Raw Materials Batch Record Continuous AUGUST 2017 Volume 41 Number 8

Volume 41 Number 8

PLUS: Quality Review Improvement

PHARMACEUTICAL TECHNOLOGY

Breaking
Through
Obstacles to
Improve Drug
Manufacturing
AUGUST 2017
PharmTech.com

PEER-REVIEWED
Establishing Acceptance Limits for
Uniformity of Dosage Units: Part Two
API SYNTHESIS & EXCIPIENTS FORMULATION TOPICAL DRUG MANUFACTURING
Optimizing Cell-Culture Media Targeting Drug Delivery with ADCs QbD in Topical Drug Manufacturing
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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
Managing Editor Susan Haigney susan.haigney@ubm.com Mid-West Sales Manager Irene Onesto irene.onesto@ubm.com
Science Editor Adeline Siew, PhD adeline.siew@ubm.com East Coast Sales Manager Joel Kern joel.kern@ubm.com
Manufacturing Editor Jennifer Markarian jennifer.markarian@ubm.com
European Sales Manager Linda Hewitt linda.hewitt@ubm.com
Science Editor Feliza Mirasol feliza.mirasol@ubm.com
Associate Editor Amber Lowry amber.lowry@ubm.com European Senior Sales Executive Stephen Cleland stephen.cleland@ubm.com
Art Director Dan Ward Executive Assistant Barbara Sefchick barbara.sefchick@ubm.com
Contributing Editors Jill Wechsler jillwechsler7@gmail.com;
C.A.S.T. Data and List Information Michael Kushner michael.kushner@ubm.com
Jim Miller info@pharmsource.com; Hallie Forcinio editorhal@cs.com;
Susan J. Schniepp sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com;
and Cynthia A. Challener, PhD challener@vtlink.net ADDRESS
Correspondent Sean Milmo (Europe, smilmo@btconnect.com) 485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA
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David H. Bergstrom, PhD of Pharmacy
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4 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m

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 August 2017 Volume 41 Number 8

Pharmaceutical Technology is the authoritative source of peer-reviewed research

and expert analyses for scientists, engineers, and managers engaged in process
development, manufacturing, formulation and drug delivery, API synthesis, analytical
technology and testing, packaging, IT, outsourcing, and regulatory compliance in the
pharmaceutical and biotechnology industries.

COVER STORY
On the cover

14 BreakingThrough
Obstacles to Improve
Drug Manufacturing
Systems that discourage continuous improvement threaten pharma
innovation, quality, and supply. Can the industry break through this deadlock?

Cover Design by Dan Ward

Images: Lightspring/shutterstock.com

FEATURES
API SYNTHESIS & EXCIPIENTS TOPICAL DRUG MANUFACTURING RAW MATERIAL QUALITY

20 Optimizing Cell- 28 Using QbD in Topical 44 The Role of

Culture Media
Media manufacturers are focused on
reducing risk, improving quality and
consistency, and managing costs.
FORMULATION
24 Targeting Drug
Delivery with ADCs
Safe and effective drug targeting
with ADCs requires careful selection
of drug, antibody, and linker.
Drug Manufacturing Quality Standards for
Characterization of the product Biomanufacturing
and process is key for process Raw Materials
development and scale-up. Managing and prioritizing risk is
essential to ensuring raw material
ANALYTICS
quality. USP is developing new
40 A Continuous guidelines to make the work easier.
Improvement Metric
for Pharmaceutical
Manufacturing
Statistical methods and novel
indices can be used to monitor and
benchmark variability, and guide
continuous improvement programs
in late-stage drug development.

PEER-REVIEWED RESEARCH SUPPLEMENT SUPPLEMENT TO THE AUGUST 2017 ISSUE OF 2017

Be sure to check

PEER-REVIEWED out this month’s

Outsourcing
30 Establishing Acceptance Limits Resources special
OUTSOURCING
RESOURCES
for Uniformity of Dosage Units: Part Two SPARKING POWER
issue for articles on CONNECTIONS

The author describes how to establish the corresponding acceptance limits

supply chain, audits,
for AV data for process validation batches, the typical characteristics of AV
distributions, and finally, how to derive relevant constants for AV control charts project management,
in annual product review and continued process verification reports. blockchain, and more!

PharmTech.com
NEWS & ANALYSIS
FROM THE EDITOR
8 Just the Pharma
Facts, Please
Amid contentious debate
about “fake news,” peer-review
papers offer vital, objective insight.
OUTSOURCING OUTLOOK
48 CDMOs: New
Administration,
New Frontier
Despite some progress, the industry is
still in a wait-and-see mode regarding
the administration, Congress, and FDA.
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/
& COMPLIANCE PRODUCTS
US REGULATORY WATCH 10 Product Spotlight
12 Gottlieb 50 Product and Services Profiles
Tackles Opioids,
Drug Costs,
62 Pharma Capsules
and Innovation 62 Ad Index
FDA urges manufacturers to
seek fast approval of “high-need”
65 Showcase/Marketplace
generics and targeted therapies.
ASK THE EXPERT
66 A Look at Batch
Record Review
The review of batch records creates a
story of the materials, manufacturing,
and packaging involved in the produc-
tion of bio/pharmaceuticals, according
to Susan Schniepp, distinguished fellow
at Regulatory Compliance Associates.
PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-
2521, Digital ISSN: 2150-7376) is published monthly,
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from the editor
Just the Pharma Facts, Please
Rita Peters
Amid contentious debate about “fake news,”
peer-review papers offer vital, objective insight.
T
he term “fake news” has been a
hot-button issue recently. By defi-
nition, “fake” news is news that is
false; this content may be disseminated
as “true” to influence opinion or to de-
ceive. In the current contentious politi-
cal environment, some people identify
any information that runs counter to
their opinions as “fake news.”
Thanks to special-interest online
publications and blogs, cable news
channels, and even traditional news
outlets, finding news that is “real” to
you is only a click away. Your “real”
news, most likely, is “fake” to those
with opposing views. Facts, scientific
consensus, and real-word evidence
have become secondary to opinion and
vested interests in the political arena.
Fact-based information, however, is
still the foundation for discussions and
decisions in science-driven industries.
The editors of Pharmaceutical Tech-
nology routinely screen pitches from rep-
resentatives of supplier companies about
the importance and capabilities of new
products or the quality of the services
they offer. Experts at bio/pharma com-
panies look to promote their capabilities
or receive recognition for their achieve-
ments. We embrace our role as gate-
keepers, sorting through the sometimes
overtly promotional pitches to compile
Rita Peters is editorial
director of Pharmaceutical
Technology. Send your
thoughts and story ideas to
rita.peters@ubm.com.
8 Pharmaceutical Technology AUGUST 2017
objective information and insight about
industry trends and developments.
We also receive article contributions
from industry experts whose primary
objective is to share information to help
advance the science and technology of
pharmaceutical development. We are
grateful for their contributions.
Fact-seeking audience
When the editors survey opinions in
our annual readership studies, read-
ers say they prefer articles that pro-
vide practical descriptions of technical
topics, as well as peer-reviewed papers.
These article formats are the founda-
tion of our coverage. While the edi-
tors interview and work with experts
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While other publications offer pay-
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Peer-review paper basics
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P h a r mTe c h . c o m
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erences to published third-party lit-
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rial guidelines for submissions, and
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PATPITCHAYA/SHUTTERSTOCK.COM
acceptable file types for figures, tables,
and images; and include a style guide
for references.
To access this information, visit
www.PharmTech.com and click the Au-
thor’s Guidelines link on the navigation
menu. Or, you can contact me directly
at rita.peters@ubm.com. PT
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PRODUCT SPOTLIGHT
Larger Peristaltic
Pumps Allow Scale-Up
Watson-Marlow Fluid Technology Group
(WMFTG) has expanded its range of peri-
staltic cased pumps for upstream and down-
stream bioprocessing tasks. The existing 120
and 530 models are now joined by 630 and
730 higher flow pumps, allowing research
projects or production to be scaled up
without changing or impacting the process.
WMFTG’s 120, 530, 630, and 730
process pumps share the same func-
tionality to enhance compliance with
cGMP. The expanded range (from
0.000000264 gal/min up to 8.7 gal/min)
covers a wide spectrum of bioprocessing tasks and simplifies scaling.
A human machine interface requires minimal key presses to
reduce the opportunity for errors. Process security is enhanced
with the addition of a 3-level PIN lock. Control options include
manual, remote, analogue, and RS485 digital communications,
along with integrated PROFIBUS networking capabilities.
The new cased pumps are designed for use with single-use
fluid path assemblies, and the low-shear pump action means
that product can be moved without degradation or damage.
Watson-Marlow Fluid Technology Group
www.wmftg.com
Single-Use Systems Expand
Scale of Chromatography
Sartorius Stedim Biotech
has expanded its range
of single-use membrane
chromatography solu-
tions with Sartobind
Cassettes, a pod-like
modular system for
commercial applications
in both capture and polishing. The cassettes offer the same flow
path, bed heights (4 and 8 mm), and void volume ratios as Sartobind
capsules, and are compatible with quaternary ammonium (Q), sul-
fonic acid (S), salt-tolerant interaction chromatography primary
amine (STIC PA), and phenyl ligands. The new design goes beyond
the previous 5-L size limitation for capsule formats, expanding
the boundaries of membrane chromatography. Multiple cassettes,
each with 0.8-L or 1.6-L membrane volume, can be set up in three
different stainless-steel holders, resulting in maximum membrane
volumes of 20, 50, or 100 L, respectively. Pressure-flow performance
and the shape of breakthrough curves are identical to the smaller
capsule sizes, independent of the number of cassettes used. Set up
can be accomplished within minutes, even at manufacturing scale.
Sartorius Stedim Biotech
www.sartorius.com
10 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
Heavy-Duty
Multi-Agitator Mixer
The VersaMix Multi-Shaft Mixer from Ross,
Charles & Son is designed for large-scale
production and enables repeatable batch
processing of high-volume viscous applications
such as solid–liquid dispersions, thickened emul-
sions, suspensions, pastes, and gels. The mixer
is adaptable for mixing at low, intermediate, and
high-shear levels, or any combination neces-
sary for powder wet-out, deagglomeration,
emulsification, homogenization, heating/cooling, and deaeration.
The Ross Model VMC-750 (pictured) features a dual-post lift,
interchangeable 750-gallon mix vessels, and a triple-agitator system
consisting of a low-speed anchor, high-speed disperser, and high-
shear rotor/stator assembly. Each agitator is independently-driven
and controlled from a human-machine interface panel. Features
such as agitator combinations, horsepower selections, and
recipe controls can be specifically tailored. Laboratory models
(one to four gallons) can be scaled to pilot/medium scale (10
and 40 gallons) and large capacity models (from 100–1000 gal-
lons). Fixed-tank designs are offered up to 4000 gallons capacity.
Ross, Charles and Son
www.mixers.com
Drying, Granulating,
and Coating System
Offers Modularity
The VENTILUS LE series for production-scale
applications from Romaco offers three versions:
LE-D for drying processes; LE-G for granulating
fine solid particles; and the LE-C for coating
them. The three machines are designed for
batch sizes from 40–1600 L. Larger batch volumes are possible
on request. These Light Edition machines are available for those
users that do not require all applications of the company’s Premium
Edition, which integrates all VENTILUS process steps and features.
Users who simply require the VENTILUS in order to dry the
fluidized bed can use the low-cost LE-D version. Integrated solu-
tions for wet granulation with an upstream high-shear mixer as
well as systems for wet and dry milling are available. All compo-
nents are connected to the VENTILUS LE-D fluidized bed dryer via
an enclosed material transfer system. Control, data recording,
and cleaning of the processing line take place centrally.
The VENTILUS V 100 LE-C combines all three processing
steps: drying, granulation, and coating. It contains the same
core components as the Premium Edition with a central
ROTOJET spray nozzle and an ORBITER booster. The rapid,
homogeneous distribution of the spray liquid helps achieve
shorter processing times and improved product quality.
Romaco
www.romaco.com
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regulatory watch
Gottlieb Tackles Opioids,
Drug Costs, and Innovation
Jill Wechsler
FDA urges manufacturers to seek fast
approval of “high-need” generics and targeted therapies.
S
ince confirmation as FDA commis-
sioner in May 2017, Scott Gottlieb
has moved aggressively to deliver
on promises to Congress and the pub-
lic to promote innovation while also
ensuring medical product safety and
patient access to needed therapies. A top
priority is to address the deadly opioid
epidemic by reducing drug misuse and
abuse and encouraging development
of safer painkillers. Although FDA of-
ficials usually avoid involvement in
drug pricing, Gottlieb has addressed the
issue head-on, mapping out strategies to
accelerate development of competitive
generic drugs and biosimilars, as well
as initiatives to bring more life-saving
therapies to patients.
In addition to these high-profile ini-
tiatives, FDA faces the considerable task
of implementing the 21st Century Cures
legislation. The new law sets tight dead-
lines for issuing guidance documents,
reports, and regulations and for hold-
ing public meetings with stakeholders
to devise and revise key programs for
product development. Cures Act provi-
sions call on FDA to better coordinate
the review of combination products and
establish a framework for approving
regenerative therapies and accelerating
the development and approval of criti-
cal medicines.
Jill Wechsler
is Pharmaceutical
Technology’s
Washington editor,
Chevy Chase, MD,
jillwechsler7@gmail.com.
12 Pharmaceutical Technology AUGUST 2017
In his first months on the job, Got-
tlieb also had to overcome adminis-
trative hurdles, such as negotiating an
exemption for FDA from the adminis-
tration’s federal hiring freeze. And it ap-
pears that Congress will provide a rea-
sonable budget for FDA by ignoring the
White House’s proposal to slash agency
appropriations and greatly increase
user fees. FDA will need considerable
resources to accomplish all the goals
within the timeframes set by Gottlieb’s
multiple action plans.
Gottlieb looks
to speed more
competitive
generic drugs
and biosimilars to
market.
Combating opioids
First on the agenda is the imperative to
curb excess prescribing and distribution
of powerful opioids and to produce safer
alternative pain therapies. To this end,
FDA is collaborating with the National
Institutes of Health and industry to
speed the development of non-addictive
analgesics, effective overdose reversal
interventions, and better diagnostics
that can prevent death from overdose.
At the same time, FDA is examin-
ing more closely whether opioids with
abuse-deterrent features (ADFs), which
FDA has encouraged manufacturers to
P h a r mTe c h . c o m
devise, are effective in resisting misuse
or actually aggravate overdosing. In
June 2017, FDA urged Endo Pharma-
ceuticals to pull Opana ER from the
market (which the company did in
July 2107) due to evidence that abusers
merely shifted from snorting the refor-
mulated product to injecting it, ignit-
ing outbreaks of HIV, hepatitis C, and
a serious blood disorder.
Agency officials are weighing the
removal of additional ADFs and ex-
amining strategies for evaluating their
safety. At a public workshop in July 2017,
experts discussed what data and ana-
lytical methods could best assess these
products, as outlined in an FDA issues
paper (1). A new Opioid Policy Steering
Committee, headed by FDA Deputy
Commissioner Rachel Sherman, is ex-
amining whether FDA reviewers suffi-
ciently consider risk of abuse during the
evaluation of new pain medicines, along
with the adequacy of current dosing rec-
ommendations and label information,
and whether mandatory education of
healthcare professionals is needed to en-
sure appropriate opioid prescribing (2).
Promoting competition
Instead of permitting broader import
of cheaper medicines from abroad to
expand access to less costly therapies,
ORHAN CAM/SHUTTERSTOCK.COM
Gottlieb looks to speed more competi-
tive generic drugs and biosimilars to
market. For example, FDA officials say
they expect interchangeable biosimilars
to appear within two years, following
publication of guidance on how to test
and develop such products (3). FDA had
approved five biosimilars as of June 1,

