-
sion). For chromium (Cr), only Cr(III)
was considered; Cr(VI) is highly un-
stable and reactive, and is unlikely to be
present in DP.
The percentage of dermal penetration
was calculated as the sum of quantities
recovered in the stratum corneum, epi-
dermis, dermis, and in the liquid recep-
tor. Skin washing procedures or tape
stripping before measuring skin con-
centrations were considered on a case-
by-case analysis. When in-vitro dermal
applications were conducted for more
than 24 hours, results were interpreted
with caution.
Calculation of dermal PDE. When oral
bioavailability data to establish the oral
PDE and human skin dermal penetra-
tion were both available with a certain
level of robustness from literature, the
ratio of the oral values versus the der-
mal values were calculated. The dPDE
was then calculated by multiplying the
oral PDE by this factor if dermal and
oral absorptions differed by at least a
two-fold factor.
Determination of concentration limits. For
each EI, a review of the dermal toxicity
was undertaken, looking for specific der-
mal toxicity, dermal irritation, and skin
sensitization. When a particular safety
endpoint was identified by the dermal
route (toxicity or sensitization), the min-
imal concentration at which such effect
is not expected to occur in the normal
population was proposed as the dermal
concentration limit. For skin sensitiza-
tion, the dermal concentration limits se-
lected were from subjects not previously
Pharmaceutical Technology JANUARY 2018 59
Elemental Impurities
Figure 1. Decision tree to evaluate elemental impurity (EI) content in dermal drug timony, barium, gold, iridium, molyb-
products (DP) using permissible daily exposures (PDEs) and concentration limits. Ni is denum, osmium, palladium, rhodium,
nickel. Hg is mercury. Co is cobalt. Cr is chromium. ruthenium, tallium, tin, selenium, and
vanadium. Oral and dermal absorption
values were within the same range for
EI to be assessed cadmium, lead, mercury, silver, copper,
and chromium. Conf licting dermal
penetration values did not allow an es-
timate for cobalt.
Calculation of
30% dermal PDE An in-vivo human skin absorption
(μg/day) data for lithium (Li) indicated no ab-
sorption; however, a high oral absorp-
Maximal daily tion value was reported in animal spe-
dose (g/day)
cies (at least 85%). As in-vivo human
skin absorption data for Li indicated no
Calculation of the absorption, the authors set the dermal
EI concentration absorption at 1% as a default and conser-
limit (μg/g)
vative approach. This led to increasing
the oral PDE by 85-fold to establish der-
For Hg, Co, Ni, and Cr,
mal PDE at 47,600 μg/day for Li. How-
compare above ever, as this value is very high, the source
EI concentration
limit with dermal
of contamination and the justification
concentration limit. for such high impurity concentration of
an EI in a DP should be provided.
A lower absorption by the dermal
Apply lowest route was also determined for arsenic
limit
(As) but this compound is known to be
toxic for the skin, regardless of route of
EI limit in (μg/day) administration, and to have a specific
and (μg/g)
tropism for it. As dermal toxicity was
observed after oral and parental admin-
Example: The dermal PDE for Ni is 110 μg/day; thus, istrations, the specific toxicity of As to
the daily exposure from a dermatological DP should
not exceed 30% of it (e.g., 33 μg/day). As the concentration
the skin is considered addressed. Nev-
limit for Ni is 5 μg/g—up to a quantity of 6.6 g/day of DP ertheless, the authors concluded that the
(33/5) —the concentration limit of 5 μg/g will be the lower dermal penetration of As does not
applicable limit. Above 6.6 g/day, the 30% of the PDE
(33 μg/day) will be the applicable limit to determine the justify a higher PDE.
maximal concentration of Ni in the dermal DP, Finally, a two-fold higher absorption
(33 μg/day divided by the daily quantity of DP);
this corresponds to a concentration of by the dermal route for nickel and plati-
3.3 μg/g for a DP applied at 10g/day. num (Pt) justified decreasing the dPDE
for each element.
The authors considered skin sensi-
sensitized for the EI and were based on summary of results for other elements tization as a specific potential concern
human studies conducted under normal can be found in Table I. A comprehensive for some EIs, justifying a concentration
conditions, excluding concomitant uses analysis of the literature search findings limit in addition to the PDE. The selec-
of irritants (e.g., sodium lauryl sulfate) and study analysis can be found online tion of each limit criteria is presented in
and occlusive patch applications exceed- at www.pharmtech.com/pt/dermalPDE. Figure 1. When a dermal concentration
ing 24 hours. limit is defined for an EI, it is neces-
Discussion sary to compare this value to 30% of the
Results Among the 24 elements in the ICH Q3D PDE considering the daily posology of
Due to missing data for oral or dermal guideline evaluated for dermal absorp- the dermal DP and to evaluate which
absorption, it was not possible to de- tion, PDEs were unchanged for 21 ele- of the two limits is the lowest. For ex-
termine dPDE for antimony, barium, ments, increased for one and decreased ample, the PDE for mercury (Hg) is 30
gold, iridium, molybdenum, osmium, for two. The literature search found μg/day; thus, the daily exposure from a
palladium, rhodium, ruthenium, se- that absorption data was not available dermatological DP should not exceed
lenium, thallium, tin, or vanadium. A for at least one route of exposure for an- 30% (e.g., 9 μg/day) and the concentra-
60 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
tion limit of 10 μg/g. Thus, up to a posol-
ogy in DP of 0.9 g/day, the dermal con-
centration limit for Hg (10 μg/g) must
be applied; whereas above 0.9 g/day
the 30% PDE (9 μg/day) will be the ap-
plicable limit.
These dermal concentration limits
will increase safety by limiting high
concentrations of products on small
skin areas, which could cause skin sen-
sitization elicitation or reactions.
The dermal concentration limits de-
fined apply only for compounds applied
on the skin without rinsing.
In case of restricted uses (e.g., sham-
poo), mitigation factors taking into ac-
count the time of contact may be applied
as described in cosmetic regulations (6).
For example, for a shampoo, a retention
factor of 0.01 can be applied, increasing
both the concentration limit and the
PDE. Evaluation of such short-contact DP
should be made on a case-by-case basis.
These concentration limits must not
be applied for DP applied as occlusive
patches as it is well recognized that oc-
clusion increases significantly the risk
of skin sensitization reaction or elicita-
tion (7). In addition, uses of occlusive
patches compromises the skin function
barrier and often increase percutaneous
absorption. Thus, for drugs applied with
occlusive patches, the skin penetration
should be measured. If the change in
dermal absorption is greater than a two-
fold factor, the concentration limit and
the dermal PDE should be corrected, or
a dPDE should be established from the
oral PDE.
Finally, these dermal concentration
limits and revised PDE are not appli-
cable for topical DP applied on skin
requiring preparations, like curettage,
keratolytic pretreatment, or abrasion, for
which a case-by-case evaluation should
be performed, taking into account
changes in dermal penetration.
In conclusion, the authors propose
the establishment of dPDEs for some
EIs to take into consideration differences
between oral and dermal penetration
levels and to set dermal concentration
limits for some EIs due to their signifi-
cant skin sensitization risk. These new
values should ensure a higher safety pro-
file of dermal DPs.
Disclaimer
The views, thoughts, opinions, and rec-
ommendations expressed in this article
belong solely to the authors, and do not
necessarily reflect the opinion or posi-
tion of Nestlé Skin Health.
References
1. F.M. Williams, et al., Regul. Toxicol. Phar-
macol. 76:174–186 (2016).
2. G. Forte, F. Petrucci, and B. Bocca, Inflamm.
Allergy Drug Targets. 7 (3) 1–18 (2008).
3. B. Bocca, A. Pino, A. Alimonti, and G.
Forte, Regul. Toxicol. Pharmacol. 68:447–
67 (2014).
4. M. Marinovich, M.S. Boraso, E. Testai,
C.L. Galli, Regulatory Toxicol. Pharmacol.
69:416–424 (2014).
5. A. Teasdale, K. Ulman, J. Domoradzki,
and P. Walsh, Pharma. Technol. 39 (9)
44–51 (2015).
6. EU, SCCS/1564/15. The SCCS Notes of
Guidance for the Testing of Cosmetic In-
gredients and Their Safety Evaluation, 9th
Revision (2016).
7. H. Zhai and H.I. Maibach, Contact Der-
matitis 44 (4) 201–206 (2001). PT

