Quality Lab Stability MARCH 2018 Volume 42 Number 3

PLUS: Agreements Operations Testing

Early
Development
Strategies

PEER-REVIEWED
A New Method for Risk Assessment
of Pharmaceutical Excipients
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 EDITORIAL SALES
Editorial Director Rita Peters rita.peters@ubm.com Publisher Mike Tracey mike.tracey@ubm.com
Senior Editor Agnes Shanley agnes.m.shanley@ubm.com West Coast/Mid-West Sales Manager Irene Onesto irene.onesto@ubm.com
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Science Editor Adeline Siew, PhD adeline.siew@ubm.com
European Sales Manager Linda Hewitt linda.hewitt@ubm.com
Manufacturing Editor Jennifer Markarian jennifer.markarian@ubm.com
Science Editor Feliza Mirasol feliza.mirasol@ubm.com European Senior Sales Executive Stephen Cleland stephen.cleland@ubm.com
Associate Editor Amber Lowry amber.lowry@ubm.com Executive Assistant Barbara Sefchick barbara.sefchick@ubm.com
Art Director Dan Ward C.A.S.T. Data and List Information Michael Kushner michael.kushner@ubm.com
Contributing Editors Jill Wechsler jillwechsler7@gmail.com;
Jim Miller jim@ludwinmiller.com; Hallie Forcinio editorhal@cs.com; ADDRESS
Susan J. Schniepp sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com; 485 Route One South,
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Correspondent Sean Milmo (Europe, smilmo@btconnect.com) Iselin, NJ 08830, USA
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Professor Emeritus Senior Director, Director, Research
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Senior Vice-President, Maik W. Jornitz Department of Pharmaceutical and
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4 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m

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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
techno
tec
technology
hnolog
logg y and
and testing,
testin
tes ting,
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COVER STORY
cover
ove r

18 Can Early Development

Strategies Avoid
he c

Later-Stage Disasters?
n tthe

Assessing potential formulation and manufacturing issues in early

development phases can improve a drug’s chances for success.
On

Cover Design by Dan Ward

Images: arbalet/Shutterstock.com
O

FEATURES
F E ATURES
API SYNTHESIS
S & MA
ANU
UFA
ACTURIN
NG QUA
ALIT
TY L AB OPERA
ATIONS

22 Small Volumes, 48 Good Quality 58 Improving

Big Challenges Agreements Support Operations in the Lab
Highly complex APIs developed to treat rare Compliance with CGMP   New and emerging products advance
and orphan diseases present big technical Drug manufacturers can improve bio/pharma laboratory operations.
questions for contract developers. use of quality agreements in
contract manufacturing. COLD CHA
AIN DIS
STR
RIBU
UTIO
ON
PART
TIC
CLE ENG
GINE
EER
RING
G

26 Dry Particle Coating— ANA

ALY
Y TICS
S 60 Poseidon Takes on the
Pharma Supply Chain
A Unique Solution for 52 Stability Testing Lower costs, fewer opportunities
Pharmaceutical Formulation Determines Proper
for temperature excursions, and a
Aston Particle Technologies has Drug Storage Parameters
smaller carbon footprint are making
developed a technology that produces Stability testing on APIs/finished drug ocean transport more attractive
functionalized particles in a one-step, product helps define optimal drug for pharmaceuticals. Poseidon, a
environmentally friendly process. packaging for shelf-life storage. new collaborative pharma initiative,
TOPICA
AL DRUG
G FO
ORM
MUL
L ATION
N seeks to leverage benefits.

32 Formulating Topical Continued on page 8

Products Containing
Live Microorganisms as
the Active Ingredient
Case studies compare efficacy
testing of preservatives for topical
formulations with probiotic actives.

PEER-REVIEWED RESEARCH SU
UPP
PLEM
MENT
Be sure to check out this month’s
PEE
ER-RE
EVIEW
WED
D special issue, Solid Dosage Drug Development
and Manufacturing, for articles on taste masking,
38 A New Method for Risk tablet development, nanoprecipitation, and more!
Assessment of Pharmaceutical Excipients
This article describes a new, combined, quantitative method for The issue also includes our
assessing excipient risks that has been developed by the authors. CPh
hI No
orth Ameerica 2018
8 Pla
annin
ng Gu
uide.

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NEWS & ANALYSIS
FR
ROM
M TH
HE EDIT
TOR
R & COMPLIANCE
10
0 Regulatory Role
in Pharma Progress
FDA enforcement efforts
and drug approvals trend upward.
OUT
TSO
OURC
CING
G OU
UTL
LO O K
64 Current Challenges in
Bioprocesses Development
Development and adoption of new
technologies create challenges that
may take years to resolve.
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.
REGULATION DEPARTMENTS/
PRODUCTS
RE
EGULAT
TORY WAT
TCH 12 Product Spotlight
14
4 FDA Heightens 66 INTERPHEX Planning Guide
Drive for
Transparency
69 Showcase/Marketplace
Manufacturers face demands for 70 Ad Index
timely information on clinical studies,
product recalls, and approvals.
ASK TH
HE EX
XPE
ERT
70 Computerized
Systems Validation
In-house experts can help select the right
systems and suppliers, making validation
and compliance easy, says Siegfried
Schmitt, principal consultant at PAREXEL.
PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-
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from the editor
Regulatory Role
in Pharma Progress
Rita Peters
FDA enforcement efforts and
drug approvals trend upward.
I
f you look back one year, the bio/
pharma industry faced a number
of questions. Drug approvals were
down. President Trump had issued an
executive order calling for reducing the
number of regulations. And, the posi-
tion of FDA commissioner was vacant.
A recent report from PwC’s Health
Research Institute (1) summarizes
long-term trends and changes in FDA
activities that occurred in 2017, and
the implications for the bio/pharma
industry, and offers a performance
evaluation for the agency and indus-
try. According to the report, FDA had a
good year in 2017; the agency approved
45 new molecular entities, the second
highest total in history, and the most
generic drugs ever (763 full approvals
and 174 tentative approvals). These ap-
proval successes came as the number of
new regulations declined but enforce-
ment efforts increased.
In addition, a record number of drugs
(476) received orphan drug designation
in 2017, an indication of the ongoing
trend of companies developing specialty
and oncology drugs for smaller patient
populations. Under the 2017 tax legisla-
tion, the tax credit for research and de-
velopment costs for orphan drugs was
cut in half, to 25%, lowering incentive
for companies to pursue such research.
Rita Peters is editorial
director of Pharmaceutical
Technology. Send your
thoughts and story ideas to
rita.peters@ubm.com.
10 Pharmaceutical Technology MARCH 2018
Regulations down, enforcement up issued by CDER in 2017 were nearly
The report notes only six economically double the amount issued in 2014.
significant regulations—all unrelated This jump in the number of warning
to pharmaceuticals or biotechnology— letters was triggered by increased en-
were released by FDA in 2017, compared forcement efforts authorized by the
with 30 or more in the previous four Drug Quality and Security Act of 2013
years. This slowdown was the sole sig- and many targeted offshore API and
nificant “sudden change” observed by drug product manufacturing facilities.
the report authors. Rulemaking, how- Drug quality and data integrity were
ever, increased in the second years of the frequently listed violations. The
the Bush and Obama administrations; number of deficiencies found dur-
the report notes that 18 pharmaceutical ing inspections held steady; failure
regulations are under development and to have or follow written procedures,
could be published in 2018. failure to scientifically validate testing
procedures, and failure to fully inves-
FDA’s strategy: tigate discrepancies in manufacturing
or testing processes were the most fre-
Provide regulatory quent offenses.
relief and promote Regulatory relief
Scott Gottlieb, who took over as FDA
competition. commissioner in May 2017, has dem-
onstrated a strategy to “provide regula-
While the number of rules decreased tory relief where appropriate, introduce
in 2017, FDA continued to make policy competitive policies and eliminate re-
by issuing guidance documents with strictive ones, and promote innovation
user fees, generic drugs, and proce- and the exchange of information” (1).
dural topics receiving the most atten- That approach should appeal to
tion. The 174 draft and final guidance pharmaceutical executives surveyed
documents exceeded the average of by PwC; 36% of the respondents would
152 per year issued under the Obama like to see standards for approval, in-
Administration. Nearly 100 guidance cluding minimized regulations for
documents are on the Center for Drug lower-risk products, streamlined. Only
PATPITCHAYA/SHUTTERSTOCK.COM
Evaluation and Research’s (CDER) 6% would like to see streamlined man-
agenda for 2018, dealing with pro- ufacturing regulations, including man-
cedural changes; quality; chemistry, ufacturing quality and inspections.
manufacturing, and controls; and ge-
neric drugs. Reference
Overall, FDA issued fewer warning 1. PWC Health Research Institute In-
letters in 2017 (510) compared with sight, “Continue to Take as Prescribed,”
previous years. However, the 85 letters February 2018. PT
P h a r mTe c h . c o m
Chemic
Laboratories, Inc.
Apostrophe Productions/gettyimages

Who We Are Services Offered

Chemic Laboratories, Inc. is a full service cGMP/GLP contract Chemic Laboratories, Inc. offers a
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The new VMC-500 model is equipped with a custom combination
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Ross, Charles & Son
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AR/VR Simulator for
Plant Personnel Training
Honeywell’s cloud-based
simulation tool uses a
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reality (AR) and virtual
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personnel. The tool,
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The training solution combines mixed reality with data analytics
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It uses Microsoft’s HoloLens, a self-contained holographic
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Specific job activities are simulated through virtual environments
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can safely experience the impacts of their decisions similar
to a flight simulator. This approach improves skill retention
versus traditional training methods by up to 100% and reduces
the length of technical training by up to 66%, as stated by the
company. Additionally, the employees’ training progress is
tracked as part of a formal competency management system.
Honeywell
www.honeywellprocess.com
12 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
Twin Screw Extruder System
The ZSE 50 MAXX twin screw
extruder system from Leistritz
Extrusion is suited for a range of
compounding tasks. The system
includes a modular design for
barrels and screws and an insulated
barrels cover. The set also has an
extended length that facilitates multiple downstream operations,
including multi-stage venting, liquid injection, and up to two of
the company’s LSB 50 XX side stuffers for filler/fiber introduction
into the melt stream. According to the company, the system
can be equipped with a 600-horsepower alternating current
motor and produce 1000 kgs+/hr at 1200 screws rpms.
Leistritz Extrusion
www.extruders.leistritz.com
Dissolved Oxygen Sensor
Endress+Hauser’s Memosens
COS81D hygienic optical
sensor can measure dissolved
oxygen in pharmaceutical
fermenters and bioreactors.
The device can be used
in all measuring points ranging from lab fermenters to
production processes and has measurement capabilities that
also include gaseous oxygen and temperature with accuracy
up to ±0.2%, in addition to temperature, partial pressure,
and raw measured values, according to the company.
The sensor is suitable for cleaning-in-place (CIP) and
sterilizing-in-place (SIP) procedures and works in process
temperatures from 15–280 °F and pressures ranging from
0–190 psi. The device also has a low sampling volume, making
it suitable for residual oxygen measurement in water treatment
and boiler feedwater. The sensor has a compact stainless
steel 12mm design with lengths currently up to 220 mm.
The device connects to a transmitter via a cable that transmits
an optical digital signal, which is continuously monitored and
analyzed. The transmitter senses unusually high or low measured
values, irregular values caused by incorrect measured values,
and aging of the sensor cap. When errors are detected, the
transmitter displays a warning and produces an error message.
Measured and calibration values in the sensor are sent to the
transmitter using a non-contact connection that has reduced potential
interference, according to the company. Memosens technology in the
transmitter generates an automatic error message if the sensor fails,
or if the connection between sensor and transmitter is interrupted.
Additionally, the sensor has integrated electronics that store
calibration data and other information, such as total hours of
operation and operating hours under extreme measuring conditions.
Calibration data are stored in the sensor, enabling the device to
be calibrated and adjusted independent of the measuring point.
Endress+Hauser
www.us.endress.com
regulatory watch
FDA Heightens
Drive for Transparency
Jill Wechsler
Manufacturers face demands for timely information
on clinical studies, product recalls, and approvals.
S
ecrecy and black-box operations
are out; public disclosure is the
mantra for regulators and manu-
facturers alike, as FDA explores more
options for communicating agency
policies, approval decisions, and con-
cerns about product quality and safety.
The drive for greater transparency in
agency decision-making fits a range of
health policy goals. More information
on drug pricing, discounts, and rebates
is considered key to limiting payer
and patient outlays for prescription
drugs. The Federal Open Payments,
or “Sunshine”, policy tracks industry
payments, gifts, and transactions with
healthcare professionals to uncover any
industry influence on prescribers. And
more timely and complete information
on product safety and recalls aims to
prevent patient harm, as do efforts to
make drug labeling more informative.
A main transparency issue involves
public access to clinical study data and
results. While industry sponsors of
clinical trials are meeting requirements
for listing new studies on the Clinical-
Trials.gov website, the record is weaker
for timely posting of research results
for newly approved medical products.
The data transparency movement also
has prompted biopharma companies to
provide scientists and researchers with
Jill Wechsler
is Pharmaceutical
Technology’s Washington
editor, 7715 Rocton Ave.,
Chevy Chase, MD 20815,
jillwechsler7@gmail.com.
14 Pharmaceutical Technology MARCH 2018
access to confidential clinical research
data and to limit publications to open
access journals. Meanwhile, academic
researchers have lagged in disclosing
clinical research activities, prompting
the National Institutes of Health (NIH)
to threaten to cancel grants to organi-
zations that fail to meet requirements.
A main demand—
from both
consumer activists
and free market
deregulators—
is for access to
complete response
letters.
Transparency also is considered im-
portant for enhancing drug quality to
reduce product recalls and shortages,
according to a white paper from the
Office of Product Quality (OPQ) in
the Center for Drug Evaluation and
Research (CDER) (1). As part of efforts
to encourage manufacturers to adopt
continuous manufacturing and sys-
tems to better ensure quality, an OPQ
pilot study is exploring strategies with
potential to enhance the transparency
and consistency of assessments and
facilitate team-based review and com-
munication.
Other nations are joining the trans-
parency movement. The China Food
P h a r mTe c h . c o m
and Drug Administration (CFDA) is-
sued draft guidance on policies for dis-
closing information regarding the ac-
ceptance, review, and approval of drug
applications. While aiming to keep
trade or technical data confidential,
CFDA will make public information
on active ingredients, dosing, license
holder, and patents 60 days following
an approval.
Seeking CRLs
Despite expanded information dis-
closure related to biomedical research,
drug marketing, and product safety,
stakeholders want to know more
about the status of drug applications
and FDA’s decision-making process in
both rejecting and approving submis-
sions. A main demand—from both
consumer activists and free market
deregulators—is for access to complete
response letters (CRLs) sent to manu-
facturers that essentially delay or reject
an application and outline what addi-
tional clinical or manufacturing infor-
mation is needed to achieve approval.
FDA currently posts summaries and
reports on newly approved drugs and
biologics and has indicated interest in
also posting CRLs. But manufactur-
ers strongly oppose such a move as
CRLs usually contain trade secrets or
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confidential information. Current law
requires FDA to redact such manufac-
turing information from public dis-
closures, and any move to change that
policy may require legislative action.
These issues are not new and reflect
decades of reviewing and updating
FDA policies on public access to in-
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formation on agency operations and
regulated products. A Transparency
Initiative launched in June 2009 under
former FDA Commissioner Margaret
Hamburg and former Principal Deputy
Commissioner Joshua Sharfstein has
established FDA online “dashboards”
that track agency actions and programs,
including inspections, recalls, imports,
and compliance actions. A “Drug Trials
Snapshots” initiative posts data from
clinical trials on products approved
since January 2015. FDA has expanded
access to agency enforcement reports
and adverse event data and has made
its guidance development process more
visible and efficient.
Last year, Sharfstein, now affiliated
with the Johns Hopkins Bloomberg
School of Public Health, organized a
group of experts to produce a Blue-
print for Transparency at FDA, which
was published March 2017 in a special
issue of the Journal of Law, Medicine,
and Ethics (2). Among its 18 recom-
mendations for making FDA decisions
less opaque, the Blueprint calls for FDA
to provide more public information on
its evaluation process for new drugs,
generics, and biosimilars, including
what products are in the review queue
and why certain applications are not
approved. The rationale is that discus-
sion of unsuccessful R&D would help
researchers avoid studies unlikely to
succeed, reducing costs and avoiding
patient exposure to potential harm.
The analysts also seek authority for
FDA to correct misleading informa-
tion issued by manufacturers, such as
incomplete factors underlying a CRL,
and for the agency to disclose data from
clinical trials for approved products
when sponsors fail to do so.
Such proposals ref lect greatly ex-
panded public access to information on
drug testing and production through
the Internet, social media, and smart
phones—not all of it accurate or unbi-
ased. Consumers and industry com-
petitors can obtain reports of adverse
events and enforcement actions, raising
questions about the value and impact of
limits on what FDA can or cannot dis-
close about a product or manufacturer.
16 Pharmaceutical Technology MARCH 2018
FDA aims to better
track drug studies
from initial Internet
posting through
FDA approval
by adding the
ClinicalTrails.gov
identifier number
to all clinical data
submitted to the
agency.
FDA Commissioner Scott Gottlieb
addressed these issues at a January
2018 forum on the Hopkins transpar-
ency report. He announced a new pilot
to test the impact of FDA posting more
data from clinical study reports (CSRs)
of approved drugs, asking that spon-
sors of nine new products voluntarily
provide CSR data, protocols, and sta-
tistical analysis plans for pivotal stud-
ies (3). In addition, FDA aims to better
track drug studies from initial Inter-
net posting through FDA approval by
adding the ClinicalTrails.gov identifier
(NCT) number to all clinical data sub-
mitted to the agency.
However, Gottlieb hedged about
publishing CRLs, proposing to further
explore FDA’s authority to release these
documents. While he acknowledged
that some information in CRLs might
enhance the safe use of already ap-
proved products, he noted that redact-
ing proprietary information from these
letters is burdensome and questioned
the value of disclosing letters that cite
manufacturing shortcomings.
Recalls and safety
Gottlieb also mentioned FDA efforts
to inform the public more quickly
about adverse events and product re-
calls, which totaled more than 9000 in
2017, including 1200 involving drugs.
P h a r mTe c h . c o m
Up until now, FDA has delayed recall
announcements until it determined
whether a safety issue raises serious
health consequences, as with a defec-
tive anesthesia product, or represents
low risk. Now FDA’s Office of Regu-
latory Affairs (ORA) will include in
weekly Enforcement Reports “not-yet-
classified” recalls while the months-
long classification process continues.
FDA issued draft guidance in January
2018 outlining when a manufacturer
should issue a public warning about a
recall, including timelines and impor-
tant data to include and what informa-
tion FDA will post in its reports (4).
Although FDA has authority to re-
quire recalls, most drug manufacturers
initiate such actions voluntarily, aware
that FDA can issue press releases and
alerts if companies are slow to act. Re-
call announcements from companies
seem to appear almost weekly, many
involving particulates or contamina-
tion of sterile injectables. Unfortu-
nately, the failures that lead to drug
recalls often create shortages in needed
medicines. FDA and manufacturers
will be looking to see if the earlier re-
call listing process generates alarms
that turn out to be unnecessary, or if
the new policy gets high-risk products
off the market more quickly.
References
1. FDA, Office of Pharmaceutical Quality,
FDA Pharmaceutical Quality Oversight,
One Quality Voice, FDA, www.fda.gov/
downloads/AboutFDA/CentersOffices/
OfficeofMedicalProductsandTobacco/
CDER/UCM442666.pdf
2. J.M. Sharfstein et al., The Journal of Law,
Medicine, & Ethics, Special Supplement
to Vol. 45 (4) 7-23 (Winter 2017), www.
jhsph.edu/departments/health-policy-
and-management/blueprint-for-trans-
parency-at-the-food-and-drug-admin-
istration/1.pdf
3. S. Gottlieb, “Fostering Transparency to
Improve Public Health, FDA.gov, Jan.
16, 2018, www.fda.gov/NewsEvents/
Speeches/ucm592549.htm
4. FDA, Guidance for Industry: Product
Recalls, Including Removals and Correc-
tions (Office of Regulatory Affairs, Nov.
3, 2003), www.fda.gov/safety/recalls/in-
dustryguidance/ucm129259.htm PT
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Coverr Sttory: E arlly Deevellopm
m ent Strateg
giees
Can Early
Development
Strategies
Avoid
Later-Stage
Disasters?
Rita Peters
A sssessin
ng pooteentiall formuu lation andd manuu factuu r ing issues inn
earrly deeveloopm
ment phasess can improove a d rug’s chan
hile some drug innovations are
the result of surprises during
research phases, a surprise that
occurs during development—such as
formulation or manufacturing prob-
lems—could result in approval delays or
failure for a drug product.
To reduce the risk of late-phase sur-
prises, some experts recommend that
additional screening efforts in early de-
velopment can smooth the pathway in
later development stages. Developers of
promising compounds emerging from
drug discovery must balance the need to
better understand potential formulation
challenges and the manufacturability of
the drug product with the reality of time
and budget constraints.
For investigational new drug appli-
cations, drug owners are expected to
provide information about the phar-
macological and toxicological effects
of a prospective drug product, as well
as its physical, chemical, or biological
18 Pharmaceutical Technology MARCH 2018
nces forr success.
characteristics and the stability of the
drug substance during the toxicological
studies and planned clinical studies. The
application also requires information
about inactive components planned for
the drug product and “any reasonable
variations that may be expected during
the investigational stage” (1).
In the regulations, FDA notes that
“modifications to the method of prepa-
ration of the new drug substance and
dosage form and changes in the dosage
form itself are likely as the investigation
progresses” (1). For a Phase I submis-
sion, drug companies should focus on
the identification and control of raw
materials and the new drug substance,
the Code specifies; the agency does not
expect final specifications for the drug
substance and drug product until the
end of the investigational process.
For drug development companies,
particularly small startups, the focus
is often short-term: get the compound
P h a r mTe c h . c o m
to clinic or get an investor or buyer in-
terested in the potential drug. This ap-
proach can be short-sighted, experts
note, and drug companies would be
better served by focusing on getting
the drug to market. In presentations,
consultants and representatives of con-
tract development and manufacturing
organizations (CDMOs) proposed that
moving some formulation steps nor-
mally conducted in Phase I or Phase II
to the preclinical stage can help identify
potential formulation and manufactur-
ability roadblocks earlier in the develop-
ment process and avoid later problems.
Building a better molecule
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While speed is the top priority for most
small pharma companies with mol-
ecules in discovery phases, drug can-
didate quality should be the top con-
sideration, said David Elder, principal
consultant, David P. Elder Consultancy,
in a webcast (2).
 If more work is done in medicinal
chemistry stages to optimize a molecule,
formulation challenges may be easier to
solve, said Elder. Historically, formula-
tion scientists were expected to “rescue”
molecules that were intrinsically insol-
uble. To get more drug candidates with
fewer solubility issues, drug companies
should focus more on the quality of the
candidate molecule—its lipophilicity,
molecular weight, and ring systems—
and not just its potency.
Drug companies that fail to evaluate
the physicochemical characteristics and
manufacturability of a drug candidate in
early development stages will not have
adequate risk assessments of challenges
that may arise later in development
stages, experts agree. Drug candidates
with demonstrated data on solubil-
ity, intestinal permeability, dissolution,
bioavailability, and dose will be more
attractive to potential partnerships, ac-
quisitions by other pharma companies,
or financing from investors.
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Often, preclinical efforts are geared dle in the development process. Drugs
to achieving a desired pharmacokinetic are frequently cited as fitting into one
response in an animal model while mini- Biopharmaceutics Classification System
mizing formulation development time (BCS) (4) classification; however, this
and cost. However, in vitro–in vivo rela-system is a regulatory tool to identify
tionships are often not straightforward efficacy and patient safety, said Julien
and, therefore, require additional time Meissonnier, vice-president, science and
and cost to establish, experts note. Phar-
technology, Catalent Pharma Solution, in
macokinetic studies using the API in a a webcast (2). A better tool for evaluating
hydroxypropyl methylcellulose suspen- new drug development issues including
sion, may not give accurate results and permeability, solubility, dose, and disso-
can result in formulation delays later inlution rate is the Developability Classifi-
the development process (3). cation System (DCS) (5), he said.
A range of in-silico modeling tools are Like the BCS, the DCS tool also catego-
available to screen drug candidates to rizes molecules based on solubility, dose,
predict degradation, metabolism, toxicity,
dissolution, and permeability. It further
solubility, and other characteristics, while
classifies Class II compounds, which
conserving valuable API. Modeling also have low solubility and high permeabil-
is used to evaluate manufacturing ap- ity: Class IIa are dissolution-rate limited
proaches and excipient selection, and forand Class IIb are solubility-limited. The
scale up and design of experiments. dissolution of Class IIa molecules can
be enhanced by reducing particle size.
The solubility question Knowing where a drug candidate fits on
As drug molecules become more com- the classification scheme can expedite the
plex, solubility has become a major hur- formulation process, Meissonnier said.
Booth 2833
Pharmaceutical Technology MARCH 2018 19
Coverr Sttorry: E arlyy Dev
v elo
opment Sttrattegies
Catalent works with drug compa-
nies to characterize a molecule using
high-throughput screening to identify
physicochemical properties and a DCS
classification. Drug metabolism and
pharmacokinetics modeling is used to
understand formulation parameters.
Parallel screening—at a small scale—of
different solubility enhancing technolo-
gies (e.g., lipids, hot-melt extrusion, spray
drying, and micronization) is used to as-
sess stability, drug load, solubility, and
concentration increase. Based on the
screening results, the best candidate mol-
ecule can be selected for animal studies.
In a presentation (6), Sanjay Konagur-
thu, a senior director at Patheon, part
of Thermo Fisher Scientific, described
a solubility enhancement formulation
platform that uses algorithms to analyze Changes in a formulation during pro-
a drug’s structure against manufactur- cess development can sidetrack a drug’s
ing methods including solid dispersions, development, and these potential risks are
lipids, particle size reduction, crystal- best assessed in early development stages,
line forms, and cyclodextrin complexes. explained Jon Sutch, senior manager of
The results indicate the potential of each formulation development, Patheon, in a
technology on a scale. The tools can be webcast (7). Drug owners need to under-
used to view a drug’s molecular proper- stand the risks involved with moving from
ties, identify potential excipients, and one phase to another and how the formu-
computationally screen excipients and lation may change moving from process to
drug loading prior to experimentation. process. Experimental work can mitigate
some of the risk, he explained.
Build for the drug’s lifecycle Drug owners should plan, in early de-
In the typical drug discovery/early devel- velopment stages, to develop a synthesis
opment scenario, a company may have platform that is sustainable—environ-
only a few grams of the compound, and mentally acceptable, socially acceptable,
most likely has not attempted to synthe- and profitable—throughout a drug’s life
size the substance on a larger scale, or to cycle, said Peter Poechlauer, innovation
formulate it to a drug product. manager, API, Patheon, in a webcast (8).