2017, and manufacturers were develop-
ing 66 additional therapies.
Furthermore, a Drug Competition
Action Plan outlines strategies for ac-
celerating the review and approval
of “high-need,” priority generics and
for addressing concerns about brands
using Risk Evaluation and Mitigation
Strategies (REMS) to block the devel-
opment of new generic competitors (4).
Gottlieb scheduled a public meeting in
July 2017 to examine whether innova-
tor firms were gaming FDA rules to
block generic-drug sponsors from ac-
cess to samples needed for bioequiva-
lence testing of abbreviated new drug
applications (ANDAs). A related issue
is the struggle to negotiate single shared
REMS programs for marketing high-
risk brand and generic therapies. At
the recent meeting, FDA experts heard
recommendations from manufacturers
and other parties on how to revise the
REMS program to halt anticompetitive
behavior without undermining new
drug development. FDA is accepting
comments on these issues through mid-
September, and Commissioner Gottlieb
is exploring with members of Congress
what legislative change is needed in this
area and what issues FDA can address
with existing authorities.
FDA also seeks to quickly approve
additional competitive generics by ex-
tending priority review of ANDAs to
products with less than three approved
alternatives to a reference drug (5). FDA
outlined in a June 2017 update to its in-
ternal procedures that accelerated re-
view (8 vs. 10 months) applies to drugs
with limited competition, as well as to
first generics and to products related to
drug shortages, public health emergen-
cies, and other special situations (6).
To encourage development of these
high-need therapies, the agency also
issued a “hit list” of more than 250
branded drugs that are off patent, have
no exclusivities, and thus qualify for
priority review. The list includes some
notorious, high-cost products that are
eligible for immediate agency evaluation,
and more complex therapies that raise
scientific and legal issues and warrant
prior consultation with FDA staff (7).
The importance of manufacturer tion and more innovation will alter that
readiness for accelerated approval of truism remains to be seen.
priority generics is highlighted in a draft
guidance that maps out a new process References
for identifying and vetting production
facilities for priority generics. To enable
faster ANDA reviews, FDA wants man-
ufacturers to provide a pre-submission
facility correspondence (PFC) two or
three months before filing an applica- 2. S. Gottlieb, “FDA Commissioner Asks
tion for a priority generic product (8).
FDA says it needs the extra time to de-
termine if testing facilities and planned
manufacturing sites require inspection
in order to schedule such visits within
the abbreviated review timeframe.
Innovation key
Ultimately, Gottlieb regards the devel-
opment of more innovative and effec-
tive therapies as key to lowering health-
care costs over the long run. Such gains
involve streamlining development of
treatments for chronic diseases and
clarifying R&D requirements to limit
unnecessary regulatory costs. The com-
missioner told the Senate Appropria-
tions subcommittee in June 2017 that a
new Medical Innovation Development
Plan will address these issues and when
FDA may approve a targeted drug based
on genetically-defined factors and de- 6.
fine more clearly a range of clinical trial
enrichment strategies (9).
An initial priority under the Inno-
vation Plan is to spur development of
treatments for rare diseases by improv- 7.
ing the process for evaluating orphan
drug designation requests, which have
more than doubled in recent years. By
mid-September, according to a new Or-
phan Drug Modernization Plan, FDA
will eliminate its backlog of 200 pend- 8.
ing designation requests and establish
procedures for vetting such requests
within 90 days (10).
Despite these efforts, medical prod-
uct costs will remain on the table at
FDA. “It’s not debatable,” Gottlieb told
the Senate Appropriations subcommit-
tee in June 2017, that the United States 10.
is subsidizing lower drug prices in other
countries through “the high prices we
pay here to support research and devel-
opment.” But whether market competi-
Regulatory Watch
1. FDA, “Data and Methods for Evaluating
the Impact of Opioid Formulations with
Properties Designed to Deter Abuse in the
Postmarket Setting,” Issues Paper, CDER,
July 10-11, 2017, www.fda.gov/downloads/
Drugs/NewsEvents/UCM562743.pdf.
Staff for ‘More Forceful Steps’ to Stem
the Opioid Crisis,” FDA Voice blog post,
FDA.gov, May 23, 2017, https://blogs.fda.
gov/fdavoice/?s=opioid+steering+commi
ttee%27.
3. FDA, Considerations in Demonstrating
Interchangeability With a Reference Prod-
uct Guidance for Industry, Draft Guidance
(CDER, CBER, January 2017), www.fda.
gov/downloads/Drugs/GuidanceCompli-
anceRegulatoryInformation/Guidances/
UCM537135.pdf.
4. S. Gottlieb, “How FDA Plans to Help
Consumers Capitalize on Advances in
Science,” FDA Voice blog post, FDA.gov,
July 7, 2017, https://blogs.fda.gov/fdavoice/
5. FDA, “FDA Tackles Drug Competi-
tion to Improve Patient Access,” News
Release, June 27, 2017, FDA.gov, www.
f d a . g o v/ N e w s E v e nt s / N e w s r o o m /
PressA n nou ncement s/ucm56 4725.
ht m?s ou rc e = govd e l i ve r y& ut m _
m e d i u m = e m a i l & u t m _
source=govdelivery
CDER, MAPP 5240.3 Rev 3, Policy and
Procedures (CDER, June 27, 2017), www.
fda.gov/downloads/AboutFDA/Center-
sOffices/OfficeofMedicalProductsand-
Tobacco/CDER/ManualofPoliciesProce-
dures/UCM407849.pdf
FDA, List of Off-Patent, Off-Exclusivity
Drugs without an Approved Generic,
w w w.fda.gov/downloads/Drugs/Re-
sourcesForYou/Consumers/BuyingUs-
ingMedicineSafely/UnderstandingGe-
nericDrugs/UCM564441.pdf
FDA, ANDAs: Pre-Submission Facility
Correspondence Associated with Priority
Submissions, Guidance for Industry, Draft
Guidance (CDER, June 2017), www.fda.
gov/downloads/Drugs/GuidanceCompli-
anceRegulatoryInformation/Guidances/
UCM563507.pdf
9. S. Gottlieb, FDA, Draft Testimony, Senate
Appropriations Hearing, June 20, 2017.
FDA, FDA’s Orphan Drug Moderniza-
tion Plan, June 29, 2017, www.fda.gov/
downloads/ForIndustry/Developing-
ProductsforRareDiseasesConditions/
HowtoapplyforOrphanProductDesigna-
tion/UCM565068.pdf PT
Pharmaceutical Technology AUGUST 2017 13
Cover Story: Obstacles to Innovation
Breaking
Through
Obstacles to
Improve Drug
Manufacturing
Agnes Shanley
Systems that discourage continuous
improvement threaten pharma innovation,
quality, and supply. Can the industry
break through this deadlock?
R
egulators, manufacturers, and even
the media (1) often ask why more
pharmaceutical companies don’t
use more of the modern manufacturing
and quality approaches and tools used
in other industries. The answer becomes
clear when one looks at the complexity
and cost involved in making process
improvements after a drug has been ap-
proved, and getting those improvements
approved by global regulators.
Simplifying the process for post-ap-
proval changes is a topic that is being
discussed more frequently at industry
events; the Parenteral Drug Association
(PDA) has launched a working group to
share best practices and brainstorm solu-
tions, and International Council for Har-
monization (ICH) Q12 (2) is tackling the
problem, yet little actual change is being
14 Pharmaceutical Technology AUGUST 2017
seen. Some in the industry ask whether
it will take a crisis to resolve this problem.
“We saw what the industry can do
and what regulators can support when
the Ebola virus struck, and vaccines,
which usually take over a decade to de-
velop and approve, were developed and
released in months,” says Maik Jornitz,
CEO of G-CON. “Why can’t we bring
these approaches for the urgent to the
normal, and create a more rapid approval
approach?” he asks.
Despite years of talk about regulatory
harmonization, and some pilot programs
and alliances, each regulatory authority
still takes its own approach to looking at
process improvements. When regulators
disagree, they sometimes force manufac-
turers to choose between moving for-
ward with an innovation or just staying
P h a r mTe c h . c o m
with the old process to simplify manu-
facturing and quality and reduce costs,
says Melissa Seymour, vice-president of
global quality control at Biogen. “Those
are the kinds of things that, if we’re not
careful as an industry, will shut down in-
novation,” she says.
Even proven technologies still run into
regulatory snags. One example would be
moving from high-performance to ultra-
high-performance liquid chromatogra-
phy (HPLC to UHPLC) , which should
be easy. “UHPLC is a better method and
it’s simple to validate, but it can still take
years to get it through the process, so
we’re still running HPLC because of the
regulatory approval structure, not the ca-
pabilities and potential of the analytical
method,” says Seymour.
Another case in point is isolator tech-
nology. When they were first intro-
duced to the pharmaceutical industry,
isolators weren’t adopted as rapidly as
expected, due to regulatory uncertainty,
says consultant Jim Agalloco. Years
later, that uncertainty persists. “If I want
to replace a curtain-segregated with an
isolator-based fill line, that change will
still undergo regulatory scrutiny, even
when the isolator-based containment is
more robust,” says Jornitz.
Tower of Babel
A pharmaceutical company that sells
its products globally must address post-
approval change requirements for each of
the regions it sells to, and that can mean
dealing with more than 100 different
regulatory agencies. “Many of our prod-
ucts are marketed in over 80 countries,
so a change approval can take more than
five years,” explains Seymour. The result,
she says, is inventory segmentation and
the need to manage several different ver-
sions of a drug over its lifecycle.
“In some instances, we’ve had to go
back to older manufacturing processes,
LIGHTSPRING/SHUTTERSTOCK.COM
or older and less efficient test methods
to generate enough inventory for coun-
tries where those changes haven’t been
approved yet,” she says. In other cases,
companies may spend resources running
two different analytical methods for one
product for up to five years, or running
under different specifications for three to
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Cover Story: Obstacles to Innovation
five years, because of the time it takes toquality officer at Sanofi. “You wind up
get changes approved globally, she adds. stacking them on top of each other.” As a
result, one year, he says, Sanofi produced
Making 83 batches 55 ways 83 batches of one of its vaccines accord-
Adding to the difficulty is the fact that, ing to 55 different configurations/varia-
in the real world, process improvements tions, depending on the region involved.
don’t just happen one at a time, but ac- The costs required can be mind-blow-
cumulate, says Anders Vinther, chief ing. Roughly 80% of the industry’s reg-
Encouraging Innovation at FDA: An Interview with CDER’s Lawrence Yu
For more than a decade, FDA’s leaders have realized that overly prescriptive
regulations can inhibit innovation in the industry. Over the past few years, FDA
has changed its organizational structure and processes to help encourage con-
sistency of inspection and review, as well as a dialogue between industry and
regulators. Lawrence Yu, Deputy Director, Office of Pharmaceutical Quality at
FDA’s Center for Drug Evaluation and Research (CDER), shared insights with
Pharmaceutical Technology.
PharmTech: FDA leadership has been encouraging industry to use more
modern manufacturing and quality methods for years. However, some
companies have sensed a disconnect between senior leadership’s position
and the day-to-day actions of inspectors and reviewers. What is FDA doing to
encourage trust and ensure that everyone within the agency understands and
supports modern manufacturing?
Yu: One of the hallmarks from the time that the Office of Pharmaceutical
Quality (OPQ) was established has been the use of team-based integrated
quality assessment, which leverages members across disciplines, including
assigned investigators from the Office of Regulatory Affairs, as part of the
extended review team. This approach helps ensure that reviewers and
inspectors are on the same page and that there is consistency in the evaluation
of modern manufacturing methods in a regulatory submission as well as
during on-site inspections.
The integrated quality assessment approach is supported by extensive
training in science, technology, and communication, covering such modern
manufacturing platforms as continuous manufacturing, process analytical
technology (PAT) tools such as near-infrared based methods, process design
tools, and process monitoring and control techniques. Guidance for industry
documents, such as FDA’s PAT guidance, provide transparency regarding the
agency’s current thinking and internal policies and procedures and also help
ensure consistency amongst agency staff. FDA is also involved in research and
development in advanced manufacturing, product analysis, data analysis, and
modeling.
When OPQ established the Emerging Technology Program, we built on
our prior experience with PAT and quality by design (QbD). The Emerging
Technology Team (ETT) features members from both review and inspection
programs, and is involved in FDA’s oversight of emerging technologies.
PharmTech: Many of the industry’s quality challenges are connected to
legacy, rather than new, drugs. Is FDA taking any actions to help reduce the
delays that can result when manufacturers submit requests for approval to
improve processes for legacy products? What is your advice to managers who
may have been putting off investing in more modern technologies due to fear
of costs and delays?
Yu: Managers considering implementing newer technology should consider
all aspects of the business case for implementation, which can include benefits
16 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
ulatory affairs professionals now spend
most of their time on post-approval
change-related issues, Vinther says.
At the same time, having to maintain
and run parallel manufacturing and
quality processes adds complexity and
can wreak havoc with workflow and
production planning, he says. Consider
such as increased reliability and lower costs due to better process efficiency
and control. Companies concerned about implementation costs and delays are
encouraged to contact the agency to have a discussion with the ETT.
PharmTech: Ever since the PAT initiative, we have heard about real-time
release and real-time release testing (RTRT), yet there seem to have been
relatively few cases where it has been approved. What issues need to be resolved?
Yu: There have been real-time release testing elements in approved
applications. Continuous manufacturing platforms support implementation of
RTRT, which can strengthen the business case for moving towards continuous
manufacturing. Regarding dissolution modeling, there has been much recent
work, including on FDA’s part, on physiologically-based pharmacokinetic
absorption models, which could be useful to support RTRT.
PharmTech: What must be done first if the industry is to be able to move to
advanced process control and, eventually, advanced manufacturing, and such
concepts as predictive maintenance?
Yu: At this point, pharmaceutical manufacturing is still at the stage of
automation, rather than advanced manufacturing. FDA has made an effort
to establish staff know-how so the workforce is ready to handle applications
involving multivariate data and statistics. Further, academic institutions have
trained a growing number of specialists in this area, providing the necessary
intelligence to support the adoption of advanced process control in the
pharma industry.
Within CDER, we have state-of-the-art research facilities in both PAT and
process/product analysis. This capability provides training opportunities for
reviewers on topics including various spectroscopy techniques and statistical
process control. Importantly, knowledge is exchanged between researchers
and reviewers to support advanced manufacturing.
Regarding predictive maintenance, any models used for release are
classified as high impact models. There is discussion of this in the International
Council for Harmonization (ICH) Points to Consider Guide for ICH Q8/Q9/Q10
Implementation. Facilities need detailed plans for maintenance of such models
throughout the life of a product. FDA is still learning, with industry, about this
evolving concept.
PharmTech: What should manufacturers focus on, first and in the short
term, if they are to begin to move toward Six Sigma quality? How about smaller
companies making lower margin product?
Yu: The ultimate focus should always be on benefit to the patient, and as
such, firms should establish specifications based on clinical relevance—that
is, potential impact on clinical performance. As companies develop a culture
of quality and a focus on continuous improvement, firms should evaluate
parameters that may limit process capability and conduct data analysis to
understand, control, and monitor those factors. The same core values apply to
companies of all sizes making all products.
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Cover Story:Obstacles To Innovation
a situation where a country needs to in-
crease the amount of a vaccine it buys,
Vinther explains. The manufacturer may
have sold out of that particular version
of product, so it may offer another ver-
sion that the country hasn’t approved yet.
Typically, the country will then expedite
approval, but the manufacturer may not
have enough of that version of product
left over to meet other customers’ needs,
forcing it into firefighting mode.
In other cases, one set of quality tests
can be effectively run on the plant floor,
while, for other markets, the same tests
on that product must be done in the lab-
oratory, says Seymour. The innovation
was adopted to improve efficiency, yet
the result is the opposite.
There isn’t a regulatory agency in ex-
istence that doesn’t support continuous
improvement, in concept. As Vinther
says, EMA regulations explicitly require
it. However, regulators may send mixed
messages. The same submission, con-
taining identical data, can receive very
different assessment from major regula-
tory agencies, resulting in the need for
fragmented implementation or duplica-
tive effort. “It is time for more harmoni-
zation amongst regulators world wide,”
says Vinther.
In the worst case, tradition may win
over good science when regulators as-
sess new technology. Jornitz recalls a
gloveless, robotic isolator-based filling
system, which came under regulatory
scrutiny because it did not allow set-
tling plates to be installed for environ-
mental monitoring.
As he notes, there is no need for tra-
ditional environmental monitoring in
a sterile, enclosed system. “You have to
be in control of your process, and not
rely on dated environmental technol-
ogy,” he says.
Another example Jornitz cites is the
European regulatory requirement that
sterilizing grade filters undergo integ-
rity tests before use and after steril-
ization. Testing is used to determine
whether a flaw occurred, which might
not be found in the post-use test due to
blocking of the filter. As Jornitz says,
the filters are scaled not to block, and
are commonly used to filter clean so-
18 Pharmaceutical Technology AUGUST 2017
lution. The Committee for Proprietary
Medicinal Products guidelines set in
April 1996 established a maximum al-
lowable bioburden of 10 colony form-
ing units per 100 mL in front of the
sterilizing filter. “There is typically no
chance that the filter will block, yet
regulators insist on the pre-use and
post sterilization test, which increases
potential risk to the patient because
the test requires manipulation of the
filtrate side,” Jornitz says.
Slow road to adoption
Bearing witness to the challenges of
adopting more modern technologies is
single-use process equipment, which,
Jornitz says, took 15–20 years to gain
acceptance in pharma, but is now
widely used. Rapid microbial monitor-
ing (RMM), which has been around for
about as long as single use, is being used
by some pharmaceutical companies, and
has received support from regulators, but
still isn’t widely applied. For many com-
panies, Jornitz says, there is a fear of the
double-edged sword, and regulators re-
quiring that the old technology be used
along with the new.
FDA and other regulators have in-
creased staff training., FDA has moved
to a team-based approach (See Sidebar)
to help make reviews and inspections
more consistent.
The role of emerging technologies
In addition, FDA established an Emerg-
ing Technologies Team (ETT) in 2014 to
help companies address concerns about
new technologies and the impact that
they might have on applications or post-
approval changes (See Sidebar). The
team promotes early engagement with
firms, for both new and legacy products,
to discuss potential challenges to imple-
mentation of new technologies and pos-
sible paths to resolution. “With early en-
gagement, the agency can move quickly
to review and act on supplements for im-
plementation of newer technology,” says
Lawrence Yu, deputy director, Office of
Pharmaceutical Quality, Center for Drug
Evaluation and Research at FDA.
Seymour’s team has met with ETT
in connection with Biogen’s candidate
P h a r mTe c h . c o m
Alzheimer’s therapy, which has been fast
tracked for approval. “It has been an en-
lightening experience. The team is open
and collaborative. We’ll have to wait to
see how everything plays out when we
file for approval, but the interactions
have been positive,” she says.
Vinther sees the team’s existence as a
positive development, but, as he notes, “It
doesn’t help if FDA can review a post-
approval change in four months, but it
takes the world five years and, in the
meantime, we have to deal with all these
different technologies and product ver-
sions at the same time.”
One of the reasons for the disconnect
between manufacturers and regulators
may be the huge difference in focus, he
says. “Manufacturers, by definition, must
think about the whole world of markets
they sell to, where regulators must think
nationally, and of protecting the health
of people in their own countries.”
Blaming the regulators is no solution,
he says. “The industry needs to do things
better, to ensure that our systems work
better and that we are better at forecast-
ing and preventing drug shortages.”
“If we could get all the regulators to
work together that would be a great help
and would allow us to innovate,” he says,
but he senses that some regulatory au-
thorities may not trust each other. “If
regulators with a ‘Strict Regulatory
Agency’ grade (the highest grade) from
the World Health Organization see a
process change as being benign or ben-
eficial, why can’t the others?” he asks.
Besides, Vinther says, most post-ap-
proval changes eventually go through.
“The International Federation of Phar-
maceutical Manufacturers and Associa-
tions surveyed leading vaccine compa-
nies and found the success rate was over
99%. Can’t we at least reduce the number
of filings required by 50-70% by doing a
thorough risk assessment?” he asks.
Rejecting innovation to save money
can be the first step to neglecting fa-
cilities, milking processes but failing to
maintain them, says Jornitz. That may
result in shortages when there is only
one manufacturing site supplying a vital
drug. Once a process and facility reach a
certain level of aging, they can go into a
death spiral. An example could be Benv-
enue Labs, where $300 million in invest-
ments proved to be too little too late. f
But companies have also created the
impasse in pharmaceutical moderniza-
tion, says Agalloco. “Comparability and
crossover studies are costly and difficult,
but you cannot blame the regulators, but
yourselves for not having enough con-
viction in the technology itself or proof
of its performance,” he says, “because
there can be major financial incentives
for using new technologies. Failing to use
any is just a big excuse. You have to take
some risks, just not huge ones.”
Besides, there may be some innovative
technologies that remain unknown, even
though they’ve matured to a point where
they could be used. “Nobody will touch
them until FDA says it’s okay, and FDA
cannot approve them until someone files
a new drug application specifying their
use, so it’s a Catch 22,” he says.
Pharmaceutical companies have to
incorporate innovative manufactur-
ing practices, to lower cost and pro-
duce the highest quality products, says
Girish Malhotra, president, EPCOT In-
ternational. Regulators suggesting the
“how and what” of innovation, he says,
is putting the cart before the horse.
“Innovative technology implementa-
tion is a team effort between regulators,
the industry and suppliers. We need to
work hand in hand if pharma is to be-
come as technologically advanced as
other industries are,” says Jornitz. “Be-
sides,” he says, “a whole new industry,
cell and gene therapy, will require re-
thinking many areas, and the adoption
of new technologies for the future.”
“For now, the key to resolving this
problem,” Vinther says, “is to take all
politics and emotion out of this issue
and base discussions purely on science.”
“We need to provide regulators with
tools and assurance to prove, with solid
data, that we have the capabilities within
our organizations to make changes,” says
Seymour. “There’s a responsibility to put
the tools out there for organizations to
use, to be able to manage change consis-
tently and appropriately,” she says.
References
1. L. Abboud, and S. Hensley, “New Prescrip-
tion for Drug Makers: Update the Plants,”
wsj.com, September 3, 2003, www.wsj.com/
articles/SB10625358403931000
2. ICH Q12 Position Paper, ich.org, www.
ich.org/fileadmin/Public_Web_Site/
ICH_Products/Guidelines/Quality/Q12/
Q12_Final_Concept_Paper_July_2014.
pdf PT

Inside FDA’s Emerging Technologies Team with Team Chair, Sau Lee
FDA established an Emerging Technologies Team (ETT) in 2014, to optimize
decisions about technologies that haven’t been widely used in the industry
previously. The team can help companies considering the use of a new tech-
nology, and also serves as a resource for inspectors and reviewers within the
agency who may be unfamiliar with a new technology. Team chair, Sau Lee,
describes the reasons for the team, and its structure.
PharmTech: Which specific technologies is the team focusing on?
Lee: The ETT does not identify technologies a priori. Technologies under
consideration are based on industry applications to the Emerging Technology
Program. Applications to the program are evaluated to assess whether the
proposed technology has the potential to improve product safety, identity,
strength, quality, or purity, or whether the technology includes one or more
elements subject to quality assessment for which the agency has limited
review or inspection experience.
PharmTech: When would a company get in touch and how? And how does
the team interact with review and inspection departments?
Lee: The Emerging Technology Program takes a collaborative approach to
engagement on the topic, both internally and externally. The ETT’s chair and
members are drawn from across FDA and bring a wealth of technical expertise,
regulatory insight, and institutional knowledge and experience to the group.
Industry participants in the program work with ETT early in the technology
development process, discussing progress and challenges and addressing
technical and regulatory concerns in advance of submitting a drug application
for FDA’s evaluation. They benefit from the program by drawing upon FDA
expertise and resolving many questions prior to submitting an application.
FDA benefits by learning about a new technology in advance of its first
appearance in an application for review and inspection, and the public will
benefit through improved access to high-quality medications.
In order for the ETT to ensure consistency, continuity, and predictability in
review and inspection-based science, the team engages in many facets of
product development and submission of a marketing application. It starts
with early engagement in the pre-submission phase.
A key opportunity for pre-submission engagement, in addition to face-
to-face meetings, is the pre-operational visit. This provides a venue to cover
technical and facility aspects in more detail and enhances shared learning
and communication. During the assessment of the regulatory application, the
ETT member will serve as the co-lead for the assessment, ensuring continuity
from the pre-submission phase. Finally, ETT is also involved in the pre-
approval inspection which is conducted by team members from FDA’s Office
of Pharmaceutical Quality and Office of Regulatory Affairs.
PharmTech: What response have you seen from industry so far? ?
Lee: Industry has started to be more engaged and open to FDA regarding
innovative technologies under the Emerging Technology Program. We have
seen an increasing number of industry proposals requesting participation in
the program.
PharmTech: What is the team doing to help with reviews of post-approval
changes?
Lee: ETT is involved and helps with the review when the change involves
the implementation of a new technology that meets the program’s criteria.
A good example is the approval for switching from a batch to a continuous
manufacturing process in April 2016 for an FDA-approved HIV drug, Prezista.
The change was requested in a supplement that was reviewed and approved
in less than four months.
PharmTech: What are the plans for the team, both short- and long-term?
Lee: In the short-term, ETT will continue to work with industry to
implement emerging technologies, and internally, to strengthen the program
management and our internal research program to support the increasing
ETT workload and requests for participation. In the long-term, ETT will be
engaging regulatory agencies in other countries to help promote international
cooperation.