Elemental impurities implementation: Ready, or not

The International Council for Harmonization released revised guidelines (1)
for evaluating elemental impurities in drug products in November 2014, sig-
nificantly changing the test methods and approaches used by drug companies
and contract testing laboratories to measure the presence of such impurities.
As of January 2018, new and existing drug products were subject to
compliance with the guidelines. Active audience attendance and questions
during webcasts on the elemental impurities process in late 2017 indicated
that some pharma companies were scrambling to comply.
The ICH Q3D guideline, subsequently adopted by regulatory authorities in
the United States, Canada, Japan, and Europe, implements a risk-assessment
approach to establish toxicologically relevant permitted daily exposure (PDE)
limits to for individual elements and replaces the previous wet chemical heavy
metal limit test.
The guideline features three sections: the evaluation of the toxicity data
for potential elemental impurities; the establishment of a permitted daily
exposure (PDE) for each element; and application of a risk-based approach to
control elemental impurities in drug products. While the guideline specifies
PDEs for oral, parenteral, and inhalation routes of administration. For other
administration routes, such as dermal, the guideline may be used to derive
PDEs; drug companies must assess an increase or decrease in PDE by assessing
factors including local effects, bioavailability, and quality attributes.
An ICH working group is developing PDEs for cutaneous and transdermal
route of administration, with an anticipated publication for public comment
in May 2018 (2).
Training and compliance guidelines
ICH has published a training series (3) to assist companies with compliance.
The modules include:
• Developing Acceptable Levels for Other Routes of Administration
• Justification for Exceeding a PDE
• Developing Acceptable Levels for EI not in Q3D
• Considerations for Large Volume Parenterals
• Risk Assessment
• Controls on Elemental Impurities
• Calculations Options.
ICH also offers case studies and a frequently asked question document.
Additional information on elemental impurities from various industry
sources can be found on www.pharmtech.com/pt/elementalimpurities.
References
1. ICH, Q3D Guideline for Elemental Impurities, Step 4 version (2014), www.ich.
org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/
Q3D_Step_4.pdf.
2. ICH, ICH Q3D(R1) EWG Work Plan (Aug. 30, 2017), www.ich.org/fileadmin/
Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3DEWGWork-
Plan_2017_0830.pdf.
3. ICH, Implementation of Guidelines for Elemental Impurities, Q3D Training,
www.ich.org/products/guidelines/quality/article/quality-guidelines.html.
The editors of Pharmaceutical Technology