FDA: Early stage drug development costs trigger higher drug costs
In a series of speeches in the latter half of 2017, FDA Commissioner Scott Gottlieb
said that high costs and delays in early development efforts are setting the stage
for more expensive drugs—and drug program failures. The agency is introduc-
ing initiatives to improve drug development efforts, but industry also needs to
change preclinical, development, and clinical trial efforts.
While researchers have been able to use science to reduce the time from a
breakthrough discovery to the creation of patient therapies, the process for de-
veloping such opportunities is more costly, uncertain, and prolonged, especially
for new drug development, he said.
“We’re on an unsustainable path, where the cost of drug development is grow-
ing enormously, as well as the costs of the new medicines. We need to do some-
thing now, to make the entire process less costly and more efficient. Otherwise,
we won’t continue to realize the practical benefits of advances in science, in the
form of new and better medicines,” he said (1).
The cost of a drug product is based on many factors, Gottlieb noted, including
development expenses and the cost of the capital required to develop the drug;
the greatest factor in the cost of capital is the risk of failure.
To support an investment with a high risk of failure, investors expect a higher
potential return, which contributes to unaffordable drug products. If a drug de-
velopment program will take a long time to get to market—and pay off—inves-
tors will pursue alternative funding opportunities that offer faster returns and
fewer risks.
Access to affordable drugs is a public health concern and FDA must “consider
all of the factors that impact the cost of new products. That includes the cost of
discovery and development,” said Gottlieb (1).
The same policies that the agency pursued to advance the science of
drug development and make that process more efficient must be di-
rected toward lowering the cost of developing medicines, he said, and
more focused clinical trials can help reduce overall development costs.
However, he said, “on a relative basis, in many cases the cost of early
stage drug development has grown at a proportionally faster rate than
the cost of late-stage drug development” (1).
“By front-loading the cost of drug discovery, the broader biomedical commu-
nity is making it harder to advance new ideas. It’s economically harder to capital-
ize the cost of an early-stage drug program, relative to funding a later-stage
project. So, frontloading the costs are a recipe for reducing the amount of new
ideas that can be advanced,” he said (1).
Gottlieb outlined broad strokes for FDA initiatives that emphasize the mod-
ernization of the agency’s science, technology, and information foundations
to meet the demands of new therapies in development, including gene and
cell therapies.
“FDA’s goal is to make sure that our policies are as scientifically advanced as the
products we’re being asked to evaluate. We need to make certain our principles for
regulation allow and facilitate beneficial new innovation while making sure that
FDA continues to meet its gold standard for safety and effectiveness,” he said (2).
The Center for Drug Evaluation and Research is piloting the creation of a com-
mon review memorandum to ensure early, cross-disciplinary interaction among
scientists and clinicians who have specialized knowledge in disease that informs
product review.
The agency is encouraging early engagement with product developers, espe-
cially small biotechnology companies who may not be familiar with the regulatory
filing process. Some sponsors sometimes overestimate the amount of information
needed to file an investigational new drug application, front-loading the costs of
development, he explained. FDA’s review staff may be able to recommend steps to
streamline the early development process by eliminating unnecessary preclinical
tests or by suggesting optimal pre-clinical or clinical designs, he said.
“Ideally, it would be easier to get products into development, with more of the
costs pushed further out, after some of the initial pre-clinical work is already
done, and there’s a better understanding of whether a new product has clinical
promise,” he said.
References
1. FDA, Dr. Gottlieb’s Speech to the Regulatory Affairs Professionals Soci-
ety (RAPS) 2017 Regulatory Conference, Sept. 11, 2017, Washington, DC.
2. FDA, Speech by Commissioner Gottlieb to Research America 2017 Na-
tional Health Research Forum, Sept. 7, 2017, Washington DC.

20 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m

 Initially, in Phase I and II clinical tri- Guidance for Industry (Rockville, MD, De- 8. Patheon, “Challenges in the Development
als, a drug’s API is expensive because cember 2017). of Complex Small-Molecule Drugs,” Web-
5. J.M. Butler and J.B. Dressman, J Pharm Sci, cast, Nov. 7, 2017. PT
there is so little material available; once 99 (12) 4940-4954 (2010).
the drug has reached Phase III trials, 6. S. Konagurthu, “Spray-Drying of Amor-
the API manufacturing process has phous Solid Dispersions: A Structure- Editor’s note
been refined and the API cost drops, based Approach to Formulation Design Pharmaceutical Technology will host
Poechlauer explained. While innovator and Scale-Up,” Presentation, AAPS An- a panel discussion, Detecting Poten-
nual Meeting, October 2017.
drugs are expensive when launched, the 7. Patheon, “Ensure the Scalability of Your tial Formulation Roadblocks in Early
API represents only 8–12% of the drug Molecule with a Science-Driven, Phase- Drug Development, on April 24, 2018
product cost. The cost of the drug prod- Appropriate Approach,” Webcast, Aug. at CPhI North America. For details,
uct declines as it moves toward patent 29, 2017. see http://cphinorthamerica.com.
expiration; however, the API represents a
greater percentage of the total drug cost.
For this reason, Poechlauer says, drug
owners must develop the foundation
for efficient, reliable, and scalable pro-
So much more
cesses in the early clinical trial phases
even before it is certain that the drug
than a clean surface
will succeed. An analysis of the original
synthesis process for the compound may
reveal alternate, more efficient methods
required for large-scale production.

How much information is needed?

A challenge for drug owners in early de-
velopment is balancing what they don’t
know, what they can afford to inves-
tigate, and what they need to know. A
better understanding of an API’s prop-
erties, polymorph forms, interactions
with excipients, and the overall per-
formance of the formulation can help
avoid problems and expensive rework
of formulation steps during scale up to
commercialization.
For small pharma companies, limited
financial resources may restrict their
ability to conduct preclinical formula-
tion screens. The added upfront costs
may slow early phase development and
increase costs, suggested FDA Commis-
sioner Scott Gottlieb (see Sidebar).

References
1. 21 Code of Federal Regulations 312, Inves-
tigational New Drug Application.
2. Catalent Pharma Solution. “From Candi-
date to Clinic: Strategies to Select, Assess,
Formulate, and Deliver the Right Drug
Candidate in the Early Phase,” Webcast,
Oct. 10. 2017.
3. A. Siew, Pharmaceutical Technology, 41 (10)
20–27 (2018).
4. FDA, Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Re-
lease Solid Oral Dosage Forms Based on
a Biopharmaceutics Classification System,
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Pharmaceutical Technology MARCH 2018 21

API Synthesis & Manufacturing
Highly complex APIs developed to treat
rare and orphan diseases present big
technical questions for contract developers.
T
he switch in emphasis in the phar-
maceutical industry from the de-
velopment of blockbuster drugs to
therapies that treat rare diseases and
smaller patient populations has led to
the need for small-volume current good
manufacturing practice (cGMP) API
manufacturing capabilities. These APIs
must meet the same regulatory require-
ments as larger-volume drug substances,
except at smaller scale and with less—but
much higher value material—available
for analytical testing, and often under
accelerated timelines. In addition, the
APIs used to formulate these products
are typically highly complex, requiring
multi-step syntheses using unusual re-
agents. Managing multiple projects can be
a challenge for contract development and
manufacturing organizations (CDMOs).
CDMOs often manage at any one time
numerous small-volume API develop-
ment projects involving a wide range
of chemicals targeting a broad array of
therapeutic indications. As a result, they
Cynthia A. Challener is a contributing
editor to Pharmaceutical Technology.
22 Pharmaceutical Technology MARCH 2018
Small Volumes,
Big Challenges
Cynthia A. Challener
must deal with many different challenges
simultaneously. “These molecules tend to
by highly complex, and most have never
been synthesized before except perhaps
at small scale in the laboratory. They also
typically require the application of spe-
cific, sophisticated technologies, some
of which must be engineered for the first
time,” says Ed Price, president and CEO
of PCI Synthesis.
Practical syntheses must be devel-
oped that can be transferred to cGMP
processes that consistently meet quality
requirements. Even though commercial
processes for these APIs involve smaller
volumes than those of APIs intended for
blockbuster drugs, scale-up issues must
still be addressed. Understanding critical
process parameters (CPPs) and their im-
pact on critical quality attributes (CQAs)
is essential to understanding the process
and conducting risk evaluations for unit
operations and equipment to ensure
“right-first-time” technology transfer, ac-
cording to Shyam Vispute, general man-
ager of tech transfer at Neuland Labs.
Analytical methods must also be de-
veloped and validated, which can be
P h a r mTe c h . c o m
challenging due to the complexity of the
molecules. In addition, given the small
quantities of high-value material being
manufactured even at commercial scale,
minimizing the quantity of material
consumed in these activities is impor-
tant. “Alternative protocols may need to
be developed in some cases to allow for
use of reduced quantities of these costly
APIs,” Vispute says.
Don’t forget the technical challenges
The complex molecules being developed
as drug candidates today require sophis-
ticated technology for their production,
such as advanced chromatography sys-
tems and specialized isolation techniques
like tangential flow filtration, according
to Price. PCI Synthesis has seen the need
for low-temperature chemistry grow sig-
nificantly. “Doing cryogenic chemistry is
manageable at the lab scale, but is much
more challenging at the 1000-gallon
scale,” he says.
Often it is necessary to design suitable
hardware for use in the laboratory and
then transfer the technology to plant
scale, according to Vispute. In some cases,
existing equipment can be modified, but
in others new systems must be purchased.
Scale-up and optimization of small-
volume processes can be challenging be-
cause for many there is little information
available in the literature. “It is essential
to consider all of the various process pa-
rameters—temperature, pressure, mass
transfer, etc.—upfront,” Vispute observes.
Risk analyses for each unit operation—
reaction and purification (extraction,
distillation, crystallization, filtration,
etc.), drying, and powder processing—
should be conducted to avoid problems
at plant scale.
Joshua Hoerner, senior director of
research and development at Noramco
Athens, notes, however, that solution
mixing, pressure, and temperature
challenges may actually be reduced on
SYDA PRODUCTIONS/SHUTTERSTOCK.COM
a small-volume basis due to the smaller
surface areas involved.
In some cases, the batch scale, which
is determined from the dosage strength
of the final formulation, will impact the
choice of technology used in a synthesis.
When developing peptides, for example,
researchers must determine whether
solid-phase, solution-phase, or hybrid
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API Synthesis & Manufacturing
technology is most appropriate, accord-
ing to Partha Pal, head of custom manu-
facturing solutions and business develop-
ment for Neuland Labs.
Because most of these molecules have
not been synthesized on any appreciable
scale before, it is also necessary to develop
practical purification strategies, accord-
ing to Price. Poorly soluble compounds
falling in Biopharmaceutical Classifica-
tion System (BCS) classes II and IV can
be particularly challenging. “Exploring
all available techniques to improve solu-
bility and bioavailability, such as employ-
ing suitable techniques to modify the
physicochemical properties or increase
the specific surface area of the API pow-
der particles, is often necessary,” notes
Girish Kavishwar, associate vice-presi-
dent of R&D at Neuland Labs.
Handle with care
Some isolated intermediates and APIs
may be oily liquids, which can create han-
dling and stability challenges, according
to Hoerner. “Managing active ingredi-
ents that are predominately viscous oily
liquids is a significant challenge, both
from a handling and stability perspective.
Noramco is working on dosage form so-
lutions to help improve the processability
of such substances while also enhancing
their commercial shelf-life,” he notes.
Crystalline powders, on the other
hand, may have different polymorphs
and crystal habits that can impact drug
product manufacturing robustness and
the bioavailability of the API, Hoerner
adds. “Identifying and stabilizing the
appropriate polymorph requires special
skills and should be performed early on
in the process to avoid problems late in
the development cycle,” agrees Pal.
Handling cytotoxic and highly potent
compounds is yet another issue. Appro-
priate facility and equipment design is
required for handling such compounds,
and appropriate disposal facilities are
also required based on their occupational
exposure limits. Automation of process
operations is also important for reduc-
ing the exposure of operators and the
environment to hazardous chemicals, ac-
cording to Pal. “A process hazard analysis
(PHA) should always be conducted prior
24 Pharmaceutical Technology MARCH 2018
to implementing a small-volume cGMP
synthesis to systematically identify and
mitigate hazards that arise from innate
chemicals or chemical reactions,” Ho-
erner asserts.
Maximizing process knowledge
One of the key technical and operational
challenges associated with cGMP manu-
facturing of small volumes of intermedi-
ates and APIs is difficulty in obtaining
reliable reaction yields and consistent
quality, according to Hoerner. Noramco
tackles this issue with thorough process
development efforts to maximize pro-
cess knowledge and understanding. In-
process controls for monitoring reaction
completion, crystallization, drying, and
other critical steps are also used to en-
sure completion.
“Overall, we emphasize a company cul-
ture that focuses on the patient/customer
and ensures our products are of optimal
quality and produced in a safe and com-
pliant manner,” Hoerner comments.
From a technical perspective, Noramco
begins at the R&D stage, selecting and
developing a phase-appropriate route
and evaluating critical raw material
sources, reagents/solvents, equipment,
and analytical controls to ensure robust
delivery of cGMP material. In addition,
Hoerner says that scale changes between
development and cGMP supply are mod-
eled with advanced software; process
analytical technology (PAT) or advanced
offline analytical technologies are ap-
plied to synthetic steps that are highly
complex or have significant risk to im-
pact product quality.
Neuland uses quality-by-design (QbD)
and design-of-experiment (DoE) ap-
proaches beginning at the development
stage to identify relevant process parame-
ters and identify the design space that will
have minimal variations at the plant scale,
according to Vispute. Use of simulation
software, such as for scale up and mixing
behavior studies, allows the evaluation of
equipment performance prior to actual
experimentation in the plant, leading to
reduced costs and development times for
Neuland. PAT tools are used for real-time
measurement of CPPs, such as focused-
beam reflectance measurement (FBRM)
P h a r mTe c h . c o m
probes for particle size distribution, par-
ticle vision and measurement (PVM)
probes for particle shape and polymorph
determination during crystallization pro-
cesses, infrared (React IR , Mettler-Toledo)
for monitoring the real-time progress
of reactions, and near infrared (NIR)
probes to perform drying profile studies
for determination of desired polymorphic
forms of temperature-sensitive products.
The internal protocol at PCI Synthesis
places emphasis on doing a good job at
building a practical process early on in a
project. “Once the chemistry and analyt-
ics are locked in, if any changes are needed,
a tremendous amount of work will need
to be repeated. That is why it is so impor-
tant to take the time upfront to choose the
right raw materials (considering cost and
availability), really understand the pro-
cess, and build into the early stage chem-
istry what will be required down the road,”
Price observes. Process optimization
using a DoE approach allows efficient yet
thorough exploration of the design space.
Method development for in-process and
final product testing and confirmation of
process robustness and reliability at larger
scale are then performed before moving
to GMP production.
Solutions for complex problems
Small-volume cGMP chemistry is clearly
an area that can pose significant chal-
lenges. “The first focus should always be
on safety and compliance during manu-
facturing and ensuring robust produc-
tion of high-quality intermediates and
active ingredients,” Hoerner says. That
cannot be achieved if small-volume API
manufacturing is treated as a commodity
business, according to Price.
“We work with many different small
companies, each with its own business
model, culture, internal resources, and
level of experience. Each project they
bring us is unique, involving vastly differ-
ent raw materials, equipment, and chem-
istry. Flexibility and the ability to respond
to the different needs of our customers
and their projects are crucial to success.
We must be able to bring a significant
number of differing resources to bear to
create custom-tailored solutions to com-
plex problems,” Price concludes. PT
Compact ⇒lling and closing machine for
automatic processing of cylindrical vials in
glass, plastic, or metal for liquid, semisolid, NYC APRIL 17-19
17-19, 2018
and powder products, in sterile areas. BOOTH #2353
• All-in-one solution: plastic
cap and pre-assembled
stopper for ISO 8362-1 vials
and ISO 8362-2 rubber
stoppers
• Elimination of crimping step
for liquid and freeze-dried
forms
• Vial closure by simple
vertical pressure
• Reduction of all risks
of environmental
contamination on the
distribution lines
• Risk reduction of
stoppers adhering to the
freeze-dryer plates
• Reduction of risks of
damaging gloves

NJMPackaging.com
800-811-6990
Particle Engineering
Dry Particle Coating—
A Unique Solution
for Pharmaceutical
Formulation
Jasdip S. Koner, Eman Z. Dahmash,
David A. Wyatt, and Afzal Mohammed
Aston Particle Technologies has developed
a technology that produces functionalized
particles in a one-step, environmentally
friendly process.
P
article surface modification is
becoming a vital strategy in the
pharmaceutical industry for “dif-
ficult to formulate” APIs. Most sur-
face modification techniques, however,
alter innate particle properties either
chemically or physically. These surface
modification technologies involve the
use of elevated temperatures, high
Jasdip S. Koner is senior formulation
scientist; Eman Z. Dahmash is chief
scientific officer; David A. Wyatt is chief
operating officer; and *Afzal Mohammed is
chief technical officer, a.u.r.mohammed@aston.
ac.uk, all at Aston Particle Technologies Ltd.,
Aston University, Birmingham, United Kingdom.
Afzal Mohammed is also a professor and chair in
pharmaceutics at Aston Pharmacy School, Aston
University, Birmingham, United Kingdom.
*To whom all correspondence should be
addressed.
26 Pharmaceutical Technology MARCH 2018
pressures, and/or solvents, making
these processes highly unsuitable for
unstable APIs that are degraded when
exposed to such conditions.
Aston Particle Technologies (APT)
has developed the world’s first aerosol-
ized dry particle coating technology.
This technology is a one-step, ambient
temperature process, with controlled
processing parameters that can deliver
repeatable product performance with
commercially available excipients.
The science underpinning this
technology requires the use of a high
G-force chamber, with a curtain of
nitrogen gas to fluidize the powder at
the chamber wall, which disperses any
agglomerated fine or coarse particles.
The co-aerosolization of the particles
results in coating of all the fine parti-
P h a r mTe c h . c o m
cles onto the surface of the coarse par-
ticles and can produce particles with
designed functionalities, even with
highly sensitive APIs. These function-
alized particles enhance the inherent
properties of API without degrading
them in any way. There is no exposure
to heat/solvent, and the particles suffer
no attrition during processing, which
is a significant advantage compared
with other current state-of-the-art dry
coating technologies (1–5) (see Table I).
The difference in this technology is
that blending occurs through particle-
particle interaction in the aerosolized
state compared to traditional solid-
solid interactions of technologies such
as high-shear blending. The intimate
contact of “clouds” of individual par-
ticles facilitates the attachment of all
the fine particles onto the surface of
the coarse particles without causing
undesirable physical/chemical modi-
fication to the constituent particles.
Dry coating principle
The principle of dry coating with
APT’s technology arises from the
difference in particle size between
the host and carrier. Under normal
mixing of a binary blend of fine and
coarse particles, the fine particles dis-
play high levels of cohesivity, which
can lead to the formation of agglom-
erates or to segregation, producing
non-homogeneous mixes in an “in-
teractive mix” (3, 4, 6–9). Dry particle
coating overcomes the high cohesive
forces associated with the fine “guest”
particles with the fines becoming
uniformly bound to surface of coarse
“host” particles by strong forces of ad-
hesion. This principle holds true as
long as the size difference between the
guest and carrier particles is at least
double. Coating occurs because the
forces of attraction between fine and
coarse are greater than the weight of
PIYAPHONG/SHUTTERSTOCK.COM
the fine particle itself (3, 4, 6, 10–12).
Dry coating using the technology
can be depicted in three primary
stages (Figure 1), which occur simul-
taneously: firstly, the dispersion of
all the agglomerates of both the fine
and coarse particles through appli-
cation of the high G-force generated non-fluorescent microcrystalline cel- the relative standard deviation (RSD)
by revolving the processing chamber lulose (MCC). The cross-sectional im- is consistently <2% with good API re-
at high speed, balanced by the injec- ages demonstrate that the microfine covery of typically >98% (see Figure 3A).
tion of nitrogen gas into the chamber; rhodamine particles form a coherent
secondly, the dispersal of the fine par- coating on the surface of the MCC host. Applications in lung delivery
ticles around the coarse particles; and Blend investigations demonstrate For consistent dose performance, the
finally, the attachment/adhesion of the that this dry coating principle can gen- pharmaceutical industry typically re-
fine particles to the surface of the host, erate highly ordered blends, using dif- quires blend concentration RSD to be
reaching a uniform spatial distribu- ferent APIs and excipients, with repro- <6% (13). This requirement is particularly
tion of the fine particles. ducibly tight content uniformities. Even crucial for inhaled formulations in which
at concentrations as low as 0.5% w/w, the therapeutic dose is often in the micro-
Coating occurs
because the forces
of attraction
between fine
and coarse are
greater than the
weight of the fine
particle itself.
Coating examples
Powders generated by APT’s dry coater
at both laboratory and pilot scale have
demonstrated proof of concept for
various formulation applications, in-
cluding blends for dry powder inhal-
ers (DPI), API solubility enhancement,
and modification of dissolution rate.
Scanning electron microscopy (SEM)
and confocal laser scanning micros-
copy (CLSM) images of the coarse host
Confidence matters.
particles loaded with the fine guest
material are shown in Figure 2. FIXED-DOSE COMBINATION PRODUCTS are
The SEM micrographs show that the great options to ensure patient compliance, lower Visit us at
costs, and improve safety and efficacy. Halo Pharma
fine de-agglomerated guest material is has extensive experience in the development CPhI NA
coating the coarse carrier as individual and manufacturing of these complex products. Booth #1549
particles. These images also show that We’re equipped with state-of-the-art equipment and
there is no free or unbound fine mate- onsite expertise to bring your fixed-dose combination
products to market in a timely, cost-effective manner.
rial and that the host particles appear Halo Pharma has developed more than a half dozen
to have mopped up all the available multi-API mini-tablet, bilayer tablet, and multi-API
fines in the field of view. coated tablets in both IR and ER formulations.
Additionally, the CLSM micro- You can place your full trust and confidence in Halo Partnerships for Life.
graphs confirm that the larger particles Pharma supporting the development and manufacturing
of your next fixed-dose combination product.
can be completely dry coated with finer
material using APT’s dry coating tech-
nology. In the case shown in Figure 2, For fixed-dose combination products you can
micronized, f luorescent rhodamine feel confident about, visit halopharma.com/combo
particles have been dry coated onto
Pharmaceutical Technology MARCH 2018 27
Particle Engineering