Pharmaceutical Technology AUGUST 2017 19

 API Synthesis & Excipients
Optimizing
Cell-Culture Media
Cynthia A. Challener
Media manufacturers are focused on
reducing risk, improving quality
and consistency, and managing costs.
I
ncreased competition, the diversifi-
cation of biologic drug substances,
and globalization of manufacturing
have accentuated the need for pro-
cesses that are not only compatible
with modular, flexible, smaller plants
but also carry reduced total costs.
Continuous and intensified processing
is an attractive alternative that fits the
needs of current and future manufac-
turing requirements.
Cell-culture media directly impact
the performance of upstream bioman-
ufacturing processes; they dictate the
potential productivity and reproduc-
ibility of specific processes while also
influencing product quality attributes,
according to Andrew Bulpin, head of
process solutions for MilliporeSigma.
“Cell-culture media must be optimized
for each process, particularly perfusion
processes and fed-batch systems that
support higher profile fed-batch pro-
cesses designed to minimize cost and
speed development,” he observes.
Cynthia A. Challener is a contributing
editor to Pharmaceutical Technology.
20 Pharmaceutical Technology AUGUST 2017
Measurable media impact
In addition to the cell line and cell-cul-
ture process parameters, cell-culture
media is a key driver of bioproduction
processes. Cell-culture media can have
significant impacts on cell growth and vi-
ability and also drive protein production
and protein quality, according to James
Brooks, manager of worldwide media
services and media development for BD.
While significant time and effort
are invested in the generation of an
optimal cell line—from transfection
to isolation and cloning, to full char-
acterization—it is often the case that
little thought is given to selection of
the optimal medium for the clone, ac-
cording to Brooks. He also notes that
sub-optimal formulations have been
shown to have deleterious effects on
bioproduction processes and limit the
potential of cell lines.
Cell-culture media provide not only
nutrients to the cell, but stimulatory
and regulatory effects. “Media can
impact cellular signaling pathways
and be involved in the regulation of
enzymatic activity within the cell,”
P h a r mTe c h . c o m
Brooks explains. For example, metals
contained within media formulations,
such as manganese, copper, and iron,
can serve as co-factors for enzyme ac-
tivation and play a key role in driving
protein titer and protein quality. In ad-
dition, sufficient levels of amino acids
are required for normal cell growth and
function, but also for the production of
the correct target protein,” Brooks says.
“Limitations in the amino acid composi-
tions in some chemically defined (CD)
media formulations have been shown to
result in amino acid substitutions and
the generation of sequence variants of
the target proteins,” he says.
Customized media is important
The inherent diversity and complexity of
animal cells limit the applicability of a
universal cell culture media that can be
used across all different production pro-
cesses with optimal performance. Each
cell line is unique, and to achieve its full
potential, it is imperative to match an
individual cell line with the optimal cell-
culture medium that specifically meets
its metabolic requirements.
From the isolation of Chinese ham-
ster ovary (CHO) cells into culture in
the 1950s, Brooks notes, the cell line
has diverged significantly, giving rise
to a multitude of CHO subtypes and
lines used for bioproduction today.
“Each CHO subtype and each indi-
vidual clone has its own specific nu-
tritional and metabolic requirements.
Through a medium optimization pro-
cess, these requirements can be met,
allowing the cell line to reach its full
potential,” he explains.
“Customization of a cell-culture me-
dium requires the right tools and a spe-
cialized team of experts that can guide
clients in the right direction and/or
modify an existing formulation or de-
sign a new one if necessary in a mini-
mum amount of time,” states Bulpin.
JARUN ONTAKRAI/SHUTTERSTOCK.COM
Facing the challenges
of chemically defined media
Companies have been moving toward
the use of chemically defined media
to avoid the potential contamination
issues associated with animal-derived
ingredients. They have been challenged,
however, to achieve the increasingly
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API Synthesis & Excipients
higher volumetric productivity levels
now expected for fed-batch systems, ac-
cording to Bulpin. “Chemically defined
media are not necessarily the optimal
process solution,” Brooks agrees.
Nutritional limitations in chemi-
cally defined media formulations
have been shown to impact protein
titer and protein quality. Additionally,
chemically defined does not mean
chemically pure, according to Brooks.
“Contaminants in CD media, such
as trace elements present in vitamin
stocks and some salts, have been re-
peatedly shown to impact cell-culture
processes, particularly protein qual-
ity,” he says. Multiple companies have,
in fact, published information where
trace element contaminants in their
CD formulations have impacted their
monocolonal antibody (mAb) titers
or glycosylation profiles, according to
Brooks. “This issue is particularly per-
tinent in the development of biosimilar
mAbs, where it is critical to match the
quality parameters of the originator
molecule,” he adds.
Bulpin notes that nutrients that were
traditionally supplied with complex so-
lutions such as hydrolysates need to be
now supplied as individual chemically
defined chemicals. Some of these nutri-
ents, such as cysteine and tyrosine, have
a maximum solubility and stability level
below the concentration requirements
for optimal performance. “In order to
overcome this issue, companies choose
different strategies; most commonly,
feed solutions are divided in multiple
parts, often with extreme pHs, and
clients need to add them separately to
the bioreactor, leading to potential un-
wanted pH shifts,” says Bulpin.
MilliporeSigma developed a single-
feed concept in which the nutrients are
concentrated to more than 130g/L, al-
lowing a reduction of the volume of feed
added to the medium and thereby in-
creasing the volumetric productivity. The
feed is added at neutral pH using a simple
reconstitution protocol and high solubil-
ity, according to Bulpin. It also contains
cysteine and tyrosine derivatives that
have been shown to release free cysteine
and free tyrosine slowly throughout the
culture. “This time-dependent release
avoids tyrosine depletion, which can
lead to sequence variants. It also results
in free cysteine release while maintain-
ing a reduced redox environment, which
has been related to higher cell growth and
productivity,” Bulpin says.
Poloxamer-188, which has tradi-
tionally been available from only a
single supplier, is a specific cell-culture
ingredient that has caused difficulties
in biopharmaceutical manufacturing
in recent years. “Significant numbers
of lots have resulted in toxic or low
shear stress-protectant effects for cells,”
Bulpin explains. MilliporeSigma de-
veloped an analytical test that allows
the identification of the desire variety
of poloxamer-188 and is employed by
the company to validate each lot of po-
loxamer-188 to be used in cell-culture
media. In addition, MilliporeSigma
worked intimately with an alternative
manufacturer and has validated this
producer as a second supplier for po-
loxamer-188, according to Bulpin.

Nominations open for 2017 CPhI Pharma Awards

Entries are now being accepted for the 2017 CPhI Pharma Awards, which recog-
nize pharma industry innovation across a record 20 categories of bio/pharma-
ceutical development, manufacturing, management, and distribution.
The awards program, now in its 14th year, honors companies and individuals
driving the pharma industry forward through innovations, technologies, and
strategies. More than 100 entries were submitted in 2016, and the organizers
expect greater interest in 2017. CPhI Worldwide, UBM, organizer of the awards
program, announced the 2017 awards categories and deadlines in a July 7, 2017
press statement.
The awards were expanded to 20 categories for 2017 to accommodate the
increased demand from companies across the full spectrum of pharma and to
reflect the increased diversity of attendees at CPhI Worldwide.
Separate awards will be presented for innovation in formulation and ex-
cipients. New categories have been created to evaluate company performance
by size. An award for sustainability practices, such as green chemistry and sus-
tainable manufacturing, has been introduced. To reflect the expansion in new
markets by CPhI Worldwide customers, an award for export promotion has
been added. Awards for excellence in over-the-counter drugs, patent centricity,
and IT, mHealth, and Digitalization also have been added.
The awards categories for 2017 are:
• Excellence in Pharma: API Development
• Excellence in Pharma: Formulation
• Excellence in Pharma: Manufacturing Technology and Equipment
• Excellence in Pharma: Bioprocessing
• Excellence in Pharma: Analysis, Testing, and Quality Control
• Excellence in Pharma: Drug Delivery Devices
• Excellence in Pharma: Packaging
• Excellence in Pharma: Supply Chain, Logistics, and Distribution
• Excellence in Pharma: Contract Services and Outsourcing
• Excellence in Pharma: Regulatory Procedures and Compliance
• Excellence in Pharma: Corporate Social Responsibility
• Excellence in Pharma: CEO of the Year.
Categories added for 2017 include:
• Excellence in Pharma: Excipients
• Excellence in Pharma: Pharma Company of the Year–Large
• Excellence in Pharma: Pharma Company of the Year–SME
• Excellence in Pharma: Sustainability Initiative of the Year
• Excellence in Pharma: Export Promotion
• Excellence in Pharma: OTC
• Excellence in Pharma: Patent Centricity
• Excellence in Pharma: IT, mHealth, and Digitalization.
Awards entry and judging
The deadline for entries has been extended to Aug. 25, 2017. Applications must
be submitted via the CPhI Pharma Awards site, http://awards.cphi.com/.
Finalists will be announced Sept. 11, 2017. Winners will be announced at the
CPhI Pharma Awards Gala Dinner on Oct. 24, 2017 during the CPhI Worldwide
event, scheduled for Oct. 24–26, 2017 in Frankfurt, Germany.
CPhI Worldwide and Pharmaceutical Technology are UBM plc brands.
—The editors of Pharmaceutical Technology

22 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m

Growing interest in peptones
The issues with chemically defined formulations are creat-
ing a renewed interest in peptone supplementation for cell-
culture media across the biopharma industry, according to
Brooks. “While chemically defined remains the ultimate
desire, peptones continue to be used as cell-culture media
supplements to enhance production and protein quality,” he
says. “Peptones are well-characterized and long-established
cell-culture supplements and feeds that can enhance cell
growth and/or protein titer while helping maintain or achieve
desired protein quality. The rich composition of peptones en-
ables them to serve as an optimal nutritional source for cell
culture. Peptones have also been shown to inhibit apoptosis
and positively affect cell cycles,” Brooks adds.
Suppliers expand service offerings
Lonza adds flexible biomanfacturing capabilites
Lonza announced on July 26, 2017 that the company began construction
in Visp, Switzerland on a new biomanufacturing complex, Ibex Solutions,
which features a biological development and manufacturing concept that
combines flexibility in facility build-out with tailored business models that
leverage the company’s expertise and service network.
Ibex biomanufacturing comprises a modular, technology-independent
development and manufacturing complex that can support multiple tech-
nologies, including mammalian, microbial, cellular, or bio-conjugates, as
well as activities for late discovery to manufacture. This flexibility allows
for freedom in facility design and implementation as well as the ability to
respond rapidly to changing needs, the company reports.

The need for perfusion solutions Avantor opens API and raw materials lab
The continued move toward perfusion-based production has Avantor, a supplier of APIs and raw materials, has opened a new research
highlighted the need for more optimally designed formula- center in Bridgewater, NJ, to help biopharmaceutical and pharmaceuti-
tions that can support the perfusion process. “It is a challenge cal customers with upstream and downstream processes, from gene to
to achieve steady-state, high-density cultures while maintaining protein expression through final formulation and drug delivery. The cen-
consistent product quality. Most media formulations today are ter includes life sciences and advanced materials research tools, including
not designed for this application,” states Brooks. The overall cost cleanroom facilities, multiple mass spectrometers, specially constructed
of the base medium for perfusion processes is also a concern. bioreactors, and particle size analyzers.
With higher perfusion rates and medium exchange rates as fre- —The editors of Pharmaceutical Technology
quent as 1–2 times per day, significant volumes of media can be
consumed during a perfusion process. “It is therefore essential
to have a medium that can achieve the desired growth, titer,
and quality parameters within a cost-effective and manageable
process,” Brooks asserts.
In response to this need, MilliporeSigma developed and re-
cently introduced a medium specifically for use in perfusion
processes. It is designed to reduce the medium exchanges per
day in a perfusion process while maintaining or even increasing
specific productivity and product quality, according to Bulpin.

Achieving acceptable protein quality

MilliporeSigma expects biopharmaceutical industry needs
for intensified fed-batch and perfusion processes and for high
control over protein quality attributes to continue to increase,
according to Bulpin.
Brooks agrees that protein quality continues to be a major
concern and focus in the industry—particularly given the
increasing numbers of biosimilars and biobetters in develop-
ment—and must be considered when developing cell-culture
medium formulations. “The best way to make sure the formula-
tion in use provides acceptable protein quality, such as N-glycan
or charge-variant profiles, is to optimize the formulation spe-
cifically to match the cell line metabolic requirements,” he says.
Protein quality supplements designed to modulate quality
parameters following addition to existing cell-culture base
media, are also beginning to emerge in the market, according
to Brooks. “The most efficient way to achieve the desired protein
quality parameters, however, is through the development and
customization of the cell-culture medium to the specific cell
line in use,” he stresses. PT
Pharmaceutical Technology AUGUST 2017 23
Formulation
Targeting Drug
Delivery with ADCs
A Q&A by Adeline Siew, PhD
Safe and effective drug targeting
with ADCs requires careful selection
of drug, antibody, and linker.
A
ntibody-drug conjugates (ADCs)
are targeted therapies that com- signed to incorporate highly potent,
bine a specific antibody or anti- normally intolerable, anticancer cyto-
body fragment linked to a drug. This
drug targeting approach has enabled
better tumor penetration with less
side effects in the treatment of cancer.De-conjugation of the drug–linker
Developing ADCs, however, requires
careful selection of drug, antibody,
and linker. David Simpson, CEO
of Glythera, and Ian Evetts, com-
mercial director of Glythera, spoke
to Pharmaceutical Technology about
the challenges involved in optimal
ADC design.
Key considerations
in ADC development
PharmTech: In ADC development, what
are the key considerations when select- of mid-potency
ing the drug, antibody, and linker?
24 Pharmaceutical Technology AUGUST 2017
Glythera: ADCs are generally de-
toxics; assuming, of course, that the
resulting ADC construct is a stable
entity with no de-drugging potential.
component from the antibody outside
of the cancer cell is the main driver of
an ADCs toxicity and adverse event
profile. ADC stability is solely con-
trolled by the linker attachment chem-
istry. With stable attachment chemistry,
highly potent payloads can be selected
with confidence, enhancing cell kill po-
tential. Although there is also premise
to combine antibodies to mid-potency
agents, especially where the antibody
itself has anti-tumor effects, the use
payloads is generally
uncommon amongst ADC innovators.
P h a r mTe c h . c o m
Drug selection. Preclinical studies
aligned with commercial consider-
ations suggest that criteria for the
ideal cytotoxic should include:
• High in-vitro potency (preferably
picomolar)
• Sensitivity of the cancer type to
the class of the cytotoxic (e.g.,
antitubulin agents are frequently
used in breast cancer)
• Pan-tumor activity, especially re-
lating to solid tumors
• Activity in multi-drug resistant
(MDR) models
• Ability to induce cell death (i.e.,
high toxicity).
The cytotoxic also should be chemi-
cally tractable and stable while bound
to the monoclonal antibody (mAb). In
addition, drugs must contain a suit-
able functional group for conjugation
and need to be stable under physio-
logical conditions. It is important that
therapeutically appropriate amounts
of the cytotoxic are linked to the mAb
to optimize the potential effectiveness
of the ADC once it reaches the target
cancer cell.
In general, we should avoid drugs
that are associated with neurotoxicity
(e.g., platinum-based therapies or vinca
alkaloids and first-generation taxanes).
The drugs currently being used
to construct ADCs generally fall
into two categories: microtubule in-
hibitors and DNA-damaging agents,
although other drugs such as poly-
merase II inhibitors are also under
investigation. Microtubule inhibi-
tors bind tubulin, destabilize mi-
crotubules, and cause G2/M phase
cell cycle arrest. DNA-damaging
agents include anthracyclines, cali-
cheamicins, duocarmycins, and pyr-
rolobenzodiazepines (PBDs). These
drugs function by binding the minor
groove of DNA and causing DNA
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stand scission, alkylation, or cross-
linking. The cytotoxins are highly
potent, with free drug IC50 of <10 -9 M.
Choice of target antigen. Tolerability
of an ADC is also affected by the spec-
ificity of antigen expression in cancer-
ous tissue vs. normal tissue; non-spe-
cific expression results in toxicity and
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Formulation
reduced efficacy due to a reduction in
the dose of conjugate available to the
tumor. Therefore, the ideal tumor an-
tigen must be specifically localized to
the tumor cell-surface to allow ADC
binding and, preferably, display dif-
ferential expression between tumor
and normal tissue, with increased ex-
pression in cancer cells.
Selecting the
right linker and
attachment
chemistry can
ensure maximum
cell-killing activity
by avoiding
de-drugging
and off-target
tolerability.
Antigen choice is also dictated by its
ability to internalize upon ADC bind-
ing. Internalization of an ADC occurs
through receptor-mediated endocy-
tosis followed by ADC degradation
in the lysosome, and this leads to free
drug release for effective cell killing.
However, endocytosis is not guaran-
teed for all cell-surface antigens, and
the rate of internalization can vary
considerably. Optimal drug release
into the cell requires minimal recy-
cling of the ADC to the cell surface as
well as enhanced delivery of an inter-
nalized antigen/ADC to the lysosome.
The ideal tumor antigen, then, should
be cell-surface expressed, highly up-
regulated in cancer tissue, internalized
upon ADC binding, and able to release
the cytotoxic agent inside the cell.
Antibody selection. Of course, an-
tibody selection also plays a critical
part in the success of an ADC. Of a
number of key attributes, high speci-
ficity for the tumor antigen is essen-
tial because an antibody that binds
26 Pharmaceutical Technology AUGUST 2017
non-specifically or cross-reacts to
other antigens can be taken up in
normal tissues, inducing toxicity as
well as elimination of the ADC before
it can reach the tumor. Efficiency of
uptake requires high affinity binding
to the target antigen (KD < 10 nM),
and antibodies should also be mini-
mally immunogenic. Ideally, antibod-
ies should also possess optimal phar-
macokinetic properties including
relatively long half-lives and slower
clearance in plasma.
Linker chemistry
PharmTech: Why is linker chemistry
important?
Glythera: We should clarify the role
of chemistry of the linker and the
chemistry used for attachment of the
drug–linker adduct to the antibody.
Linkers are generally selected based on
the preferred method for drug release
from the antibody (i.e., depending on
whether cleavable or non-cleavable
linkers are used). However, the attach-
ment chemistry used to conjugate the
drug–linker adduct to the antibody
determines the overall stability of
the ADC and is, therefore, crucial in
maximizing efficacy and minimizing
intolerability. So, although the selec-
tion of linker to attach to a drug is an
important factor in the manufacture
of an ADC, the ADC stability and,
hence, clinical performance is wholly
governed by selection of appropriate
attachment chemistry to attach the
drug–linker adduct to the antibody.
Selecting the right linker and attach-
ment chemistry can ensure maximum
cell-killing activity by avoiding de-
drugging and off-target tolerability.
ADC stability. Developed linkers
have all suffered from stability is-
sues largely due to use of maleimide
chemistr y for attachment of t he
drug–linker conjugate to the anti-
body, and reductions in drug: an-
tibody ratios (DAR) over time have
been shown for both cleavable and
non-cleavable linker formats. In
this situation, the drug–linker ad-
duct is cleaved before entering the
tumor cell, reducing the potency of
P h a r mTe c h . c o m
the treatment and releasing the cyto-
toxic drug into systemic circulation.
Several groups have focused on
enhancing the stability of ADCs
through stabilizing conjugation, al-
though most have concentrated on
next-generation maleimide chemistry
approaches, primarily via catalysis of
ring hydrolysis. Through control-
ling the microenvironment around
the succinimide thioether, stabil-
ity of maleimide conjugation can be
improved, because solvent accessible
sites slow down retro-Michael reac-
tions. If cysteine is close to positively
charged entities, rapid succinimide
hydrolysis occurs, preventing further
linker-maleimide exchange. Also,
modifying maleimide with the inser-
tion of an amine group can shift the
reaction through hydrolysis. How-
ever, these approaches don’t neces-
sarily lead to the desired reduction
in adverse events or to an increase
in in-vivo efficacy, at least for cleav-
able linker systems, for which less
obvious increases in exposure have
had no real impact on ADC efficacy.
Although ring-opening stabilizes the
conjugate, the long-term stability of
the ring-opened product is not pre-
cisely known. High pH conditions re-
quired for mild hydrolysis methods of
stabilizing conjugation induce uncon-
trollable de-drugging and asparagine
deamidation.
Recent advances
PharmTech: What recent advances have
you seen in linking technologies?
Glythera: A recent development of
linker systems has actually been fo-
cused on the conjugation platform
with a need to improve stability due to
significant advances in toxin potency
and the potential for off-target toxic-
ity. In addition, our improved under-
standing of the stoichiometry associ-
ated with maximal ADC efficacy has
re-focused innovation to alternative
conjugation solutions and, in particu-
lar, site-directed technologies.
A focus area for many major pharma
companies has been to improve the
tolerability of ADCs by reducing the
de-drugging potential of highly po-
tent toxins from the antibody, which
results in free and active drug capable
of circulating to alternative and off-
target sites. Recent developments have
included modification of existing ma-
leimide-based technologies to reduce
the potential for the retro-Michael re-
action in vivo, to the development of
fundamentally changed, novel chem-
istry solutions that no longer employ
the maleimide component, resulting
in significantly improved stability pro-
files and tolerability.
The ongoing innovation in toxin
development has improved both po-
tency and broad tissue type efficacy
resulting in the increased use of en-
gineered cysteines to overcome the
instability issues associated with
many of the approved platforms. In
addition, we see the development of
entirely novel approaches through al-
ternative conjugation targets, many of
which focus on the use of sugar-based ity. As the clinical pipeline has grown,
conjugation to the antibody which, by with more lead candidates requiring
definition, reduces the potential drug cGMP manufacturing, many contract
loading and, therefore, reduces the manufacturing organizations (CMOs)
risks associated with high levels of have been quick to adapt to the mar-
free drug and tolerability. ket needs through expansion of their
own biologics or chemistry capa-
Manufacturing challenges bilities with additional conjugation
PharmTech: Can you elaborate on the suites. However, as with all contract
manufacturing challenges for ADCs? manufacturing models, the ability to
Glythera: Bringing together biolog- undertake multiple manufacturing
ics and toxic payloads has presented campaigns using different toxins and
major challenges through the history antibodies presents its own challenges
of drug conjugates and more so now in terms of control and segregation.
with the rapid expansion of target With the advent of increasingly potent
products entering human trials, which cytotoxins used in the development of
require cGMP manufacturing. Drug ADCs, facility design and the contain-
substance manufacturing to date has ment systems have required significant
generally been achieved through the redesign to be able to cope with scale,
combined efforts of multiple partners demand, and operator safety. Work-
for the production of both the biolog- ing procedures have been a keen focus
ics and toxin chemistry components to reduce operator risk of exposure to
as drug substance and then their these toxins through either inhalation or
combination safely in a single facil- transdermal contamination. PT

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Pharmaceutical Technology AUGUST 2017 27