Pharmaceutical Technology JANUARY 2018 61

Packaging
Boosting Functionality
of Container Closures
Hallie Forcinio
Advanced closures and capping equipment have
new product-protecting features.
F
or solid-dosage forms, capping is
a primary operation on the pack-
aging line. Cappers and related
equipment integrate seamlessly with
up- and downstream systems, ensure
proper application and removal torque,
maximize overall equipment effective-
ness (OEE), and offer quick changeover
across a range of cap sizes and styles.
Caps, or closures, not only close the
container and protect the product, but
often offer additional functionality
such as easy dispensing, child resis-
tance, tamper evidence, and shelf-life
protection. Demand for additional
Hallie Forcinio
is Pharmaceutical
Technology’s
Packaging editor,
editorhal@cs.com.
62 Pharmaceutical Technology JANUARY 2018
functionality, particularly child-resis-
tant (CR) and tamper-evident designs,
is helping spur a 5% compound annual
growth rate through 2020 for pharma-
ceutical caps and closures, according
to a market study from Technavio (1).
Increasing shelf-life
To address stricter requirements related
to drug stability, there’s considerable
action in closures with enhanced shelf-
life protection capabilities. Activ-Seal
scavenging closures from CSP Technol-
ogies streamline the packaging process
for products needing added protection
from relative humidity (RH), oxygen,
or other gases by building the scaven-
ger into the closure, thereby eliminat-
ing the need to purchase and insert a
scavenging canister or sachet into each
bottle, which also avoids the risk of ac-
cidental ingestion. “Depending on the
customer’s need, we can maintain tar-
get RH that is between a designated set
P h a r mTe c h . c o m
of ranges or draw down close to zero,”
says James McGetrick, associate direc-
tor of Business Development for CSP
Technologies. Launched in 2016 and
designed to work with existing caps,
containers, and packaging equipment,
several pharmaceutical manufacturers
are completing testing of Activ-Seal
closures. “We expect a commercially
approved product to enter the market
soon,” he adds.
Another built-in scavenger, the Sil-
ica Gel Capsule from Italy’s Bormioli
Rocco, integrates scavenger and clo-
sure. “This solution allows for im-
provements both in terms of machin-
ability and patient safety,” explains
Anna Malori, a member of the business
development staff at Bormioli Rocco.
“Because the cap contains the desiccant,
no additional filling processes are re-
quired, and filling times are greatly
reduced. Furthermore, this solution
avoids the risk of accidental ingestion
that can occur with silica gel packets.”
Senior-friendly CR closures
Greater efficiency and sustainability
benefits prompted the development of
a one-piece, thread-free polypropyl-
ene closure by Comar. Designed to re-
place traditional two-piece push-and-
turn CR closures, the senior-friendly
Secure-Cap QuarterLoc closure re-
duces part weight and manufacturing
complexity and offers a potential cost
savings up to 25%. The bayonet-style
neck finish enables application and
removal of the closure in a quarter
turn and eliminates concerns about
application torque, cross-threading,
and cocked closures. Compatible with
CR and non-CR containers, the clo-
sure can be manufactured in standard
sizes. It does not require a liner but can
accommodate a pulp-backed, glued-in
foil induction liner and is compatible
SHAWN HILL/SHUTTERSTOCK.COM
with conduction liners, which are heat-
sealed in place before the cap is applied.
The closure can be applied on standard
capping equipment and will not back
off after application (2). Although
there are no commercial users yet,
Sue Benigni, business segment direc-
tor at Comar notes, “the closure mold
 is under construction. We have been
doing customer trials for gummy vita-
min products with several of the major
manufacturers.”
Applying consistent torque
Although torque measurement is not a
factor when applying the QuarterLoc
closure, it’s a critical parameter for
many other closure styles. “Manufac-
turers are moving toward a zero-defect
philosophy where applying caps pro-
duces reject rates less than 0.5%, and
every cap torque application is mea-
sured with torque profile monitored
for consistency, standard deviation,
and conformity,” notes Alan Shuhaibar,
president of BellatRx.
Monitoring is particularly impor-
tant on lines with induction sealing.
“To achieve a proper seal, you have to
have the proper applied torque,” ex-
plains Omar Azam, inside sales man-
ager at NJM Packaging, a ProMach
Product Brand.
Shuhaibar agrees. He says monitor-
ing the actual torque applied accom-
plishes multiple goals: “First, a guaran-
tee of proper induction seal adherence
and second, the migration away from
the need to test for removal torque when
controls are set for application torque.”
Cappers equipped with intelligent
torque-monitoring capabilities address
this need. For example, the BellatRx
Secure Chuck Capper incorporates
servo torque technology and advanced
software to monitor torque application.
“The software behind the torque control
on our cappers is sophisticated enough
to be able to detect stripped caps and
worn grippers,” reports Shuhaibar. The
latest monitoring advancement cap-
tures the actual torque reading at the
cap to measure the torque profile ex-
erted by the servo and make decisions
FIGURE IS COURTESY OF NJM PACKAGING
about the pass or fail of each cap going
through the capper. Other features
of the Secure Chuck Capper include
recipe control for easy and repeatable
setup and GMP design to maximize
cleanability of surfaces and eliminate
entrapment areas. Full installation, op-
erational, and performance qualifica-
tion protocols facilitate the validation
Figure 1. The NJM Packaging beltorque BT-IC capper monitors applied torque and triggers
a reject device to remove capped bottles that are under or over pre-set thresholds.
and commissioning process.
The beltorque BT-IC capper from
NJM Packaging (see Figure 1) also
monitors applied torque and trig-
gers a reject device to remove capped
bottles that are under or over pre-set
thresholds. “We can measure applied
torque on every container as the cap
is applied so we can make sure each
one is in specification,” says Azam. To
further protect quality, the beltorque
capper offers an inspection option.
Sensors identify containers with miss-
ing or skewed caps and missing induc-
tion seals. Another inspection option,
using infrared technology from DIR
Technologies, can verify the integrity
of each induction seal.
On the inline beltorque capper, two
pairs of belts gently rotate and tighten
caps. Using patented technology, one
drive synchronizes the linear displace-
ment speed of the container with the
rotating speed of the closure, even
when the cap stops turning. This de-
sign minimizes slippage to achieve
more consistent torque values. It also
maximizes product quality by elimi-
nating damage to the cap knurling
and cap finish. Rated at 300 bottles per
minute, the capper competes with ro-
tary cappers and offers simple mechan-
ics, fast changeovers, and low mainte-
nance. A servo-driven elevator-feeder
with cleats that automatically adjust to
cap size supports the high-speed op-
eration. A sequential on-demand ad-
vance indexes the elevating conveyor,
smooths the operation, and reduces
compressed air use by 50% to lower
energy costs (3). The beltorque cap-
per can orient and place popular, but
difficult-to-handle closures, such as
gear-shaped and rubberized arthritis
screw caps and f lip-top screw caps.
Without good control, f lip-top caps
can pop open, notes Azam. “We have
devices inside the capper that keep
the top closed, and we inspect a cap to
make sure it stayed closed,” he explains.
Improving induction seals
Beneath the flip-top cap, an induction