Table I: Common issues associated with the different commercialized dry particle coating techniques compared to Aston
Particle Technologies’ advantageous processing method.
Suitable for
No risk of No effect on
Technology name No heat generated No particle attrition pharmaceutical
contamination stability of API
applications
Mechanofusion
x x √ x x
(Hosokawa Micron, Japan)
Hybridizer
x x √ x x
(Nara Machinery, Japan)
MAIC
Magnetically assisted
x x x √ x
impaction coating
(Aveka, US)
APT
dry particle coating
√ √ √ √ √
technology
(APT, UK)

Figure 1. This schematic highlights the key steps in Aston Particle Technologies’ unique gram range. Through optimized process
dry coating process where the processes occur in parallel and allow the new composite development, a platform for the applica-
particles to be formed. Process parameters define the extent of coating and can be tion of the technology to a DPI formula-
controlled to produce powders with key quality attributes. tion has been registered as APT-Hale.
The controlled nature of the APT-
Hale process for DPIs leads to consis-
tent API delivery, which means that
the technology also determines the
dosing performance of the formulated
blend. The technology produces tight
Fine “guest” Coarse “host” Step 1 – Deagglomeration of Step 2 – Dispersion of fine Step 3 – Adherence of fine “guest” material on to
content uniformity and can also be
particles particles cohesive fine particles as well as any and coarse particles the surface of the “host” particles. Process
agglomerated coarse particles throughout blend conditions are controlled to drive complete
adsorption of guest on to carrier
tuned to deliver a particular fine par-
ticle fraction (FPF) as demonstrated
in Figure 3B, where a single-blend for-
mula processed in a designed set of
Figure 2. Scanning electron microscopy (SEM) and confocal microscopy images indicate experiments has been “dialled up” to
proof of concept of dry coating. A1 to A4 show deagglomeration of the fine particles deliver increasing FPF. The strength of
and adherence to the surface of the carrier. A1 and A2 show no fines in the field of view, adhesion between the fine and coarse
indicating they are all attached to the carrier. B1 to B4 highlight confocal results whereby particles can be controlled, thereby
a fluorescent guest has been coated on to non-fluorescent microcrystalline cellulose determining the amount of API that
(MCC); clear coating is observed on B1 and B3 with cross sectional images showing will detach from the carrier when
adsorption of the carrier to the surface of the MCC with the dark area highlighting the tested in the Next Generation Impac-
non-fluorescent core of the particle. tor. Because the blends carry little or
no electrostatic charge, they can be
handled immediately after processing
and require no conditioning or quar-
ALL FIGURES ARE COURTESY OF THE AUTHORS.

antine period.
To demonstrate the potential of the
technology in respiratory medicine de-
velopment and manufacture, a series
of designed experiments, using a QbD
approach, has been completed with
two different, commercially sourced
lactose carriers. The object of these ex-
periments was to optimize an API/lac-
tose formulation based on key critical
quality attributes. Optimizing time and
28 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
 pda.org/2018Sterile

2018 PDA Sterile Medicinal

Products Manufacturing
Conference

The 2018 PDA Sterile Medicinal Products Manufacturing Conference

will bring sterile product experts together with the sterile products
community to highlight contemporary approaches to aseptic
processing using case studies and personal experiences.

With tightening regulatory expectations for sterile product quality and safety-based on
patient risk, this conference is a “must-attend” for anyone involved in sterile manufacturing!

With special reference to the recently released draft revision of the EU GMP Annex 1, this
Conference will explore sterile manufacturing essentials, including:

• Risk- and science-based assessment and approaches in sterile product facility design and
manufacturing processes
• How to better use existing sterile product technologies
• PDA and industry responses to the proposed revision to Annex 1 and other regulatory
trends and expectations
• New thinking on sterile product manufacturing validation and process simulation

Register now to join the dialogue between manufacturers, suppliers, and regulators working
together to solve issues and improve sterile manufacturing processes!

To learn more and register, please visit pda.org/2018Sterile

May 14-15, 2018 | Bethesda, MD

CONNECTING
Exhibition: May 14-15
#PDASTERILE PEOPLE+
SCIENCE
REGULATION ®
Particle Engineering
Figure 3. A) Content uniformity of blends containing model drug at concentrations ranging from 0.5–10%, all showing relative standard
deviation (RSD) of <2% and recovery more than 98%. B) Process parameters of the dry coating technology can be controlled to deliver
various fine particle fraction (FPF) of model drug using the same formulation recipe.

A % Recovery % RSD B
8 APT-5 APT-6 APT-7 APT-8 APT-9 APT-10 APT-11 APT-12
100 120

6 100
80
% Recovery

Percentage/ μg
80

% RSD
60 4 60
40
40
2
20 20
0 0 0
0.5 0.75 2 5 10 Respirable material (μg) % Emitted % FPF Theoretical
Concentration (%w/w)

been designed so that operators can

Figure 4. Quality by design (QbD) sweet spot for two different carriers used in dry powder
quickly access and store the required
inhaler (DPI) formulation. Optimal ranges of the critical process parameters are shown for
process conditions for specific pro-
the desired profile of critical quality attributes (relative standard deviation 0–5% and fine
duction batches. Operational quali-
particle fraction 25–50 mcg). The ability of the dry particle coating technology to control
fication at this pilot scale is ongoing
process outputs opens the possibility of altering process parameters to deliver multiple
but the process is proving to be com-
doses using the same formulation recipe.
pletely scalable.
carrier = SV010 carrier = SV003
15
14 References
13 1. Q. Zhou et al., International Journal of
Pharmaceutics, 413 (1) 36-43 (2011).
Time [minute]

12
11 2. Q.T. Zhou et al., European Journal of
10 Pharmaceutical Sciences, 40 (5) 412-421
9 (2010).
8 3. T. Ishizaka et al., Chem Pharm Bull, 36
7 (7) 2562-9 (1988).
6 4. T. Ishizaka et al., J Pharm Pharmacol, 41
5 (6) 361-8 (1989).
1,000 1,200 1,400 1,600 1,800 1,000 1,200 1,400 1,600 1,800 2,000 5. L.E. Beach, Effect of Dry Particle Coating
Speed [rpm] Speed [rpm]
Sweet Spot Criterion met 1
on the Properties of Cohesive Pharma-
ceutical Powders, Dissertation, Otto H.
York Department of Chemical, Biological
and Pharmaceutical Engineering (New
Jersey Institute of Technology: New Jer-
sey, May 2011).
6. E.Z. Dahmash and A.R. Mohammed,
Expert Opinion Drug Delivery, 12 (12)
1867–1879 (2015).
7. J.A. Hersey, Powder Technology, 11 (1)
41-44 (1975).
8. C.W. Yip and J.A. Hersey, Powder Tech-
nology, 16 (2) 189-192 (1977).
9. H. Honda et al., Colloids and Surfaces A:
Physicochemical and Engineering Aspects,
82 (2) 117-128 (1994).
rotation speed of the blending process, Future work 10. R. Pfeffer et al., Powder Technology, 117
which were identified as critical process Although many of these experiments (1-2) 40-67 (2001).
parameters, demonstrated that the car- were carried out at laboratory scale, 11. V.A. Saharan and P.K. Choudhury, Acta
rier influences the processability of the APT recently collaborated with the Pharm, 61 (3) 323-34 (2011).
formulation (see Figure 4). The resultant automation engineering team at GB 12. L.J. Jallo et al., International Journal of
Pharmaceutics, 423 (2) 213-225 (2012).
design space enables the formulator to Innomech, which has designed and 13. USP 40-NF 35 (United States Pharma-
visualize a manufacturing control space developed a system to scale up the copoeial Convention, Rockville, MD,
for a formulation using either carrier. technology 100-fold. The system has 2017). PT

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

Global Reach With A Breadth of Services
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 Topical Drug Formulation
Formulating Topical
Products Containing
Live Microorganisms
as the Active Ingredient
Jason Carbol, Pia Isabel Tan, Yug Varma, and David W. Osborne
Case studies compare efficacy
testing of preservatives for topical
formulations with probiotic actives.
I
n recent years, many topical probiotic
personal care products have been
launched into the market (1). In an
August 2016 review for Dermatology
Times (2), dermatologist Patricia Farris
concluded, “The studies reviewed sug-
gest that topical prebiotics, probiotics,
and bacterial cell lysates do provide
demonstrable skin benefits … At this
time, it appears that more studies are
warranted to determine if these prod-
Jason Carbol is manager of Chemistry,
Manufacturing, and Controls at Dow
Development Laboratories (DDL), a division
of Symbio, jcarbol@dowdevelopmentlabs.
com; Pia Isabel Tan was a 2017 Dow
Development Institute Intern who is currently a
biochemistry major at UCLA;
Yug Varma, PhD, is CEO at Phi
Therapeutics; and David W. Osborne,
PhD, is executive fellow at Dow Development
Institute and senior vice-president of Product
Development at Arcutis.
32 Pharmaceutical Technology MARCH 2018
ucts are really worth the hype.” These
scientific reviews are quick to point
out that well-crafted, vehicle-controlled
clinical trial results are not generally
available for topical semisolids contain-
ing live microorganisms. One reason
that topical probiotic therapies have
not advanced beyond the personal care
“post-marketing surveillance regula-
tory environment” into the controlled
clinical trial “new drug approval regu-
latory environment” is the difficulty
in reconciling FDA microbiological
requirements for a product containing
live microorganisms. More specifically,
how can a topical suspension contain-
ing more than 50,000 colony form-
ing units (CFU) of probiotic active
pharmaceutical ingredient (API) pass
United States Pharmacopeia (USP) mi-
crobial enumeration testing (USP <61>)
(3), tests for specified organisms (USP
P h a r mTe c h . c o m
<62>) (4), and antimicrobial preserva-
tive effectiveness (USP <51>) (5)?
Two case studies are being presented
here to explore the strategy of adequately
preserving the formulation, but using
a preservative of sufficiently narrow
spectrum to maintain viability/potency
of the probiotic active. The first case
study uses a probiotic strain of Propi-
onibacterium acnes (P. acnes). P. acnes
is a lipophilic, gram-positive anaerobic
bacillus that resides in the pilosebaceous
unit of human skin. Hundreds of differ-
ent strains of P. acnes exist. The lipases,
proteases, and hyaluronidases secreted
by certain strains of P. acnes injure the
lining of the pilosebaceous unit and ac-
tivate production of proinflammatory
cytokines that in turn lead to acne vul-
garis. Other strains of P. acnes produce
no inflammatory response and thus do
not induce the symptoms of acne vul-
garis. One of these non-inflammatory
strains of P. acnes has been chosen to be
used as an “active ingredient” in a topi-
cal formulation product. In the second
case study, the microorganism is a bac-
teriophage (phage), which is a virus that
infects and replicates within a bacterium,
ultimately causing bacterial death. The
phage used in this study was isolated
from the follicular casts obtained from
volunteers with facial comedones. Bac-
teriophages were identified and isolated
from the comedones and were then
propagated using an amplification pro-
cess and plated against different P. acnes
strains to determine breadth of efficacy
to assure the selected phage was suitable
to infect and eradicate pathogenic (in-
flammatory) P. acnes strains.
Formulating a living microorganism
is fundamentally different from formu-
lating a small-molecule active topical
product. Because the P. acnes probi-
otic or phage products will be dosed as
suspensions, active solubility, solvent
MOTOROLKA/SHUTTERSTOCK.COM
compatibility, and penetration across
the stratum corneum do not factor in
to the development of a topical probi-
otic. In contrast, the aqueous probiotic
formulation does require that pH and
osmolality be adjusted to values that as-
sure a favorable environment for the mi-
croorganisms to remain viable. In these
 two case studies, eight different formu- Figure 1: Deactivation of a probiotic Propionibacterium acnes (P. acnes)
lations containing preservatives were in aqueous product with hydroxyethyl cellulose (HEC) or Carbopol (Cp) in
tested for live microorganism viability preservative systems of methylparaben and propylparaben (Para), phenoxyethanol
over six weeks after compounding. (Phen), or potassium sorbate (Sorb).

Material and methods Probiotic P. acnes in Traditional Preservative Systems

The low immunogenic strain of P. acnes 1.00E+08
(probiotic bacterial active) and phage 1.00E+07 Cp+Sorb
that attacks pathogenic P. acnes (mi- Cp+Phen
1.00E+06
crobiome editor) were provided by Phi

Titer (CFU/mL)
Cp+Para
Therapeutics. Two gelled aqueous prod- 1.00E+05
HEC+Sorb
ucts were made with the intent of for- 1.00E+04
mulating cosmetically elegant products: HEC+Phen
1.00E+03
hydroxyethyl cellulose (HEC) at 1.5% HEC+Para
w/w and polyacrylic acid polymer or car- 1.00E+02

bomer (Carbopol 980, Lubrizol) at 0.75% 1.00E+01

w/w, both titrated with propylene glycol 1.00E+00
until isosmotic (~285 mOsm/k). Both 0 1 2 3 4 5 6 7
gels were prepared with the following Weeks
preservative systems: preservative free, Note: The data for Cp+Sorb, Cp+Para, and Cp+Phen coincide with the two and four week data of HEC+Para.
methylparaben (0.1%) and propylpara-
ben (0.02%), phenoxyethanol (1.0%), and
potassium sorbate (0.2%). In addition, two solution products As shown in Figure 4, however, the use of a negatively
were made: an 80:20 water:propylene glycol blend (w/w) and charged polymeric gelling agent (polyacrylic acid polymer)
an 80:20 water:ethanol blend (w/w). Both solution blends were did deactivate the phage by about 95% two weeks after
considered self-preserving. The pH of all the products were
taken, but no pH modifiers were added. Active viability and
stability testing were conducted every two weeks after addition
of active microorganism by diluting the formulated products to
a known concentration of active microorganisms and plating Twin Screw
them out. P. acnes concentration was calculated using diluted
growth promotion plating and back calculating; the number
of phage was calculated by plating the dilutions onto bacterial
Extruders and Systems
lawns and looking for the presence of kill zones.

Results
When added individually to the probiotic formulations, the • nano-scale twin screw extruders
parabens, phenoxyethanol, and potassium sorbate com- • Production twin screw extrusion systems
pletely deactivated the product gelled with HEC or Car-
bopol by more than 99.95% within the first four weeks of • Pharmaceutical Extrusion Seminars
compounding (see Figure 1). • Process laboratory for melt/granulation extrusion
For the probiotic P. acnes strain, as shown in Figure 2, only
• Validation documentation and services
the 20% propylene glycol solution was reasonably tolerated.
The 20% propylene glycol solution initially lost 90% activity
at two weeks, but remained at a consistent level of activity
from two to six weeks. The 20% ethanol and the Carbopol Leistritz Extrusion
gelled water (non-preserved) products lost their potency by
FIGURES COURTESY OF THE AUTHORS

A Business Unit of Leistritz Advanced Technologies Corp.

more than 99.95% within the first four weeks of compound- 175 Meister Avenue, Somerville, NJ 08876, USA
Ph 908-685-2333(PDLOVDOHV#OHLVWULW]H[WUXVLRQFRP
ing with the HEC gelled water (non-preserved) product per-
www.leistritz-extrusion.com
forming no better than 20% propylene glycol product.
The parabens, phenoxyethanol, and potassium sorbate
in isotonic HEC formulations did not deactivate the phage
six weeks after compounding. Formulating the phage with
ethanol or propylene glycol up to 20% solvent did not have
Melt extrusion + Granulation + Dosage Forms + Transdermals
any effect on phage activity (see Figure 3).
Pharmaceutical Technology MARCH 2018 33
Topical Drug Formulation
aerogenesis as determined by specified
Figure 2: Comparison of Propionibacterium acnes (P. acnes) in self-preserved
organisms of USP <62> is necessary for
solutions with ethanol (EtOH) or propylene glycol (PropGly) and non-preserved
the safety of any topically applied phar-
systems with hydroxyethyl cellulose (HEC) or Carbopol.
maceutical. It is passing antimicrobial
preservative effectiveness testing (USP
Probiotic P. acnes in Self-Preserving or Non-Preserved Systems <51>) that is the biggest hurdle to the de-
1.00E+08 velopment of a topical product contain-
EtOH
1.00E+07 ing a living microorganism as the active.
PropGly As seen for the probiotic P. acnes
1.00E+06
HEC strain used in the first case study, only
Titer (CFU/mL)

1.00E+05
Carbopol the addition of 20% propylene glycol
1.00E+04 was reasonably tolerated by the living
1.00E+03 microorganism active. The parabens,
phenoxyethanol, potassium sorbate,
1.00E+02
and ethanol, when added individually
1.00E+01 to the probiotic formulation, deacti-
1.00E+00 vated the product by more than 99.95%
0 1 2 3 4 5 6 7 within four weeks of compounding. The
Weeks 20% propylene glycol liquid initially lost
90% activity at two weeks, but remained
at a very consistent level of activity from
Figure 3: Bacteriophage in hydroxyethyl cellulose (HEC) with preservative systems two weeks through to six weeks. While
of methylparaben and propylparaben (Para), phenoxyethanol (Phen), or potassium a certain segment of the probiotic ac-
sorbate (Sorb) and with self-preserved solutions with ethanol (EtOH) or propylene tive appears susceptible to the cell mem-
glycol (PropGly). brane function interference exerted by
a glycol, sufficient quantities of viable
probiotic remain to manufacture an ef-
Bacteriophage in HEC and Self-Preserving Systems
ficacious topical product. Blending pro-
1.00E+09 HEC pylene glycol with other glycols to opti-
1.00E+08 HEC+Sorb mize antimicrobial activity has been an
1.00E+07 HEC+Phen area of active research within the field
1.00E+06 of dentistry (7). The results of the first
Titer (PFU/mL)

HEC+Para
1.00E+05 case study, combined with the literature
EtOH
1.00E+04 concerning the bactericidal activity of
PropGly
1.00E+03 propylene glycol, indicate that addi-
1.00E+02 tion of glycols to a fluid suspension of
1.00E+01 probiotic P. acnes is a reasonable devel-
1.00E+00 opment strategy for complying with 21
0 1 2 3 4 5 6 7 CFR 211.113(a).
Weeks As expected, the phage was more
resilient to the addition of preserva-
tives to the formulation. Addition of
compounding and caused more than objectionable microorganisms in drug ethanol to the formulation did not ap-
99.95% loss in phage titer by four weeks.products not required to be sterile, shall pear to have any effect on the phage.
be established and followed” (6). It The parabens, phenoxyethanol, potas-
Discussion should be noted that a topical probiotic sium sorbate, and propylene glycol did
The basis for microbial enumeration product should not have greater diffi- not appear to deactivate the phage six
testing (USP <61>), tests for specified culty in passing USP <61> or USP <62> weeks after compounding. The use of
organisms (USP <62>) and antimicro- than topical products containing non- a negatively charged polymeric gell-
bial preservative effectiveness (USP living actives. For topical probiotics, the ing agent did deactivate the phage by
<51>) of topically applied non-sterile living microorganism active is not “ob- approximately 95% two weeks after
pharmaceutical products is the state- jectionable” and thus is not required by compounding and caused more than
ment in US 21 Code of Federal Regula- USP <61> to be below 1000 CFU. Like- 99.95% loss in phage titer by four weeks.
tions (CFR) 211.113(a) that “Appropriate wise, the absence of pathogens such as Obtaining a preserved bacteriophage
written procedures, designed to prevent Staphylococcus aureus or Pseudomonas probiotic topical gel is possible pro-
34 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
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Topical Drug Formulation
have been relatively stable from weeks
Figure 4: Bacteriophage in Carbopol (Cp) with preservative systems of
2–6, indicating that this is a reasonable
methylparaben and propylparaben (Para), phenoxyethanol (Phen), or potassium
development strategy. From the results
sorbate (Sorb).
obtained from these two case studies, it
can be concluded that it is possible to
Bacteriophage in Carbopol Systems formulate a preserved topical product
1.00E+09
containing living microorganisms.
Carbopol
1.00E+08
Cp+Sorb References
1.00E+07
Titer (PFU/mL)

Cp+Phen 1. M-CJ Huang and J. Tang, “Probiotics in

1.00E+06
Cp+Para Personal Care Products,” Microbiol. Dis-
1.00E+05 cov. http://dx.org/10.7243/2052-6180-3-5
1.00E+04 (2015).
1.00E+03 2. P.K. Farris, “Are Skincare Products with
Probiotics Worth the Hype?” Dermatol-
1.00E+02
ogy Times, Aug. 8, 2016.
1.00E+01 3. USP, USP Chapter <61> “Microbiologi-
1.00E+00 cal Examination of Nonsterile Products:
0 1 2 3 4 5 6 7 Microbial Enumeration Tests” USP 41–
Weeks NF 36 (US Pharmacopeial Convention,
Rockville, MD, 2018), p. 5965.
4. USP, USP Chapter <62> “Microbiologi-
cal Examination of Nonsterile Products:
Tests for Specified Organisms” USP 41–
vided that an uncharged gelling agent gelling agent (such as HEC) is used. NF 36 (US Pharmacopeial Convention,
such as HEC is used as the thickener. However, formulating a final product Rockville, MD, 2018), p. 5971.
containing the probiotic P. acnes will 5. USP, USP Chapter <51>, “Antimicrobial
Conclusion be challenging, and certain amounts of Effectiveness Testing” USP 41–NF 36 (US
The phage has the capacity to toler- care will need to be taken in working Pharmacopeial Convention, Rockville,
MD, 2018), p. 5959.
ate a wide range of typical pharma- with the bacteria and choosing the best 6. CFR, Title 21, 211.13(a)
ceutical preservatives, and it appears method of preserving the final prod- 7. T.M. Nalawade, K. Bhat, and S.H.P. Sogi,
possible to formulate a cosmetically uct. Nonetheless, bacterial levels in the J. Int. Soc. Prev. Community Dent. 5 (2)
elegant final product if a nonionic 20% propylene glycol aqueous solution 114-119 (2015). PT

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Pharmaceutical Technology and Pharmaceutical Technology Europe cover all
aspects of pharmaceutical drug development and manufacturing, including
formulation development, process development and manufacturing of active
pharmaceutical ingredients (both small molecule and large molecules) and
finished drug-products (solid dosage, semisolid, liquids, parenteral drugs and
topical drugs), drug-delivery technologies, analytical methods development,
analytical testing, quality assurance/quality control, validation and advances
in pharmaceutical equipment, machinery, instrumentation, facility design and
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Manuscripts are reviewed on a rolling basis.