Topical Drug Manufacturing
Using QbD in
Topical Drug Manufacturing
Jennifer Markarian
Characterization of the product and process
is key for process development and scale-up.
A
topical drug is typically a semi-solid
formulation and may be a gel, cream,
lotion, or ointment. Other topical
dosage forms (e.g., powders, sprays, and
solutions) are beyond the scope of this
discussion. A quality-by-design (QbD)
approach can be used to develop an un-
derstanding of the process and identify
process parameters that will affect the
quality of the product. Pharmaceutical
Technology spoke with Jeffrey S. Reyn-
olds, associate director, Pharmaceutical
Sciences, at Tergus Pharma, a pharma-
ceutical research, development, testing,
and clinical manufacturing company
specializing in topical drug formula-
tion and in using QbD for drug product
design, about what to consider when
developing a manufacturing process for
topical drugs.
Early process development
PharmTech: What are the key considerations
for manufacturing of a topical drug?
28 Pharmaceutical Technology AUGUST 2017
Reynolds (Tergus): A suitable process
can be tricky to develop for a semi-solid
product, particularly in the early stages of
development when the product and pro-
cess may not be understood fully. The first
aspect of deciding how to proceed with
manufacturing is the type of semi-solid
dosage. A cream or lotion will require a
different approach for manufacturing
than a gel or ointment. The type of mix-
ing, the need for side vessels, heating, and
cooling are all aspects essential to iden-
tifying the appropriate starting point for
process development and subsequent
technology transfer for scale up.
In general, one must consider a num-
ber of process parameters and material
attributes to determine criticality and
associated acceptable ranges for those
critical parameters. Some parameters of
interest are process temperature, heat/
cooling rates, order of addition, mixing
type, mixing speeds, mixing times, level
of batch in tank, vacuum usage, inert at-
P h a r mTe c h . c o m
mosphere, and so on. There is no one set
of parameters that will be important for
every type of batch. For each product and
process, its design space requires a com-
prehensive understanding of the critical
process parameters (CPPs) and critical
material attributes (CMAs) as they per-
tain to critical quality attributes (CQAs)
of the drug product. Only then can the
quality of the technology transfer and end
product be guaranteed with a reasonable
degree of confidence.
PharmTech: When designing a manufac-
turing process for a topical drug, what are
some examples of CQAs and CPPs?
Reynolds (Tergus): The pre-development
phase of drug product development will
establish the quality target product pro-
file (QTPP). The QTPP defines the de-
sired end-product characteristics. These
characteristics may include disease state
to be addressed, dosage form, appear-
ance, aesthetic qualities, color, viscosity,
container/closure, drug concentration,
dispensing configurations, pH, and mi-
crobial considerations. The preceding list
is not intended as a complete or compre-
hensive listing of all attributes, but repre-
sents many of the quality attributes that
the drug product developer would con-
sider as part of the QTPP. Not all of these
characteristics ultimately will be critical.
However, the QTPP starts the process and
helps to ensure a development program
aligned with the desired end-product.
Many, but not all, of the attributes identi-
fied in the QTPP will become CQAs. The
criticality of a particular quality attribute
will arise during the development phase
as the understanding of the product and
process becomes more comprehensive
and complete.
Often, the initial QTPP will evolve
and the final QTPP may not be exactly
the same as the original one. It is a work
in progress and intended to be dynamic
document that facilitates interaction be-
tween R&D and marketing/sales. As the
RACOBOVT/SHUTTERSTOCK.COM
product development moves into under-
standing the process, the QTPP becomes
the guiding light in identifying which
process parameters are critical. Some of
the typical process parameters to consider
are mixing type, mixing speed, mixing
time, temperature ramps, need for nitro-
gen or argon blanketing, UV light pro-
tection, and so on. Again, this list is not
comprehensive, but it represents many of
the key process parameters that may be
critical to the final drug product quality.
Raw material variability
PharmTech: What challenges does raw
material variability present, and how can
these challenges be addressed?
Reynolds (Tergus): Raw materials or ex-
cipients in a semi-solid drug product can
be some of the more challenging param-
eters to evaluate. On the surface, it would
appear that a given material that meets
the United States Pharmacopeia (USP) or
European Pharmacopoeia (Ph Eur) mono-
graphs should be adequate to provide an
equivalent effect in the drug product, but
this is not necessarily true. In many cases,
one USP/Ph Eur excipient is as good as
another. Depending on the excipient,
however, the specific supplier of a mate-
rial may be a critical attribute. Addition-
ally, potential CMAs can include where
a specific test performed on the excipient
falls within the acceptable range. In other
words, for a material that routinely has
been used at the upper end of a specific
test range, it may not be suitable to use a
lot of material that comes in at the lower
end of the specification range.
Furthermore, the USP/Ph Eur mono-
graphs do not contain every critically
relevant test for the material and how the
material will behave in the drug product.
Oftentimes, the design space analyses
during development will reveal additional
CMAs beyond the specific compendial re-
quirements. For example, as many semi-
solid excipients are derived from fatty
alcohols and fatty acids, the chain length
distribution may influence the perfor-
mance of material in the drug product,
even to the extent of resulting in an unac-
ceptable product if the chain length shifts
to either the shorter or longer distribu-
tion. A clear example was the pastillation
of polyoxyl-2 stearyl ether. The original
form (block hot pour) gave acceptable
product, but the direct substitution of the
pastillated form resulted in poor emulsion
stability. Both met the requirements of the
USP, but only the original block form was
acceptable in the cream product.
Stability testing Reynolds (Tergus): The scale up and tech-
PharmTech: What are some of the consider-
nology transfer of a semi-solid drug prod-
ations for stability during storage and for
uct can be fraught with pitfalls and chal-
stability testing? lenges. There is no one size fits all (or even
Reynolds (Tergus): Drug product stabil-
most). Many of the challenges in scale-up
ity is guided by International Council for
arise from an inadequately understood
Harmonization requirements. Typically,
product or process, more specifically the
samples are stored at a variety of conditions
CMAs and CPPs. A semi-solid drug prod-
dependent upon the intended long-termuct that has well defined CMAs and CPPs
storage condition of the product. In other
typically has less challenges on scale-up.
words, if the drug product is intended for
Furthermore, when encountering chal-
room temperature storage while on shelf,
lenges, this knowledge of CMAs and
the stability study likely will have samples
CPPs gives the manufacturing team an
stored at 25 °C/60% relative humidity (RH),
enhanced chance of successfully overcom-
30 °C/65% RH, and 40 °C/75% RH. Theseing the challenges. Problems encountered
conditions are, respectively, the so-called
during the development phase along with
real time, intermediate, and accelerated
the design space analyses gives a better un-
conditions for most stabilities. Other con-
derstanding of how the materials and pro-
ditions relevant for alternative storage (re-
cess behave and their effects on the product
frigerated, frozen) will have a different set
performance. This is not to say that statis-
of conditions representing the real time,
tical experimental design is the answer to
intermediate, and accelerated storage.
everything. A well-defined and under-
The intervals chosen for testing typi-
stood product and process design space
cally include 1, 3, 6, 9, 12, 24, and 36
gives the best chance of overcoming any
months. Additional intervals often are
challenges during technology transfer and
included in the design to provide en-scale-up. To enhance the chances of getting
hanced statistical and regression evalua-
the right product on the first attempt, one
tion to assist in setting the initial expiry
must ensure the CMAs as identified dur-
term of the drug product. Furthermore,
ing the development program are matched
some studies, particularly early in the de-
or demonstrated as equivalent. Using the
velopment phase, may proceed only to the
same suppliers for each of the excipients is a
three-month interval. good starting point. The next step is to use
Once the stability schedule is defined,
the same type of manufacturing vessels as
selection of the testing requirements fol-
used in the design space work, but this is
lows. At a minimum, the CQAs should not always practical. Many contract manu-
be considered as part of the stability test-
facturing organizations (CMO) have only
ing requirements. Early development one or two types of equipment capable of
programs may evaluate only the activeproducing semi-solids. Selecting a CMO
pharmaceutical ingredient in the drugthat has the most similar (or identical)
product for the purposes of screening out
equipment will give the best probably of
unacceptable dosage prototypes. success on transfer. But what does one do
Once a product moves to the preclini-
when the equipment used in development
cal/clinical stage, the stability program will
is not available at commercial scale? Select-
include all tests that are stability indicating,
ing a manufacturing unit that has similar
that is tests that directly reflect those char-
mixing styles to what was used in the de-
acteristics that will limit the expiry term of
velopment program is the next best path
the product. Typically, these include the ac-
forward. Having an awareness of where
tive ingredient, related substances, viscosity,
the product will go for commercial manu-
pH, within container content uniformity,
facturing helps the development team to
and any ancillary stability indicating tests.
design a process suitable for the intended
CMO. None of these challenges should be
Tech transfer insurmountable provided the development
PharmTech: What are some key consid- scientists, formulators, and engineers have
erations in scaling up to commercial done a thorough job of characterizing the
manufacturing? product and process. PT
Pharmaceutical Technology AUGUST 2017 29
 Peer-Reviewed

Establishing Acceptance
Limits for Uniformity of
Dosage Units: Part Two

Pramote Cholayudth
The concept of sampling distribution of acceptance
value (AV) was introduced in Part One of this
article series. In Part Two, the author describes
how to establish the corresponding acceptance
limits for AV data for process validation batches,
the typical characteristics of AV distributions,
and finally, how to derive relevant constants
for AV control charts in annual product review
and continued process verification reports.
P
art One of this article (1) introduced the concept
of sampling distribution of acceptance value
(AV)—the only quality attribute in Uniformity
of Dosage Units (UDU). For different sample
sizes, such as n = 10 and 30, their AV distributions
will be different in pattern, thus resulting in different
critical AV values (i.e., values that have a 95% coverage
in the distributions where they are equal to 12.5 and
9.1 for n = 10 and 30, respectively). Such critical values
will be applied as AV acceptance limits instead of the
single United States Pharmacopeial (USP) compendial
limit of not more than (NMT) 15 (2). The key benefit
of the two working limits is to guarantee that no lot of
dosage unit products (i.e., tablets, capsules, etc.) with
poor quality is released into the market. Another key
application is to provide the acceptance limits dedi-
cated to the average values of AV data in, for example,
annual product review (APR) and continued process
verification (CPV), to evaluate if the overall process
capability index (CpK) across those between-lot data
is greater than 1.33 (understanding that the process
benchmark at lot CpK 1.33 is the baseline for construc-
tion of the AV distributions). In summary, Part One is
a discussion of the theory and key application of using
two release limits for routine release of lots of products.
Part Two describes how to establish the correspond-
ing acceptance limits for AV data for process validation
batches, the typical characteristics of AV distributions,
and finally, how to derive relevant constants for AV
control charts in, for example, APR and CPV reports.
AFRICA STUDIO/SHUTTERSTOCK.COM

Case studies using routine batch data in APR, with

discussion and illustrations, are also provided to dem-
onstrate the benefits of applying AV acceptance limits.

Acceptability constants (k) for various sample sizes

Submitted: Jan. 17, 2017
Accepted: Mar. 8, 2017
30 Pharmaceutical Technology
The following formula is used to compute the accept-
ability constants (k) for calculation of AV parameters
a nd const r uct ion of AV dist ribut ions for va rious
sample sizes:
AUGUST 2017 P h a r mTe c h . c o m
Peer-Reviewed

Table I: Acceptability constants computed on MS Excel spreadsheet. CI is confidence interval.

A B C D
Acceptability constant (k, 90%
1 Sample size (n) k (United States Pharmacopeia) k1 (90% CI, 99.9% coverage)
CI, 90% coverage)
2 10 2.53 2.4* N/A
3 30 2.03 2.0 4.05
4 60 1.89 – 3.77
5 70 1.87 – 3.73
6 140 1.79 – 3.58
7 B2 =(NORMSINV(1-(1-90/100)/2))*((1+1/A2)^0.5)*(((A2-1)/(CHIINV(90/100,A2-1)))^0.5) = 2.53
8 B4 =(NORMSINV(1-(1-90/100)/2))*((1+1/A4)^0.5)*(((A4-1)/(CHIINV(90/100,A4-1)))^0.5) = 1.89
9 B6 =(NORMSINV(1-(1-90/100)/2))*((1+1/A6)^0.5)*(((A6-1)/(CHIINV(90/100,A6-1)))^0.5) = 1.79
10 D3 =(NORMSINV(1-(1-99.9/100)/2))*((1+1/A3)^0.5)*(((A3-1)/(CHIINV(90/100,A3-1)))^0.5) = 4.05
11 * Approximately 88% coverage.

where,
Figure 1: Acceptance value (AV) distributions (n = 30, k = 2.00). k n-10 : acceptability constant for n = 10.
CpK is process capability index. NMT is not more than. Z 0.9 : Z score for 90% coverage = 1.645 (2-tailed).
r20.9,10-1 : chi square for 90% confidence interval with 10-1
5.5%
or 9 degrees of freedom = 4.168; where in Microsoft (MS)
5.0% Simulated AV Distribution: Dist.
4.5%
Mean = 7.44, Lot CpK = 1.33 Excel, chi square (n = 10) =CHIINV(0.9,10-1) = 4.16816.
4.0%
Theoretical AV Distribution: Dist.
3.5% Mean = 7.44 Table I provides a short summary on acceptability con-
Frequency

3.0%
Note: Coverage for AV ≤ 9.1 = stants (k) for those sample sizes relevant to this article.
2.5%
95.05% i.e, about 95% of AV
2.0% data are NMT 9.1

1.5% Construction and simulation of AV distributions

1.0% for sample sizes other than n=10 or 30
0.5%
The samples sizes 70 and 140 are normally taken for
0.0%
validation UDU testing plans 30/70 (i.e., n = 30 and 70
00

50

00

50

0
50

00

50

00

00

0
00

50

0
50

.0

.5

.0

.0
.0

.5

.5

.5
4.

5.

6.

8.
4.

5.

6.

8.

9.
7.

9.
7.

10

10

12

13
11

11

12

13

Acceptance Value (AV) in stage 1 and 2, respectively) and 60/140, respectively.

Sampling plans should be chosen based on product qual-
ity risk (e.g., 60/140 testing plan is used in highly potent
low-dose products such as hormone products).
1 n 1 Construction and simulation of AV distributions for
k = Z0.9 1+ 2 such sample sizes is executed in the same way as Part
n 0.9,n 1
[Eq. 1] (3) One using the corresponding acceptability constants (k)
where in Table I. Figures 1–4 illustrate the simulated and theo-
k : tolerance factor (acceptability constant) retical AV distributions for n = 30,70, 60, and 140, re-
Z0.9: Z score for 90% coverage (p = 0.90) = 1.645 (2-tailed) spectively. According to the figures, Table II provides a
n : sample size summary on the working acceptance limits for AV data
n – 1 : n-1 degrees of freedom and AV average data for relevant sample sizes.
ALL FIGURES ARE COURTESY OF THE AUTHOR.

r20.9,n-1 : chi-square for 90% confidence interval with n-1

degrees of freedom. Typical characteristics of AV distributions
AV distributions in general have the typical characteris-
The acceptability constant (k) is in fact called “toler- tics and applications as follows:
ance factor” in statistical textbooks with its expression in • Distribution pattern: The distributions look approxi-
Equation 1. For example, if n = 10, k is computed as follows: mately normal especially for larger samples (n ≥ 30,
Figures 1–4). However, upon analysis of AV = M x + ks
1 10 1 expression (2), AV is partly a function of standard
k n=10 = 1.645 1+ = 2.53 deviation (s) where its distribution is non-normal.
10 4.168
Therefore, according to the expression, AV distribu-
tions are also non-normal.
32 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
 • AV acceptance limit: The critical AV values at ap- Figure 2: Acceptance value (AV) distributions (n = 70, k = 1.87).
proximately 95% coverage in the distributions are CpK is process capability index. NMT is not more than.
established as the working AV acceptance limits
as shown in Table II. 5.5%

• AV average acceptance limit: The means of AV 5.0% Simulated AV Distribution: Dist.

Mean = 6.99, Lot CpK = 1.33
distributions may be established as AV average 4.5%

4.0%
acceptance limits as shown in Table II. Theoretical AV Distribution: Dist.
3.5% Mean = 6.99
• Standard AV distribution: When individual AV

Frequency
3.0%

data are divided by their distribution mean, the 2.5%

Note: Coverage for AV ≤ 8 =
95.23% i.e, about 95% of AV
new distribution of “AV/Mean” ratio data will be 2.0% data are NMT 8

similar in shape (not identica l) to the origina l, 1.5%

1.0%
with its mean equal to one (1.00). Figure 5 illus- 0.5%
trates and confirms the validity of the ratio dis- 0.0%

tributions for sample size n = 70 by comparison

85

15

45

75

05

35

65

95

25

55

85

15

45

75

05

35

65

95

5
.2

.5
4.

5.

5.

5.

6.

6.

6.

6.

7.

7.

7.

8.

8.

8.

9.

9.

9.

9.

10

10
between the theory and simulation. Acceptance Value (AV)

Furthermore, when fixing the sample size but vary-

ing the lot CpK, the resulting ratio distributions will
be identical in shape to each other as illustrated in Fig-
ure 6. In the figure, the distributions for sample sizes
n = 30, 60, 70, and 140 with ver y different lot CpK
values (1 versus 10) are illustrated. Such an identical-
Figure 3: Acceptance value (AV) distributions (n = 60, k = 1.89).
CpK is process capability index. NMT is not more than.
5.5%

ity in the so-called standard AV distributions will be 5.0% Simulated AV Distribution: Dist.
Mean = 7.06, Lot CpK = 1.33
4.5%
useful for AV control chart construction. 4.0%
Theoretical AV Distribution: Dist.
■ AV chart factors (constants): One of the key ap- 3.5% Mean = 7.06
Frequency

plications of standard AV distributions is to es- 3.0%

Note: Coverage for AV ≤ 8.2 =
tablish AV chart factors (i.e., lower control limit 2.5%
95.74% i.e, about 95% of AV
2.0% data are NMT 8.2
[LCL] and upper control limit [UCL] factors) for
1.5%
AV charts. The factors can be easily computed 1.0%

using control chart principles (i.e., mean±3SD 0.5%

[4]). For example, n = 10; LCL = mean-3SD = 0.0%

75

09

43

77

11

45

79

13

47

81

15

49

83

17

51

85

1
1-3x0.237* = 0.29, UCL = mean+3SD = 1+3x0.237*

.1

.5

.8

.2
4.

5.

5.

5.

6.

6.

6.

7.

7.

7.

8.

8.

8.

9.

9.

9.

10

10

10

11
= 1.71 (* SD pooled = ((0.234^2+0.239^2)/2)^0.5 = Acceptance Value (AV)

0.237). The identicality in smaller samples, such

as n = 10, has a minor deviation (i.e., different
SDs) (see Figure 7).
Justification of AV acceptance limits
As explained in Part One, “ … Such a 95% coverage will
Figure 4: Acceptance value (AV) distributions (n = 140, k =
1.79). CpK is process capability index. NMT is not more than.
5.5%

also confirm that the minimum validation sample size 5.0% Simulated AV Distribution: Dist.
Mean = 6.7, Lot CpK = 1.33
4.5%
n = 30 is justified. For n = 70 or the other validation 4.0%
Theoretical AV Distribution: Dist.
sampling plans such as 60/140, all the coverages will be 3.5% Mean = 6.7
Frequency

100%. … ” (1). In Part Two, Figures 8–9 provide the 3.0%

Note: Coverage for AV ≤ 7.4 =
illustrated evidence, through Bergum simulation test 2.5%
95.72% i.e, about 95% of AV
2.0% data are NMT 7.4
results (5–7), to such 95% coverages.
1.5%

1.0%

Application in validation batches 0.5%

The key applications of AV and AV average acceptance 0.0%

20

40

60

80

00

20

40

60

80

00

20

40

60

80

00

20

40

60

80

00

limits relevant to process validation acceptance criteria

5.

5.

5.

5.

6.

6.

6.

6.

6.

7.

7.

7.

7.

7.

8.

8.

8.

8.

8.

9.

Acceptance Value (AV)

are as follows.
Acceptance criteria 1: AV data. For sampling plan n ≥ 70
with testing plan 30/70:
• Stage 1 (n = 30): AV result is NMT 9.1. If exceeded
(see acceptance criteria 2), go to stage 2.
• Stage 2 (n = 70): AV result is NMT 8.0.
For sampling plan n ≥ 140 with testing plan 60/140:
• Stage 1 (n = 60): AV result is NMT 8.2. If exceeded
(see acceptance criteria 2), go to stage 2.
• Stage 2 (n = 140): AV result is NMT 7.4.

Pharmaceutical Technology AUGUST 2017 33

Peer-Reviewed

Table II: Summary of proposed acceptance value (AV) acceptance limits.

AV limits (95% AV chart factors (99.73% coverage)
Sample sizes (n) AV average limits 95% UCL factors
coverage) LCL factors UCL factors
Routine batches
10 9.0 12.5 1.39 0.29 1.71
30 7.5 9.1 1.22 0.60 1.40
Process validation (PV) batches
30 7.5 9.1 1.22 0.60 1.40
60 7.1 8.2 1.15 0.72 1.28
70 7.0 8.0 1.14 0.74 1.26
140 6.7 7.4 1.10 0.82 1.18
LCL: Lower control limit, UCL: Upper control limit. For information only.
Calculation example: n = 10, AV limit = 9.0x1.39 = 12.5
For AV charting purpose, AV average limits may be adjusted to 7.3 (12.5/1.71; n = 10) and 6.5 (9.1/1.40; n = 30) so that the UCL values will not exceed 12.5
and 9.1 respectively.