seal often provides tamper evidence
and protects product quality. Unfortu-
nately, when a consumer removes the
cap for the first time, the seal can be
hard to remove. A pull tab on the Easy
Peel induction liner from Bormioli
Rocco solves that problem. Compat-
ible with all of the company’s closures
and bottles for solid doses, the tabbed
design eliminates the need to use po-
tentially dangerous tools to remove
the liner without changing its ability
to protect tablets or capsules from hu-
midity, oxygen, and other environmen-
tal factors.
contin. on page 68
Pharmaceutical Technology JANUARY 2018 63
Pharmaceutical Serialization
Everyone may not be ready for the deadline,
but open standards based on GAMP and GS1
will soon be released; more companies are
also leveraging what they’ve learned from
serialization to improve overall efficiency.
F
or more than a decade, the bio/
pharmaceutical industry has strug-
gled to establish a true electronic
pedigree that would allow its products
to be traced and verified at any point
along the supply chain. The US Drug
Supply Chain Security Act (DSCSA)
and the European Union’s Falsified
Medicines Directive set timelines and
requirements for serializing product
packaging, aggregating product and
lot-level transaction data electronically,
and sharing information with distribu-
tors and at the point of use or sale.
Even though serialization is only the
first leg of the journey toward full trace-
ability, the technical challenges and costs
are significant. This is due to a fundamen-
64 Pharmaceutical Technology JANUARY 2018
Pharma
Serialization
Nears a
Tipping Point
Agnes Shanley
tal mismatch of applied integration tech-
nologies for inter-plant, plant-to-enter-
prise, and distribution repack exchanges,”
says Charlie Gifford, technical director of
the Open Serialization Communication
Standard (OPEN-SCS) Working Group.
In addition, he says, distinct data el-
ements required for serialization and
traceability are interrelated. Examples
include workflow rules; serial number
formats; data sets (i.e., those established
by regulators vs. those used by vendors
vs. those for users); provisioning and se-
rialization events; master data and asso-
ciated technologies (e.g., for production,
ordering, and reporting) so the data and
their relationships must be agreed upon
and specified for data accuracy and ex-
P h a r mTe c h . c o m
change interoperability. Understand-
ing and agreeing on data relationships
across the overall serialization process
is extremely challenging, Gifford says.
Open standards
Four large life-sciences companies and
five solution providers established the
OPEN-SCS working group in Febru-
ary 2015 to sort through these issues.
Their goal was to stem pharmaceutical
counterfeits by developing open, ven-
dor-neutral data-exchange solutions
that would simplify integration of the
components and systems required for
product serialization and traceability.
The group now has more than 25
ative members and 100 interested sup-
porters. OPEN-SCS achieved a num-
ber of important goals in 2017 (see
Sidebar), establishing a collaborative
agreement with the International So-
ciety for Pharmaceutical Engineering
(ISPE) and approving the first version
of the OPEN-SCS Packaging Serializa-
tion Specification (PSS 1.0).
Plans call for OPEN-SCS to release
Good Automated Manufacturing Prac-
tices (GAMP)-compliant user require-
ment specifications (URS), functional
specifications (FS), and operational and
installation qualification (OQ/IQ) tem-
plates in March 2018. A core group of
vendors (ACG Inspection Systems, Ad-
vanco, Antares Vision, Arvato Systems,
Optel Vision, Systech, TraceLink, Tra-
deticity, Uhlmann, Vantage Consulting,
and Wipotec-OCS) are developing vali-
dation test interfaces for one or more of
the four use cases of PSS 1.0, says Gif-
ford. Each vendor may commercialize
compliant interfaces by the end of the
third quarter of 2018.
The group expects these efforts to
reduce the cost and time required to
implement serialization and traceabil-
ity projects by at least 50% when ap-
plied across multiple packaging plants.
HUMPHERY/SHUTTERSTOCK.COM
“For most companies today, integra-
tion typically means custom projects,”
says Evren Ozkaya, founder and CEO
of Supply Chain Wizard. “OPEN-SCS
will improve the standardization of
contin. on page 66
Moving toward open standard specifications for serialization integration
It was a busy year for the Open-SCS working group. Charlie Gifford, technical direc-
tor of the group, summarized developments that occurred in 2017.
PharmTech: How did you decide to use good automated manufacturing
principles (GAMP) lifecycle best practices for the serialization standards?
Gifford: The User Requirement Specification (URS) and Functional Specification
(FS) for the standard Packaging Serialization Specification (PSS) version 1.0 were
approved by members in August. Three member companies are already using them
as templates for projects, and providing feedback into ongoing validation testing.
However, in June, we took the International Society for Pharmaceutical
Engineering (ISPE’s) recommendation and adopted the GAMP lifecycle best practice
of conducting a full validation test and report using prototype OPC-UA interfaces
in order to refine PSS 1.0’s URS, FS, and operational and installation qualification
(OQ/IQ) templates. The new PSS 1.0 package is set for formal release in March
2018, depending on available member resources. Eleven vendor members have
committed a developer to build prototype interfaces for the validation test. This
design-build-test exercise has already brought out many updates to functional
requirements that had not been addressed in the previously approved draft.
In December, work began on a PSS 2.0 URS working draft, which is scheduled for
member review in February. Six inter-plant solution providers and two end users
are working on this project. Depending on availability of member expert resources
in 2018, the technical committee hopes to accelerate and release PSS 2.0 by the
fourth quarter of 2018.
PharmTech: What kind of participation are you seeing among pharma
companies and contract manufacturing organizations (CMOs)?
Gifford: Membership is now over 25, with 100 interested companies saying that
they will join the group, either when PSS 1.0 is released addressing plant operations
(Level 3), to enterprise (Level 4) exchange use cases for regulation reporting, or once
the PSS 2.0 addresses Level 2-Level 3 exchange use cases.
PharmTech: What have been the most challenging technical aspects of
developing this standard? How are they being resolved?
Gifford: One major challenge was dealing with the high-level complexity of
the packaging serialization scope and problem data (product, order, reporting)
and their associated integration technologies. As we’ve learned after working on
these problems for the past 24 months, the root of the problem often lies with
pharma customer requirements. Most pharmaceutical manufacturers’ serialization
exchange requirements force their vendors to customize GS1’s Electronic Product
Code Information Services (EPCIS) schema into forms that are not interoperable
across systems. These interfaces don’t scale, corrupt good data, and do not apply
required interoperable transaction methods. GS1’s EPCIS experts have worked
directly on our team to ensure that the PPS 1.0 [specifications for each use case]
comply with EPCIS, or at least are as closely aligned as the scope permits.
Because EPCIS’s scope does not address serial number management and
serialization events between the packaging plant and enterprise, another major
challenge was developing a Serialized identifier (SID) event lifecycle model for the
events, states, and transition for serial number management and serialization