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outsourcing, solid dosage and more.

Please visit our website, www.PharmTech.com/pharmtech-author-guidelines-and-editorial-calendars, to view our full Author

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36 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m

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 Peer-Reviewed

A New Method for

Risk Assessment of
Pharmaceutical Excipients
Yurii Pidpruzhnykov, Olena Ruban, and Tetiana Kolisnyk

According to the modern requirements of the
European Union’s Good Manufacturing Practice for
Medicinal Products, a manufacturing authorization
holder should guarantee the suitability of
excipients included in the finished medicine.
For this purpose, a formalized, documented
assessment of risks associated with safety, quality,
and function for each excipient should be carried
out. Though the EU-GMP guidelines give an
indicative list of parameters that should be taken
into consideration when assessing the excipient
risks, none of the known and cited sources specifies
how to perform such an assessment. The present
article, therefore, describes a new, combined,
quantitative method for assessing excipient risks
that has been developed by the authors as one
possible risk evaluation method. This method
represents a combination of a quantitative risk
assessment (based on the risk index method)
and a qualitative risk ranking method. The risk
components related to safety, quality, and function
of excipients as well as parameters included in
them are considered, and the score points are
assigned to each excipient. The developed method
was used for excipient risk assessment of some
marketed finished medicines manufactured
N
ormative requirements for finished medicine produc-
tion are constantly being improved. These changes
are associated with progress in science and technol-
ogy, improvement of control methods and engineer-
ing support systems for manufacturing, development and
launch of next-generation drugs to the market, enhance-
ment of the control systems for technological process and
products, and the introduction of new pharmacopoeial and
regulatory requirements, for example. The European Union
good manufacturing practice (EU-GMP) requirements (1)
are meant to be mandatory rules in the field of pharmaceuti-
cal production, and the EU-GMP rules are amended almost
every year. These changes encompass both the structure
and the content of the document, including modification of
the conceptual framework for GMP. The most recent GMP
changes were comprehensive (2).
In the new requirements of the EU-GMP Chapter 5, it
is noted that the level of supervision over starting material
manufacturers should be proportionate to the risks associ-
ated with particular types of starting materials, taking into
account the source, production technology, supply chain,
and its use in the composition of a finished medicine (1).
The new regulation is focused on assuring the quality of the
excipients that influence the quality of the finished phar-
maceuticals. Finished medicine manufacturers, therefore,
should monitor manufacturers and suppliers of excipients.
For this purpose, it is necessary to use an approach based on
a documented risk assessment, which is described in the new
guidelines, adopted in 2015 (3) and entered into force in the
EU since March 21, 2016. In turn, these guidelines (3) have
MONA MAKELA/SHUTTERSTOCK.COM

by Ukrainian pharmaceutical enterprises.
Submitted: Nov. 21, 2017
Accepted: Jan. 4, 2018
38 Pharmaceutical Technology
been developed and adopted in pursuance of the Directive of
the European Parliament and the EU Council 2011/62/EU (4),
which has made appropriate changes in the Directive 2003/81
(the primary regulation for the drug distribution chain) (5).
According to the normative documents (3–5), the manu-
facturing authorization holder (MAH) should guarantee the
suitability of excipients used in finished medicine manufac-
ture by determining an appropriate set of GMP requirements.
In turn, this set should be determined on the basis of a for-
MARCH 2018 P h a r mTe c h . c o m
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 Peer-Reviewed
Table I: Instructions for assigning parameters and score points to the Safety (S) malized overall assessment of excipient
excipient risk component. risks. The task to guarantee the quality
of the excipients is quite complicated
Safety (S) Score
because the manufacturers of excipients
Spongiform encephalopathy: S1
mostly aren’t MAHs and are not covered
Raw materials of animal origin are used for the manufacture of excipient 1 by regulatory GMP-inspections. More-
Raw materials of animal origin are not used for the manufacture of excipient 3 over, such manufacturers may refuse to
Potential for viral contamination: S2 be audited by MAHs. Thus, one way a
Impossible 1 MAH can determine if an excipient is
Possible but not significant for this particular pharmaceutical form 2 of appropriate quality and can be used
Possible and significant for this particular pharmaceutical form 3
safely in finished drug manufacturing
is by doing a risk assessment.
Potential for microbiological or endotoxin/pyrogen contamination: S3
An overall risk assessment should
Excipient has a synthetic origin and is resistant to microbial contamination 1
take into account the requirements of
It is possible, but not significant for this particular pharmaceutical form 2 other relevant quality systems to deter-
It is possible and significant for this particular pharmaceutical form, 3 mine the origin and the intended use
in instance, raw materials of animal and/or vegetable origin are used
of the excipients, as well as previously
in the excipient manufacturing process or the excipient could serve
as a substrate and stimulate the growth of micro-organisms recorded cases of defects in their qual-
Potential for any impurity originating from the raw materials (e.g., aflatoxins or
ity. A system of an overall assessment
S4 and management of excipient risks is
pesticides):
Raw materials of vegetable origin are not used in the excipient manufacturing process 1
incorporated in the pharmaceutical
quality system of a finished medicine
Raw materials of vegetable origin are used in the excipient manufacturing process 3
manufacturer. All actions within ex-
Potential for any impurity generated as part of the process and carried over (e.g.,
S5 cipient risk assessments are docu-
residual solvents and catalysts):
mented and are subject to GMP inspec-
Low potential for such an impurity 1
tion. A risk management approach has
High potential for such an impurity 3
been implemented in pharmaceutical
Sterility assurance for excipients claimed to be sterile: S6 manufacturing for more than 10 years,
The excipient sterility is ensured 1 and methods and tools that can be
There are some problems with the excipient sterility ensuring 2 used in the risk management prosess
The excipient sterility is not ensured 3 are described in International Council
Potential for any impurities carried over from other processes, in absence of for Harmonization (ICH) Q9 (6). This
S7 list, however, is not exhaustive and
dedicated equipment and/or facilities:
Low potential for such impurities 1 could be expanded using other tools or
High potential for such impurities 3
combinations. Numerous examples of
risk assessment methods and tools are
described (7, 8), but information about
Figure 1: Low-, medium-, and high-risk areas (respectively, which approach is useful for excipient risk evaluation and
from left to right) derived from the risk components: safety (S), details of how this evaluation could be done are lacking.
quality (Q) and excipient function (F), expressed in score points This article, therefore, aims to provide such information.
from one to three. The guidelines (3) establish the fundamental principles
that should guide a finished medicine manufacturer in the
excipient risk assessment and note that the instruments
and methods described in ICH Q9 (6) can be used for this
purpose. The guidelines (3) provide an indicative list of
parameters that should be taken into consideration when
FIGURE IS COURTESY OF THE AUTHORS

assessing the excipient risks, but in the authors’ opinion, it

is not complete and the parameters included in a particular
risk component need more in-depth study and additional
individual assessment. In a previous publication (9), the
authors have considered the possible algorithms for the
risk assessment of excipient function in every particular
pharmaceutical formulation. The present work was aimed
at the development of a quantitative, combined method
for the overall risk assessment of excipients that can be
40 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
applied by industrial pharmaceutical axes in three-dimensional space: Q, S, which can be designated by the letter
enterprises. and F (see Figure 1). The total risk index that corresponds to the component
(TRI) is calculated using Equation 1: name and the index that corresponds
Risk method development to the parameter number. For example,
The method developed by the authors TRI = S × Q × F [Eq. 1]. Q3 denotes the third parameter related
is a combination of a quantitative risk to the quality component, and F1 to F7
assessment based on the use of the risk For simplicity, a three-point scale denotes the parameters of the excipient
index method using scores (10) and a (from one to three) is used for each function component (see Tables I–III).
qualitative risk ranking method. The component. Each of these parameters is quantified
quantitative characteristic used in the In turn, each of these components from one to three points, and the risk
first stage ensures the objectivity of includes a number of parameters, value is calculated for the components
the assessment and a more accurate
characterization of the risk level. The
qualitative ranking method applied in
the second stage enables interpretation
and further practical use of such an as-
sessment. Applying the method using
Proven Innovation for
quantitative analysis of the risk com- Non-destructive Testing of
ponents and the parameters included
in them determines a risk category as Parenteral Packaging
low, medium, or high risk.
To develop this method, the following
tasks were performed:
• The components that affect the ex-
cipient risk and that can be consid-
ered as independent variables were
studied.
• A set of parameters within each
of the risk components was deter-
mined.
• A scoring system for the param-
eters, and accordingly for the risk
components, was established.
• An algorithm for the quantitative Data Driven
Robust Inspection
assessment of the risk components
was developed.
• Low-, medium-, and high-risk

Solutions
areas in the resulting three-di-
mensional space were determined.
• From the three-dimensional space
in the risk assessment, one can
move to a simpler and more un-
derstandable qualitative rank (low,
medium, or high risk).
• The developed method is tested
by assessing risk of commercial
excipients from Ukrainian phar-
maceutical enterprises.
E-

Ve
D

ca L y
S

nM HV riP ca
ic r o C u r re n t a c Va c u u m D e
The guideline (3) identifies quality (Q),
safety (S), and function (F) of excipients
in a finished medicine as the components
that affect excipient risk. Each of the risk PTI - Packaging Technologies and Inspection
914.337.2005 | www.ptiusa.com | Tuckahoe, New York
components for an individual excipient
is represented in the form of coordinate
Pharmaceutical Technology MARCH 2018 41
Peer-Reviewed
Table II: Instructions for assigning parameters and score points to the Quality With a chosen scale of one to three
(Q) excipient risk component. Parameters not included in guidelines (3) are in score points for each risk factor, the
italics. maximum total risk index will be equal
to 27, using Equation 1:
Quality (Q) Score
Control of transportation and storage conditions, including cold chain management: Q1
TRI = S × Q × F = 3 × 3 × 3 = 27
No cases of non-observance of established conditions 1
for transportation and storage upon delivery
The minimum possible risk will be
Only one case of non-observance of the conditions for 2
one, using Equation 1:
transportation and storage as delivered
More than one case of non-observance of conditions for 3
transportation and storage upon delivery
TRI = S × Q × F = 1 × 1 × 1 = 1
Supply chain complexity: Q2
Within the framework of this ap-
Direct supply chain from excipient manufacturer 1
proach, the risk indexes of each excipi-
Supply through one distributor 2 ent in each finished medicine are cat-
Supply through two or more intermediaries 3 egorized by Equations 2–4:
Stability of the excipient: Q3
No problems with stability of the excipient 1 Low risk: 1 ≤ TRI < 6 [Eq. 2]
Problems with stability of the excipient 3
Assurance of package integrity: Q4
Medium risk: 6 ≤ TRI <12 [Eq. 3]
No package defects or integrity failure have been identified 1
High risk: 12 ≤ TRI ≤ 27 [Eq. 4].
A few single cases of package defects have been identified 2
Multiple cases of significant package defects have been identified 3 Additional requirements may be used
Related to the excipient quality defects or adulterations, identified both globally and when assigning a category. For example,
Q5
at a local company level:* if the value of at least one of the com-
No defects and adulterations have been identified 1 ponents (S, Q, or F) is three, then the
Single defects have been identified 2 overall risk in any case cannot be attrib-
Adulterations have been identified 3 uted to a low risk area, but should be at-
Results of sterility input control for the excipient claimed to be sterile: Q6 tributed to the medium or high risk. It
At least one recorded case of a nonconformance of the excipient in this parameter 3
should also be understood that although
Figure 1 gives an idea of the risk areas in
Any excipient defects recorded during reported period, which were identified in the
Q7 the chosen three-dimensional space, it
input control:
A proportion of identified defects less than 1% 1
is rather simplistic, because in practice,
calculated values of risk components
A proportion of identified defects from 1% to 10% 2
will not be round numbers, but non-
A proportion of identified defects more than 10% 3
integral values, as described previously.
Results of input control for the critical quality attributes of the excipient (e.g., Defining component parameters.
Q8
identification, pyrogenicity, toxicity):
An important aspect of risk assessment
At least one recorded case of a nonconformance of the excipient 3 within the framework of this algorithm
Results of input control for significant quality attributes of the excipient (e.g., assay
Q9 is identifying the parameters that are in-
content, impurity content, microbiological purity): cluded in each of the risk components.
At least one recorded case of a nonconformance of the excipient in this parameter 3 Certainly, the choice of the main param-
*This parameter was included in F in the guidelines, but here is included in Q. eters should be guided by the norma-
tive document (3), but it insufficiently
S, Q, or F as the arithmetic mean of the parameters included defines which parameters are included
in each of the components. To decrease the error of the over- in each of the components. In addition, the normative docu-
all risk assessment, when calculating the arithmetic mean of ment does not contain a clear separation of the parameters
the parameters at the stage of component assessment, one included in the individual components of excipient risk. In
should not round the obtained values to whole numbers. the authors’ opinion, for some components, the listed param-
Rounding should be limited to the first significant digit eters should relate to another risk component. For example,
after the decimal point. By substituting such values into the following parameters are assigned to the functional char-
the formula (1), a more accurate assessment of the overall acteristic of excipients in the finished medicine (3):
risk index is obtained, and the resulting value is rounded • The pharmaceutical form and use of the finished medi-
to whole-number values at the final stage of the calculation. cine containing the excipient
42 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
 • The excipient function in the fin- Table III: Instructions for assigning parameters and score points to the
ished medicine (examples are given) excipient function (F) risk component. Parameters not included in guidelines
• The proportion of the excipient in (3) are in italics.
the finished medicine composition
Excipient function (F) Score
• Daily patient intake of the excipient
Pharmaceutical form and use of the finished medicine containing the excipient: F1
• Any known excipient quality de-
fects/adulterations, both globally External (topical) administration 1

and at local company level Oral administration 2

• Whether the excipient is a mixture
• Known or potential impact on the
critical quality attributes of the fin-
ished medicine
• Other factors affecting patient
safety.
In the authors’ opinion, a parameter
Sterile pharmaceutical product 3
Technological function of the excipient in the finished medicine composition
Functionality-related characteristics are absent in the F2
European Pharmacopoeia (Ph.Eur.) monograph or are not significant
For this particular excipient function in the pharmaceutical form 1
Not more than 2 functionality-related characteristics, described in the 2
Ph.Eur. monograph, are related to this particular excipient function

associated with defects of excipient Three or more functionality-related characteristics described in the 3
quality or adulterations refers not to Ph.Eur. monograph are related to this particular excipient function

a functional characteristic, but to the The proportion of the excipient in the finished medicine composition: F3
quality risk component (Q). Moreover, Proportion of the excipient does not exceed 10% 1
the parameters referred to the safety Proportion of the excipient is between 10% and 40% 2
and quality risk components in the Proportion of the excipient exceeds 40% 3
guidelines (3) are not separated and are Daily intake of the excipient administered with the finished medicine to a patient F4
given in one list. Understanding how
Up to 100 mg 1
these parameters relate to precisely
From 100 mg to 500 mg 2
those risk components is unclear, and
additional information is needed. To More than 500 mg 3

better define the F component, the au-
thors used the approach of the European
Pharmacopoeia (Ph.Eur.) Chapter 5.15
“Functionality-related characteristics of
excipients” (11). Although this chapter
is not mandatory, it is useful in the au-
thors’ excipient risk assessment method.
The authors also added several param-
eters to the Q component.
The final step in developing risk as-
sessment algorithm was to determine
what points (and in what cases) should
be assigned to each of the parameters
included in each risk component. Tables
I–III list the instructions and the point
values developed by the authors.
Whether the excipient is a mixture: F5
The excipient is not a mixture, but an individual substance 1
The excipient is a premixed blend of two individual substances 2
The excipient is a premixed blend of more than two substances 3
The impact of the excipient (its function) on providing established biomedical
F6
requirements to the finished medicine:
The excipient does not affect biomedical requirements 1
The excipient function is directly linked to providing 3
biomedical requirements to the finished medicine
Known or potential impact of the excipient on the critical quality attributes of the
F7
finished medicine:
The finished medicine meets specification criteria even when a 1
proportion of the excipient is changed by ±50% of the nominal
The finished medicine meets specification criteria when a proportion of 2
the excipient is changed by not more than ±25% of the nominal
The finished medicine meets specification criteria when a proportion of 3
the excipient is changed by not more than ±10% of the nominal

Table IV: The results of the risk assessment for the excipients included in the medicinal product “Insular Stabil”.
Excipients, included in the medicinal product Risk components Total risk index
No
composition S Q F (TRI)
1 Protamine sulfate 1.7 1.9 2.1 7
2 Di-Sodium hydrogen phosphate dehydrate 1.4 1.6 2.0 4
3 Glycerol 1.6 1.7 2.0 5
4 Meta-cresol 1.3 2.0 2.0 5
5 Phenol 1.3 1.6 2.0 4
6 Water for injections 1.4 1.3 2.1 4

Pharmaceutical Technology MARCH 2018 43

Peer-Reviewed
Method validation
Assessment of the authors’ method for the risk assessment
of excipients in finished medicines was carried out by four
Ukrainian manufacturers of finished medicines. At least
five specialists at each company participated.
The risk assessment for excipients in a medicinal product
(Insular Stabil) produced by one of these companies (Arte-
rium) is presented in Table IV as an example. This medicinal
product is produced in the form of a suspension for injec-
tion, in which 1 mL contains 100 IU of human recombinant
insulin. The authors’ method was used to obtain values of
the S, Q, and F risk components for each excipient (see Table
IV). The TRI value of each excipient, listed in Table IV, was
calculated according to Equation 1 using the values of the
parameters from Tables I–III. The arithmetic mean was cal-
culated and rounded to two significant digits. The TRI value
for each excipient was rounded at the end of the calculation.
To transition from a quantitative assessment to a qualita-
tive rank, the authors used the inequalities in Equations 2–4.
As shown in Table IV, only protamine sulphate is character-
ized in expert assessments by an average risk level (i.e., the
value is in the range of 6 < TRI < 12); other excipients have
a low risk level (i.e., TRI value < 6).
From this and similar assessments carried out at the other
companies, the authors found that only some of the excipi-
ents included in the corresponding finished medicines have
an average (medium) risk level. The overwhelming majority
of the examined excipients were of low risk, and none of
them were of high risk.
Conclusion
A new method for assessing the risks of excipients in the fin-
ished medicine composition has been developed and can be
used as one of the possible methods for excipient risk evalu-
ation. This method represents a quantitative assessment of
risks using the scoring system within the risk indexes with
subsequent ranking and transition to the final qualitative
assessment of the excipient risk level. The advantage of the
method is more objective quantitative evaluation that uses
a comprehensive list of parameters. The authors’ method
has been introduced at one of the Ukrainian enterprises as
a component of the standard operating procedure for as-
sessing the risks of excipients that are part of the finished
medicines produced by this enterprise.
This work is the first stage in solving a more general task
of establishing an appropriate set of good manufacturing
practices requirements for excipients used in the manufac-
ture of finished medicines. The authors plan to publish fur-
ther approaches to solving this broader problem.
References
1. EC, EudraLex—The Rules Governing Medicinal Products in the
European Union. Volume 4—Medicinal Products for Human and
Veterinary Use: Good Manufacturing Practice, https://ec.europa.
eu/health/documents/eudralex/vol-4_en, accessed 10 Nov 2017.
44 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
2. Y. V. Podpruznikov and V.N. Shestakov, J. Drug Development &
Registration 3, 202-218 (2016).
3. EC, Guidelines of 19 March 2015 on the formalised risk assessment
for ascertaining the appropriate good manufacturing practice for
excipients of medicinal products for human use (2015/С 95/02),
http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%
3A52015XC0321%2802%29, accessed 10 Nov 2017.
4. EU, Directive 2011/62/EU (2011).
5. EU, Directive 2001/83/EC (2001).
6. ICH, ICH Harmonised Tripartite Guideline: Quality Risk Manage-
ment Q9 (2005) International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for
Human Use, www.ich.org/products/guidelines/quality/article/
quality-guidelines.html, accessed 10 Nov 2017.
7. PDA, “Quality Risk Management for Aseptic Processes, Technical
Report 44” PDA J. Pharm. Sci. and Technol. 68 (S-1) 1-43 (2008).
8. PDA, Implementation of Quality Risk Management for Pharma-
ceutical and Biotechnology Manufacturing Operations, Technical
Report No. 54. (Bethesda, MD, 2012).
9. O. Ruba, Y. Pidpruzhnykov, and T. Kolisnyk, J. Pharm. Investiga-
tion DOI:10.1007/s40005-017-0354-4 (Aug. 16, 2017).
10. ISO, ISO/IEC 31010:2009. Risk management — Risk assessment
techniques (Geneva, 2009).
11. European Pharmacopoeia 9.0, Chapter 5.15, “Functionality-re-
lated Characteristics of Excipients” (EDQM, Strasbourg, France,
2016) 753-754. PT
Additional Reading
Visit PharmTech.com to read the following:
• Managing Risk in a Complex Excipient Supply Chain
www.PharmTech.com/managing-risk-complex-excipient-supply-chain
• The Real Complexity of Excipient Composition
www.PharmTech.com/real-complexity-excipient-composition
• Characterization of Polymeric Excipients
www.PharmTech.com/characterization-polymeric-excipients
• Collaboration Key to Meeting Excipient GMP Requirements
www.PharmTech.com/collaboration-key-meeting-excipient-gmp-requirements
• Understanding How Excipients Affect Drug Quality
www.PharmTech.com/understanding-how-excipients-affect-drug-quality-1
• Dealing with Complexity in Excipients and Formulations
www.PharmTech.com/dealing-complexity-excipients-and-formulations
• Excipients for Formulation Success
www.PharmTech.com/excipients-formulation-success
Yurii Pidpruzhnykov is a professor of the Department
of Quality Management, Olena Ruban is a professor of
the Department of Industrial Technology of Drugs, and
Tetiana Kolisnyk* is a PhD student of the Department of
Industrial Technology of Drugs, all at the National University
of Pharmacy, Kharkiv, Ukraine; Tel: 380682474033,
kolisnyktatyana@gmail.com.
*To whom all correspondence should be addressed.
 Real-Time Process Control for
Healthy, High-Purity Water Systems