Figure 5: Standard acceptance value (AV) distributions calculated from x = 100.50 and s = 2.25. Tolerance interval
(n = 70, lot CpK = 1.33, same condition as Figure 2). (TI) = 100.5±4.05x2.25 = (91.39, 109.61). In this example,
99.9% of the dosage units in the lot will fall within the range
4.5% 91.39–109.61% of the label claim.
4.0% Simulated AV Ratio Distribution: An additional approach to the tolerance interval is to
Dist. Mean = 1, Dist. SD = 0.086
3.5%
Theoretical AV Ratio Dist.: Dist.
compute the percentage proportion (P) of the lot stay-
3.0% Mean = 1, Dist. SD = 0.086 ing exactly within the range 85–115% of label claim i.e.,
Note 1: UCL factor = 1.26, LCL
the lot coverage (8). Using the Z scores computed from
Frequency

2.5%
factor = 0.74 (99.73% Coverage)

2.0% Note 2: 90% UCL factor = 1.11 lot mean and SD estimates as appropriate, the probabil-
1.5%
Note 3: 95% UCL factor = 1.14
ity using MS Excel is that P = MIN(NORMSDIST(Z UU)-
1.0% NORMSDIST(ZLU),NORMSDIST(ZUL)-NORMSDIST(ZLL))
0.5% = MIN(NORMSDIST((115-101.52)/2.87)-NORMSDIST((85-
0.0%
0.712 0.784 0.856 0.928 1.000 1.072 1.144 1.216 1.288 1.360 1.432
101.52)/2.87),NORMSDIST((115-99.48)/2.87)-NORMS-
‘AV/AV Mean’ Ratio DIST((85-99.48)/2.87)) = 99.999867%.

where,
The expression will be employed using k con- In Excel, the upper bound for lot SD = 2.25*((30-1)/(CHI-
AV = M x + ks

stants in Table I as applicable. Based on the same coverage at INV(0.9^0.5,30-1)))^0.5 = 2.87 (square root of 0.9 or 90%
approximately 95% in Figures 1 and 8, a correlation may be confidence interval is used so that joint confidence in-
tied up and described that meeting the criteria for n = 30 will terval is 90%).
guarantee that at least 90% of the routine samples (Figure 8)
will meet the compendial (i.e., USP) acceptance criteria (i.e., if I n E x c e l , t h e u p p e r b o u n d f o r l o t m e a n =
AV result is 9.1, the probability would be 90% on average). For 100.5+2.87*NORMSINV(1-(1-0.9^0.5)/2)/30^0.5 = 101.52
sample size n = 70 as shown in Figures 2 and 9 (also practically (square root of 0.9 is also used with the same reason).
the same coverage at approximately 95%), it may be described
that at least 99.87% of the routine samples (Figure 9) will meet In Excel, the upper bound for lot mean = 100.5-2.87*NORM-
the compendial limit (i.e., if AV result is 8.0, the probability SINV(1-(1-0.9^0.5)/2)/30^0.5 = 99.48 (square root of 0.9 is
is 99.87%, which can be considered100%). also used).
Alternative to acceptance criteria 1: Tolerance interval. Because
AV is a special format of tolerance interval, the alternative ZUU and ZLU: Z scores computed from the upper and lower
is to demonstrate that 99.9%, for example, of the dosage limits (115 and 85) using the upper bound (UB) for lot
units in the process validation (PV) lot(s) will fall within mean (and UB for SD).
the range called tolerance interval (TI) calculated using the
expression TI = x ± k1s (3) where x is the sample mean, k1 is Z UL and Z LL : Z scores computed from the upper and
the tolerance factor (e.g., 4.05 for n = 30; Table I) and s is the lower limits (115 and 85) using the lower bound (LB) for
standard deviation. For example, AV result 4.5 (n = 30) is lot mean (and UB for SD).
34 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
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Peer-Reviewed
Figure 6: Standard acceptance value (AV) distributions (n = 30, If AV acceptance limits are met in combination, for ex-
60, 70, and 140). CpK is process capability index. ample, passing stage 2 in some batch(es), the average of all
AV data in stage 1 (both pass and fail) is required to meet the
6.0%
average limit for stage 1. The failure result is, therefore, also
5.5% N = 30, Lot CpK = 1, Dist. Mean = 1, Dist. SD = 0.132 taken into account, but it needs to be evaluated as follows:
N = 30, Lot CpK = 10, Dist. Mean = 1, Dist. SD = 0.132
5.0%
N = 60, Lot CpK = 1, Dist. Mean = 1, Dist. SD = 0.093
• For example, AV data (n = 30) for five PV batches are
4.5%

4.0%
N = 60, Lot CpK = 10, Dist. Mean = 1, Dist. SD = 0.093 4.5, 6.2, 7.1, 6.8, and 9.4* (* failing stage 1, [i.e., NMT
N = 70, Lot CpK = 1, Dist. Mean = 1, Dist. SD = 0.086
3.5%
N = 70, Lot CpK = 10, Dist. Mean = 1, Dist. SD = 0.086
9.1], but passing stage 2). The average is 6.8, (i.e.,
Frequency

3.0%
N = 140, Lot CpK = 1, Dist. Mean = 1, Dist. SD = 0.061 passing the average limit of NMT 7.5). Subsequently,
2.5%

2.0%
N = 140, Lot CpK = 10, Dist. Mean = 1, Dist. SD = 0.061
the average value will be used for calculation of lot
1.5% CpK on average (see true CpK estimation below) to
1.0%
pre-estimate the actual process benchmark. The cal-
0.5%

0.0%
culated acceptance range for this particular set of
0.568 0.640 0.712 0.784 0.856 0.928 1.000 1.072 1.144 1.216 1.288 1.360 1.432 1.504 1.576 1.648
‘AV/AV Mean’ Ratio
AV data is between 4.1 (6.8x0.60) and 9.5 (6.8x1.40);
the factors 0.60 and 1.40 are from Table II. Overall,
the data are acceptable because 9.4 (the maximum)
is also within the range. If the maximum data is out
Figure 7: Standard acceptance value (AV) distributions (n = 10). of the range, an investigation with further review
CpK is process capability index. and/or verification is required prior to releasing all
the PV batches.
Standard Acceptance Value (AV) Distributions
4.0% Special cases. In some groups of products, their process
3.5%
optimization is limited—i.e., the design is without auto-
N = 10, Lot CpK = 1, Dist. Mean = 1, Dist. mation (e.g., no automatic check-weighing unit in subdi-
3.0%
SD = 0.234
viding process of sterile dry powders). A real case of this
2.5% N = 10, Lot CpK = 10, Dist. Mean = 1, Dist.
SD = 0.239
is demonstrated by Cefoperazone-Sulbactam injection,
Frequency

2.0% where the AV results (Cefoperazone, n = 30) for three

1.5% PV batches are 8.94, 12.66, and 14.01 fail to meet the AV
1.0%
limit NMT 9.1. Using the MS Excel functions above, the
P values are 97.46, 79.82, and 78.14% respectively. Note
0.5%
that the percentages are those falling within 85–115% of
0.0%
0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 label claim (LC), if within 75–125% (LC), P values would
‘AV/AV Mean’ Ratio
be 99.99xx, 99.99xx, and 99.80xx% respectively. The P
value within 75–125% (LC) for Sulbactam in each batch
is 100%. So the criterion using the range 75–125% (LC)
Figure 8: Distribution of simulated “probability of meeting seems to be more justified;the AV acceptance criteria are
Uniformity of Dosage Units (UDU)” results (n = 30). not appropriate for this particular case.
A c c e p t a n c e c r i t e r i a 3: L o t C p K o n a v e r a g e d a t a
8.0% (limit: NLT 1.33). The lot CpK on average can be estimated
7.0%
53.42%
using the calculation method demonstrated in the fol-
Simulated Probability Distribution (n
6.0% = 30): Dist. Mean = 98%, Lot CpK = lowing (True CpK estimation).
1.33, Coverage for Probability ≥
5.0% 90% = 95.17%
Frequency

4.0%
Application in routine batches
In routine batches where n = 10 or 30, the AV results are
3.0%
directly documented in the reports. Based on a simula-
2.0%
tion (lot CpK = 1.33), meeting the AV acceptance limit
1.0%
(n = 10 i.e. routine batches) will indicate that only 29.xx%
0.0%
of the future samples n = 10 will have the AV results
%

0%

7%

3%

0%

7%

3%
.0

.7

.3

.0

.7

.3

.0

.7

.3

.0

.7

.3

.0

.7

.3

meeting the relevant limits (i.e., not applied for valida-

0.

0.

1.

2.

2.

3.
90

90

91

92

92

93

94

94

95

96

96

97

98

98

99

10

10

10

10

10

10

Probability of Meeting CU Test (%)

tion purpose). Application in routine batches may be
demonstrated typically in an APR. Three real cases
Acceptance criteria 2: AV average data. The average of all AV about AV data (n = 10) are illustrated in Figures 10–12.
data from three or more PV batches is required to meet the When the new limits are adopted, the key elements may
AV average limits such as NMT 7.5 (n = 30), 7.1 (n = 60), etc. be summarized as follows:
(see Table II). Meeting the acceptance criteria will indicate • AV acceptance requirement: All the AV data are
that lot CpK on average will be not less than (NLT) 1.33. required to meet the limit of NMT 12.5 (Table II).
36 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
 ■ Actual data: All the data in Figures 10–11 (but not Figure 9: Distribution of simulated “probability of meeting
Figure 12) pass the limit. Uniformity of Dosage Units (UDU)” results (n = 70).
• AV average acceptance requirement: The AV average
data are required to meet the limit of NMT 9.0 (Table II). 5.0%

■ Actual data: The average data in Figures 10–12 pass the 4.5%
Simulated Probability Distribution (n=
4.0% 74.01%
limit. 70): Dist. Mean = 99.97%, Lot CpK =
3.5% 1.33, Coverage for Probability ≥
• AV chart requirement: All the AV data are required to 3.0%
99.87% = 95.28%
7.11%

Frequency
stay consistently within AV chart limits. The limits may 2.5%
Coverage for Probability ≥
be computed using AV constants for construction of the 2.0%
90% = 100% (Minimum

charts so that in-trending and/or out-of-trending of AV 1.5% Value ≅ 96%

data is demonstrated. 1.0%

■ Figure 10 (for example): UCL = 4.01x1.71 = 6.86  6.9

0.5%

0.0%
and LCL = 4.01x0.29 = 1.16  1.2 (factors 1.71 and 0.29

0%

3%

7%

0%

3%

7%

0%

3%

7%

0%

3%

7%

0%

3%

10 %

10 %

10 %

10 %

10 %

10 %

%
7

00

03

07

10

13

17
.5

.5

.5

.6

.6

.6

.7

.7

.7

.8

.8

.8

.9

.9

.9

0.

0.

0.

0.

0.

0.
99

99

99

99

99

99

99

99

99

99

99

99

99

99

99
from Table II). Probability of Meeting CU Test (%)
■ From the three figures, one can see that the plotted
AV data in Figures 10–11 stay within the limits that use
the introduced AV constant method while Figure 12 Figure 10: Acceptance value (AV) chart for an annual product
fails in that one datapoint (14.2) exceeds the upper review of a tablet product (AV data: n = 10). USL is upper
specification limit (USL) of 12.5 and three datapoints specification limit. UCL is upper control limit. CL is control limit,
exceed UCL 11.6. LCL is lower control limit.
• True CpK estimation and trending capability: Described
14
separately in the following.
USL = 12.5
12
Trending Capability Index = 2.94

True CpK estimation 10

Lot CpK on Average = 2.93
Acceptance Value (AV)

The term “true CpK” may be applied to lot CpK (calculated

8
using within-lot AV data such as in-process control data) 6.7
USL = 6.9
or lot CpK on average (calculated using between-lot AV 6
AV Data
data such as PV data) as applicable. The previous sections 4 CL = 4.01

described how to qualitatively evaluate whether or not the

2
true CpK is equal to or greater than 1.33. To quantitatively LCL = 1.2

obtain the best point estimate for lot CpK, the calculation 0
1 3 5 7 9 11 13 15 17 19 21 23 25 27
example in the following may be used. The expressions Lot No.: Tablet Product (27 Lots)

AV = M x + 2.4s and CpK = Min((USL x) / 3s,(x LSL) / 3s) (4) are

used for the calculation assuming that M x is zero. This

is based on the zero results obtained at about 80% of the
time in a simulation test. From Figure 10, s = 4.01/2.4 = 1.67,
so sample CpK average (content uniformity data) = 15/3s
= 5/1.67 = 3.0 and lot CpK on average = (1.33/1.36)x3.0 =
2.9338. For Figures 11–12, the calculated values are 3.33 and
1.73, respectively. Such CpK values will be the point esti-
Figure 11: Acceptance value (AV) chart for annual product
review of a capsule product (AV data: n = 10). USL is upper
specification limit. UCL is upper control limit. CL is control limit,
LCL is lower control limit.
14

mate for the actual process benchmarks for the products. 12

USL = 12.5
Trending Capability Index= 3.62
Note that the estimator (1.33/1.36) or 0.98 is taken from Lot CpK on Average = 3.33
10
Figure 13. For samples NLT n = 30 (i.e., n = 30, 60, 70, or
Acceptance Value (AV)

140), the calculated sample CpK results may be the direct 8

estimates for the true CpK values since those estimators 6

5.9
UCL = 6.0
AV Data
are approximately equal to 1.00 (9). Figure 14 illustrates the
4
relationship between AV averages, true CpK on average, and CL = 3.52

lot coverage on average. For example, if AV average is 8.9 (n 2

LCL = 1.0
= 10), the true CpK and lot coverage (85-115% LC) on aver- 0

age are 1.33 and 99.997%, respectively. 1 3 5 7 9 11 13 15 17 19 21 23 25

LotNo.: Capsule Product (38Lots)
27 29 31 33 35 37

where,
AV : acceptance value = 4.01
M : reference value CpK : process capability index
x : sample mean = 100 (% of label claim) USL : upper specification limit = 115 (% of label claim)
s : sample standard deviation LSL : lower specification limit = 85 (% of label claim)
Pharmaceutical Technology AUGUST 2017 37
Peer-Reviewed
Figure 12: Acceptance value (AV) chart for annual product to express the relative degree of AV data trending
review of Tablet Product 2 (AV data: n = 10). USL is upper (i.e., trending capability). It may be def ined as the
specification limit. UCL is upper control limit. CL is control limit, ratio of specif ication tolerance to data spread tol-
LCL is lower control limit. erance (e.g., USL-CL and UCL-CL respectively in
Figure 10). To compute the capability index in Figure 10, for
16.0
Trending Capability Index = 1.19 example, is to proceed as shown in the following.
Lot CpK on Average = 1.73
14.0 Because USL = 12.5, UCL = 6.9 and CL (mean) = 4.01,
12.0
USL = 12.5
UCL = 11.6
the trending capability index = (12.5-4.01)/(6.9-4.01) =
Acceptance Value (AV)

10.0
2.9. In Figure 11, the calculated index is 3.6. With the rule
8.0
of thumb criteria, the acceptance limit for the index is
CL = 6.77 NLT 1.33. Figure 12 demonstrates how the trending ca-
6.0
AV Data pability index less than 1.33 (1.2) has a correlation with
4.0
failure conditions, such as 3 out of 20 data points exceed-
2.0 LCL = 2.0 ing the UCL. A trending capability index (denoted C TK)
0.0 is expressed as follows:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Lot No.: Tablet Product 2 (20 Lots)

USL CL
CTK = 1.33
UCL CL ………(one-tailed)
Figure 13: Process capability index (CpK) distributions (n = 10,
Lot CpK = 1.33). CTK = MIN
USL CL CL LSL
, 1.33
UCL CL CL LCL
……… (two-tailed)
5.0%

4.5%
Simulated CpK Distribution where,
4.0% (n = 10): Mean = 1.36, Lot
3.5%
CpK = 1.33 CTK : Trending capability index
3.0%
Theoretical CpK Distribution USL : Upper specification limit
Frequency

(n = 10): Mean = 1.36, Lot

2.5% CpK = 1.33 LSL : Lower specification limit
2.0% UCL : Upper control limit = CLxUCLfactor
1.5% LCL : Lower control limit = CLxUCLfactor
1.0% CL : Center line
0.5%

0.0%
Discussion
49

3
77

91

05

9
33

47

61

75

89

03

17

31

45

59

73

87

01

15

9
6

2
0.

0.

0.

0.

1.

1.

1.

1.

1.

1.

1.

2.

2.

2.

2.

2.

2.

2.

3.

3.

3.

Sample CpK The constant method for AV chart construction is similar

to that of s charts (using B3 and B4) or R charts (using
D3 and D4) (4). In fact, B3 and B4 for n = 10 (B3 = 0.284,
Figure 14: True process capability index (CpK) vs. sample CpK B4 = 1.716) and 30 (B3 = 0.604, B4 = 1.396) may be used
average vs. lot coverage (%) relationship. in place of those constants in Table II. When using the
traditiona l control chart met hod (i.e., mean±3SD
10.00 100.005%
ignoring the knowledge of AV distribution), UCL and
LCL would be 8.4 and 0, 7.1 and 0, and 16.1 and 0 in
Lot Coverage (85-115% LC) on Average (%)

9.00 100.000%
Figures 10–12, respectively, which are not effective. The
Acceptance Value (AV) Average

8.00 99.995%
introduced method is much more powerful than the
7.00 99.990% traditional one by NLT 40% (e.g., in Figure 11; ((7.1-0)-(6.0-
6.00 99.985% 1.0))/(6.0-1.0) = 42%).
5.00 99.980% From the figures, it may be summarized that the higher
4.00 99.975%
the lot CpK on average, the higher the trending capabil-
ity index. However, within the same product data, the
3.00 99.970%
trending degree may be higher or lower than the lot CpK
27
33
40
47
53
60
67
73
80
87
93
00
07
13
20
27
33
40
47
53
60
67
73
80
87
93
00
1.
1.
1.
1.
1.
1.
1.
1.
1.
1.
1.
2.
2.
2.
2.
2.
2.
2.
2.
2.
2.
2.
2.
2.
2.
2.
3.

True CpK on Average

level. In Figure 12, for example, although lot CpK is more
than 1.33 (1.73), the trending degree is less than 1.33
(1.19). This implies that, to be successful, both lot CpK
and trending index values need to be greater than 1.33.
Trending capability To va lidate processes automated using process
For those non-normal data such as AV data where analytical technology (PAT), Bergum and Vukovinsky’s
a control char t is sti l l required, t he term “trend- approach relevant to “A Proposed Content-Uniformity
i ng c apabi l it y i ndex” is i nt roduced a nd appl ied Test for Large Sample Sizes” is recommended (10).
38 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
 Although CpK for non-normal data may be computed using the
transformed data or special method depending on their applicability,
quality metrics other than CpK would be more practical. Trending
capability, introduced in this article, is a more practical term for
measuring capability. Get to Know
Conclusion
In routine batches, meeting the established AV acceptance limits will
Metrohm
indicate that NLT 90% of the dosage units in the lot will fall within
85–115% of the label claim. The 95% coverage implies that the AV
limits, such as 12.5 for n = 10, are the critical values at 95% of AV
distributions. The requirement for AV average limits is intended to
evaluate whether or not the lot or process (as applicable) is equal to
or better than the process benchmark at CpK 1.33. When handling Titration

multiple AV data in an APR for example, AV char t construction

and calculation of true CpK and trending capability index can be
accomplished.
In validation batches, tolerance limits and/or percent proportions
Ion Chromatography
may be additionally calculated as appropriate so that lot conformance
requirements are fulfilled.
Overall, all the established limits are intended to prevent:
• False release of routine batches with poor quality into the market,
• False acceptance of out-of-trend data in annual product review
Electrochemistry
(routine batches), and
• False release of validation batches with poor performance.

References
1. P. Cholayudth, Pharmaceutical Technology, 40 (12) 34–43 (2016). Spectroscopy
2. USP General Chapter <905> “Uniformity of Dosage Units” (US Pharmacopeial
Convention, Rockville, MD, 2014).
3. Tolerance Intervals for a Normal Distribution, section 7.2.6.3, www.itl.nist.gov.
4. D.C. Montgomery, Introduction to Statistical Quality Control (John Wiley and
Sons, New Jersey, 6 th ed., 2009).
5. J.S. Bergum and H. Li, Pharmaceutical Technology, 31 (10) 90–100 (2007).
6. ASTM Standard Number E2810—11: Standard Practice for Demonstrating Capa-
bility to Comply with the Test for Uniformity of Dosage Units, October 2011.
7. ASTM Standard Number E2709—09: Standard Practice for Demonstrating Capa-
bility to Comply with a Lot Acceptance Procedure, September 2009. Laboratory Process
8. J. Bergum, ISPE Pharmaceutical Engineering, 35 (6) 68–79 (2015).
9. P. Cholayudth, Journal of Validation Technology, 19 (4) 2013, www.ivtnetwork.
com/article/cpk-distribution-fact-underlying-process-capability-indices—part-
i-theory.
10. J Bergum and K.E. Vukovinsky, Pharmaceutical Technology, 34 (11) 2010, http:// Find out more at
www.metrohmusa.com/technology
www.pharmtech.com/proposed-content-uniformity-test-large-sample-sizes. PT

www.metrohm.com

Pramote Cholayudth is validation consultant to Biolab Co., Ltd. in Thailand. He

is the founder and manager of PM Consult, cpramote2000@yahoo.com.