events between the packaging plant and enterprise. Along the way, we’ve had
to respond to the challenge that any new collaborative organization faces: how
to fund all this work. We are still working to find the best business model that will
support new projects and updates from changed and new regulations.
PharmTech: How difficult has it been to establish consensus among
members from such different groups?
Gifford: It was especially challenging during 2015 and 2016, when there
was a great deal of debate on whether PSS 1.0 should address data exchange
between the site serialization manager-actor (Level 3) and the enterprise seri-
alization manager-actor (Level 4) or between the packaging line serialization
manager-actor (Level 2) and Level 3. We held four workshops on this topic
alone during that period.
PharmTech: How difficult is it to get the high-level IT help that serialization and
traceability programs demand?
Gifford: Hiring skilled developers, for the funding that is available, is a
challenge for all manufacturing and business sectors, especially as Manufacturing
4.0 initiatives take shape. Integration-specific developers are a rare breed. They
need to have over five years of experience and mentoring in order to be competent
enough not to compromise data accuracy and security. This challenge has
dramatically affected the quality of serialization solutions deployed in the life-
sciences industry. Having a standardized integration approach will significantly
reduce risks.
At this point, though, life-sciences companies are not openly acknowledging
and reacting to the supply of talent. For example, the going hourly pay rate for
developers with the necessary skills has increased to $180–200 per hour. Pharma
companies are paying $80–120 per hour, so many developers in life sciences get
serialization experience and additional training and leave the sector for better-
paying jobs elsewhere.
PharmTech: What has made you most proud of OPEN-SCS’ achievements so far?
Gifford: First, it’s important to recognize that the top solution providers,
which compete against each other on a daily basis, are working together on this
project and exchanging proprietary know-how to in order to reach a common
result. These efforts have all been driven by the desire to benefit patients by
reducing deployment timeframes and the cost of ownership, while ensuring data
integrity and security across the supply chain. It has also been gratifying to see
the contributions of experts from GS1, ISPE, the OPC Foundation, and solutions
providers align in these efforts.
On the technical side, the working group made some significant progress in
developing the SID event lifecycle model and the packaging order and product
master data use cases and their supporting interfaces.
PharmTech: What have you learned from the pilot tests?
Gifford: We achieved a number of benefits by using OPC Universal Architecture
(UA), which allowed us to find and fix holes in the original draft standard
specifications. We used UA to develop the validation test, FS, and associated OQ
and IQ modules. The validation tests have provided a foundation for certification
programs, and, as previously mentioned, solutions providers are participating in
the validation test by developing interfaces.
PharmTech: What are you planning for the next phase of this work?
Gifford: We began working on a draft of the PSS 2.0 URS in December for
review by members in February or March. The approved scope of this standard
specification will extend use cases for serial number provisioning and return as well
as serialization master data, and event reporting.
It will also address use cases for rework and multistep processing and incorporate
new use cases determined through customer surveys and an April 2017 workshop,
including serial number provisioning for lot start; end-of-lot issues such as unused
serial number returns and unused, decommissioned, orphaned, or sampled serial
numbers; end-of-lot issues with full batch data and mid-lot runs; production order
downloads for new and rework orders, including aggregation hierarchies; and
handling exceptions.
Pharmaceutical Technology JANUARY 2018 65
Pharmaceutical Serialization
contin. from page 64
exchanged data and their data struc-
ture in communications between
plants, and between plant and enter-
prise systems, which will reduce cost.”
Reducing integration complexity
and cost will be crucial to advancing
traceability initiatives within smaller
companies, especially generic-drug
manufacturers and smaller contract
manufacturing organizations (CMOs),
whose margins are extremely tight.
“These companies don’t typically see any
direct benefits by investing in expensive
systems to track their products through-
out the supply chain,” says Marcel de
Grutter, OPEN-SCS executive director.
“Even major multinationals struggle with
the fact that they are currently releasing
fewer blockbusters so they are continu-
ously restructuring to support their com-
mercial products,” he says. As a result,
implementations are delayed, as serial-
ization competes with priorities such as
ensuring a continuous supply of product.
In 2017, after realizing that many smaller
firms had not even begun serialization
efforts, FDA extended DSCSA’s original
serialization enforcement deadline by
one year, to November 2018 (1).
Still, a readiness gap remains under-
estimated. Most large pharma compa-
nies are ready, or were a while ago, but
some companies still haven’t begun
formal serialization programs, while
others that see themselves as ready.
have only serialized part of their pack-
aging lines, says Ozkaya (see Sidebar).
“Painful days are ahead of them,” he
says, because serialization efforts can
lower productivity and line efficiency
during early implementation stages.
The number one issue is CMO readi-
ness, says Ozkaya. “FDA’s enforcement
delay was a welcome move, but compa-
nies need to staff project teams prop-
erly, partner more closely with solution
providers, and manage their internal
site and external CMO compliance
risks more proactively,” he says.
Observers see industry mindset as
part of the problem. Until recently,
most pharma company leaders viewed
serialization as a compliance need, with
no return on investment, says Gifford.
At a time when more countries around
the world are setting serialization re-
quirements, regulators often underes-
timate what it takes for any company
to implement a full track-and-trace
system. “Changing requirements and
timelines do not help,” he says.
Even though basic compliance issues
remain unresolved, more companies
are starting to explore ways in which
their efforts and investments in seri-
alization can be leveraged to improve
overall operations. One common focus
is to improve overall equipment effec-
tiveness (OEE) in packaging, to offset
decreases in efficiency. “Some com-
panies have assigned dedicated lead-
ers to work on this, while others have
invested in finding business use cases
to extract value from serialization data
and their ecosystems,” says Ozkaya.
Instead of keeping these efforts to
themselves, more companies are talk-
ing about them at industry conferences,
conducting internal pilot projects and
collaboration initiatives with trade
partners to create long-term strategies.
“A few years ago, we were trying to con-
vince companies to look into supply
chain and operational improvements in
the serialized world. Today, more firms
are taking the initiative and reaching out
for help, a positive sign,” says Ozkaya.
“The industry is moving in the right di-
rection, even though its initiatives may
still lack speed and momentum,” he says.
Reference
1. Pha rmTech Ed itors, “FDA Pushes
DSCSA Seria lization Enforcement
Deadline to 2018,” pharmtech.com,
July 6, 2017, www.pharmtech.com/fda-
pushes-dscsa-serialization-enforce-
ment-deadline-2018 PT