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EVENT OVERVIEW: Key Learning Objectives

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oftentimes, the results are not available at the time the water is used. This guidance for high-purity waters
webcast will discuss current regulations and the implementation of a new ■ OWBA system operation and key
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high-purity water systems for the purpose of gaining a more meaningful ■ Strategy for coupling disparate
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■ A user-friendly monitoring and
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bioburden data—in concert with data from other sensors on a water support water system operational
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result in a more cost-effective water management system strategy.
Participants will come away with a roadmap for ensuring optimal water
system operation, including how to structure a robust system monitoring Presenters
Allison Scott, Ph.D.
practice that provides the foundation for future system optimization. Senior Principal Scientist
Azbil North America Research
The webcast will include guidance on: and Development, Inc.
■ Using real-time, continuous bioburden data to connect and augment
Lisa Graham, Ph.D., PE
sensor information already present on a high purity water loop to gain CEO and founder
a more informed and actionable view of water system health. Alkemy Innovation, Inc.
■ Implementing a tool that can be used to develop predictive models
and extend beyond the basic trending supported by standard data
historians and off-line data analysis. Michael J. Miller, Ph.D.
President of
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Who Should Attend Owner of
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■ Validation Personnel Moderator
■ Rita Peters
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Front &Center
On-Demand Film Coating Process
Is Close to Continuous Processing
Film coating dispersion batch sizes in manufacturing can reach hundreds
of liters depending on the scale of coating and may require large tank
and mixing areas that can lead to batch to batch variation. Colorcon
set out to evaluate the feasibility of on-demand, and continuous
coating dispersion preparation using an innovative powder injector
system. This new system allows for rapid and consistent preparation of
coating dispersion, enabling the coating process to be truly continuous.

he batch size for film coating dis- The goal of the study was to evalu- Colorcon found that better way

T persions in manufacturing can

reach hundreds of liters, depend-
ing on the scale of manufacture, and
may require large tank and mixing
areas. In current batch manufacturing
processes, mixing times for coating
dispersions usually take 30–60 min-
utes to ensure homogeneity and avoid
the presence of lumps or agglomer-
ates that clog spray guns. Tank size,
mixer configuration, mixer placement,
volume of liquid in the mix tank, and
many other factors affect the process.
Improperly designed mixing processes
can result in foam or lumpy disper-
sions that require additional time for
deaeration or further hydration. If
mixer diameter and stirring speeds are
not optimized, excessive settling of
suspended solids can occur over time.
In addition, preparation in advance of
large batch sizes intended for use over
several days, may introduce the risk of
microbial growth.
At the 2017 AAPS Annual Meet-
ing, a poster session presented by
Colorcon highlighted the results of
a dispersion preparation study us-
ing the ILC Dover PST Jet Mixer.
ate whether this “on-demand,” con-
tinuous coating preparation avoid-
ed some of the aforementioned chal-
lenges often faced with batch process
film coating preparation.
Dispersion Preparation
Typically for film coating preparation,
a large tank of water with a propeller-
type mixing blade (one-third of the ves-
sel diameter) is used. The goal is to use
sufficient mixer speed to prevent large
clumps as powder is manually added
to the water, but low enough speed that
excessive foam is not generated. This is
often a difficult balance to reach. Further,
as the tank level depletes upon use, the
mixing blade can often become exposed
above the liquid surface resulting in fur-
ther foam generation or settling of solids.
The ideal scenario is to create a
homogenous dispersion that can be
maintained throughout the coating
process. One objective of Colorcon’s
study was to completely do away with
the traditional mix tank and mixing
blade and find a better way of incor-
porating the solid coating polymer
into the water.
with the ILC Dover PST Jet Mixer, and
began a series of pilot tests. “The idea
was to incorporate the powder into
the water in a very controlled fashion
so that no lumps are formed and there
is no settlement,” says Charles Cun-
ningham, senior manager of product
development, Colorcon. “When pow-
der is added to a traditional mix tank,
you have to let it mix for 25–45 min-
utes to an hour to get all the lumps to
dissolve and become totally dispersed.
With the Jet Mixer, we were able to
incorporate the powders into the liq-
uid stream uniformly and evenly to
avoid any lumps.”
Cunningham explains that the
process begins by pumping water
through an injector restriction to
create a high velocity jet and vacuum.
The powder valve is opened and the
powder gets drawn into the liquid
jet. The liquid travels down a pipe
and into a small holding tank. Once
powder addition was completed, the
powder valve was closed and the dis-
persion was continually recirculated
from the holding tank through the
pump and injector.

Sieves Study
At periodic intervals, the dispersion was
passed through individual 60-mesh sieves
for a fixed time of 45 seconds. The screens
were dried at 60 ºC for one hour. Based on
the dried screen retains, Colorcon could
see how much lumping had occurred.
Two coating systems were studied:
Opadry QX at 30% solids and Opa-
dry II at 20% solids. “The sieve study
confirmed that the mixer eliminated
the lumping seen with traditional
batch mixing processes,” explains
Scott Patterson, vice president of
commercial sales, at ILC Dover.
Within one minute of recirculation,
less than 0.5% dry solids were re-
tained on the screen. The QX system
performed slightly better as it con-
tains a very rapidly hydrating poly-
mer that can be used at 30% solids
concentration.
A Top-Off Operation
As part of the experiment, Colorcon
looked at the volume of dispersion in
the holding tank. A “top-off” operation
or system replenishment was performed
using Opadry QX at 20% solids. As the
tank was depleted, the powder valve was
manually opened and powder flowed
into the injector. At this time, a second
valve is opened to add water to the in-
jector in such a ratio that keeps the sol-
ids concentration consistent. Samples
taken throughout the process indicated
no change in solids concentration of the
dispersion being recirculated from the
holding tank.
“It is really compelling that com-
panies are used to putting hundreds
of liters of powder in a tank, but
this study shows that a company can
work with smaller amounts and add
only what they need, reducing waste,”
says Patterson.
Neither Pigment nor Polymer Affected
Colorcon wanted to be certain that
constant recirculation over time would
BROUGHT
TO YOU BY
SPECIAL SPONSORED SECTION
not impart enough shear to change the
“It is really polymer or change the mix color. Thus,
further tests using Opadry QX at 30%
compelling that solids concentration were performed
to determine if constant recirculation
companies are over time, through the jet mixer, would
change coating color or polymer prop-
used to putting erties. Colorcon used a red iron oxide-
hundreds of based Opadry QX and let it recirculate
for five hours. Periodically, in as little as
liters of powder three minutes or as long as 300 minutes
of recirculation, samples were taken and
in a tank, but tablets were coated. A spectrophotometer
this study shows measured the color and showed no color
change after five hours of recirculation.
that a company “We took each of these samples to
our analytical lab to make sure that
can work with we hadn’t made any changes to the
molecular weight distribution of the
smaller amounts polymer itself,” adds Cunningham of
and add only Colorcon. “There were no changes to
the polymer.”
what they need,
Almost Continuous Processing
reducing waste.” After reviewing the results of all
Colorcon’s experiments, Patterson is
—Scott Patterson, confident that the PST Jet Mixer per-
ILC Dover formed beyond expectations. “All of the
challenges associated with film coating
dispersion preparation that Colorcon set
out to eliminate, they eliminated,” he says.
The ILC Dover PST Jet Mixer pro-
vided Colorcon with a rapid method
for preparing fully formulated coat-
ing dispersions. This will allow for
dispersions to be prepared as needed
or in a continuous manner. The study
found that the injector was extremely
unique from anything that was being
used in the marketplace in batch mix-
ing, as well as the future of continu-
ous processing.
“We all know that the future is
continuous processing,” says Patter-
son. “What doesn’t exist is a real-
time continuous process for coating
preparation. We are approaching that
with this on-demand system, which
does meet the FDA definition of a
continuous process.”
Quality
Good Quality Agreements
Support Compliance
with CGMP
Paula Katz, Tamara Ely, Linda Joy, and Jessica Ritsick
Drug manufacturers can improve use of
quality agreements in contract manufacturing.
F
DA finalized its guidance on con-
tract manufacturing, Contract Manu-
facturing Arrangements for Drugs:
Quality Agreements, in November 2016
(1). This document explains how parties
that engaged in contract manufacturing
can use quality agreements to delineate
their roles and ultimately ensure compli-
ance with current good manufacturing
practice (CGMP).
In the months since FDA finalized this
guidance, how has industry responded?
Are manufacturers that establish contracts
for specific manufacturing activities using
quality agreements effectively? The an-
Paula Katz is director, Guidance and Policy
Staff in the Office of Manufacturing Quality,
Office of Compliance; Tamara Ely is senior
policy advisor in the Office of Manufacturing
Quality; Linda Joy is writer/editor in the Office
of Manufacturing Quality, Office of Compliance;
and Jessica Ritsick is regulatory counsel
in the Office of Manufacturing Quality, Office
of Compliance; all at the Center for Drug
Evaluation and Research, FDA.
48 Pharmaceutical Technology MARCH 2018
swer is mixed; yes, many are, but there is
room for improvement. In this article, the
authors cover the scope and legal under-
pinnings of the guidance, as well as what
FDA investigators may consider regarding
a quality agreement during an inspection.
The article also provides some examples
of issues related to quality agreements that
FDA has called out in warning letters since
the guidance was finalized.
In talking about the parties involved in
contract manufacturing of drugs, the term
“owner” is used to mean manufacturers of
APIs, drug substances, in-process materi-
als, and finished drug products, including
biological products and combination prod-
ucts. This excludes retail pharmacies, drug
stores, supermarkets, discount warehouse
stores, or other retailers who purchase fin-
ished drug products to sell over the counter
(OTC) as a store brand. “Contract facilities”
refers to parties that perform one or more
manufacturing operations on behalf of an
owner or owners.
P h a r mTe c h . c o m
The guidance document emphasizes
the need for good communication be-
tween owners and contract facilities. It
also emphasizes the shared nature of
the responsibility to comply with CGMP.
Neither party can blame the other for its
failure to meet CGMP.
Scope of quality agreements guidance
In Contract Manufacturing Arrangements
for Drugs: Quality Agreements, FDA de-
scribes its current thinking on defining,
establishing, and documenting manufac-
turing activities for all the parties involved
in contract drug manufacturing. The drug
product types include:
• Human drugs
• Veterinary drugs
• Certain combination products
• Biological and biotechnology prod-
ucts
• Finished products
• APIs
• Drug substances
• In-process materials
• Drug constituents of combination
drug/device products.
The scope of the guidance is limited to
CGMP-related roles, responsibilities, and
manufacturing activities between owners
and contract facilities. The scope includes
activities such as processing, packing,
holding, labeling operations, testing, and
quality unit operations.
Owners and contract facilities interact
in a variety of ways. An owner could be a
product sponsor or an entity that decides
to make and market products. An owner
could contract out all the manufactur-
ing activities, but when an owner uses
a contract facility, the owner’s quality
unit remains responsible under CGMP
for approving or rejecting drug products
manufactured by the contract facility, in-
cluding for final release.
There are numerous reasons for owners
DOCSTOCKMEDIA/SHUTTERSTOCK.COM
to turn to contract facilities to outsource
portions or all manufacturing activities.
Owners typically benefit in terms of exper-
tise, cost, efficiency, or capacity. To ensure
CGMP conformance, product quality, and
successful collaboration, all parties must
clearly understand their CGMP-related
roles and manufacturing responsibilities.
Failure to define roles for manufacturing
activities can lead to misunderstandings or misinterpretation
by the owner and contract facility. These misunderstandings or
erroneous assumptions can have significant consequences for
product quality. Each party engaged in the manufacture of a
drug is responsible for ensuring compliance with CGMP for the
manufacturing activities it performs. Delineating the CGMP-
related roles, responsibilities, and manufacturing activities to
be performed by each party is paramount in assuring product
quality. Above all, remember that quality agreements cannot be
used to delegate responsibility to comply with CGMP.
After an owner and contract facility establish a quality agree-
ment, they may find they need to adapt to changes that affect
their manufacturing activities. Either party should be able to
initiate a conversation as change can originate from various
sources—changes to facilities, raw material sources, processes,
test methods, specifications, or the site of production. The qual-
ity agreement should address how changes made by either party
are communicated and agreed upon and which changes will
require prior approval to implement. Although periodic reviews
are useful to ensure the agreement remains current, these peri-
odic reviews do not replace essential real-time communication
of changes between the parties.
Owners and contract facilities are responsible for ensuring
that their quality agreements are working for them. Issues arise
from poor communication, misinterpretation, assumptions on
the scope of work or activities to be performed, terminology,
escalation/notification procedures, and control of change over
the project/product’s life cycle. To assure product quality, own-
ers must take steps to fully understand the contract facility’s
scope of activities and capabilities. Similarly, contract facilities
should not over-promise or make assumptions about a client’s
expectation. Quality agreements are not only a way of meeting
CGMP requirements; they make sound business sense to as-
sure all parties involved understand their role in producing a
compliant product.
The CGMP regulations recognize that many owners use con-
tract facilities, such as production facilities, testing laboratories,
packagers, and labelers, to perform manufacturing activities.
FDA regards contract facilities as extensions of the owner. Con-
tract facilities are responsible for ensuring CGMP compliance
with the manufacturing activities they perform for the owner.
While FDA’s regulations do not require quality agreements, they
do require that firms put their quality unit procedures and re-
sponsibilities in writing and follow them. The regulations make
clear that the owner’s quality unit is responsible for the drug
products it manufactures, and such responsibility includes the
approval or rejection of products manufactured, processed,
packed, or held under contract by another company.
What does FDA do with a firm’s quality agreement?
When owners work with contract facilities, one way to ensure
that both entities are CGMP-compliant is via quality agreements.
“Quality agreements should clearly describe the materials or ser-
vices to be provided, quality specifications, and communication
mechanisms between the owner and the contract facility,” the
guidance says (1). During an inspection, FDA may review and col-
lect copies of quality agreements as a way of verifying compliance
with FDA’s regulations. Quality agreements, however, are not the