Pharmaceutical Technology AUGUST 2017 39

Analytics
A Continuous
Improvement Metric
for Pharmaceutical
Manufacturing
Statistical methods and novel indices can be
used to monitor and benchmark variability,
and guide continuous improvement
programs in late-stage drug development.
P
ublished in 2004, FDA’s Phar-
maceutical cGMPs for the 21st
Century, A Risk-Based Approach
(1) provided the initial momentum
needed to help promote collaborative
efforts within the pharmaceutical in-
dustry. Designed to modernize phar-
maceutical manufacturing and make it
more efficient, the guidance highlights
the importance of continuous improve-
ment to improve efficiency by optimiz-
ing processes, reducing variability, and
eliminating wasted effort.
Jordan Collins is manager of statistical
support; Naheed Sayeed-Desta is
manager of process validation;
Ajay Pazhayattil is associate director of
technical operations; and Chetan Doshi
is vice-president of product development,
all at Apotex, Inc.
40 Pharmaceutical Technology AUGUST 2017
Jordan Collins, Naheed Sayeed-Desta,
Ajay Pazhayattil, and Chetan Doshi
Reducing variability benefits both
patients and manufacturers; there-
fore, regulators have voiced strong
support for continuous improvement
activities. For example, FDA and the
International Council for Harmo-
nization (ICH) support quality-by-
design (QbD)-based product devel-
opment.
QbD, advanced in ICH Q8 (2), fo-
cuses on the use of multivariate anal-
ysis in combination with knowledge
management tools to understand the
impact of critical material attributes
and critical process parameters on
drug product quality attributes. The
heightened product and process un-
derstanding that result from using
this framework provides a foundation
for continuous improvement.
P h a r mTe c h . c o m
Continuous process verification
With the implementation of a contin-
ued/ongoing process verification pro-
gram at Stages 3A and 3B of product
development, continual assurance is
now available to detect any unplanned
departures and allow manufacturers to
adjust for them. As outlined in regu-
latory guidance on process validation
established by regulatory agencies that
include FDA (3), the European Medi-
cines Agency (EMA), the Pharmaceu-
tical Inspection Cooperation Scheme
(PIC/S), and the World Health Orga-
nization (WHO), process verification
identifies any potential risks and initi-
ates continuous improvement activities
when essential, thus helping prevent
likely product failures.
Statistical assessment tools
However, in order for process verifi-
cation to succeed, adequate statistical
assessment tools are mandatory. These
tools must simultaneously detect unde-
sired process variability while guard-
ing against overreactions.
The pharmaceutical industry uses
multiple quality metrics to drive con-
tinuous improvement efforts, and FDA
is developing guidance (3) to help sim-
plify and standardize reporting of
metrics. The agency’s draft guidance
recognizes the utility of metrics, and
recommends that FDA also use them
to develop compliance and inspection
policies and practices.
Regulators at FDA also see these
metrics as key to developing practices,
such as risk-based inspection schedul-
ing, that will help improve the agency’s
ability to predict future shortages and
to encourage manufacturers to adopt
better technologies with low process
variability. Senior FDA officials have
voiced the agency’s full support and
WAVEBREAKMEDIA/SHUTTERSTOCK.COM
endorsement of continuous improve-
ment and innovation in the pharma-
ceutical industry.
A best estimate of process and
method variability identifies the need
for continuous improvement, enhances
product and process understanding,
and allows manufacturers to develop a
better control strategy. Sources of vari-
 Table I: The random-effects analysis of variance (ANOVA) table.
Degrees of
Source of variation
freedom
Between groups
r-1
(Process)
Within groups
r(n-1)
(Analytical)
Total rn -1
ability can usually be attributed to the
“six Ms:” man, machine, material, mea-
surement, method, and mother nature.
By developing measures of the major
sources of variability, a best estimate of
the process’ variability (manufacturing
method) and analytical (measurement)
method variability can be deduced.
The first step in isolating the vari-
ability due to the manufacturing pro-
cess from the variability due to the
analytical method involves defining
the response variable, or the critical
quality attribute, and the source of
data wherein the other sources of vari-
ability may be minimized.
The Stage 3A batches, post-Stage 2 pro-
cess performance qualification batches,
are processed on the same model of
qualified equipment (minimizing vari-
ability due to machine) by the same pool
of trained operators, according to stan-
dard operating procedures (reducing any
variability that might be created by man).
Raw material used in the process
must meet testing specifications and
come from a common supplier (to
minimize variability due to material),
while environmental and facility con-
trols and monitoring control the en-
vironmental variability (reducing the
potential effects of mother nature). By
minimizing these four sources of vari-
ability, the sources of manufacturing
process and analytical method vari-
ability can be isolated.
Overall variability can be broken
down to its main sources, as shown
below [Equation 1].
S2Overall = S2Process + S2Analytical + S2Other
[Eq. 1]
Sum of squares Mean square Expected mean square
SSA
SSA = n∑ri=1(yi.– y..)2 MSA =
(k-1) nσa2 + σe2
SSE
SSE = ∑ri=1∑nj=1(yij– yi.)2 MSE =
k(n-1) σe2
SST = ∑ri=1∑nj=1(yij– y..)2
Given the controls on other sources mean zero and variance σa2 and σe2, re-
of variability found in Stage 3A batches, spectively (5–7).
S2Other can be assumed to be negligible.
Any remaining variability can then be IPV measures
subsumed under the process and ana- batch-to-batch variability
lytical sources to yield the partition of Inherent process variability (IPV) is a
interest, namely [Equation 2]: measure of batch-to-batch variability,
while analytical (method) variability is
a measure of the variability of material
S2Overall = S2Process + S2Analytical
within the same batch (8). As such, es-
[Eq. 2] timates of σa2 measure inherent process
variability, while σe2 measures analyti-
cal method variability.
Variance component analysis Other measures of interest can be
An estimate of the variability inherent obtained from the above model. For
to the process (IPV) and the variability instance, the ratio of these two variance
due to the analytical method can then components θ = σa2 σe2, provides a stan-
be attained by variance component dardized measure of the variance of the
analysis. population group means, while the in-
Variance component analysis is a tra-class correlation ρa = σa2 σa2 + σe2 =θ θ+1
statistical tool that partitions overall is a measure of the proportion of the
variability into individual components. total variance due to the process.
The statistical model underlying this Estimates for these values can be ob-
tool is the random-effects analysis of tained from the ANOVA data provided
variance (ANOVA) model, which can in Table I as follows [Equation 4]:
be written as [Equation 3]:
〈
σe2 = MSE
yij = m + ai + eij where i = 1,…,r and j = 1,…,n
MSA-MSE
〈
[Eq. 3] σa2 =
n
MSA-MSE
〈
where y ij is the jth measurement in θ=
nMSE
the ith group, m is the overall mean (an
unknown constant), a i is the effect at- ρa = MSA-MSE
〈
tributable to the ith batch, and eij is the MSA+(n-1)MSE
residual error. [Eq. 4]
It should be noted that, in this
model, as opposed to a fixed-effects Other estimators are available, in
ANOVA model, a i is considered to particular for unbalanced data where a
be a random variable, where random different number of measurements are
conditions include different chemists, taken per batch. The restricted maxi-
equipment, batches, and numbers of mum likelihood (REML) estimator is
days (4). The random variables a i and a viable alternative available in most
eij are assumed to be independent, with statistical software packages.
Pharmaceutical Technology AUGUST 2017 41
Analytics
This model can be fit to situations calculated using the following equa- In addition, APV and the PaCS
in which the batch effect is considered tion [Equation 5]: Index may be used to decide such
random, and each batch has n samples. things as who should be primarily
For example, 20 batches might be con- PaCS = IPVP/ IPVB responsible for a specific continuous
sidered to be a random sample from [Eq. 5] improvement project (i.e., whether
a larger pool of batches for a specific process, analytical, or a combination).
product. For each of these 20 batches, where IPVB is the benchmark in- This is often a point of contention.
a random sample of 10 samples would herent process variability and IPVp It could also be used to determine
be taken to measure finished product is the inherent process variability which site has the best PaCS index with
dosage uniformity. for the product under consideration. respect to a product. This factor will
The variability in the mean finished IPVB is the median process variabil- be considered when deciding for or
product dosage uniformity between ity of the selected products with pro- against site product volume increases.
〈

the batches, σa2 , would yield an esti- cesses similar to the current product. In summary, the PaCS can provide
mate of the inherent process variability, valuable insight to decision makers,
while ρa would provide an estimate of Lower value preferred
〈

and help to drive continuous quality

the proportion of variability due to the A PaCS index greater than 1 indicates improvement programs in biopharma-
process. Confidence intervals can be the process variability is high, while ceutical and pharmaceutical develop-
constructed for these estimates and a PaCS less than 1 indicates that pro- ment as well as manufacturing.
are available in common statistical cess variability is low compared to the
software packages. benchmark. Therefore, a PaCS value References
that is less than 1 is preferred. 1. FDA Final Report, Pharmaceutical
Focusing on process improvement Because the distribution of the cGMP’s for the 21st Century- A risk based
approach, fda.gov, Sept. 2004, www.fda.
The estimated IPV, as well as the PaCS index is not analytically deriv-
gov/Drugs/DevelopmentApprovalPro-
ratio of total variance due to the able, confidence intervals can be esti- cess/Manufacturing/
process, can be used during Stage 3 mated using Monte Carlo simulation. 2. ICH Q8 (R2), Pharmaceutical Develop-
batch monitoring to focus efforts on The PaCS index together with IPV ment, (ICH, August 2009), ich.org, www.
process improvement. As more in- values and the other derived statis- ich.org/fileadmin/Public_Web_Site/
formation is gathered for a product, tics provide a platform upon which ICH_Products/GuidelinesQuality/
3. FDA, Draft Guidance, Submission of
a rise in the IPV itself, or a rise in further decision making can take Quality Metrics Guidance, (FDA, No-
the proportion of total variance due place. For instance, high PaCS values vember 2016), fda.gov, www.fda.gov/
to the process ( ρa ) could indicate the would indicate that the process for a
〈

downloads/Drugs/GuidanceCompli-
need to investigate possible process specific product is not performing as ance Regulator yInformation/Guid-
improvements. expected. ances/UCM455957.pdf
On the other hand, a decrease in Estimation of inherent process vari- 4. K. Barnett K et al., “Analytical Tar-
get Profile: Structure and Application
IPV or the decline in ρa would indi- ability (IPVP) allows for determining a
〈

Throughout the Analytical Lifecycle,”

cate that the process is improving. In PaCS index for the product, and helps USP Stimuli to the Revision Process (42)
order to obtain a picture of how well in understanding the contribution to 2016, pp. 1-15.
the process is performing overall for variability that comes from the manu- 5. R.K. Burdick, and F.A. Graybill, Confi-
a specific product, a comparison with facturing process and the analytical dence Intervals for Variance Components
other products employing the same method used. In addition, PaCS is (Marcel Dekker, New York, 2006).
6. S.R. Searle et al., Variance Components
process can be made by generating a a metric developed in relation to the (John Wiley, New York, 2006).
benchmark. manufacturing process at a particular 7. H. Sahai, H. and M. Ojeda, Analy-
The novel PaCS index (named production site. sis of Variance for Random Models.
for the first letters in the authors’ (Birkhäuser, Boston, 2006).
last names: Pazhayattil, Collin, and Decision making tool 8. B. Nunnally, “Variance Component
Analysis to Determine Sources of Varia-
Sayyed-Desta) provides an indication The index can be effectively used to
tion for Vaccine Drug Product Assays,”
of a current product’s process perfor- determine continuous improvement Journal of Validation Technology, Sum-
mance in comparison to other similar projects at the site or for site transfer mer 2009; pp. 78-88, available online at
products. To derive the PaCS index, a initiatives. PaCS provided with a tan- www.ivtnetwork.com/sites/default/files/
representative set of other products gible quantitative robustness figure for ProductAssays_01.pdf.
generated with the same process would various supply chain decision making. 9. ICH, Q10 Harmonized Tripartite Guide-
line, Pharmaceutical Quality Systems,
be chosen. The index can be a component of pe-
(ICH, June 2008), ich.org, www.ich.org/
For each of these chosen products, riodic process performance review by fileadmin/Public_Web_Site/ICH_Prod-
the IPV would then be calculated as senior management as recommended ucts/Guidelines/Quality/Q10/Step4/
above. The PaCS index could then be by ICH Q10 (9). Q10_Guideline.pdf PT

42 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m

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Supported by
Raw Material Quality
The Role of Quality
Standards for
Biomanufacturing
Raw Materials
Fouad Atouf
Managing and prioritizing risk is essential to
ensuring raw material quality. USP is developing
new guidelines to make the work easier.
S
uccessful pharmaceutical manu-
facturing strategies depend on raw
materials that are of good quality.
While much effort is spent to develop
active ingredient specifications, excipi-
ents and other non-active raw materi-
als are often taken for granted.
This is especially true in biological
manufacturing, in which a variety of
raw materials may be used in a single
process. Some materials can increase
the risk of introducing adventitious
agents into the process and final prod-
uct. Thus, raw material qualification is
extremely important in ensuring pro-
cess control and final product quality.
Qualification programs rely on risk
Fouad Atouf, PhD, is vice president,
Science—Global Biologics for USP.
44 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
assessment strategies that may include
testing raw materials before they are
introduced into manufacturing.
This article describes some of the
challenges involved in qualifying raw
materials for use in biologics produc-
tion, and how quality standards may
evolve to support biologics manufac-
turing. The International Council on
Harmonization (ICH) Q7 guidelines
define raw materials as “starting ma-
terials, reagents, and solvents intended
for use in the production of intermedi-
ates or APIs” (1). With biopharmaceu-
ticals, however, this definition can be
expanded to include other materials
that are added to the manufacturing
process, or that may come in contact
with the active ingredient, including
process materials such as buffer and
media, selection devices, ancillary
materials, packaging materials, and
excipients. Each of these types of ma-
terials must be qualified before manu-
facturing can safely begin.
Regulatory guidelines
Quality by design (QbD) principles call
for the use of systematic approaches to
development, starting with predefined
objectives and an emphasis on prod-
uct and process understanding and
process control. This approach under-
scores the importance of raw materials
and all the components of the manu-
facturing processes. In addition to
regulations and guidances, standards
developed by the United States Phar-
macopeia and other pharmacopeias
can help biopharmaceutical manufac-
turers meet requirements.
The use of raw materials that have
been manufactured in a GMP-compli-
ant environment provides assurance
that the processes used to make the
materials are reproducible and that the
quality of final products is controlled.
In such cases, changes to the process
cannot be implemented without assess-
ing their impact on the finished prod-
uct. However, when raw materials are
procured from commercial, non-GMP
compliant sources, the risks of manu-
facturing failure increase. Raw mate-
rial specifications may change with-
out an assessment of their impact on
finished product quality. In addition,
specifications for non-GMP compli-
ant raw materials are often wider than
would be acceptable for GMPs.
Qualification programs
It is important to use formal pro-
grams to qualify raw materials used
in biopharmaceutical manufactur-
ing to ensure the safety of finished
products. For biologics, raw material
qualification can be a lengthy, multi-
TONHOM1009/SHUTTERSTOCK.COM
step process. When choosing a supplier,
finished drug manufacturers should
consider the type of quality systems in
place at the supplier’s manufacturing
facility, the possibility of referencing a
drug master file (DMF), and the sup-
plier’s financial stability. The technical
information (e.g., certificate of analy-
 Table I: Levels of risk.
Level of risk Definition and criteria that define the level of risk
Intended for use as licensed drugs, biologics, or medical devices. Suitability for use as a
manufacturing component is required because the formulation, stability profile, and other quality
Tier 1: Low risk
aspects of these materials may change once the material has been introduced in the manufacturing
process.
Intended to be used as ancillary materials. These materials are well-characterized and produced
Tier 2: Low risk under quality systems well-suited for biological manufacturing, but the materials are not licensed
medical products. Many are produced specifically for use in the manufacture of biological products.
Research-grade materials not intended for use in biological manufacturing. Sometimes, these
Tier 3: Moderate risk products are approved by regulatory agencies as part of an in vitro diagnostic device. Tier 3 requires
more qualification than Tier 1 or Tier 2 materials.
Materials produced as industrial or research-grade materials and may contain harmful
impurities. They may also contain animal- or human-derived components with potential
Tier 4: High risk
contaminants. This tier requires extensive qualification before use as component in biological product
manufacturing.

sis [CoA]) obtained from the supplier
provides insight into specifications for
these materials, which may need to be
considered when evaluating their po-
tential impact on the quality attributes
of finished products. The CoA alone
may not be sufficient, however.
Risk-based assessment
Risk-based assessment can be used to
determine the criticality of the raw ma-
terial, which will determine the level of
testing required, beyond the informa-
tion found in the CoA.
Generally, a raw material that is
used in large quantities in the down-
stream process will pose a higher level
of risk than one that is used in small
amounts in an upstream process. Simi-
larly, a material that is used in steps of
the process with long holding times
will pose a greater risk than one used
where there are shorter holding times.
The use of animal- or human-de-
rived materials presents the additional
risk of introducing adventitious agents
or communicable diseases. When
these materials are used in a process,
screening for potential contaminants
is a crucial part of the control strategy.
The risk-based approach will depend
on the potential for raw materials to
remain present, at trace levels, in fin-
ished product.
It is also important to study the im-
pact of the raw material on the devel-
opment and manufacture of biological
drug substances, as per ICH Q11 (2).
USP <1043> Ancillary Materials
for Cell, Gene and Tissue-Engineered
Products provides guidance for assess-
ing the risk, and qualifying the use of
materials used to manufacture cell,
gene, and tissue-engineered products.
However, the principles described in
<1043> may be extended to raw ma-
terials used in biomanufacturing in
general (3). In <1043>, raw materials
are grouped in four different tiers, de-
pending on the level of risk they pres-
ent, and guidance is offered on how
to reduce risk so these materials can
safely be used in biological manu-
facturing. Table I shows the criteria
that define the level of risk for these
four tiers of raw materials used in the
manufacturing of cell therapy prod-
ucts and biological manufacturing in
general.
Building on USP <1043>, USP began
to work with expert committees on
documentary standards, including test
procedures and acceptance criteria,
for some of the critical materials that
are used in the manufacturing of bio-
logical products, such as cell therapies.
These efforts also resulted in reference
standards that support the test. An ex-
ample of this work, and the hierarchy
of approach, is presented in Figure 1.
These reference standards may be
used as calibrators as well as critical
materials to develop residual testing
for these materials and control the
level of their removal from finished
therapeutic products.
Standards for the raw and ancillary
materials used in pharmaceutical and
biopharmaceutical manufacturing
have always been included in United
States Pharmacopeia–National Formu-
lary (USP–NF), in the form of mono-
graphs and supported by reference
standards. Examples include standards
for inorganic salts, vitamins, amino
acids, carbohydrates, and other buf-
fers and components of raw materials.
The test procedures and associated
reference standards for these materials
may address their quality as excipients
and when they are used as raw mate-
rials in a manufacturing process. If
they are used as other components in
manufacturing, additional work may
be required to show that these tests
adequately address questions about the
material’s quality, in its new use.
Developing test methods
Risk assessment strategies are key to
successful manufacturing processes;
they help set proper specifications
for raw materials and ensure that ad-
equate testing approaches are in place.
Developing test methods to verify the
identity and quality of materials used
in biopharmaceutical manufacturing
can help prevent the use of unsuit-
able raw materials, providing a solid
foundation for a successful process.
Pharmacopeial standards provide
valuable tools, saving users the time
and expense required to develop and
validate test methods themselves. The
Pharmaceutical Technology AUGUST 2017 45
Raw Material Quality
Figure 1: Standards for raw and ancillary materials: from general to specific.
<1043> Ancillary Materials (AMs) for
Cell-, Gene-, and Tissue-Engineered
Products
Specific AM Chapters
<90> FBS Quality Attributes
<130> Protein A
<92> Cytokines and Growth Factors
<89> Enzymes
Reference Standards:
- FBS
- Protein A
- Interleukin-4
- Trypsin
- Collagenase I and II
reference standards, when available,
serve as calibrators or comparators to
ensure users that the material can pass
the required tests. Suppliers may say
that their products comply with USP
standards when they meet compendial
analytical specifications.
Raw materials that have been pro-
cessed under GMP conditions and
meet compendial monographs have
established some base level of quality,
but their suitability for use in the pro-
cess must still be proven. For example,
pharmaceutical-grade human serum
albumin is available for use as a cell
culture supplement, and its quality can
be tested against existing monographs.
However, in order to establish human
serum albumin’s quality, the impact of
the albumin’s lot-to-lot variability on
cell growth as well as its stability in the
process, and its possible interactions
with other processing components
must also be assessed.
Role of pharmacopeial standards
Numerous regulatory guidelines spell
out the need for raw materials to be
46 Pharmaceutical Technology AUGUST 2017
General
Information
Chapter
Ancillary Material
Requirements for
Specific AMs
Ancillary Material
Reference Standards
included in manufacturing strategies.
However, these guidelines don’t de-
scribe specifically how to do this.
Pharmacopeial standards can be
used to fill this gap because they can
provide tools for compliance. Refer-
ence standards can be used as calibra-
tors to ensure that the materials are
used consistently, that they meet the
same specifications and, subsequently,
that they will be translated into consis-
tent manufacturing.
Additionally, the standards can be
used to measure residual amounts of
materials, especially with the increased
risk of raw material components re-
maining in the finished dosage form.
In USP–NF, procedures that support
the use of such standards are pre-
scribed, either in general chapters or
in monographs.
The use of raw materials in multiple
sites adds complexity to risk and qual-
ity assessment, particularly regarding
.the transfer of processes from site to
site. In these situations, the type of
comparability testing that will be re-
quired will be crucial in ensuring that
P h a r mTe c h . c o m
raw material quality does not have a
negative impact on product quality.
Use of pharmacopeial standards can
help mitigate associated risks.
USP’s approach to setting standards
for biologics is evolving, as it focuses
on developing standards for some of
the critical raw materials used in bio-
manufacturing, and on developing sys-
tem suitability and performance stan-
dards that can be used to demonstrate
method and process performance.
As it evaluates the type of raw ma-
terials to be included in this strategy,
USP is considering different types of
standards that can help industry es-
tablish consistency in bioprocesses.
For example, it is developing reference
standards, without documentary stan-
dards, when a well characterized mate-
rial can be used as a standard against
which raw materials suppliers or end
users can calibrate their batches. Situ-
ations may arise in which the reference
standard has a value only when proce-
dures and acceptance criteria are avail-
able; in this case, USP will develop a
documentary standard into a mono-
graph or a chapter.
Materials to be assessed include:
• Cell culture media
• Enzymes used in bioprocesses
• Complex extracts used as cell-
culture supplements (e.g., protein
hydrolysates)
• Polymers used in therapeutic pro-
tein-polymer conjugates.
USP welcomes feedback and recom-
mendations from the industry, as it de-
velops a comprehensive list.
References
1. ICH, Q7, GMP Practice Guide for Ac-
tive Pharmaceutical Ingredients, ich.org,
www.ich.org/fileadmin/Public_Web_
Site/ICH_Products/Guidelines/Quality/
Q7/Step4/Q7_Guideline.pdf
2. ICH, Q11 Guidelines for Development
and Manufacture of Drug Substances,
ema.gov, www.ema.europa.eu/docs/en_
GB/document_library/Scientific_guide-
line/2011/06/WC500107636.pdf
3. USP, <1043> Proposed General Chapter
Revisions, Ancillary Materials for Cell,
Gene and Tissue Engineered Products,
USP-NF, usp.org, w w w.usp.org/usp-
manufacturers/biologics/raw-ancillary-
materials PT
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outsourcing outlook
CDMOs: New Administration,
New Frontier
Gil Roth
Despite some progress, the industry is still in a
wait-and-see mode regarding the administration, Congress, and FDA.
U
ncertainty about the White
House’s agenda has impacted
pharma and the contract manu-
facturing organization (CMO)/contract
development and manufacturing or-
ganization (CDMO) sector. There’s
been some progress in the past few
months, including the appointment
of FDA Commissioner Scott Gottlieb,
MD, but there remains a great deal to
be worked out.
In the near term, one of the most
critical areas to be resolved is the
FDA Reauthorization Act (FDARA),
which reauthorizes four major FDA
user fee packages: the Prescription
Drug User Fee Act (PDUFA), the
Gener ic Dr ug User Fee A mend-
ments (GDU FA), t he Biosi mi la r
User Fee Act (BsUFA), and the Medi-
cal Device User Fee Amendments
(MDUFA). The new packages will
kick in on Oct. 1, 2017 (when the
federa l government’s FY2018 be-
gins), and without timely approval of
FDARA, FDA will be compelled to
issue intent-to-furlough notices this
summer to staff who are paid with
user-fee funds. That would cause
drug approval timelines to skyrocket
for both innovator and generic drugs,
and potentially hazardous facilities
to go uninspected.
Gil Roth is the
President of the Pharma
& Biopharma Outsourcing
Association (PBOA,
www.pharma-bio.org),
a nonprofit trade group
for CMOs and CDMOs.
He can be reached at gil.
roth@pharma-bio.org.
48 Pharmaceutical Technology AUGUST 2017
On July 12, 2017, the House of Rep-
resentatives approved FDARA (HR
2430) by voice vote; the bill was final-
ized in pre-conference with the rele-
vant Senate committee, so this version
should be the same one that the Senate
will vote on. It retains the negotiated
agreements between FDA and industry,
while adding amendments intended to
prioritize the review of generic drugs
where they can help drive down drug
prices. FDARA also includes stricter
accountability and reporting of FDA’s
use of user fee funds.
The Pharma & Biopharma Out-
sourcing Association (PBOA) was
deeply involved in the negotiations
with industry and FDA for GDUFA II,
and subsequently worked with Con-
gress to explain some of the changes
to the program, how they’re intended
to increase patient access to affordable
generic medicines, and how the new
fee structure is fairer to various indus-
try stakeholders. PBOA also worked
through the amendment process to en-
sure that additions to FDARA wouldn’t
harm the CMO/CDMO sector.
That doesn’t mean everyone’s happy
with FDARA. The White House has is-
sued statements and an FY18 budget
that runs counter to the negotiated
agreements, zeroing out the federal
funding that is part of each UFA pro-
gram and increasing the user fee totals
to offset that cut. The day HR 2430
was passed, the White House’s Office
of Management and Budget (OMB) is-
sued a statement that included the fol-
lowing: “The Administration urges the
Congress to provide for 100% user fee
P h a r mTe c h . c o m
funding within the reauthorized pro-
grams. In an era of renewed fiscal re-
straint, industries that benefit directly
from FDA’s work should pay for it” (1).
Congress has turned down the
White House’s request, retaining the
existing UFA budget models. This
should provide a degree of predictabil-
ity for the user fee-paying sector.
However, if FDARA isn’t passed by
Congress and signed into law by the
President by August, it’ll be a bad sign
for FDA, the pharma sector, and pa-
tients.
Supply chain worries
FDARA isn’t the only worrisome dead-
line the industry faces. Under the Drug
Supply Chain Security Act (DSCSA),
the federal law mandating FDA secure
the drug supply chain, drug manufac-
turers and packagers had a deadline
of Nov. 27, 2017 to make sure that all
packages are marked with a product
identifier, serial number, lot number,
and expiration date.
This has proved to be an immensely
complex project (actually, a series of
immensely complex projects). PBOA’s
Serialization Working Group held nu-
merous meetings to discuss the CMO
sector’s readiness for that deadline,
exchanging best practices and sharing
other aspects of implementation. The
LIGHTSPRING/SHUTTERSTOCK.COM
lack of standardization, especially for
data exchange, can put CMOs in an
especially tough position, where they
must accommodate the platforms of
their various customers.
In recent months, PBOA has met
with FDA to discuss the CMO/CDMO