Surveys redefine “ready”

In December 2017, TraceLink released findings from a survey of 660 serialization
partners, including 174 pharmaceutical companies and 155 contract manufactur-
ing organizations (CMOs) (1). Results, due to be published during the first quarter
of 2018, suggest that only one third of the pharma company and CMO executives
surveyed see their companies as being “very ready” for the US Drug Supply Chain
Security Act (DSCSA) serialization deadline in November 2018.
Most of the companies who feel well prepared had taken many of the
necessary steps, but there were some notable gaps. For example, only 8% had
integrated efforts with most (i.e., 81–100%) of their CMOs. Only 11% reported
that 81–100% of their CMOs were ready to ship serialized product, while only
12% reported that internal packaging line equipment had been ordered and
fully installed, and that 81–100% of their internal packaging lines were ready.
In addition, 23% were not concerned about equipment and skills shortages
affecting serialization compliance, and only 37% had moved away from paper-
based lot transaction records. Half of CMOs surveyed felt very ready for DSCSA,
but only 23% reported that they are integrated with their pharma customers,
while 22% say brand owners are ready for integration. Only 9% are concerned
about equipment shortages having an impact on compliance. For pharma
companies and CMOs, only one third reported feeling “very ready” for the EU’s
Falsified Medicines Directive (FMD).
An earlier 2017 survey (2) by the Healthcare Distributors Association
examined the industry’s readiness for serialization based on responses from
professionals at 67 manufacturers, including 15 of the top 20 based on product
sales. This survey also found readiness gaps, with 3% of generics and 34% of
branded-product manufacturers expecting to ship 100% serialized product to
distributors by November 2017. By November 2018, however, 69% of generics
and 91% of branded pharma companies are expected to do so.
By November 2017, 24% expected to send serialized data to distributors, 33%
said they will send it by November 2018, and 30% expect to send it between
2018 and 2023. However, 13% are unsure that they will send serialized data.
References
1. Tracelink Webcast, “The 2017 Global Drug Supply, Safety and Traceabil-
ity Report,” tracelink.com, Dec. 7, 2017, www.tracelink.com/events/2017/
global-drug-supply-safety-traceability-2017
2. Healthcare Distribution Alliance, Manufacturer Serialization Readiness Sur-
vey: Executive Summary, healthcaredistribution.org, www.healthcaredis-
tribution.org/~/media/pdfs/industry-relations/manufacturer-readiness-
survey-results-report.ashx?la=en