Legal background
Drugs not manufactured in conformance with CGMP are deemed
adulterated under Section 501(a)(2)(B) of the Federal Food, Drug,
and Cosmetic Act (FD&C Act). Under this statute, a drug is adul-
terated “if the methods used in, or facilities or controls used for,
THE BEST DESERVES THE BEST
manufacturing, processing, packing, or holding do not conform
Since 1992, Marchesini Group USA
with CGMP.” Manufacture, processing, packing, or holding of a
drug product is defined as “includ[ing] packaging and labeling
has been one of the leading companies
operations, testing, and quality control of drug products” (2). supplying the most technologically
In 2012, the Food and Drug Administration Safety and In- advanced packaging solutions
novation Act (FDASIA) amended Section 501 of the FD&C Act, to the North American pharmaceutical
clarifying that CGMP “includes the implementation of over- and cosmetic industries.
sight and controls over the manufacture of drugs to ensure qual- MARCHESINI GROUP USA: info@marchesiniusa.com
ity, including managing the risk of and establishing the safety PROVIDING THE BEST SINCE 1992. WWW.MARCHESINI.COM
of raw materials, materials used in the manufacturing of drugs,
and finished drug products.” This amendment clarified the
link between a firm’s quality management activities and CGMP. BOOTH 3125
CGMP regulations require that the quality unit’s procedures Jacob Javits Center, NY | April 17-19, 2018
and responsibilities are in writing, and that they are followed (3).
Pharmaceutical Technology MARCH 2018 49
Quality
only mechanism for ensuring that owners • Firms attempted to contract away re-
and contract facilities comply with CGMP. sponsibility.
What is important is that the respective Many of these examples also illustrate
parties’ quality unit responsibilities and how poor practices can put patients at
procedures are in writing and are followed. risk due to the failure of the parties to en-
As noted earlier, FDA regards contract sure product safety and quality. In some
facilities as extensions of the drug owner. of these cases, FDA sent warning letters
Owners’ quality units retain legal respon- to the contract facility with a courtesy
sibility for approving or rejecting drugs copy to the owner. In other cases, both
manufactured by the contract facilities, the owner and the contract facility re-
including final release of drugs. That is to ceived warning letters.
say, CGMP responsibilities cannot be con-
tracted away with quality agreements. As When the owner falls short
FDA has made clear in numerous warn- In a recent case, FDA investigators found
ing letters, owners are responsible for the that a drug manufacturer failed to vali-
quality of drugs they produce, regardless date its manufacturing processes and to
of the agreements in place with contract test components used in drug manufac-
turing. In response to the FDA 483 ob-
facilities (4). Similarly, contract facilities
are responsible for the drugs they produce servations, the company claimed that it
and activities they perform, regardless of was not a manufacturing facility. It said
the agreements in place with the product that it “is a private label distributor, which
owner or application sponsor. If a party has no manufacturing capabilities,” and
performs manufacturing activities, it is re- noted that it uses a contract facility. Its
sponsible for complying with CGMP, and contract facility happened to be located
no written instrument between the parties at the same address and shared person-
can remove or shift this obligation. nel with the distributor. FDA put the firm
It is important to note that, while FDA on import alert and sent a warning letter
may uncover issues at a contract facility saying, “it is important to note that qual-
that extend to the owner, and vice versa, ity agreements cannot be used to delegate
FDA sends warning letters only to facilities statutory or regulatory responsibilities to
it has inspected. However, FDA may add comply with CGMP.”
the owner or contract facility as a CC line In another recent case, an owner con-
in a warning letter. In addition, findings attracted out product release testing, but
one facility may trigger an FDA inspection failed to ensure that the contract testing
at another facility. lab’s methods were validated. FDA issued
a warning letter to the owner saying, “Your
Mistakes that a good quality assurance agreement with [contract
quality agreement could prevent facility] does not specify method validation
Since finalizing the guidance document, responsibilities … You and [contract facil-
FDA’s Office of Manufacturing Quality ity] have a quality assurance agreement re-
(OMQ)—within the Center for Drug Eval- garding the testing of your products. You
uation and Research’s Office of Compli- are responsible for the quality of drugs you
ance—has issued at least a dozen warning produce, regardless of agreements in place
letters that point out problems stemming with your contract testing laboratory. You
from failure to fully comply with CGMP are required to ensure that drugs are made
requirements and failure to communicate in accordance with section 501(a)(2)(B) of
roles and responsibilities in contract manu- the FD&C Act for safety, identity, strength,
facturing relationships (4). The following quality, and purity.”
illustrate problems FDA sees when:
• The owner and contract facility failed When the contract facility errs
to follow their quality agreement FDA investigators found that a contract
• Owners failed to ensure contract fa- manufacturing facility had shipped drugs
cilities were CGMP-compliant to the United States without expiration
• Firms failed to communicate issues dates. In response to the FDA 483 obser-
or changes vations, the firm said, “As we understand,
50 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
our customers conduct testing to confirm
stability and expiration dating.” The firm
also responded that it was contacting its
customers to confirm responsibilities and
OTC drug product expiration dating. FDA
put the company on import alert and sent a
warning letter with a courtesy copy to the
owner. In this example, the contract facil-
ity made a bad assumption. This illustrates
why all parties must be aware of their roles
and responsibilities to ensure adulterated
product is not marketed.
In another example, FDA cited a con-
tract facility making OTC drugs with nu-
merous violations the same as or similar to
those in past inspections, such as failure to
validate processes and failure to verify the
suitability of analytical methods. In its
warning letter, FDA told the firm, “FDA is
aware that many pharmaceutical product
manufacturers use independent contrac-
tors, such as production facilities, testing
laboratories, packagers, and labelers. FDA
regards contractors as extensions of the
manufacturer. You are responsible for the
quality of drugs you produce, regardless of
agreements in place with product owners.
You are required to ensure that drugs are
made in accordance with section 501(a)
(2)(B) of the FD&C Act for safety, identity,
strength, quality, and purity.”
When both parties violate CGMP
In one recent matter, both the owner and
contract facility received warning letters
explaining their shared responsibilities.
The contract facility used the same fa-
cilities and equipment for manufacturing
toxic car-care products and oral solution
drugs and received an FDA warning letter
citing three CGMP violations. FDA also
sent a warning letter to the product owner,
saying, “You are responsible for ensuring
that all your products are manufactured
in accordance with CGMP, including
oversight of the manufacturing opera-
tions conducted by your contractor … on
your behalf. Contractors are extensions of
the manufacturer, and you are required
to ensure that your drugs are made in ac-
cordance with section 501(a)(2)(B) of the
FD&C Act.”
In another situation, FDA found that an
owner and contract facility had released
product even though neither the owner
nor the contract facility had conducted release tests. The FDA Conclusion
warning letter said, “You explained to our investigator that you Neither owners nor contract facilities can contract around
make finished product release decisions over the phone with your CGMP. FDA recommends that owners and contract facili-
contract manufacturer, based on whether test results meet pre-es- ties use quality agreements to help ensure that both par-
tablished specifications … During the inspection, you confirmed ties understand and document the actions they will take
that your contract manufacturers do not make your OTC drug to ensure compliance with CGMP. Without a well-drafted
products in conformance with drug CGMP. For example, you quality agreement, the quality of products manufactured
have released some drugs for which neither you nor your contract under contract may be affected and patient safety may be
manufacturers conducted release tests for identity and strength of jeopardized.
active ingredients. As a result, some of your drugs are distributed
without confirmation that they meet specifications for identity References
and strength of their active ingredients.” 1. FDA, Contract Manufacturing Arrangements for Drugs:Quality
Agreements, Guidance for Industry (CDER, Silver Spring, MD,
November 2016), www.fda.gov/downloads/drugs/guidances/
‘We didn’t think we needed to share that information’ ucm353925.pdf
Issues can arise through the failure to communicate a product 2. Federal, Food, Drug, and Cosmetic Act, United States Code, Title
quality issue. In this example, a contract facility was producing 21, www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/
bottles of a sterile solution. Over a four-year period, it received FederalFoodDrugandCosmeticActFDCAct/default.htm
more than 1500 complaints about leaking, under-filled, and 3. Food and Drug Administration Safety and Innovation Act, Public
Law 112–144, July 9, 2012, www.fda.gov/RegulatoryInformation/
empty bottles. The firm investigated and attempted to correct
LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDA-
the problem, but failed to notify the owner about the complaints. SIA/default.htm
In its warning letter, FDA said, “Your failure to follow the provi- 4. FDA, Warning Letters, FDA.gov, www.fda.gov/ICECI/Enforcemen-
sions of your quality agreement and appropriately notify your tActions/WarningLetters/default.htm PT
customer of the quality problems
discussed in this letter may have
delayed your customer’s ability to
take important actions to ensure
the quality, safety, and efficacy of
its products, including notifying
FDA via a field alert report (FAR)
NEARLY 50 YEARS
under 21 CFR 314.81.” SUPPORTING
In another example, a contract
facility used certain materials in PHARMACEUTICAL
production of a drug substance for
a sterile drug product. In addition
MANUFACTURING
to failing to thoroughly investigate
product quality deviations, the Today, our decades of research, development, nt,
contract facility did not communi- and experience in clean wipes manufacturing
cate with FDA about changes in its supports the most critical environments better
materials, even though the changes than ever before.
should have been reviewed and ap-
proved by FDA before being imple- From controlled manufacturing areas to aseptic
mented. FDA issued a warning let- environments, our speciality wiping products
ter and sent a courtesy copy to the deliver the highest levels of quality for every
owner. “You and your customer, …,
application.
have a quality agreement regarding
the manufacture of … Regardless
of this agreement, you and … are Visit FGCleanWipes.com/pharma to see how oww
both responsible for the quality our expertise can improve your processes. s.
of drugs released and ultimately
administered to patients. You are
required to ensure that drugs are
made in accordance with section Cleaning critical environments
nment
ents
for nearly 50 years.
501(a)(2)(B) of the FD&C Act to
ensure safety, identity, strength, 1-800-628-8606
quality, and purity.”
Pharmaceutical Technology MARCH 2018 51
Analytics
Stability testing on APIs/finished
drug product helps define optimal
drug packaging for shelf-life storage.
S
tability testing is essential for
maintaining the integrity and
quality of biopharmaceuticals
and for assessing an accurate shelf-
life. It is an important aspect of
quality control and is an important
step in evaluating product safety
and efficacy. It is also important for
examining how critical quality at-
tributes (CQAs) of a drug substance
vary with time under different envi-
ronmental factors.
Drug packaging to
ensure shelf-life
T h roug h stabi l it y test i ng , pha r- ce ut ic a l
maceutical companies can ensure
the most suitable packaging and/
or container closure for the storage
and distribution of biopharameuti-
52 Pharmaceutical Technology MARCH 2018
ensu res t hat t he opt i ma l qua l-
ity control strategy is in place to
monitor the continued efficacy
a nd sa fet y of a ny t herapeut ic,”
Wake says.
“Imag ine the sit uation where,
in the first instance, the degra-
dation route of a molecule had
not been assessed through forced
Stability or ‘stressed’ studies. Not under-
standing this pathway could lead
Testing to fa i lu re i n ident i f y i ng per t i-
nent degradation products [that]
impact the safety and/or efficacy
Determines of t he pro duc t a nd t hus ne e d
to be controlled during product
Proper Drug release,” says Wake.
Wake goes on to note that if the
potential formation of impurities
Storage is not evaluated prior to the release
of t he produc t, t hen met hods
Parameters will not be in place to monitor
levels. This could lead to a rise or
change in profile, which might not
Feliza Mirasol be detected until an “effect” in
patient population is observed.
“More so, without understand-
ing the stability both of drug sub-
stance and drug product, the shelf
life cannot be effectively estab-
lished. This may not only risk the
safety and efficacy of a product
supplied to patients but can lead
to unrealistic or even untenable
pr ic ing, espec ia lly for biolog ic
cal products, according to Russell molecules, which are expensive
Crothers, supervisor, Sample Con- to produce, thus impeding their
trol Unit, Alcami. availability,” she adds.
“With the right storage, appro-
priate shelf life determined, and Stability test design
d ist r ibut ion met hods i n place, There are several important factors
t he qu a l it y of ac t ive ph a r ma - to consider when designing and con-
c e ut ic a l i n g r e d ie nt (A PI ) a nd ducting stability studies.
d r ug pro duc t s is sa feg u a rde d,” “Sa fet y, qua l it y, a nd produc t
Crothers says. efficacy work together in stabil-
I n a d d it io n , u nd e r s t a nd i n g ity studies of APIs and finished
potential degradation routes in drug products. Through stability
POZNYAKOV/SHUTTERSTOCK.COM
relation to storage environment testing, pharmaceutical compa-
is an important factor in estab- nies have the ability to identify
lishing t he CQA s of a pha r ma- a nd t re nd she l f l i fe a nd t he i r
or biopha r mace ut ic a l, effects on efficacy as samples are
a c c o r d i n g t o A s h l e i g h Wa k e , exposed to time, light, and tem-
d i r e c t o r, B i o l o g i c a l S e r v i c e s , perature,” Adam Keisker, supervi-
Intertek Pharmaceutical Services. sor, Laboratory Support Services,
“Ultimately, this understanding Alcami, states.
P h a r mTe c h . c o m
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Analytics
Deg radat ion fac tor s t hat a re
fundamental to consider for the
ef f icac y a nd shelf life of A PIs/
f inished dr ug products include
physica l, chem ica l, a nd m ic ro -
biological factors. Physical factors
encompass changes to the physi-
cal nature of the dr ug, such as
appearance, properties, hardness,
brittleness, and particle size, that
occ u r in tablets, capsu les, a nd
semisolids.
From a chemical perspective, sci-
entists look for separation of the
chemical compound into elements
or simpler compounds or a change
in the drug’s chemical nature via
hydrolysis, oxidation, isomeriza-
tion, polymerization, or photodeg-
radation, according to Keisker.
Fi na l ly, m ic robiolog ica l con-
tamination of a product, depend-
ing on the type of microbe and
its level of toxicity, can also play
a role in the design and functions
of the studies, he adds.
T he st rateg y used for test ing
p r o d u c t s t a b i l it y i s t he mo s t
i mpor ta nt considerat ion i n
the design of a pertinent study,
according to Wake.
“If, prior to a formal stabilit y
evaluation, work is not performed
to understand all potential deg-
radation routes of the molecule
through stressed studies, method-
ologies cannot be effectively cho-
sen for inclusion in the formal
st udy to encompass assessment
of degradation product formation
and thus all such species moni-
tored,” says Wake.
“ F o r a ny d r u g s u b s t a nc e o r
pro duc t, a n e f fe c t ive st abi l it y
st udy cannot be desig ned on a
‘t ick box’ approach for a na ly t i-
cal assessments to be included for
testing at timepoints,” she adds.
Wa ke add s t hat a l l st abi l it y
prog rams should include meth-
ods to con f i r m ident it y, assay,
purity, and impurities. “However,
t he choice of t he ac t ua l a na ly-
sis a nd nu mber/mode of met h-
ods utilized cannot be a ‘standard
54 Pharmaceutical Technology MARCH 2018
set’, but should be designed on a
bespoke basis.”
“Choice of storage condition or
conditions should also be care-
fully determined prior to initia-
tion. [International Council for
Ha r mon i z at ion ( ICH )] Q1 a nd
Q5C (1,2) prov ide g uidance on
study design for pharmaceutical
and biopharmaceutical products
and should be the basis for all
desig n; however, t he event u a l
prog ra m requ ires considered
input,” explains Wake.
Degradation
factors that are
fundamental
to consider for
efficacy and shelf
life include physical,
chemical, and
microbiological
factors.
As an example, Wake points out
that, if the intended storage con-
dition is ref r igerated, this con-
dition should be considered as
the long-term storage condition
to be evaluated for a minimum of
12 months, typically longer. An
accelerated condition would then,
in most instances, relate to stor-
age at 25 °C/60% relative humid-
it y ( R H ) for s i x mont h s a nd ,
importantly, the need for assess-
ment at 40 °C/75% RH, would not
typically be required.
“L og i st ic a l ly, t he a mou nt of
mater ia l, d r ug substa nce, a nd/
or drug product required to sup-
por t what ca n be as long as a
five-year program with multiple
time points needs to be consid-
ered at onset. Not only should
this include a realistic amount
P h a r mTe c h . c o m
for t he de f i ne d prog r a m, b ut
should incor porate a minimum
of an additional 25% to ac t as
back-up mater ia l in case of re -
test,” according to Wake.
“ I n a d d it io n , I C H g u id a nc e
requires that a minimum of three
batches of material be included
in formal stability studies, again
this can put pressure on sample
requirement and timely availabil-
ity,” she adds.
Strategic stability testing
Having a strategic approach and
considering a plan for a “worse-case”
scenario is important to addressing
the challenges of stability testing
and to conducting a successful test-
ing program. It is also important to
approach each study with a bespoke,
considered design for storage and
testing, rather than a “tick box” ap-
proach, Wake says.
“Perhaps the biggest challenge
is to ensure that the testing pro-
gram incorporates sufficient ana-
lytics to ensure all potential and
k now n deg radants are continu-
a lly mon itored. W hen consid-
er ing complex molec ules, such
as biolog ics, the complex it y of
d e g r a d at io n a n d t h e nu m b e r
of potent ia l routes ma kes t h is
assignment extremely difficult,”
Wake explains.
I f a p ote nt ia l i mpu r it y is
missed and later seen to appear,
this may detrimentally affect the
integrity of the stability study. In
a worst-case scenario, the missed
impurity may require re-testing,
which wou ld int roduce sig nif i-
cant delay to product registration,
Wake notes.
“K now i ng a l l t he ways a f i n-
ished produc t or A PI cou ld be
affected by degradation is crucial
in performing successf ul stabil-
it y tests. For instance, stabilit y
studies are executed to simulate
climatic effects. The studies are
based on where the products are
going to be sold. From those stud-
ies, scientists are able to better
Analytics
establish a shelf life of the medi-
c i ne, d e te r m i ne t he b e s t w ay
to store the medicine, and ulti-
mately help ensure the safety of
the consumer,” says Keisker.
A na ly t ica l met hods for ef fec-
tive stabilit y testing var y f rom
d r ug produc t to d r ug produc t.
T he desig n of stabi l it y st ud ies
must take into account the prod-
uc t for m, cont a i ner t y pe, a nd
packaging, Keisker notes.
“For example, commercial drug
produc t test i ng wou ld i nc lude
studying the degradation effects
from the conditions on both the
drug product and the container it
is sold in,” Keisker says.
“There are many variables but
it ultimately depends on the cli-
ent and their interests as well as
requirements for the climate zone
they intend to sell their product,”
he adds.
In terms of methodology, most
sma l l-molec u le pha r maceut ica l
s t a b i l it y s t u d y p r o g r a m s a r e
t y pically based around the
need for some a na lysis t hat is
dependent on the presentation of
the substance or product, such as,
for example, water content only
being necessary on lyophilized or
solid material, Wake says.
Not all analy tics w ill be
required at each timepoint, their
inclusion would be driven by the
likelihood of change, for example,
sterilit y is t y pically assessed at
s i x- mont h i nte r v a l s , u n le s s a
specific indication warrants more
frequent analysis.
I n compa r ison, for biolog ics,
the nature of the stability testing
to be included in any prog ram
differs, driven by the complexity
of biologic molecule structure. In
many ways, biolog ics require a
more diverse analytical capability,
accord ing to Wa ke. Def ining a
typical stability testing protocol
is consequent ly more d if f ic u lt,
but as a minimum would
include assessment of the quality
attributes.
56 Pharmaceutical Technology MARCH 2018
“O t he r c r ite r i a s uc h a s p r o -
cess related i mpu r it ies, sol-
vents, metals, etc. are t y pically
not included in a stabilit y pro -
gram but determined on product
release. Again there can be excep-
tions where there is a potential
for the amount of such species to
increase on storage,” says Wake.
In-use stability testing
In the case of multi-dose product
types, in-use stability testing can
be used. The intent of an in-use
stability study is to simulate the
u s e of t he pro duc t i n pr ac t ic e ,
t a k i n g i nt o c o n s i d e r a t i o n t h e
f i l l i ng volu me of t he conta i ner,
any dilution/reconstitution before
use, the hold-time before use, and
various diluents that could be used
for administration, Crothers says.
The purpose of conducting in-
use stability testing is to establish
a period of time during which a
multi-dose product may be used
while retaining quality within an
acceptable specification, once the
packag ing is open or broached,
Wake says, citing the European
Medicines Agency’s definition of
the term (3).
“ I n- u s e st abi l it y te st i ng c a n
therefore be considered for multi-
dos e pro duc t t y p e s, a s a ss e ss -
ment of the continued eff icacy
and safet y (as def ined through
critical quality attribute testing)
of a pharmaceutical (or biophar-
maceut ica l) d r ug produc t once
in its final administration form,”
according to Wake.
Typically, an in-use assessment
i s p e r f o r m e d o n a m i n i mu m
of t wo batches of mater ia l,
w it h, idea l ly, one batc h ta ken
f r o m a ne a r e nd - o f- s he l f- l i f e
produc t. T he protocol involves
reconstituting the drug product
to its ad m inist rat ive for m a nd
testing over a pre- defined
storage period at the condition
recommended.
“The analytics performed will
be in line with those identified
P h a r mTe c h . c o m
for long-te r m a nd acce le r ate d
storage st ud ies w it h perhaps a
g reater in f luence on m ic robia l
c r ite r ia a nd p ote nt ia l i mpu r i-
ties derived from pertinent envi-
ronmental factors, for example,
impurities formed through oxy-
gen exposure which is unavoid-
a ble i n a mu lt i - d o s e fo r m at ,”
according to Wake.
Analytical methods
for effective
stability testing
vary from drug to
drug.
Establishing an effective in-use
shelf-life is of significant bene-
fit. Without such, a multi- dose
product design becomes signifi-
cantly less practical in terms of
ensuring patient safety and prod-
uct efficacy in this format. “This
can lead to huge produc t wast-
age which, specifically in the case
of biological materials, has huge
consequence i n ter ms of prod-
uct cost and maintaining supply
which ca n lead to t he produc t
b e i n g non -v i a ble i n te r m s of
patient access,” says Wake.
References
1. ICH, Q1 (A-F) Stability, Step 5 version
(ICH, 2003), www.ich.org/products/
g u idel i nes/qu a l it y/a r t icle/qu a l it y-
guidelines.html.
2. ICH, Q5C Quality of Biotechnological
Products, Stability Testing of Biotech-
nological/Biologic Products, Step 4
version (ICH, 1995), www.ich.org/fil-
eadmin/Public_Web_Site/ICH_Prod-
ucts/Guidelines/Quality/Q5C/Step4/
Q5C_Guideline.pdf.
3. EMA, Note for Guidance on In-Use
Stability Testing of Human Medici-
nal Products (EMA, September 2001),
w w w.ema .eu ropa .eu /doc s/en _GB/
document_library/Scientific_guide-
line/2009/09/WC500003475.pdf. PT
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Lab Operations
Improving
Operations in the Lab
Amber Lowry
New and emerging products advance
bio/pharma laboratory operations.
S
taying up to date on the most
advanced technologies is impor-
tant for improving operational
tasks, especially in the laboratory. The
following is a sampling of the latest
products available to optimize labora-
tory operations for biological products.
Automated fraction collector
The NGC Fraction Collector from Bio-
Rad Laboratories provides flexibility
and collection capacity for analytical
or preparative chromatography appli-
cations when used with the company’s
NGC Chromatography System (1). Fea-
tures include a benchtop Peltier cool-
ing module for temperature-sensitive
biomolecules and an optional enclo-
sure to protect samples from environ-
mental conditions while allowing full
access during a run. Because the en-
closure is optional, the same fraction Bioreactor control system
collector can also be used for reverse- Automated Control Concepts’ (ACC)
phase chromatography applications. Lab Owl is a bioreactor control and in-
58 Pharmaceutical Technology MARCH 2018
The unit, which runs on ChromLab
5.0 Software, allows researchers to
choose how to collect and when to
access their fractions. The system
can be activated to collect based on
slope, percent of buffer from pump B,
pH, and detector signals. According
to the company, front-to-back dis-
pensing provides access to frac-
tions before method completion for
improved speed of downstream analy-
sis. Researchers can also choose the
type of collection vessel they prefer
for each phase in a method, including
deep-well plates, tubes, bottles, and
carboys (with prep-rack adaptors for
large-scale purification). Adding two
new fraction collectors to each NGC
System can further expand capacity,
according to a company press release.
P h a r mTe c h . c o m
formation system that integrates labora-
tory instrumentation for data collection
and analysis for labs using cell culture
and fermentation applications (2). Its
user-friendly interface can be used with
bench-top bioreactors in development
labs, in pilot plants, and in manufactur-
ing, according to company. The system
is available in flexible and scalable form
factors to meet the needs of labs depen-
dent on bioreactors for cell culture and
fermentation experiments.
“We’ve discovered that most scien-
tists felt that there had to be a bet-
ter way to control their experiments
and collect and analyze their data,”
said ACC CEO Michael Blechman,
in a press release. “Lab Owl provides
that better way. Developed in col-
laboration with scientists from sev-
eral major biotechnology companies,
Lab Owl is easy to configure, flexible
in control, and integrated with ana-
lytical instruments—allowing scien-
tists to focus on innovation.”
Cell counting device
Corning and CytoSMART Technologies,
a company spin-off from The Nether-
lands’ Eindhoven University of Technol-
ogy that manufacturers ultra-compact,
live-imaging systems and cell counters
for biological laboratories, have part-
nered to simplify mammalian cell count-
ing in laboratories (3). The new Corning
Cell Counter uses technology developed
by CytoSMART and offers enhanced
speed for automated cell counting. The
device, which is exclusively supplied
by Corning, will be available through
Corning´s global sales team and world-
wide distribution network.
Cell counting is a crucial sub-
cultivation step in the cell-culture
workflow, according to the compa-
nies. Many laboratories still perform
manual cell counting using a hemo-
PRESSMASTER/SHUTTERSTOCK.COM
cytometer or a counting slide viewed
under a microscope. In comparison,
the Corning Cell Counter returns an
accurate and precise digital cell count
in a few seconds. The device can
accommodate the standard reusable
contin. on page 69
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10:30am – 11:15am Bioreactor System with a Production of a Semi- MasterControl Inc. Advanced Materials Delivery of Biologics
Manufacturing Practices for Pre-Use Making From Feasibility Important Considerations
Biochemical Analyzer for Continuous Aseptic Industry through and Complex Small
10:30am - 10:55am Post-Sterilization Through Detailed Design Necessary to Successfully
Real-time Analysis Spray Freeze-Dryer Decision Support Molecule Compounds
Employing the Internet Integrity Testing Bring a Biologic Molecule
Information
of Things and PAT for to Market
Solutions
Solid Dosage Forms
Manufacturing
11:00am-11:25am
PCMM (Portable,
Continuous, Miniature Data Integrity and
and Modular) OSD Building the Foundation Impact of Tank Cone 11:15am - 12:00pm
Management in the Cleaning Validation
Manufacturing Facility for Continued Bottom Interior Angle on Advantages
Pharmaceutical Industry. Different Approaches
11:30am – 12:15pm Platform Process Verification Agitator Design, Lowest MilliporeSigma Coming Soon Coming Soon of Continuous
Understanding and to Limit Setting for
11:30am - 12:30pm with Industry 4.0 Mixable Volume, and Manufacturing for Solid
Complying with GMP & Detergents
Continuous Manufacturing Analytics Process Results Dosage
FDA Requirements
Manufacturing
Roundtable: Best
Practices for
Implementation
Pharmaceutical Start-ups: Moving out
Technology CRB TECH TANK Tablet Press and 1:00pm 1:30pm – 2:15pm
of the Incubator Into a Remediation Challenges
1:30pm – 2:15pm Keynote Series Flexible Manufacturing - Encapsulating Machine Rockwell Coming Soon Coming Soon Pharma Intelligence:
New Pilot/Manufacturing of Aging Facilities
Aseptic, Sterile, Adapt or Die! Transactions Automation 2018 Industry Outlook
Facility
and Biologics Drug
Manufacturing
1:30pm - 2:10pm
Analytics and On-dose Identification
Single Use Viable Air
Instrumentation: CRB TECH TANK for Tablets and Capsules
Optimized Manufacturing Monitoring in Critical
Best Practices for Keep’em separated! Dosage Design and
of mAb-based Products: Environments of a 2:00pm 2:15pm – 3:00pm
2:30pm – 3:15pm Lyophilization Integrating segregation Equipment Innovation Coming Soon Coming Soon
Flexibility, Speed, and Specialty Multi-Purpose LB Bohle LLC Biosimilars 4.0
2:15pm - 3:00pm for gene vector to Mitigate Risks in
Efficiency can Co-exist Contract Manufacturing
Continuous production Patient Safety and Brand
Organization
Manufacturing for Protection
Biopharm, Visions of an
End-to-End Approach

Case Study: Capacity

Case Studies: Steam A Case Study for an 3:00pm – 3:45pm
Expansion and CRB TECH TANK
Sterilization Regulatory Improved Approach to Risk Analysis: Present Automated Visual
Conversion to Single- Solving the riddle 3:00pm
3:30pm – 4:15pm Requirements and End Cleanroom Disinfection, State and Industry’s Coming Soon Coming Soon Particle Inspection
Use BioProcessing at an of flexible facilities - Sika Corp.
User Impact Analysis Minimizing the Impact Demand for Hard to Inspect
Existing cGMP CDMO biotech & fill/finish
and Common Mistakes and Reducing Downtime Containers
Facility

Settling the Frontier of 3:45pm – 4:30pm

Process Economics: The
Driving Force Behind the
4:15pm – 5:00pm Coming Soon
Criteria for Cell Therapies
Facility Design
Continuous OSD: A Novel, Real Time Fill-Finish Operations The Impact of Critical
Designing a Controls Adaptive Process Control - High Tech Filling 4:00pm Utilities
Coming Soon Coming Soon
Model (Continuous System for Optimizing in a Proper Abode SP Scientific/PennTech
Manufacturing track) Feeding in Bioreactors (Optimizing 4:30pm – 4:45pm
Facilities track) Show Wrap Up Day 1

WEDNESDAY, APRIL 18, 2018

MEETING ROOM 1 MEETING ROOM 2 MEETING ROOM 3 MEETING ROOM 4
INTERPHEX Optimizing Facilities PDA, CRB Tech Tank Manufacturing Quality Metrics and MEETING ROOM 5 INTERPHEX LIVE
FORMULATIONX CMO/CDMO
INNOVATION STAGE through Innovation and and Continuous Efficiencies and Systems/Risk (Vendor Presentations) Crystal Palace
Technology Manufacturing Improvements Management
10:00am - 12:00pm IPS TECHNOLOGY TOUR (Tour Registration Required)
10:30am – 11:00am
10:00am - 11:00am 10:30am – 11:00am ELSEVIER: 10:15am – 11:00am
Cleaning Agent
FDA Presentation with Ensuring Reliable, Linking Data to New Regulations, Real
Screening: Key Aspects 10:30am – 11:00am
10:00am – 11:00am PDA: The Future of Consistent Production Boost Discovery Coming Soon Case Studies: ASME
Pharmaceutical Quality and
in Selecting a Suitable Rockwell Automation
in Pharmaceutical Water and Manufacturing BPE Cabinet Washer
the Path to Get There Cleaning agent for a GMP
Systems Productivity Standards (SD-5.3.1)
Cleaning Procedure
Pharmaceutical
Technology 10:30am – 11:30am
Keynote Series FACILITY FOCUS 1:
Information Flexibility by Design:
Technology Trends and GMP Manufacturing for
Best Practices the Diverse Product Integrating IoT into your
The use of Extractables
Portfolio Life Sciences Packaging Verifiable Containment 11:15am – 12:00pm
11:00am - 11:30am Data from Single Use
11:00am – 12:15pm and Supply Chain Performance of Isolator ADENTS Coming Soon Coming Soon Automation Trends
Regulatory Requirements Components for Risk
for Data Integrity, Strategy - Best Practices Technologies Facing the Industry
Assessment
Applying ALCOA+ to Take this Valuable Leap
11:30am - 12:30pm
Best Practices in Data
Integrity and Process
Security with Automated
Systems

1:00pm - 3:00pm IPS TECHNOLOGY TOUR (Tour Registration Required)