sector’s readiness for that deadline, both in concert with
other industry groups and in a one-on-one setting. In pre-
vious years, the agency had heard from a few individual
CMOs, but most of their perspective came from other trade
groups that represent the customer-client side of the equa-
tion. This necessarily led to an incomplete picture of the
pharma manufacturing supply chain, and FDA seemed
glad to talk directly with CMOs about the pending DSCSA
deadline.
One of the most critical
areas to be resolved is the
Outsourcing Outlook
The White House issued an Executive Order calling for
federal agencies to repeal two regulations for every one
that they introduce (2). That order also called for the in-
cremental cost of new regulations to be zero (when offset
by repeal of other regulations). While those are somewhat
basic goals, it’s clear that quality metrics would carry a
massive cost to industry to implement, and needs to be
put on the back-burner.
Drug pricing, immigration, tax reform, and other topics
could impact CMO/CDMOs. In some respects, the industry
is still in a wait-and-see mode regarding the administration,
Congress, and FDA, but as an industry, we’re more involved
now than we’ve ever been.

FDA Reauthorization Act. References

At the end of June 2017, FDA announced that it will use
enforcement discretion for 12 months following that No-
vember 27 date. Effectively, the agency will not cite manu-
facturers that are not ready to introduce serialized products
into the marketplace. This gives CMOs and their customers
some breathing room, but CMOs should be reminded that
12 months is not a lot of time when it comes to implementing
a serialization solution.
1. Statement Of Administration Policy, H.R. 2430–FDA Reau-
thorization Act of 2017. Executive Office of the President, Of-
fice Of Management And Budget, Washington, DC, July 12,
2017, www.whitehouse.gov/sites/whitehouse.gov/files/omb/
saphr2430h_20170712.pdf
2. The White House, Reducing Regulation and Controlling Regu-
latory Costs, Federal Register, Feb. 3, 2017, www.federalregister.
gov/documents/2017/02/03/2017-02451/reducing-regulation-and-
controlling-regulatory-costs PT

Quality metrics and CMOs

Nothing has brought PBOA and its member companies to
the table with its industry peers as FDA’s Quality Metrics
initiative has. Since the agency’s first draft guidance for
quality metrics was introduced, PBOA’s Quality Technical PharmSource
Group has worked with a cross-industry consortium—in-
cluding Pharmaceutical Research and Manufacturers of Lead Sheet
America (PhRMA), Biotechnology Innovation Organiza-
tion (BIO), Association for Accessible Medicines (AAM),
dŚĞĚĞĮŶŝƟǀĞƐŽƵƌĐĞĨŽƌ
Bulk Pharma Task Force (BPTF), International Society for ƚĂƌŐĞƚĞĚŶĞǁďƵƐŝŶĞƐƐ
Pharmaceutical Engineering (ISPE), and the Parenteral ŽƉƉŽƌƚƵŶŝƟĞƐŝŶ
Drug Association (PDA)—to push FDA to clarify the many ďŝŽƉŚĂƌŵĂĐĞƵƟĐĂů
ambiguities (and occasional contradictions) contained in ĐŽŵƉĂŶŝĞƐ
that document and its successor.
Both iterations of FDA’s draft guidance would have placed
X “A superb direct source to Used and respected
CMO/CDMOs in a position where they would be respon-
current, well-suited leads so we can by the top CMOs,
sible for reporting data that are either confidential or outside ŽƉƟŵŝnjĞŽƵƌĐůŝĞŶƚďĂƐĞ” CDMOs and CROs
of their purview (such as data from their customers’ other –Head of Sales, NA around the world.
contract service providers). Reporting timelines that dif- X /ƚƐĂƉŚĞŶŽŵĞŶĂůůĞĂĚ
fer from those of Annual Product Reviews (APRs) would ŐĞŶĞƌĂƚŽƌ/ǁŽƵůĚƐĂLJŝƚŚĂƐ Focused.
create new workflow and staffing requirements for CMOs. ĚŽƵďůĞĚŽƵƌŽƉƉŽƌƚƵŶŝƟĞƐ
Other aspects of the program could also penalize CMOs, or –Dir., Global BD
Timely.
incentivize them to avoid certain types of products for fear X dŚŝƐŚĂƐůĞĚƚŽŵĂŶLJŝŵƉŽƌƚĂŶƚ Accurate.
of getting a “bad score”. ŵĞĞƟŶŐƐĂŶĚŽƉƉŽƌƚƵŶŝƟĞƐ
PBOA worked to convey to FDA that the quality metrics –VP of Business Development,
compliance burden would be immense for both in-house Global CMO
and outsourced manufacturing processes, and that the нϭϳϬϯϯဒϯϰဓϬϯDirect
agency had yet to make a strong case for the benefits that ϭဒဒဒϳϳϳဓဓϰϬToll-free in USA
would accrue from the program. Docket submissions and info@pharmsource.com | www.pharmsource.com A GlobalData company

industry presentations have carried that message.

Pharmaceutical Technology AUGUST 2017 49
PRODUCT AND SERVICE PROFILES

Aenova
8009 Industrial Village Road
Greensboro, NC 27409
tel. 862.881.4439
info.us@aenova-group.com
www.aenova-group.com

Aenova is a global leader in contract

manufacturing of finished dose forms for
pharmaceutical and dietary supplements.
Offering a large portfolio of services and
manufacturing expertise at every stage within
your product lifespan, from development
to commercial manufacturing. With 20
manufacturing sites located throughout the
United States and Europe, Aenova distributes
products worldwide. Our core customer service
foundation is built on a simple but important
principle; consistently deliver high quality and
excellent customer service. Operating under
common cGMP practices backed by global and
local regulatory agency approvals, quality is
never an afterthought. Aenova stands by its
strong financial performance, offering contract
manufacturing supply stability in a wide variety
of dosage forms such as, Softgel Capsules,
Solids, Semi-Solids, Liquids, Parenterals and
other specialty dosage forms.

Solids Liquids & Semi-solids Packaging Specialty Injectables

• Tablets • Pure or Colloidal Solutions • Blisters • Cytotoxics • Lyophilization

• Hard Capsules • Emulsions, Suspensions • Bottles • Hormones • Aseptic Manufacturing
(Solids & Liquids)
• Softgel Capsules • Ointments • Beta-Lactam • Terminal Sterilization
• Cartons
• Granules • Gels Antibiotics
• Labeling
• Pellets • Cephalosporins
• Pouches

Members of the Aenova Group:

C.P.M. · Dragenopharm · EVP · Haupt Pharma · Swiss Caps · SwissCo · Temmler

50 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m

 PRODUCT AND SERVICE PROFILES

Catalent Pharma Solutions

14 Schoolhouse Rd
Somerset, NJ 08873
Tel. 888.765.8846
www.catalent.com
solutions@catalent.com

New OptiForm® Solution Suite

Catalent’s new OptiForm Solution Suite is
the quick and efficient path from late-stage
discovery to Phase I clinical trials.

Designed to assist small and mid-sized

innovators, and now extended to include in
silico DMPK modeling and Pharmatek® SD
spray dry solubility enhancement, OptiForm
Solution Suite offers comprehensive
and flexible early-phase development,
incorporating preclinical and clinical
formulation development, solid state
screening, bioavailability enhancement and
cGMP manufacturing.

Built on Catalent’s experience in early phase

development, which has seen the company
support more than 500 INDs, OptiForm
Solution Suite integrates multiple tools and
services to deliver a customized development
program that provides data to support a
molecule’s progress towards the clinic:
• Preclinical formulations: solubility for
efficacy screening, DMPK modeling
• API characterization and optimization:
polymorph screening, salt-form
selection, and pre-formulation testing
• Bioavailability enhancement: particle
size reduction, lipid-based systems,
and amorphous dispersion evaluation
• GLP test materials: formulation
development for GLP toxicology
and PK/PD studies
• GMP clinical materials: delivered for with the broadest selection of enabling
Phase I studies in as few as 12 weeks. technologies to ensure that a molecule
gets on the right track fast and that the
Start Early and Start Smart right decisions are made throughout its
with New OptiForm Solution development.
Suite
To ensure a program’s success, strategic More products. Better treatments.
decisions need to be guided by the right data Reliably supplied.™
at the right time. Catalent provides innovators
with a data-driven approach and a thorough
analysis of a drug molecule, including
consideration of downstream processing and
optimal dose design for the intended patient
group, to improve the chances of success in
both the clinic and beyond.
OptiForm Solution Suite is fast, flexible, and
fact-based; providing an agnostic approach

Pharmaceutical Technology AUGUST 2017 51

PRODUCT AND SERVICE PROFILES

Eppendorf
102 Motor Parkway
Hauppauge, NY 11788
www.eppendorf.com

The Eppendorf
BioFlo 320—Flexible by design
Whether your process includes fed-batch or
perfusion in single-use bioreactor vessels or
autoclavable glass the BioFlo 320 seamlessly
combines form and function in one state of
the art package. A robust industrial design,
intelligent sensors, Ethernet connectivity,
and enhanced software capabilities are only
a few of the features that set it apart from
everyone else. Combined with a sincere com-
mitment to quality, the BioFlo 320 truly is the
premium choice in bench-scale bioprocess
control stations.

Small Footprint—Big Impact

From R&D laboratories to pilot-scale produc-
tion facilities, space is a major factor when
selecting the right equipment. The BioFlo
320 offers flexibility, better control, and max-
imum functionality while occupying a fraction
of the valuable lab space of similar systems.
This means greater efficiency and productiv-
ity at a lower operating cost for your lab.
BioBLU® Single-Use
Bioreactor Vessels
• Compatible with 250 mL–40 L rigid-
walled BioBLU single-use bioreactor
vessels including the BioBLU 5p, the first
single-use bioreactor to utilize the exclu-
sive packed-bed impeller for perfusion or
continuous applications.
• Built-in optical pH sensor technology.
• Eliminates potential for tears, pits, and • Trend display with up to twelve process
folds during installation. values within a single view.
• Single-layer polymer removes uncertain- • Remote access via PC or tablet.
ties for leachable and extractable data.
The BioFLO 320 offers flexibility, accurate
Advanced Software Solutions control, and maximum functionality while
• Control eight units from a single user providing greater efficiency and productivity
interface. at a lower operating cost no matter what your
• Automatic gas mixing algorithms for application may be.
simplified control (4-gas, 3-gas, O2
enrichment, N2 enrichment)
• New ten-point cascade feature for so-
phisticated control strategies.
• Built-in elapsed fermentation timer for
batch management.

52 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m


Eurofins Lancaster Laboratories Professional Scientific Services®
www.EurofinsLancasterLabs.com/PSS
Eurofins Lancaster Laboratories Professional
Scientific Services® (PSS) is a global, award-
winning insourcing solution that places our
people at your site dedicated to running and
managing your laboratory services while
eliminating headcount, co-employment and
project-management worries.
We infuse our 55-year track record of
scientific and laboratory operations expertise,
as well as HR and great place to work
best practices, to recruit, hire, train and
manage highly qualified scientists to perform
laboratory services at your site, using your
quality systems and equipment. Our teams
will even help you set up your laboratory and
PRODUCT AND SERVICE PROFILES
2425 New Holland Pike
Lancaster, PA 17601
717.656.2300
pha@EurofinsUS.com
validate equipment according to your SOPs
and Lean laboratory practices as needed.
Eurofins Lancaster Laboratories PSS employs
and manages full-time employees and
provides a comprehensive benefits package,
as well as training, development, and career
advancement opportunities. Offering these
additional benefits allows us to attract, retain,
and motivate high-caliber employees to serve
you. Our on-site dedicated leaders manage
our full-time employees and provide you with
scientific insourced services free from co-
employment. PSS also solves the challenges
associated with the EU Temporary Agency’s
Workers Directive 2008/104.
Our PSS Insourcing Solution® provides
services for clients who require scientists
and related support staff at their facility. We
have proven success providing dedicated
staffing for a variety of technical disciplines
that span the drug development pipeline
from early phase development to finished
product testing, as well as comprehensive
laboratory management, including GMP Lean
Laboratory Design and Validation, Regulatory
and Technical Training, Lean Project
Support/Management, and Upstream and
Downstream Services.
With more than 1,400 employees worldwide,
Eurofins Lancaster Laboratories PSS provides
services at more than 65 sites in over 14
countries throughout North America, Europe,
and Asia-Pacific and is part of Eurofins
BioPharma Product Testing, which operates
25 laboratory locations, totaling more than
700,000 ft2 across 13 countries worldwide.
Pharmaceutical Technology AUGUST 2017 53
PRODUCT AND SERVICE PROFILES
Fette Compacting America, Inc.
www.fette-compacting-america.com
Fette Compacting America, Inc., the leading
supplier of tablet press equipment for
pharmaceutical and nutritional applications,
is located in Rockaway, New Jersey. A
direct extension of Fette Compacting GmbH
of Schwarzenbek, Germany, it was one of
the first companies to develop and perfect
the high-speed, rotary tablet press. Fette
Compacting America offers complete
services to clients in the United States,
Canada, and Puerto Rico, including new and
used machine sales, technical assistance,
and machine installations. Other products
and services include training classes and
seminars, laboratory trials, validation,
maintenance, trouble-shooting and repairs,
spare parts, and tooling.
FEC40 Capsule Filler—World’s
Fastest Capsule Filling Machine
This year, Fette entered a new pharma
manufacturing sector when it introduced
its first—and the world’s fastest—capsule
filling machine: the FEC40 Capsule Filler.
The FEC40 has an output volume of up
to 400,000 capsules per hour—nearly
twice the production capacity of any other
54 Pharmaceutical Technology AUGUST 2017
400 Forge Way
Rockaway, NJ 07866
Tel. 973.586.8722
sales@fetteamerica.com
capsule filler on the market.
The FEC40 accomplishes
this elevated production
bar in a remarkably small
footprint, making machine
reconfiguration due to floor
space issues unnecessary.
The extraordinarily high ratio
of performance-to-footprint
is made possible by Fette
Compacting’s patented Duplex
Concept, which enables
the FEC40 to feature a dual capsule filling direct compression, enabling the machine to
process. The result is significant production operate with two intermediate pressures.
savings—up to 30% per 1000 capsules.
The FE35 and FE55 tablet presses share
Innovative Tablet Presses several technologies with the FE75, including
Fette’s premium family of tablet presses are a new, patent-pending conical filling unit, a
headlined by its three-member FE Series: highly accurate manually adjustable filling
smallest to largest, the FE35, FE55, and table, innovative compression rollers, trouble-
FE75. The FE75 Tablet Press is a double- free tablet discharging through the column,
sided rotary press that can be equipped with a revamped operating terminal, and the
up to 115 punch stations to produce more connection of process equipment through a
than 1.6 million tablets/hr. Ideal for producing standardized plug-and-play interface.
large batches, the FE75’s four compression
rollers feature a special control system for TRI.EASY Design Concept
Fette machines embody the company’s
TRI.EASY design concept, based on the
notion that technology’s efficiency runs
parallel to its ease of use during production,
changeover, and maintenance. The Tri.Easy
design focuses on the user and ensures
trouble-free production irrespective of an
operator’s experience and qualifications.
P h a r mTe c h . c o m
 PRODUCT AND SERVICE PROFILES

Fluid Metering Inc

5 Aerial Way, Suite 500
Syosset, New York 11791
Tel. 1.516.922.6050
Toll-Free: 1.800.223.3388
pumps@fmipump.com
www.fmipump.com

processing to precision production dispensing

of cyclohexanone solvent in the manufacture of
disposable medical component kits (IV tubing
sets), dispensing monomers for contact lens
manufacturing, coating of drug eluting stents,
dispensing electrolytes used to made button cell
batteries for hearing aids, and much more.

Versatile, Ceramic Dispensers and
Metering Pumps for Medical OEM
Applications
Fluid Metering, Inc. has manufactured their dis-
pensers and metering pumps for more than 55
years. The valveless design and Sapphire-hard
internals provide drift-free accuracy without
recalibration for millions of maintenance-free
dispenses.
The applications where FMI’s valveless piston
technology is used are numerous, ranging from
micro-volume reagent fluid control in OEM
clinical diagnostic instrumentation, hemodialy-
sis machines, and automated immunoassay
Application Summary:
• Micro-volume fluid control of samples,
reagents, and buffers in clinical chemistry
instrumentation
• Dialysate recirculation pumps for hemodialy-
sis machines
• Fluid control for automated microplate wash-
ing and preparation
• Coating of drug-eluting stents with slow-
release drugs to prevent cell proliferation
• Dispensing of cyclohexanone for solvent
welding for IV tubing kit assembly
• Dispensing of UV curable and two-part
epoxy adhesives for medical component
assembly
• Dispensing of lubricants for assembly of
catheters
• Dispensing of monomers in the manufacture
of contact lenses
• Dispensing of electrolytes used in the
manufacture of button cell batteries used in
hearing aids
• Dispensing of marking inks used for packag-
ing of medical components
• Dissolution systems for pharmaceutical
testing.
In each application, the key features of the FMI
pump, including: one moving part, ceramic
internals, and valveless design, provide what
medical manufacturers are looking for, that
being long-term, drift-free accuracy and virtually
no maintenance or downtime.
For complete information on FMI’s dispens-
ers and pumps, go to www.fmipumps.com
or call and speak with one of our Application
Specialists.