66 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

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6)$%/#!34s0/$#!34s02).4s% .%73,%44%23s7%"#!34s7770(!2-4%#(#/-
pharma capsules

HTG Molecular
Diagnostics
Expands
Collaboration
with Merck KGaA
On Dec. 26, 2017, HTG
Molecular Diagnostics, a
provider of instruments,
reagents, and services
for molecular profiling
applications, announced
that it has entered into a
new master collaboration
agreement with Merck
KGaA, Darmstadt, Germany.
According to HTG, this
master collaboration
agreement complements
a previously announced
master companion
diagnostic agreement
with Merck KGaA and
includes a statement of
work with EMD Serono, the
biopharmaceutical business
of Merck KGaA in the United
States and Canada.
Under the terms of the
agreement, HTG plans to
develop and manufacture
a custom profiling assay to
support biomarker research
for six indications within Merck
KGaA’s drug development
pipeline. The assay is expected
to be kitted for use on HTG
EdgeSeq instruments acquired
by Merck KGaA and/or their
contract research organization
partners.
“We are pleased to expand
our relationship with Merck
KGaA, Darmstadt, Germany, into
earlier research stages of their
programs, and have already
begun work on an initial custom
assay development program,”
said TJ Johnson, president and
CEO at HTG, in a company press
release.
MilliporeSigma to
Offer End-to-End
MAb Manufacturing
Using the iCON
Platform
MilliporeSigma will collaborate
with IPS-Integrated Project
Services and G-CON
Manufacturing to provide a
2000-L monoclonal antibody
(mAb) facility and single-use
process technology platform,
the company announced in a
Dec. 20, 2017 press release. The
deal will extend MilliporeSigma’s
BioReliance End-to-End offering
by integrating MilliporeSigma’s
single-use process equipment,
end-to-end process
development capabilities,
and cGMP manufacturing
experience into the iCON
facility design platform, which
is a modular facility solution
from IPS and G-CON that was
announced in September 2017.
The integrated end-to-end
offering will deliver a platform
for fast and flexible deployment
of 2000-L mAb production
facilities. The hallmarks of the
combined solution will include
pre-fabricated cleanroom
units, a structural platform
based on cost-effective pre-
engineered building delivery,
bioprocess and single-use
equipment expertise, and
turnkey facilities capable
of fast-track deployment.

Packaging— contin. from page 63

Induction liners are fused on bottle orifices by in-
duction sealers. Like many packaging machines, today’s
induction sealers use energy more efficiently and require
less power than their predecessors. Other features in-
clude touch-screen control and integrated cap inspec-
tion. “The reason cap inspection is so integral to the
success of induction sealing is two-fold,” explains Mark
Plantier, vice-president of Marketing at Enercon Indus-
tries. “A liner must be present in each cap, and the cap
cannot be misapplied in a cocked fashion. Cap inspec-
tion is able to detect these variations. Prior to this inno-
vation, cap inspection was controlled by an independent
control system. By integrating it both mechanically and
electrically into the induction sealer, packagers are able
to quickly set up their systems and rely on a single con-
trol and diagnostics for both cap inspection and sealing.”
Changeover is simpler too. For example, an all-in-one
sealing head, designed by Enercon for contract packag-
ers, provides operators with indicators and positive lock-
ing mechanisms for properly positioning the head for
To ensure induction sealing performs at the highest
OEE possible, Plantier advises looking at the process ho-
listically. Equipment should be designed for the specific
sealing application, and induction sealing experts should
be involved early in the design process for the cap and
bottle. “The type and range of caps, bottles, liners, and
line speeds will help the induction sealer manufacturer
recommend the best sealer and sealing head for the ap-
plication,” says Plantier. With equipment properly speci-
fied, the original equipment manufacturer should provide
detailed setup instructions including alignment, air gap,
line speed, and sealing power.
Induction sealing success, however, is dependent on ex-
ternal variables, including the quality of the cap, liner, and
container materials, as well as the capping process itself.
“Properly torqued caps are required for induction sealing,
and in fact, improperly torqued caps are the most frequent
cause of partial or failed seals,” concludes Plantier.
References
UDOMSOOK/SHUTTERSTOCK.COM

each application. 1. Technavio, “Global Pharmaceutical Caps and Closures Market

Enercon’s Deluxe Cap Inspection package provides even
more control. An advanced laser-light curtain for cocked
cap detection allows users to set specific tolerances for de-
tecting out-of-spec cap application. The system also offers
remote control and monitoring of all data collected by the
induction sealer.
2016–2020,” www.technavio.com/report/global-packaging-
global-pharmaceutical-caps-and-closures-market-2016-2020,
accessed Oct. 31, 2017.
2. Comar, “QuarterLoc Child Resistant (CR) Closure,” Press Release,
Undated.
3. NJM Packaging, “NJM Packaging Introduces New beltorque
High-Speed In-line Capper,” Press Release, July 8, 2015. PT