Pharmaceutical 1:00pm - 2:00pm
Technology FACILITY FOCUS 2:
Keynote Series Restrictive Access
1:15pm – 2:00pm Barriers: Best industry
1:30pm - 2:10pm Practices for Retrofitting
The Industrial Internet of a Legacy Filling Lines
Things, Blockchain, and with a RABS Barrier
Smart Contracts 2:15pm - 3:15pm
FACILITY FOCUS 3:
2:15pm - 3:00pm
Central Utilities for
2:15pm – 3:00pm Serialization: Moving
GMP Manufacturing: A
Beyond Compliance
Practical Dialog on Cost
to Value
and Reliability
Current Trends &
Considerations for Drug
3:15pm – 4:00pm Delivery Device Assembly
of Self-Administered
Products
Coming Soon
Lessons Learned from
Microbial Contamination
in Pharmaceutical
4:15pm – 5:00pm
Manufacturing; Benefit
of End User and Supplier
Collaboration
Global Pharmaceutical Mass Spectrometry in
Harmonized Method for 1:30pm – 2:15pm
Packaging Trends, Freeze Drying, Over 25
Cleanroom Hard Surface 1:00pm Utilizing AR/VR in
Beyond Serialization Years Since the First Coming Soon Coming Soon
Disinfectant Efficacy Eschbach GmbH Pharma Development
(Optimizing Facilities Installation: How Far
Evaluations and Manufacturing
track) have we Come?
Data Driven Control 2:15pm – 3:00pm
2:00pm - 3:00pm
Strategy for Critical Emerging and
PDA Roundtable Making ‘Spray and Pray’ 2:00pm
Drug Container Transformational
Technology and Process Obsolete with New Bimba Manufacturing Coming Soon Coming Soon
Closure Systems Technologies in
for Cell and Gene Technologies Company
(CCS) Performance at Personalized Medicine
Therapy Manufacturing
Digital Age – A Paradigm Shift
A Comprehensive
Approach to Cleanroom
Single Use Applications Total Organic Carbon for
Certification for Reduced 3:00pm – 3:45pm
in Continuous Enhanced Verification 3:00pm
Risk of Environmental Coming Soon Coming Soon Data Security/Data
Biopharmaceutical of Bioprocess System MilliporeSigma
Contamination and Lockdown
Processing Cleaning CQ
Improved Regulatory
Compliance
3:45pm - 4:30pm
Facility Prefabrication
FDA Inspection
– Coupling Flexibility, Bridging the Gap
Real-Time Analytics Preparations: What’s
Mobility and Rapid Between Rinse Water
with Timeline View for Vendor Presentation Coming Soon Coming Soon New, What’s Different
Deployment into Turnkey Analysis and Surface
Improved Analytics
Solutions (Optimizing Cleanliness
4:45pm - 5:00pm
Facilities track)
Show Wrap Up Day 2

THURSDAY, APRIL 19, 2018

MEETING ROOM 1 MEETING ROOM 2 MEETING ROOM 3 MEETING ROOM 4
INTERPHEX Optimizing Facilities PDA, CRB Tech Tank Manufacturing Quality Metrics and MEETING ROOM 5 INTERPHEX LIVE
FORMULATIONX CMO/CDMO
INNOVATION STAGE through Innovation and and Continuous Efficiencies and Systems/Risk (Vendor Presentations) Crystal Palace
Technology Manufacturing Improvements Management
10:00am – 3:00pm Show Floor Open & IPX/BPI Poster Hall

The Theory Behind 10:30am - 11:30am

Automatic Inspection 10:15am – 11:00am
Life Cycle Cost for PDA Roundtable Work Smart: Risk based
Technologies for Subvisible- Endotoxin Remediation 10:30am Regulatory
10:30am – 11:15am Multiple-Effect Water
to-Visible Particle Detection
Use of Big Data for Approach for Cleaning Coming Soon Coming Soon
Strategies Rockwell Automation Requirements Relating
Stills and Container Closure Predictive Process Validation
to Water
Integrity Control

How Understanding Loss in 11:15am - 12:00pm

Prescriptive Maintenance Weight Feeder Principles Achieving Manufacturing Process Control
Leveraging IIoT and Optimization of Feeder Efficiencies with Interpretation within a
Vendor
11:30am – 12:15pm Technology Can Become Refill and Overall Design Advanced Batch Coming Soon Coming Soon Manufacturing Line
can actually improve the Presentation
Your Competitive Management
Advantage Continuous Pharmaceutical Technology 12:15pm - 12:30pm
Process Show Wrap-in Day 3

*As of February 15, 2018. Schedule subject to change.

REGISTER FOR YOUR FREE TECHNICAL CONFERENCE AND EXHIBIT HALL PASS AT:
WWW.INTERPHEX.COM/REGISTER
Cold Chain Distribution
Poseidon
Takes on the
Pharma Supply Chain
Agnes Shanley
Lower costs, fewer opportunities for
temperature excursions, and a smaller
carbon footprint are making ocean transport
more attractive for pharmaceuticals.
Poseidon, a new collaborative pharma
initiative, seeks to leverage benefits.
T
ransporting sensitive pharmaceuti-
cals is a risky and complex business.
“The lower deck conditions within
a Boeing plane or a typical intermodal
freight container are a long way from
the GMP-validated cleanrooms and con-
trolled laminar-flow environments of the
pharma production environment,” says
Alan Kennedy, founder and executive di-
rector of TEAM UP, an organization that
focuses on pharma supply chain issues.
According to the International Air
Transport Association (IATA), the global
pharmaceuticals logistics market is valued
at $64 billion and is one of the most regu-
lated, expensive, and fragile cargo mar-
kets in the world today (1), says Kennedy.
60 Pharmaceutical Technology MARCH 2018
crossed the ocean by ship. It has histori-
cally been the Cinderella of pharma dis-
tribution, says Kennedy, but, IATA notes
that 3.5 million metric tons of pharma-
ceuticals are still shipped by ocean each
year, compared with 0.5 million metric
tons by air (3).
Over the past five years, ocean trans-
port has taken on much greater visibility
in the pharma industry. Cost competitive-
ness is one factor driving acceptance, he
says, since it is up to 80% less expensive
than air transport.
In addition, Kennedy notes, although
it takes much longer than air travel it is
often more reliable, because there are far
fewer product handoffs. According to
some studies, air freight accounts for 80%
of all reported temperature excursions,
compared with 1% for sea journeys (4,5).
With ocean freight, customs clearances
and other time-consuming paperwork
procedures can often be arranged dur-
ing transit. “The fact that ocean freight
entails a greater stock tie-up can also be
mitigated through use of ‘floating ware-
house’ principles whereby goods in transit
are recognized as inventory,” he says.
In addition, ocean transport has a
carbon footprint that is 1/25th the size of
air travel’s (i.e., 1000 grams per m.t./km
of CO2 are released during air transport,
compared with less than 40 grams by
ocean transport (6), says Kennedy.
Risk reduction
A 2013 report by analysts from The Sea-
bury Group (7) found significant quality-
Pharmaceutical transport typically control problems with air freight. As a
combines different modes, explains Ken- result, Kennedy says, air cargo carriers
nedy. Air transport, prized for its speed began to set higher standards, establish-
and flexibility, is used mainly for long dis- ing the IATA Center of Excellence for
tance, intercontinental distribution of the Independent Validators (CEIV) Pharma
most valuable therapeutics, he says, while program to interpret general European
road is the most widespread method and Union and other good distribution prac-
AUN PHOTOGRAPHER/SHUTTERSTOCK.COM
is also used to connect with both air and tices (GDPs) for air cargo (8).
sea freight. That same year, the EU extended GDP
Rail remains an insignificant factor, but regulations to cover controlled room
this may change, Kennedy says, as new temperature (CRT) products, which
“silk route” connections between Asia and must nominally be kept from 15–25 °C,
Europe are established (2). which only accelerated a switch from air
to ocean transport, Kennedy says.
Ocean: Cold Chain’s Cinderella? So far, most of the growth in pharma
Ocean transport may conjure 1940’s im- ocean transport has been around rela-
ages of the days when most people still tively low value, high-volume products
P h a r mTe c h . c o m

2018 PDA Annual Meeting
Agile Manufacturing
Strategies: Driving Change
to Meet Evolving Needs
NEW FOR 2018:
Same high-quality content in an ALL NEW
meeting format!
Please note these important changes to the 2018 PDA
Annual Meeting Schedule:
• The Conference will now begin with the Opening
Plenary at 1:00 p.m. on Monday, March 19
• The Grand Opening Celebration will kick off in the
Exhibit Hall at 5:00 p.m. on Monday, March 19 –
Ì>i>`Û>Ì>}ivÞÕÀwÀÃÌ««ÀÌÕÌÞÌÃiiÌi
latest products and services and meet with exhibitors!
• Interest Group sessions will be held at the same time as
the breakout sessions, giving attendees more sessions
from which to choose during the day and allowing for
more free time in the evening.
• The Closing Reception will take place on Wednesday,
March 21 at 7:00 p.m. – Be sure to stay and
celebrate with us!
And, on March 22-23, 2018, PDA Education will host a choice of seven courses as part of the 2018 PDA Annual Meeting
Course Series to help you further advance your knowledge. Learn more and register at pda.org/2018AnnualCourses
March 19-21, 2018 | Orlando, FL
Exhibition: March 19-21
Post-Meeting Workshop: March 21-22
Courses: March 22-23
#PDAANNUAL
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The 2018 Annual Meeting will explore areas
focused on innovation, agility, and technology
and how these topics are changing the world
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on the future of patient therapies, digital information
strategies, transformations in manufacturing facility
design and process technology, and how best to
navigate the complex regulatory environment.
Don’t miss the Exhibit Hall where vendors and
suppliers will showcase their latest technologies and
offer solutions to current and future pharmaceutical
manufacturing challenges.
Be a part of one of the most exciting events of 2018 –
Attend to network and hear about the technological
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CONNECTING
PEOPLE+
SCIENCE
REGULATION
®
Cold Chain Distribution
From supply chains to supply networks: Poseidon aims to redefine pharma cold-chain logistics
Alan Kennedy, executive director of TEAM UP, shared perspectives on
Poseidon and ocean transport with Pharmaceutical Technology.
PharmTech: Why was Poseidon established and what do you hope to
achieve with the program?
Kennedy: Like-minded individuals at the 2017 European Temperature
Controlled Logistics Conference agreed that, in order for any degree of
wholesale, across-the-board improvement in the pharma-cold chain, there
would need to [be] more alignment between supply-chain stakeholders.
Poseidon’s model is built around some of the principles of supply-chain
collaboration and integration that are being successfully applied in
other industries. Instead of a supply chain, Poseidon is a supply network
that involves all of the stakeholders that are responsible for transporting
pharmaceutical products. Currently, 19 companies are involved in the
Poseidon project, including eight pharmaceutical manufacturers.
Driven by pharmaceutical companies, the program is designed so that each
pharma firm and its shippers, logistics companies, and suppliers sit around
the same table as equal partners. A network partner agreement governs the
relationships between all these parties, and they work together as a single
team with common goals, rules, and performance incentives.
Poseidon is putting together an end-to-end integrated network for pharma
logistics. We hope that the model will serve as a template for pharmaceutical
companies in their quest for more efficient, more competitive, and more
concerted supply chains that are fit for purpose in today’s rapidly changing
environment.
PharmTech: How are you connecting the many stakeholders who would
be involved in ocean transport?
Kennedy: A cloud-based Poseidon Collaboration Hub enables members
to communicate in real time or whenever needed. Stakeholders around the
world facilitate network communications, exchange ideas, disseminate news,
share information, access up-to-date documentation, and manage projects.
The Hub is also used for non-transactional network communications, for
meetings, and to store documentation.
PharmTech: What types of technology (e.g., temperature and condition
monitoring) are being refined for ocean transport, and how would they differ
from solutions that were developed for air transport?
Kennedy: The challenges of sea freight broadly mirror those of air, although
some of the protection and monitoring equipment had to be adapted to the
different time parameters and operating conditions. For example, one of our
participants, DuPont, is currently exploring new cargo-cover materials for
ocean freight use.
One of the advantages of sea freight is that it offers better shipment
visibility so that shippers can monitor the geographical position and physical
condition of freight in real-time. At this point, Poseidon is only using Maersk
‘smart’ reefers and US-built Klinge ‘redundancy’ reefers.
For air freight, the US Federal Communications Commission requires
transmitting devices such as data-loggers to be auto-switched off during
flight for safety reasons. Although the loggers continue to capture data
during the flight, this information can only be retrieved later. As a result,
there is reduced opportunity to receive alerts or to intervene quickly, to fix a
problem that has been reported while it is happening, such as an unexpected
temperature excursion that might compromise product quality.
62 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
PharmTech: Are insurance costs more of an issue for sea than air freight?
Kennedy: Ocean transport insurance can sometimes be perceived
as a black hole by shippers, who are often more comfortable with the
comprehensible and comprehensive insurance provisions associated with air
freight. Shipping lines, for instance, tend to apply inconsistent liability limits,
which, in any case, are invariably much lower than the typical value of a full
container consignment of pharma products. It’s a problem that currently
prevents many otherwise suitable products from being shipped by water.
Poseidon is actively addressing this issue and has brought the insurance
industry into negotiations from the project’s start. As a result, Poseidon
can now offer a wide-ranging insurance framework specially devised to
provide satisfactory cover for all pharma shipment risks and values. Poseidon
insurance will provide significantly improved coverage while demystifying
the marine protection process.
PharmTech: Have there been any regulatory changes regarding ocean
shipment or position pronouncements by the World Health Organization
(WHO) or other global authorities on ocean transport of pharmaceuticals?
Kennedy: GDP legislation is indiscriminate, non-prescriptive and applies
universally to all transport modes. So, the same standards must be met by
all (The IATA CEIV program is a translation of these regulations to make them
more air-freight-friendly).
Although a high proportion of vaccines are currently transported by sea,
the use of ocean freight has not yet been officially endorsed by WHO due to
concerns surrounding the perceived implications of a ‘total’ loss situation
(i.e., where a huge volume of urgent vaccines or drugs might be lost in a
single event). WHO is expected to review this position, however.
PharmTech: Have there been any detailed risk benefit analyses of ocean
transport performed recently?
Kennedy: Different pharmaceutical companies have launched proprietary
pilot studies to ascertain savings and quantify results.
However, Poseidon is working with several pharma manufacturers to
design and implement the largest ocean freight transport validation exercise
to date. This study will involve multi-container intercontinental shipments
of different pharmaceutical dosage forms (oral solid dosage forms, vial
parenterals, and topical creams), which will be rigorously monitored and
documented. This exercise will be completed by June 2018.
PharmTech: Are there types of pharma companies that tend to rely more
on ocean transportation? What interest are you seeing in the industry?
Kennedy: For the first time, the 2017 IQPC Temperature Controlled Logistics
conference in London included a Sea Freight Focus Day. This event was sold
out, and 70% of those attending worked at pharmaceutical manufacturers,
almost all seeking to enter sea freight or to upgrade their sea freight usage.
Most of Big Pharma is already shipping some of its products by sea. However,
these companies typically deal in huge volumes that lend themselves well to
full container load (FCL) shipments.
Small- and mid-sized pharma companies, which contribute half the
industry’s output, do not currently have access to a GDP-compliant less than
container load (LCL) service, also known as ‘groupage’ or shared container
service. Therefore, they are forced to send materials by air. We expect this
restriction to be lifted once Poseidon introduces its GDP-compliant LCL
service later this year.
such as solid-dose tablets, generic pharmaceuticals, APIs, and
excipients. However, advocates see that it also has potential to
handle more sensitive large-molecule biologics as well as per-
sonalized medicine therapies.
Studies at Eli Lilly and Bayer
Among ocean transport’s strongest pharma advocates is As-
traZeneca, which has increased the percentage of products
it ships by sea from 5% in 2012 to nearly 70% in 2017 (9). Eli
Lilly, which has been conducting studies of ocean transport
of biologicals, has found that transporting products by sea
saves 80% in costs, reduces carbon footprint, reduces staff-
ing requirement, packing, and storage needs, and also re-
duces vibration and shock to materials during transport (10).
Lilly has partnered with Modality Solutions for protocols and
reports, with Q Products for thermal covers, and with Sensitech,
using TempTales, monitors that allow for simultaneous tracking
of both temperature and location.
One test involved simulating worst-case scenarios for a 40-foot
reefer transporting 18 pallets of placebo, evaluating temperatures
ranging from 0 –115 °F. The studies used Locus Traxx GPS and
Lansmont’s Saver to monitor product shock and vibration. Other
tests compared results of trucking product to Long Beach, CA,
a two-to-three-day trip, with shipping product to Australia, a
45-day trip one way.
A Bayer study (11), meanwhile, showed ocean transport plus
trucking to be an efficient way to transport pharmaceuticals in-
land in Brazil. Logistics efforts in that country can be challeng-
ing, because they involve driving long distances overland and, in
some areas, facing potential security issues.
Poseidon to improve sea transport
In 2016, at the European Temperature Control Logistics Confer-
ence, a number of stakeholders in pharma cold-chain shipping
joined forces to form TEAM UP. Their aim was to explore ways
to improve the shipping of pharmaceuticals. In January 2018,
TEAM UP established Poseidon, a network involving the
different types of companies involved in the ocean transport
of pharmaceuticals (see Sidebar).
Led by pharmaceutical manufacturers, but involving shippers,
logistics companies, and suppliers as full partners, the group is
focusing on applying best collaborative and integration practices.
Its goal is to leverage the latest technology to address any perfor-
mance gaps that might still separate ocean from other transport
modes. Technology vendor members currently include Maersk,
H. Essers, Marsh, DowDuPont, Pelican Biothermal, Klinge Corp.,
Logtag Recorders, and Controlant. Members are collaborating
on new projects, including a major validation study that will be
completed in June 2018, as well as new insurance and container
options for sea freight.
References
1. “Pharmaceutical Transportation: How to Increase Air Cargo’s
Share,” aircargopedia.com, 2017, www.aircargopedia.com/phar-
malandingpg.htm.
2. J. Webb, “The New Silk Road: China Launches Beijing-London Freight
Train Route,” forbes.com, January 3, 2017, www.forbes.com/sites/
jwebb/2017/01/03/the-new-silk-road-china-launches-beijing-london-
freight-train-route/#69bae8221f13
3. IATA, “Putting Pharmaceuticals Back in the Air,” iata.org, 2017, www.
iata.org/whatwedo/cargo/pharma/Pages/ceiv-pharma.aspx
4. M. Roebuck, “Astra-Zeneca Eyes Major Shift from Air Freight to
Ocean: A More-Controlled Environment for Drugs,” theloadstar.co.uk,
December 15, 2015, www.theloadstar.co.uk/coolstar/astrazeneca-eyes-
major-shift-from-air-freight-to-ocean-a-more-controlled-environ-
ment-for-drugs/
5. Climate Killing Airplanes, fluglaerm.de, 2015, www.fluglaerm.de/
hamburg/klima.htm
6. Opinion Editorial, “Unreliable Air Cargo Industry Loses Pharma
Traffic to Sea While IATA Sleeps,” coolchain.org, www. coolchain.org/
unreliable-air-cargo-industry-loses-pharma-traffic-to-sea-while-iata-
sleeps
7. Seabury Group Pharma Market Overview, coolchain.org, May 14, 2013,
www.coolchain.org/Websites/cca/images/AGM2013/Seabury_-_The_
View_of_the_Analyst.pdf
8. IATA, Centers of Excellence for Independent Validators, iata.org, www.
iata.org/whatwedo/cargo/security/ceiv/Pages/default.aspx
9. A. Guisbert-Wiliams, “Eli Lilly and Company NALO Logistics Para-
digm Shift Air to Ocean (A2O),” 15th Cold Chain GDP and Tempera-
ture Management Logistics Summit, Canada, 2017.
10. J. Wann, “Air, Ocean, Road Strategy at AstraZeneca,” Logipharma,
April 2017.
11. R. Velazquez Trevino, “Modal Shifts: Where Are We Going?” TCL
London 2017, January 31, 2016. PT
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outsourcing outlook
Current Challenges in
Bioprocesses Development
Ronald A. Rader
Development and adoption of new technologies
create challenges that may take years to resolve.
M
odern bioprocessing and antibody
manufacturing are mature fields;
however, challenges remain, and
the advances themselves often bring new
challenges. This is the nature of progress.
The current challenges are exemplified by
the ongoing advances and industry adop-
tion of technologies such as continuous
processing, the importance of modeling
bioprocesses, increasingly seamless down-
scaling of processes, and other factors
that are expected—and even required—by
regulatory agencies.
Over the past 15 years, the industry
has evolved into a mature, productivity-
oriented segment. Of the dozens of trends
evaluated in the annual BioPlan Associates
survey (1), productivity continues to show
the highest focus as an industry objective
(See Figure 1). This suggests that other op-
erational aspects must address industry
challenges around improving productiv-
ity and efficiency.
But to achieve successes, operational
challenges must be worked out. As an ex-
ample, continuous bioprocessing is one of,
if not the most, challenging area for process
development. Continuous processing—
including both upstream perfusion and
downstream continuous purification pro-
cessing—remains rare and elusive despite
the fact these technologies have been es-
tablished for some time. These challenges
particularly stand out when continuous
and conventional batch processing op-
tions are compared. Figure 2 shows survey
results when bioprocessing professionals
were asked to indicate issues with adop-
Ronald A. Rader is senior director,
Technical Research, at BioPlan Associates,
+1.301.921.5979, info@bioplanassociates.com.
64 Pharmaceutical Technology MARCH 2018
tion of upstream perfusion that are much
or somewhat bigger.
Upstream continuous processing
Bioprocessing professionals clearly
see a number operational problems
remaining with upstream perfusion
versus conventional batch processing.
In 2017, a number of concerns were
cited by more than 50% of respondents
to BioPlan’s survey:
• Process operational complexity
• Contamination risks
• Upstream [process] development and
characterization time
• Process development control chal-
lenges.
This daunting collection of concerns
about perfusion persists despite it being in
use and marketed for multiple decades—
including for commercial biopharmaceu-
tical manufacture—notably for Factor VIII.
In many respects, perfusion may be viewed
as a technology adoption model in biopro-
cessing that demonstrates the slow nature
of adoption of rational, effective technolo-
gies. BioPlan market research studies (1)
have shown that approximately 5% of
bioreactors use perfusion, with many of
these being feeder and not production bio-
reactors. Further, while perfusion is seen
by users as highly productive, often better
and cheaper versus batch processing, most
using it in early manufacturing continue to
avoid its use in commercial manufactur-
ing, viewing the challenges as high and the
risks significant, in terms of regulatory ap-
provals. One challenge for perfusion pro-
cess adoption is that single-use perfusion
units only recently became available. This
lack of familiarity could be a factor in the
P h a r mTe c h . c o m
reporting of high levels of concerns with—
and even fears of—perfusion versus batch
bioreactors likely among those not using
the technology. Many challenges remain
before the industry gains experience and
confidence in this option for continuous
upstream processing.
Downstream processing challenges
Downstream continuous operations, par-
ticularly chromatography, has more chal-
lenges; suitable hardware with built-in data
systems are just starting to become avail-
able from suppliers. Downstream continu-
ous bioprocessing was cited as the second
single-most important bioprocessing trend
or operational area on which the industry
must focus its efforts. In BioPlan’s study,
perceived need for improvements carries
over to facility budgets with interviewees
reporting an average increase of 8.8% in
their 2017 downstream technology budgets
vs. 7.7% for upstream; 33.8% cited continu-
ous chromatography as a “top area where
suppliers should place their efforts on.”
Adoption of continuous chromatogra-
phy, generally involving use of multiple in-
terfaced columns with integrated controls,
is growing more rapidly than perfusion
adoption; however, adoption has only re-
cently started from a near zero baseline and
is low. Combined with other downstream
advances (e.g., increasing use of mem-
branes in place of resin-filled columns, au-
LIGHTSPRING/SHUTTERSTOCK.COM
tomated in-line buffer dilution and column
packing, better resins, and more single-use
and recyclable columns), downstream pro-
cessing is in many respects changing and
evolving more rapidly than upstream, but
the adoption and integration into actual
bioprocessing remain slow. When asked
 Outsourcing Outlook
to cite the top downstream areas where Figure 1: Single most important biomanufacturing trend or operational
suppliers should focus their development area, 2014–2017.
efforts, disposable purification systems
were cited by 35.9% of respondents, fol- 0% 5% 10% 15% 20% 25%
lowed closely by continuous purification
16.4% Year 2017
cited by 33.9%. Geographically, European Manufacturing 18.9% Year 2016
Productivity/Efficiency 17.2% Year 2015
respondents are much more interested in 20.1% Year 2014
continuous purification compared with
those in the United States (44.4% vs. 25.3%). 12.3%
Continuous BioProcessing - 10.0%
But basic problems remain with Downstream
broader adoption of both upstream and
downstream continuous bioprocessing, 4.8%
Continuous BioProcessing - 5.7%
including the inability to integrate related 7.2%
Upstream
manufacturing systems. Currently, im- 9.1%
plementation of end-to-end continuous
bioprocessing, or even upstream or down-
stream segments, remains rare or nonexis- Figure 2: Selected concerns, perfusion vs. batch-fed processes.
tent, with at best one or a few unit processes Red is much bigger concern with perfusion. Blue is somewhat more
implemented as continuous. concern. White is at least somewhat of a concern, 2017.
Process scalability challenges
Contamination risks 37.0% 39.5% 76.5%
Bioprocessing modeling and understand-
ing of implications of changes in scale Process development control challenges 24.4% 52.1% 76.5%