Pharmaceutical Technology AUGUST 2017 55

PRODUCT AND SERVICE PROFILES

Metrics Contract Services

1240 Sugg Parkway
Greenville, NC
www.metricscontractservices.com

meet the various regulatory requirements of

international agencies.

An additional investment in facilities is our new

Your ‘Concept to
Commercialization’ Partner
The parent company of Metrics Contract Ser-
vices, Mayne Pharma, is investing $80 million
to expand facilities and equipment at its site
in Greenville, NC.
Construction includes a new 26,000-
square-foot, oral-dose commercial manu-
facturing facility that will quadruple the
company’s US manufacturing capacity. The
company also will dedicate 10+ new manu-
facturing suites and analytical laboratories
for pre-commercial activities, more than
doubling current development and clinical
capacity.
Once construction is complete, Metrics
Contract Services will offer a more compre-
hensive “concept to commercialization” solu-
tion for clients—providing larger scale and
increased capabilities for seamless scale-up
in one contiguous location.
stability storage “Center of Excellence.” The
$3.5-million standalone facility earned the
classification by integrating best-in-class op-
erational standards and equipment during con-
struction. The Stability Center of Excellence,
which is 17,000 square feet in size, triples the
company’s previous stability storage capacity.
While we are making enormous changes to
Our areas of expertise include:
• Quality pharmaceutical
formulation development
• First-time-in-man formulations
• Phase I-III clinical trial
materials manufacturing
• Analytical method development
and validation services leading to
commercial-scale manufacturing.
Metrics Contract Services’ technical capa-
bilities include highly potent, cytotoxic and
unstable compounds; Schedule II-V controlled
substances; and products with poor bioavail-
ability, for which the organization offers an
impressive proprietary portfolio of advanced
delivery methods.
To learn more about our expansion or Metrics
Contract Services’ capabilities, visit online at
www.metricscontractservices.com.

One highlight of the expansion includes com-

mercial-scale manufacturing capability with
solvent-based, fluid-bed processing and film
coating. Other benefits of our expanded new
facilities include custom-engineered solu-
tions to support the handling of highly potent
and toxic compounds and mitigate cross-
contamination risks, and deliberate design to
our facilities in Greenville, NC, some things
at Metrics Contract Services will never
change—such as delivering proven scientific
and operational excellence in oral dosage
forms for clients worldwide.

56 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m


Corporate Description
A recognized leader in contract manufac-
turing, Mikart specializes in the develop-
ment, 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 experi-
ence, a responsive working relationship,
and the ability to take products from formu-
lation development through full-scale com-
mercial production.
Technical Services
• Formulation development
• Analytical methods development
• Process validation
• Stability testing
• Clinical supplies manufacturing and
packaging
PRODUCT AND SERVICE PROFILES
Mikart, Inc.
1750 Chattahoochee Ave.
Atlanta, GA 30318
www.mikart.com
• Immediate- and controlled-release Markets Served
tablet manufacturing Mikart provides products and services to the
• Capsule manufacturing pharmaceutical industry, including PhRMA,
• Liquid manufacturing specialty pharmaceutical and biotechnology
• CII–CV controlled-drug manufacturing companies.
• Film coating
• Fluid-bed and high-shear granulating
• Solid-dose and liquid-bottle packaging
• Bottle powder filling
• Blister packaging/card sealing/cartoning
• Laminated foil pouch packaging
• Liquid unit dose
• Low humidity manufacturing
• Cold storage
• Regulatory services.
• Serialization
Facilities
Mikart has more than 234,000 ft2 of devel-
opment and production facilities located in
Atlanta, Georgia. The company’s Science
Center provides product development and
analytical services. Equipped with advanced
technologies, this 40,000-ft 2 center houses
quality control, analytical services, and a
complete pilot-scale manufacturing opera-
tion. Processes include fluid-bed granulating,
roller compacting, and high-shear granulat-
ing. The facility enhances Mikart’s ability
to take products from initial development
through commercial production. The com-
pany has recently completed an expansion
of its manufacturing operations and now has
an annual production capacity in excess of 2
billion tablets and 2 million pints.
Pharmaceutical Technology AUGUST 2017 57
PRODUCT AND SERVICE PROFILES
MPI Research, globally headquartered in
Mattawan, Michigan, provides discovery,
safety evaluation, bioanalytical and
analytical services, clinical, surgical
services, and medical device evaluation to
the biopharmaceutical, medical device, and
animal health industries worldwide. MPI
Research exceeds expectations through
consistency and quality, with a commitment
to communication and innovation,
delivering benefits throughout all phases of
development.
58 Pharmaceutical Technology AUGUST 2017
MPI Research
54943 North Main Street,
Mattawan, MI 49071
Phone: +1.269.668.3336
info@mpiresearch.com
www.mpiresearch.com
allows it to respond and adapt rapidly, from
making last-minute scheduling changes to
developing new capabilities as needed.
The company researches a wide and diverse
range of compound classes, provides all
routes of administration (exception: inhalation)
and offers studies with numerous species and
models. With ample physical and technical
capacity, they can accommodate multiple
requirements simultaneously, adjust schedules
readily, and produce results quickly.
MPI Research Study Directors and scientists
are uniquely accessible on a real-time basis
and proactive in keeping Sponsors informed
as developments unfold, from collaboration on
the initial program design through final report.
MPI Research has conducted thousands Take a closer look at MPI Research by visiting
of drug safety, discovery, bioanalytical and www.mpiresearch.com.
analytical, surgical, and medical device
evaluation studies in both small and large
molecules. Although the company built its
reputation in toxicology testing primarily with
small molecules, it has greatly expanded its
scope. The company’s a discovery sciences
center, which focuses on efficacy testing,
has a strong presence within the cellular and
molecular biology fields, biomarkers, and gene
therapy. The company’s internal structure
P h a r mTe c h . c o m
 PRODUCT AND SERVICE PROFILES

Charles Ross & Son Company

710 Old Willets Path,
Hauppauge, NY 11788
www.mixers.com

problem. In the United States alone, Ross

operates five manufacturing plants, one of
the largest test centers in the mixing equip-
ment industry, and a vigorous R&D program.
Overseas, Ross Mixers and Blenders are
manufactured in four state-of-the-art plants
in China and India.

The Ross Test & Development Center, located

at the corporate headquarters in Hauppauge,
NY, is able to simulate most any application.
Experienced engineers in the Ross Technical
Services Group work with customers in the
test center to confirm their equipment selec-
tions and optimize their processes.

Ross’s investment in its people and facili-

ties for more than 170 years has yielded a
proud history of innovation in sanitary mix-
ing and blending. In the early 1900s, Ross
introduced the “Pony Mixer,” the world’s first
change-can mixer, which later evolved into
the modern Double Planetary Mixer. With the
“VersaMix” Multi-Shaft Mixer, Ross was the
first to offer the flexibility and efficiency of
three independently-driven agitators in one
piece of mixing equipment. The “MegaShear”
ultra-high shear rotor/stator mixer and the
“SLIM” high-speed powder induction technol-
ogy have advanced processing productivity
even further. Today, Ross innovations are
producing significant advances in high-preci-
sion powder blending, emulsification, particle
size reduction, specialized pharmaceutical
compounding, as well as process controls
and data acquisition.
Ross is well-equipped to solve virtually
any mixing, blending, dispersion, or drying
Ross Processing Equipment
for the Pharmaceutical Industry
• Double Planetary Mixers and Planetary
Dispersers: Ideal for processing viscous
applications such as bone graft substi-
tutes, hydrogels, pastes, dental compos-
ites, encapsulation materials, and many
others. Ross planetary-style mixers are
also used in the preparation and vacuum
drying of pharmaceutical granulations.
• Multi-Shaft Mixers and High Shear Mix-
ers/Homogenizers: A wide range of Ross
mixing equipment are available for pro-
ducing creams, lotions, ointments, and
other semisolids for the pharmaceutical,
cosmetic, and personal care industries.
Equipped for sub-surface powder induc-
tion, these mixers can complete very
challenging dispersions of fumed silica,
CMC or gums, and thickeners faster and
more efficiently than any other method.
• A full line of Tumble Blenders, Ribbon
Blenders, and Vertical Blenders for pow-
der mixing and drying applications, as
well as coating free-flowing solid par-
ticles with minor liquid ingredients.
• Sanitary Tanks, Storage Vessels, Reac-
tors, and Transfer Vessels

Pharmaceutical Technology AUGUST 2017 59

PRODUCT AND SERVICE PROFILES
Shimadzu Scientific Instruments
Integrated HPLC/UHPLC
The i-Series system is designed to deliver
reliable results with minimum effort. It offers
easy-to-understand instrument control and
an advanced interactive design that allows
users to monitor run status and results re-
motely with your smart phone. In addition, it
offers easy methods migration and reduced
operating costs with an automatic power
economy mode.
LCMS-8060 Triple
Quadrupole LC-MS/MS
The new LCMS-8060 offers unmatched ultra-
fast technologies, including a polarity switch-
ing time of 5 msec and a data acquisition
scan speed of 30,000 u/sec, a redesigned ion
optical system, and outstanding durability to
expand the limits of LC-MS/MS quantitation
and achieve new levels of data quality.
60 Pharmaceutical Technology AUGUST 2017
7102 Riverwood Drive
Columbia, MD 21046
tel. 800.477.1227
fax 410.381.1222
www.ssi.shimadzu.com
EDXRF Spectrometers
Compliant with US FDA 21 CFR Part 11,
the EDX-7000/8000 can analyze residues
such as residual metal catalysts, hazardous
metals, and metal impurities contained in
active pharmaceutical ingredients easily and
non-destructively without requiring any pre-
treatment. As compared to time-consuming
chemical analysis procedures, the EDX-
7000/8000 offer simplified operation in any
pharmaceutical production process.
Precise FTIR Analysis
From raw materials to finished products &
packaging, Shimadzu FTIR spectrometers
offer the speed, sensitivity, and reliability to
meet your application. They offer long-term
stability, easy maintenance, and shorter
warm-up times. Powerful software and au-
tomated contaminant analysis and identifica-
tion test programs enable easier analysis.
Laboratory TOC Analyzers
From inspections of the water used in drug
manufacture to cleaning validation, Shi-
madzu’s TOC analyzers are ideally suited for
the measurement of residual pharmaceutical
products and their constituent substances.
They feature ultra-wide measurement range,
patented 680°C Combustion Catalytic Oxida-
tion/NDIR detection method, fully automated
sample pretreatment, and multiple autosam-
pler options.
GC Designed with the
Analyst in Mind
Incorporating a host of technologically
advanced features, the Nexis GC-2030 im-
proves user connectivity and ease of use,
increases throughput, produces superior re-
sults, and ultimately yields a higher return on
investment. Specialized accessories enable
configurations geared to specific markets,
and is ideal for the analysis of residual sol-
vents as described in USP<467>.
P h a r mTe c h . c o m

Since 1981, Veltek Associates, Inc. (VAI) has
played an innovative role in the reduction in
contamination for the pharmaceutical, bio-
technology, and medical device industries.
By partnering with our clients to develop
strategic products and services, VAI has
been able to notably improve operations and
reduce costs associated with the ingress of
contamination.
VAI is a registered manufacturing facility
located in Malvern, Pennsylvania, USA. This
facility houses four main divisions: the Ster-
ile Chemicals Manufacturing Division (SCMD),
PRODUCT AND SERVICE PROFILES
Veltek Associates, Inc.
15 Lee Blvd.
Malvern, PA 19355
Tel. 610.644.8335
Fax 610.644.8336
vai@sterile.com
www.sterile.com
the Environmental Control Manufacturing
Division (ECMD), the Disposable Products
Manufacturing Division (DPMD), and VAI
Labs. VAI’s manufacturing and testing opera-
tions mirror current GMP and GLP standards.
SCMD features a comprehensive range of
sterile pharmaceutical grade disinfectants,
sporicides, residue removers, lubricants, pro-
cess cleaners/detergents, and quality water.
To streamline the application of our disinfec-
tants, VAI developed the Core2Clean® Plus
System. The Core2Clean Plus incorporates
spray, mop, and fog into one device and can
reduce cleaning time up to half, among other
benefits. VAI Labs, provides microbiological testing
services ranging from the identification of
ECMD manufactures viable monitoring sys- microorganisms to antimicrobial effective-
tems including: a portable sampler the SMA® ness studies. Included in this division is our
MicroPortable, a SMA Compressed Air/Gas consulting services. VAI’s consulting service,
Sampler, and the SMA OneTouch® ICS with Aseptic Processing Inc., can work to combine
complete, facility-wide, digital control panel all contamination control aspects within an
monitoring. organization into one overtone system that is
compliant and effective. Repeatable success
DPMD offers two recently redesigned gar- has been and will be assured.
ment lines available in a patented Easy-
2Gown® Fold. The two material lines are
available in coveralls, hoods, boots, and
frocks to address all needs. In addition, face-
masks, shoe covers, sweat-less headbands,
and bouffant hats are available. DPMD, fur-
thermore, features a line of cleanroom paper
and supplies. This line includes cleanroom
paper, custom documentation materials, and
a HEPA-filtered cleanroom printer.
Pharmaceutical Technology AUGUST 2017 61
pharma capsules

expected to start in the second because FBS is used in bio-

CordenPharma Adds
Manufacturing
Line for Vet
Drug Products
CordenPharma, a contract de-
velopment and manufacturing
organization (CDMO) for APIs,
drug products, and packaging,
will invest €10 million (almost
$12 million) in a new manufac-
turing line dedicated to produc-
ing veterinary drug products for
500-kg scale batch sizes. This
new line is part of a produc-
tion plant that is dedicated to
veterinary drug products.
The expansion of the pro-
duction capabilities at Corden-
Pharma Plankstadt (Germany)
is the result of a new, long-term
custom manufacturing agree-
half of 2018.
The new production line
will allow the fully contained
handling of highly potent APIs
in a dedicated facility for the
manufacturing of veterinary
drug products, said Frank
Hähner, managing director of
CordenPharma Plankstadt, in a
press release.
GE, Oritain Partner
on Bovine Serum
Traceability
GE Healthcare and Oritain, a
New Zealand-based company
specializing in the scientific
verification of food origins, have
launched an independent test-
based traceability program to
manufacturing, and different
countries pose different risk
levels for virus contamination.
Using FBS from low-risk
countries is a priority in
biomanufacturing.
GE is currently traceability-
certified by the International
Serum Industry Association.
To verify that raw serum from
Australia, New Zealand, and
the United States is from that
country of origin, GE will also
put its sera products through
a testing process that goes
beyond industry-standard
traceability practices.
With GE’s new testing
program, Oritain will perform
independent testing on FBS
batch samples from Austra-
lia, New Zealand, and the US.
STA Merges
with WuXi’s
Pharmaceutical
Development
Services Division
STA Pharmaceutical announced
on July 31, 2017 that it has
merged with WuXi AppTec’s
Pharmaceutical Development
Services (PDS) division. The PDS
division offers pre-formulation
development, formulation
development, as well as clinical
trial material (CTM) manufactur-
ing, packaging, and labeling of
oral solid-dosage forms. The
portfolio also includes various
enabling technology platforms
for poorly soluble drugs such
as spray dried dispersion,

UDOMSOOK/SHUTTERSTOCK.COM
authenticate the country of Oritain’s scientific traceability hot-melt extrusion, micro- or
ment for an animal health ap-
origin of fetal bovine serum method does not rely on paper nanosuspension, and liquid-
plications. Work began in the
(FBS), a cell growth supplement or labels, but rather authenti- filled hard-gelatin capsules.
second quarter of 2017, with a
used for manufacturing bio- cates the origin of the product Following the merger, STA
targeted mechanical comple-
pharmaceuticals and vaccines. itself, according to Oritain in Pharmaceutical will provide
tion by the 2nd quarter of 2018
FBS is also used in basic re- a company press release. fully integrated small-mol-
and commercial supply for
search and drug discovery. The ecule API and drug product
the global launch campaign is
country of origin is important solutions to global clients.

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Aenova . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Fluid Metering Inc . . . . . . . . . . . . . . . . . . . . . 55 Ross, Charles and Son Co . . . . . . . . . . . . 9, 59

Ashland Specialty Ingredients . . . . . . . . . . . . 2 Metrics Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Samsung Biologics Co Ltd . . . . . . . . . . . . . . 67

Catalent Pharma Solutions . . . . . . . . . . 51, 68 Metrohm USA Inc . . . . . . . . . . . . . . . . . . . . . 39 Shimadzu Scientific Instrument . . . . . . . 25, 60

CPhI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43, 47 Mikart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Suheung-America Corporation . . . . . . . . . . 23

Emergent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 MPI Research . . . . . . . . . . . . . . . . . . . . . . . 3, 58 US Pharmacopeial Convention . . . . . . . . . . 35

Eppendorf North America . . . . . . . . . . . 21, 52 Parenteral Drug Association . . . . . . . . . 15, 17 Veltek Associates . . . . . . . . . . . . . . . . . . . 5, 61

Eurofins Lancaster Laboratories . . . . . . . . . 53 PharmSource Information Services Inc . . . 49

62 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m

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Ask The Expert— contin. from page 66

More Expert Insight
The next photograph in the batch record tale is the packaging
of the final product into its primary container. The foreground For more advice from industry experts,
in this photograph should be on the release of the labeling visit PharmTech.com to read the following:
and confirmation that the lot number and the expiration date
• Ensure Quality in a Contract Test Laboratory
assigned are appropriate. The main picture should center on
making sure there were no component mix-ups or line stoppages
www.pharmtech.com/ensure-quality-contract-test-
that would compromise the product during the packaging phase laboratory
of the operation. Again, attention needs to be paid to make sure • Engaging with Interest Groups
that any deviations during this phase of production have been or Industry Associations
resolved. Background for this photo includes container-closure
www.pharmtech.com/engaging-interest-groups-or-
integrity and stability.
There is actually no specific order in which the information/
industry-associations
photo should be reviewed. Some reviewers like to wait until • Making the Most of Internal Audits
they have everything before they start their review so they www.pharmtech.com/making-most-internal-audits
can see the whole story upfront; others like to disposition or • Covering Global Regulations in a Quality System
view the pictures as they come in and try to visualize the final
www.pharmtech.com/covering-global-regulations-
picture. Either way is acceptable for batch record review. Many
companies use a checklist to make sure all the elements of the
quality-system
master batch record are included in the product batch record. • Ensuring Sterility in Small-Scale Production
This is an acceptable practice and, when coupled with a thorough www.pharmtech.com/ensuring-sterility-small-scale-
review of the contents of those elements, you should be able to production-0
rest assured that you will be able to have confidence in releasing
product batches. PT

Pharmaceutical Technology AUGUST 2017 65

ask the expert
A Look at Batch
Record Review
The review of batch records creates a story of the materials, manufacturing, and
packaging involved in the production of bio/pharmaceuticals, according to Susan
Schniepp, distinguished fellow at Regulatory Compliance Associates.
Q: I have just been promoted to a new position in the quality
organization at my company and will now be responsible
for batch record release. I am a little nervous about this respon-
sibility. Can you give me some tips for reviewing and releasing
batch records?
A: This is a great question. Batch record review and release
is an important responsibility in any company and it
should not be taken lightly. The best way to visualize a ‘batch’
record is to think of it as a series of photographs that, if put
together in the proper sequence and with the correct back-
ground, tell a story about the quality and suitability of the
product.
The first picture in this story begins with the incoming raw
materials that include the active ingredient(s), excipients,
primary packaging, and labeling. Each one of these items
should be properly received, sampled, and put into quarantine
until the incoming quality group establishes their suitability
for use. This includes testing of the water that might be used
in manufacturing the product. The background of this picture
would be making sure the laboratory equipment was properly
calibrated, the methods validated, and the analysts properly
trained. Once the materials are deemed suitable, they may
be released to the manufacturing line for formulating and
processing. The foreground in this picture should be the
results from the laboratory testing, the inventory control
procedures, and the certificate of analysis from the supplier(s).
It is important to make sure that any deviations or errors
associated with this activity have been properly investigated.
The next picture in the story is the actual manufacturing
of the product. The picture here is a master batch record
where the actual amounts of the actives and excipients
are mixed together and formulated into the final product.
In this particular photograph, it is important to notice the
foreground as well as the back ground. The foreground
should be the confirmation that all the materials used were
appropriately discharged using calibrated equipment in
a suitable environment. Also in the foreground should be
some indication as to whether the manufacturing rooms were
properly cleaned and cleared before the start of the next
batch. The main focus of the picture should be the details of
the batch manufacturing itself. Things to notice would be:
66 Pharmaceutical Technology AUGUST 2017 P h a r mTe c h . c o m
• Were the materials sequenced/combined in the proper
order (if this matters)?
• Were the materials mixed and stirred for the required
length of time?
• Were the results of any in-process testing with in
specification(s)?
Attention needs to be
paid to make sure that
any deviations during this
phase of production have
been resolved.
Another focus of the picture should be the behavior of the
operators, especially if your product is processed aseptically.
It is also important to make sure that operators signed (this
could be electronically) in the appropriate places indicating
they performed the work. If required, there should also be an
indication that another employee or a supervisor witnessed
the work. This is particularly important when verifying the
right ingredients were discharged to the line to make the right
product with the right dosage amount. Attention should also
be paid to making sure any deviations or investigation have
been thoroughly investigated and closed before releasing the
product. The background of this activity should focus on the
training of the operators to perform their functions, robust
process validation, the qualification of cleaning materials to
DAMIAN PALUS/SHUTTERSTOCK.COM
prevent cross or microbial contamination, and other routine
maintenance and monitoring procedures that maintain the
manufacturing area and lines to an acceptable state of control.
The background also should include results of environmental
and personnel monitoring (if appropriate), media fills for
aseptic processed product, particulate-matter monitoring,
smoke study results, etc.
Contin. on page 65
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