68 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m

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Ad Index
COMPANY PAGE COMPANY PAGE

Abitec Corp ................................................................................................ 21 IQVIA ................................................................................ Covers 1–3, 18–19

Albemarle................................................................................................... 13 Parenteral Drug Association .................................................................... 35

AMRI ........................................................................................................... 71
Patheon Pharmaceutical Svc INC......................................................26–27
Avista ............................................................................................................ 9
Perfex Corp .................................................................................................51
Catalent Pharma Solutions ................................................ Cover 4, 44–45
PharmSource Information Services Inc .................................................. 57
Coating Place Inc....................................................................................... 15

Contec ........................................................................................................ 23 Pyramid Laboratories ................................................................................. 7

CPhI USA .................................................................................................... 37 Ross, Charles And Son Co.......................................................................... 3

Eppendorf North America.........................................................................11

Samsung Biologics Co Ltd ........................................................................ 72
Eurofins Lancaster Laboratories ............................................................... 2
Savillex ........................................................................................................ 25
Federal Equipment Co .............................................................................. 17
Suheung-America Corporation ............................................................... 39
Gemu Valves Inc ........................................................................................ 29

Grand River ................................................................................................ 31 TruTag Technologies, Inc.,......................................................................... 33

INTERPHEX ................................................................................................. 41 Veltek Associates ........................................................................................ 5

Pharmaceutical Technology JANUARY 2018 69

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ask the expert

Meeting Data
Integrity Requirements

Enterprise-wide processes, procedures, and systems are the keys to data integrity
and peace of mind, according to Siegfried Schmitt, PhD, principal consultant at PAREXEL.

Q: Given the current focus on the subject of data integrity

in regulatory inspections, we have performed an internal
You did the right first step (i.e., assessing the as-is situation);
however, you should not stop there. Now you must implement
assessment. We found several pieces of equipment, in par- a company-wide data integrit y policy and embed data
ticular analytical instruments, which do not meet the require-
ments (e.g., shared user access). We are concerned whether
we can continue using this equipment under these circum-
stances. Can you advise?
[One must] implement
a company-wide data
A: Although data integrity is not a new concept, it is true
that there has been an increased focus on data integrity
in inspections by regulatory agencies globally, and this is very
integrity policy and embed
likely to continue unabated. You certainly did the right thing by
assessing your current compliance level, which, it turns out, is
data integrity into a quality
not in substantial compliance with the regulations.
First, you must determine whether is it accept able
management system.
to continue to use these non-compliant systems for the
manufacture of pharmaceutical products, and if so, under
which circumstances. The regulators encourage a risk- integrity into your quality management system. Only by taking
based approach to compliance, though this must not be data integrity seriously, and implementing the appropriate
misinterpreted as being allowed to be non-compliant, rather, processes, procedures, and systems within your company, will
this compliance approach requires you to perform a risk you be able to achieve full compliance with the data integrity
assessment (i.e., you need to ascertain the risk to the requirements. This will give you peace of mind when an
patients should you continue using your out-of-compliance agency inspector calls next time. PT
equipment).
Take for example, a tablet press that has been in operation
for 15 years, which is in perfect working order and has no More on data integrity
access controls. Anyone working on the machine can
To learn more about ensuring data integrity, visit PharmTech.com to read
change the parameters and edit the stored data. This is not
the following:
an acceptable situation. Preferably, one would implement
technical solutions (perhaps a software upgrade), but where • Data Integrity Expectations of EU GMP Inspectors
this is not an option or would take too long, one needs to www.pharmtech.com/data-integrity-expectations-eu-gmp-inspectors
consider procedural remedial actions. In this instance, this
• Data Integrity Best Practices
could include the verification of the settings by a second
www.pharmtech.com/data-integrity-best-practices-0
person, plus an amendment to the operating procedure,
which would clearly define acceptable and unacceptable data • Establishing an Effective Data Governance System
handling (e.g., changing parameters). If neither technical nor www.pharmtech.com/establishing-effective-data-governance-system
procedural solutions lead to an acceptable risk level, I’m afraid, • Tackling Breaches in Data Integrity
DAMIAN PALUS/SHUTTERSTOCK.COM

this piece of equipment must no longer be used.

www.pharmtech.com/tackling-breaches-data-integrity
Another example would be the use of a laborator y
information management system (LIMS) by several operators
sharing a user ID and password. If this is the case because
of cost savings (purchasing a minimum number of licenses
only), then this issue can be remedied almost immediately by Your opinion matters.
purchasing the appropriate number of licenses and revising Have a common regulatory or compliance question?
the operating procedure to mandate individual user IDs and Send it to susan.haigney@ubm.com and it
may appear in a future column.
passwords for all LIMS operators.
70 Pharmaceutical Technology JANUARY 2018 P h a r mTe c h . c o m
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