remains another challenging area. The Process operational complexity 42.9% 31.1% 73.9%
industry has naturally concentrated on Upstream development and
26.1% 46.2% 72.3%
characterization time
scale-up, as drug product volumetric re-
24.4% 47.1% 71.4%
quirements increase as products advance Need for greater process control

in development. More is known about Validation challenges 32.8% 37.8% 70.6%

scaling up versus scaling down. But the

importance of scaling down is rapidly in-
creasing, including the ability to model
and predict what happens in research
and development by using smaller scales,
rather than having to run experimental
studies at various scales, including full
scale. Having scale-down capabilities
and understanding is increasingly ex-
pected, if not required, in FDA and other
major market regulatory filings, particu-
larly for product approvals. Being able to
scale down and have related models and
knowledge are now key parts of process
analytical technology, quality by design,
and other regulatory/quality initiatives.
In addition, validated process down-
scaling methods often are required for
cost-effective design and refinement of
FIGURES COURTESY OF THE AUTHOR
Bioprocess system designers also want
the ability to conduct computer-based
modeling to scale up and scale down a pro-
cess using bioprocessing equipment from
the same product line.
This particularly applies to purchases
of bioreactors, mixers, chromatography,
and other major bioprocessing systems,
but also extends to filters and other
equipment. Scalability, particularly
including scale-down ability, is a top
equipment/technology selection factor
cited in bioprocessing supplies-related
market research studies. Many facilities
will not purchase equipment unless rea-
sonable scalability is known and docu-
systems at scales higher than anticipated
use to provide better assurance of actual
scalability throughout the range of scales
they actually will use, such as from mini/
desktop to 2000-L or larger production
bioreactors.
Conclusion
To move forward, industry and its inves-
tors need to recognize this segment has
historically been one of the slowest, but also
the most persistent, in terms of adopting
the advances that the industry requires.
To achieve success, operational challenges
must be worked out, but in this regulated,
high-stakes environment, the timelines for

bioprocessing. This is exemplified in the
use of down-scaled bioprocesses to vali-
date process biosafety, including reduc-
tion in virus titers from virus filtration
and chromatography steps. The costs of
validating virus removal and inactiva-
tion would be too expensive and time-
consuming if run for full-scale processes.
mented among products throughout a
product line, particularly for bioreac-
tors and chromatography and filtration
systems. Bioprocessing professionals
regularly cite an expectation that bio-
processing systems will seamlessly scale
up and down. In addition, the users want
to model or predict the operation of the
development and adoption of new tech-
nologies create challenges that, sometimes,
require years to resolve.
Reference
1. E.S. Langer, et al., Report and Survey of Bio-
pharmaceutical Manufacturing Capacity and
Production, 13th annual (BioPlan Associates,
2016). PT

Pharmaceutical Technology MARCH 2018 65

INTERPHEX 2018 PLANNING GUIDE AND INDUSTRY PIPELINE
INTERPHEX
2018
Planning
Guide
Plan Your Visit to
INTERPHEX 2018
April 17–19, 2018
New York, New York
VISIT US AT INTERPHEX 2018
Avista Pharma
Solutions is a contract
development,
manufacturing, and
testing organization that understands what
it takes to rapidly advance products through
every stage of development. With over 200,000
square feet of laboratory and manufacturing
space in the US and UK, we offer a broad
suite of scientifically differentiated services
ranging from early stage discovery, API and
Drug Product development, and cGMP
manufacturing to stand-alone analytical and
microbiology testing support.
Avista Pharma Solutions • 3501
Tricenter Blvd, Suite C, Durham, NC 27713 •
919·544·8600 • www.avistapharma.com
INTERPHEX Booth #1153
VISIT US AT INTERPHEX 2018
DJA has partnered with some of the finest
Pharmaceutical machine manufacturers
in the World. As a diverse and World-Wide
organization, DJA-Pharma can provide ma-
chinery for all your tablet and Liquid manu-
facturing needs.
Daiichi Jitsugyo (America), Inc. • 939 AEC Drive,
Wood Dale, Illinois 60191 •
Tel: 630·776·2459 • www.dja-pharma.com •
rnelson@djausa.com
Visit us at Booth #2827
66 Pharmaceutical Technology MARCH 2018
VISIT PHARMTECH AT BOOTH 1430
• Meet the editors
• Review current issues of Pharmaceutical Technology
• Answer surveys
• Meet colleagues and peers
STAY CURRENT ON TECHNOLOGIES AND SERVICES
Visit Pharmaceutical Technology sponsors that are
exhibiting at INTERPHEX 2018. See descriptions and
booth information on the following pages.
Chemic Laboratories, Inc. is a full service cGMP/
GLP contract analytical chemistry laboratory.
Chemic provides an array of R&D and cGMP
contract testing services including; Extract-
ables/Leachables analysis, CMC Method Devel-
opment & Validation, Quality Control analysis,
Release testing, Raw Materials analysis, Com-
pendial testing, Organic Synthesis/Formulation
Development & ICH Stability testing.
Chemic Laboratories, Inc., 480 Neponset St.,
Building 7, Canton, MA 02021 • www.chemic
labs.com • lcw@chemiclabs.com •
tel. 781.821.5600 • fax 781.821.5651 •
INTERPHEX Booth #1372
The FEC40 Capsule
Filler can produce up
to 400,000 capsules/
hr—nearly twice the
volume of any com-
petitor. Its remarkably
small footprint makes machine reconfigura-
tion due to floor space issues unnecessary.
Extraordinarily high performance-to-footprint
ratio is made possible by Fette Compacting’s
patented Duplex Concept, enabling FEC40
to feature a dual capsule filling process. The
result is significant production savings (up to
30% per 1000 capsules).
Fette Compacting America, 400 Forge Way,
Rockaway, NJ 07866 •
www.fette-compacting-america.com •
tel. 973.586.8722 • INTERPHEX Booth #2505C
P h a r mTe c h . c o m
TAIGA/SHUTTERSTOCK.COM
Contec, Inc. is a leading manufacturer of
contamination control products for mission-
critical cleaning in manufacturing environ-
ments worldwide. Our extensive product
line for cleanrooms and critical environ-
ments includes knitted, woven, and nonwo-
ven wipes; presaturated wipes; sterile and
non-sterile wipes; disinfectants; mops; wall
washing systems; sponges; and swabs.
Contec, Inc. • 525 Locust Grove, Spartanburg,
SC 29303 • tel. 864.503.8333 •
www.contecinc.com • wipers@contecinc.com
INTERPHEX Booth #1234
IMA is a world leader in the
design and manufacture
of automatic machines
for the processing and packaging of
pharmaceuticals. At INTERPHEX 2018, visitors
will have a chance to discover what’s new from
IMA for the pharmaceutical industries.
A special area is dedicated to IMA Digital,
which summarizes all of the projects that
represent IMA’s commitment to the evolution
toward the Smart Factory and Smart Products.
IMA’s leadership in terms of innovation and
technology imposes a highly competitive posi-
tion, also in the challenges of Industry 4.0.
IMA S.p.A. • via Emilia, 428-442, Ozzano
dell’Emilia (Bologna), Italy • +39 051 6514111 •
www.ima.it • www.ima-pharma.com •
INTERPHEX Booth #2545
ŅŞ}ƚ±ĬĜƋƼųåĺÚŸüŅųƗljŏí×
Pharma Quality Survey Report
ON-DEMAND EBCAST eĜųåÚa±ųÏĘƁØƗljŏí

Register for this free webcast at www.pharmtech.com/pt_p/goals

Event Overview Who Should Attend

While compliance is still the king of quality, nearly half ■ Quality and Regulatory Professionals
of pharmaceutical quality professionals surveyed listed ■ Senior Leadership
“economic performance” as a top objective for 2018.
Senior quality executives are pointing to a new set of
goals aimed at reducing costs, improving operations,
and speeding time-to-market. Does your team have
what it takes to impact company-wide performance?
Presenters
Join Brandon Henning, product management director Brandon Henning
for Sparta Systems, as he discusses leading trends and Director,
objectives for quality teams in 2018, as well as the Product Management
Sparta Systems
obstacles they must quickly overcome. Learn how you
can set your team up for success in 2018.

Moderator
In this Webcast You’ll Learn
Rita Peters
■ Top quality goals and obstacles for 2018 for pharma
Editorial Director
quality teams
Pharmaceutical
■ How quality data can improve economic Technology
performance

■ How technology can streamline compliance and

performance

Sponsored by Presented by

For questions contact Ethan Castillo at ethan.castillo@ubm.com

 INTERPHEX 2018 PLANNING GUIDE AND INDUSTRY PIPELINE
VISIT US AT INTERPHEX 2018
Lonza Pharma &
Biotech provides
global contract
development and
manufacturing
services that enable pharma and biotech
companies to bring medical innovations
to patients in need. We are recognized for
our reliability and high-quality, our global
capacity, our innovative technology platforms,
and our extensive experience. We have helped
to commercialize pioneering therapies and
we continuously invest and innovate to meet
your expectations also for future medicines.
Our belief is that the best outcome—for you
and for your patients—comes as a result of a
successful collaboration. Lonza Pharma & Biotech
INTERPHEX Booth #1730
VISIT US AT INTERPHEX 2018
PTI will showcase MicroCurrent HVLD
technology, the optimal inspection method
for all parenteral and biologic products
at INTERPHEX. PTI’s E-Scan 655 is a
deterministic, non-destructive test method
for prefilled syringes, vials, ampoules,
cartridges, and BFS products.
PTI Inspection Systems • tel. 914.337.2005 •
www.ptiusa.com • info@ptiusa.com
INTERPHEX Booth #3305-A
NEW PRODUCTS AND SERVICES
As a member
of Eurofins’
BioPharma
Product Test-
ing Group—
the largest
network of harmonized bio/pharmaceutical
GMP product testing laboratories world-
wide—Eurofins Lancaster Laboratories
supports all functional areas of bio/pharma-
ceutical manufacturing, including method
development, microbiology, process vali-
dation and quality control throughout all
stages of the drug development process.
Eurofins Lancaster Laboratories, Inc,
2425 New Holland Pike, Lancaster, PA 17601
www.lancasterlabs.com • tel. 717.656.2300
68 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
NJM Packaging, a Pro-
Mach product brand
in the Pharma Business
Line, is a trusted automated packaging systems
manufacturer, integrator, and support resource.
We offer a broad range of technology, specializ-
ing in the needs of pharmaceutical, nutraceutical/
vitamin, and personal care product packagers. At
NJM, we focus on delivering superior value to our
customers by exceeding expectations with high-
end equipment and the best service in the indus-
try. These standards defined our young company
100 years ago, and we are proud to continue the
tradition by constantly evolving and improving
products and service offered to our customers.
NJM Packaging, 5600 Kieran, Montreal, QC
• 800·811·6990 • info@NJMPackaging.com •
www.NJMPackaging.com
INTERPHEX Booth #2353
VAI’s manufactur-
ing and testing
operations mirror
current GMP/GLP
standards. With
over 35 years of contamination control
experience, our products and services in-
clude a comprehensive line of disinfectants,
sporicides, residue removers, process clean-
ers, quality water, saturated and dry wipes,
disposable garments, cleanroom paper,
documentation materials, printing systems,
viable monitoring, cleanroom cart systems,
cleaning equipment, consulting, and labora-
tory services.
Veltek Associates, Inc. • 15 Lee Blvd, Malvern,
PA 19355 • tel. 610.644.8335 • vai@sterile.com
• www.sterile.com • INTERPHEX Booth #2527
Mikart specializes in the development,
manufacturing, and packaging of solid-dose
and liquid-oral dose products. The company’s
services include formulation development;
analytical, manufacturing, packaging, and
regulatory services; and complete project
management. Mikart offers clients more than
40 years of experience, a responsive working
relationship, and the ability to take products
from formulation development through full-
scale commercial production.
Mikart, Inc., • www.mikart.com • tel. 404.351.4510
Connecting People,
Science, and
Regulation®
The Parenteral Drug Asso-
ciation (PDA) is the leading
global provider of science,
technology, and regulatory information
and education for the pharmaceutical and
biopharmaceutical community. Founded
in 1946 as a nonprofit organization, PDA
is committed to developing scientifically
sound, practical technical information and
resources to advance bio/pharmaceutical sci-
ence and regulation through the expertise of
its more than 10,000 members worldwide, so
members can better serve patients.
Parenteral Drug Association (PDA) •
www.pda.org • INTERPHEX Booth #1653
The ASEP-TECH® Blow/Fill/Seal (B/F/S) system
has been marketed by Weiler Engineering,
Inc. for more than 58 years to the world’s
leading pharmaceutical and healthcare com-
panies. This advanced aseptic technology
combines blow molding of plastic bottles,
sterile filling of liquid products, and hermetic
sealing on one compact machine frame in
bottle sizes ranging from 0.2mL to 1000mL.
Weiler Engineering, Inc. • 1395 Gateway Drive,
Elgin, Illinois 60124 • tel. 847.697.4900 •
fax: 847.697.4915 • www.weilerengineering.
com • solutions@weilerengineering.com
INTERPHEX Booth #1845
Dual-Shaft
Mixers
Ross Dual-Shaft
Mixers, suitable for
mixing 50-, 100-,
and 200-gallon
batches, are
equipped with two independently-driven,
variable-speed agitators: a high-speed
disperser and a two-wing anchor. Working
in combination, both agitators provide
adjustable shear and efficient turnover of
low-to-high viscosity materials including
pastes, gels, suspensions, slurries, and fine
dispersions up to several hundred thousand
centipoise.
Ross, Charles & Son • Hauppauge, NY,
1.800.243.ROSS • www.mixers.com.
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Lab Operations— contin. from page 58

hemocytometer or disposable slides,
but microscopic viewing in order to
perform the cell count will no longer
be needed, as stated by Corning.
Freeze dryer for life-science labs
The Freezemobile freeze dryer from
SP Scientific is suited for high-qual-
ity preparation of peptides, proteins,
plant materials, and organic tissue (4).
Unlike many traditional freeze dry-
ers that employ coil condensers, these
freeze dryers use a smooth-walled
condenser that enables fast defrost and
removal of ice for faster turn-around
time and also alleviates vapor port ice
blockages other systems are prone to,
according to the company.
The freeze dryer is offered in 25-
and 35-liter condenser sizes and is
suitable for labs with multiple users,
as well as labs with high quantity
of product through-put. The device
has a -85 °C condenser to enable the
removal of a variety of solvents and
can be configured for exact user pro-
cessing requirements.
Individual samples can be added
or removed without interrupting the
instrument, thereby enabling users to
continue their experimental process
without having to wait for another
freeze dryer to become available.
The freeze dryer also includes a
range of single- and multi-tiered hori-
zontal “T” type manifolds, which can
be used to dry multiple flasks simul-
taneously, and provides an optimized
platform for drying large quantities
of samples in bulk flask format. To
improve the laboratory operating envi-
ronment, the freeze dryer can also be
supplied with a low noise, oil-free vac-
uum pump, as stated by SP Scientific.
Additionally, the company offers
a cont rol system t hat of fers a
range of control features to meet
the demands of various applica-
tions. Vacuum levels, condenser
temperature, ambient room tem-
perature, and component status
are all displayed on a clear LCD
display, while alarms warn of any
unwanted process deviations.
The company’s Freezemobile Shell
Bath helps to decrease manifold
freeze-drying time. The tool rotates
sample flask on its axis, thereby coat-
ing the interior surface of the flask
with frozen product. According to the
company, this increases the surface
area of the product-to-energy input,
as well as vapor removal, helping to
reduce the freeze-drying process to
the shortest time possible when utiliz-
ing flasks and a manifold system.
References
1. Bio-Rad Laboratories, “Bio-Rad Launches
NGC Fraction Collector for NGC Chro-
matography Systems,” Press Release, Jan.
8, 2018.
2. Automated Control Concepts, “New Bio-
reactor Control System Integrates Lab
Instrumentation for Optimal Data Col-
lection and Analysis, and Aims to Liber-
ate Labs From Routine Processes,” Press
Release, Jan. 16, 2018.
3. Corning, “Corning and CytoSMART
Announce Agreement for Cell Counting
Device,” Press Release, Feb. 2, 2018.
4. SP Scientific, “Flexible Freeze Drying for
Life Science Labs,” Press Release, Feb. 8,
2018. PT
Pharmaceutical Technology MARCH 2018 69
ask the expert

Computerized
Systems Validation

In-house experts can help select the right systems and suppliers, making validation
and compliance easy, says Siegfried Schmitt, principal consultant at PAREXEL.

Q. We are planning to upgrade several of our automated systems

in production and in the laboratories. These upgrades are
necessary so that we can implement functionality like audit trails,
which are now required to achieve data integrity compliance. We
contacted suitable vendors and some have now offered to sell to us
fully 21 Code of Federal Regulations (CFR) Part 11 and data integrity-
compliant software packages. Such a package seems like a very
good deal, but it is not offered by the majority of suppliers. Can you
give some insight on how other companies address this situation?
it is not in human readable form, or that it only captures a fraction
of the transaction, or that the amount of data in the audit trail is
so overwhelming that it becomes unmanageable.
Savvy companies have in-house experts with a sound
understanding of the regulations covering automated systems,
how to perform computerized systems validation, and how to
optimally harness the vendors’ expertise. These experts will
put together the user requirement specifications (URS) for the
various systems. The URS is the document that will steer how the

A. You are in a very typical situation where not all your auto-
mated systems are of a technical standard that make compli-
ance with the applicable regulations possible, unless you upgrade
or replace certain systems. It is an unfortunate fact that there are
still vendors out there who make misleading claims, either out of
ignorance, or worse, knowingly. The only party that can legally com-
mission and operate a computerized system in a fully compliant
manner is the system owner (i.e., someone within your organiza-
tion). Only you know how you are going to use the specific system
and for what purpose. No vendor can do this for you. Therefore,
automated system suppliers can merely offer to sell you systems
system (or system upgrade) will help you to operate in compliance
with the regulations (i.e., what it takes to make sure that data
are trustworthy and your system is fully validated). In the URS,
companies will specify what they expect from the audit trail (e.g.,
it must be human readable, sortable, exportable, searchable, etc.).
The URS also forms the basis for the testing requirements,
namely the testing by the users. Users may be quality unit
personnel who need to verify that on an analytical instrument
the series of injections for an analysis tally with the method,
or that there were no rogue injections. Only these people
will know what they are looking for and how they want to

that are designed and built in a manner that allows you, the cus-
tomer, to operate them in a compliant manner (e.g., complying with
21 CFR R Part 11 or other regulatory requirements).
Let me give you an example to clarify this: You may purchase
a system upgrade that provides audit trail functionality. Although
the vendor gives you an audit trail as you requested, you may
choose not to activate it (perhaps because it slows the system
down too much). Now you may be in a non-compliant situation. Or,
you decide to activate the audit trail, but upon review you find that
DAMIAN PALUS/SHUTTERSTOCK.COM
perform their review. Your system vendors are now tasked with
providing you with a system that meets your needs, and not just
a ‘one-size-fits-all’ solution.
Don’t be lulled into a false sense of security by sales
promises; instead, make sure you have experts at hand who
can help you select the systems and suppliers who best meet
your needs. Once you do this, you will find that validation and
compliance even with the most demanding regulations become
not only possible, but exciting. PT

Ad Index
COMPANY PAGE COMPANY PAGE

Aenova .........................................................31 Excipient Fest ..............................................55 NJM ..............................................................25

AirBridgeCargo Airlines ............................. 63
BIO International Convention .....................57
Biovigilant ................................................... 45
Catalent Pharma Solutions.........................72
Chemic Laboratories Inc ............................11
Coating Place Inc ........................................23
Contec .........................................................21
CPhI USA ......................................................71
Daiichi Jitsugyo America, Inc. ....................35
Eurofins Lancaster Laboratories ................39
Fette Compacting America Inc ..................15
FG Clean Wipes ...........................................51
Halo Pharmaceuticals .................................27
ILC Dover LP ..........................................46, 47
IMA Spa ........................................................37
INTERPHEX ..................................................59
Jost Chemical Co...........................................3
Leistritz Extrusion ...................................... 33
Lonza Biologics Inc .......................................2
Marchesini Group Usa ................................49
Parenteral Drug Association ................ 29, 61
PTI ................................................................41
Pyramid Laboratories .................................13
Ross, Charles and Son Co ............................7
Sparta Systems Inc .....................................67
Tomi/Sterimist ...............................................9
US Pharmacopeial Convention ..................17
Veltek Associates ..........................................5
Watson-Marlow Pumps Group ...................19
Weiler Engineering Inc ............................... 53

70 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m


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regulatory and operational expertise to
support successful technology transfer at
any phase of the development cycle.
Global infrastructure and business models
to provide unique manufacturing solutions.
Flexibility to design dedicated suites, and
scalable capacity and integrated services to
support small orphan programs through to
large network rationalization strategies.
Expertise in manufacturing technologies
to improve efficiency, reliability, and
safety, packaging technologies for
serialization, and special handling
experience across +300 potent, cytotoxic,
hormonal and controlled substances.

Catalent. More products. Better treatments. Reliably supplied.™

us + 1 888 SOLUTION (765-8846) eu 00800 8855 6178 catalent.com/manufacturing