Professional Documents
Culture Documents
American Pharmaceutical
SHOW ISSUE:
CPhI North America
BIO International Convention
The Application
of Risk Assessments
for the Design and
Development of Devices
for Biological Products
Low-Frequency Raman
Mapping and Multivariate
Image Analysis for
Complex Drug Products
www.americanpharmaceuticalreview.com
Our Complicated
Relationship with Fungi
www.americanpharmaceuticalreview.com
The Foundations for
Single-Use Manufacturing.
Redefined from A–Z.
In the past, biopharma companies were struggling with various risk
factors which kept them from implementing single-use solutions.
www.sartorius.com/single-use-redefined
FDA REGISTERED / cGMP / USP • EP • JP • FCC • ACS
Purity.
Traceability.
Trust.
We manufacture everything we sell.
Visit jostchemical.com
jostchemical.com 314-428-4300 US +1 314 428 4300 EU +32 85 552 655
Corporate American Pharmaceutical Review (ISSN 1099-8012) is published
CEO | Paul Gatti seven times a year (February, March, April, June, August, October,
PRESIDENT | Rich Marino December) by CompareNetworks, Inc. 395 Oyster Point Blvd.
GROUP PUBLISHER | Laura Zoibi Rice #300 South San Francisco, CA 94080. Subscription Rate (7 issues)
1 year $135.00. Periodicals postage paid at South San Francisco,
ACCOUNT COORDINATOR | Dorothy Fuentes
CA 94080 and additional mailing offices.
Editorial
POSTMASTER: Send change of addresses to American
EDITOR-IN-CHIEF | Mike Auerbach American Pharmaceutical Review Pharmaceutical Review, 395 Oyster Point Blvd. #300, South San
mauerbach@comparenetworks.com Published by Francisco, CA 94080. Publication Agreement #40739004.
WEB CONTENT EDITOR | Andrea Lyn Van Benschoten
Return undeliverable Canadian addresses to: IMEX, PO
avanbenschoten@comparenetworks.com Box 25542, London, ON N6C 6B2, Canada, Email: info@
comparenetworks.com
Sales CompareNetworks, Inc.
NATIONAL SALES MANAGER | Laura Zoibi Rice Copyright rests with the publishers.
395 Oyster Point Blvd. #300
lrice@aprpub.com All rights reserved ©2019
South San Francisco, CA 94080
CompareNetworks, Inc.
Production
www.comparenetworks.com
ART DIRECTOR | Jennifer Campbell No part of this publication may be reproduced, stored in a
E-mail: info@comparenetworks.com retrieval system or transmitted in any form or by any means
jcampbell@comparenetworks.com
Website: www.americanpharmaceuticalreview.com electronic, mechanical, photocopying, recording or otherwise
PRODUCTION MANAGER | Allison Chelminiak
without the prior written permission of the copyright holder.
achelminiak@comparenetworks.com
Printed in the USA While the publishers believe that all information contained in
this publication was correct at the time of going to press, they
can accept no liability for any inaccuracies that may appear or
loss suffered directly or indirectly by any reader as a result of
any advertisement, editorial, photographs or other material
published in American Pharmaceutical Review.
ON-DEMAND WEBINAR
Therapeutics that manipulate gene expression are a rapidly growing segment of biopharmaceuticals that address
unmet medical needs. However, gene therapies usually include both nucleic acid and protein components, Jonathan
exponentially increasing the complexity of the development tasks needed to meet the Chemistry, Manufacturing, Neidigh
and Control (CMC) requirements of the FDA. A development strategy that leverages the experience and unique Associate Director of
skills of contract research and manufacturing organizations that specialize in biopharmaceuticals is essential to Pharmaceutical Development
meet the aggressive timelines for orphan drug designation or Fast Track programs. The novelty of these gene Wolfe Laboratories
therapy drugs require the design of new analytical methods to satisfy the intended purpose outlined by the CMC
Jonathan W. Neidigh is an Associate
strategy. Discriminating analytical methods are needed for the protein and nucleic acid components, as well as for
Director of Pharmaceutical
the fully assembled biotherapeutic, and the methods are leveraged to characterize the drug and efficiently conduct
Development at Wolfe Laboratories,
formulation and process development. Done correctly, the early development activities will aid identification of the
an integrated CMC drug product
critical quality attributes that are needed to demonstrate drug product quality.
development CRO. Jonathan is
In this webinar you will learn: an expert in the analytical and
biophysical characterization of
• Strategies to accelerate analytical and formulation development of gene therapy drugs
biological molecules with academic
• Characterization approaches for drugs containing both protein and nucleic acids
and industry experience working
• Methods needed for process and analytical control of gene therapy drugs SPONSORED BY
on the development of nucleic acid,
Who should attend: peptide, and oligonucleotide drugs.
• Analytical Development Scientists Jonathan is the author or co-author
PRESENTED BY of twenty six publications and
• Formulation Scientists
• Gene Therapy Researchers recieved his PhD in Chemistry from
• Vaccine Development Scientists the University of Washington.
2 | | April 2019
April 2019 | Volume 22, Issue 3
COVER FEATURES
28 MICROBIOLOGY
Our Complicated Relationship with Fungi
Jeanne Moldenhauer
Excellent Pharma Consulting, Inc.
40 BIOPHARM DEVELOPMENT
The Application of Risk Assessments for the Design and Development of Devices for Biological Products
Manfred Maeder, PhD
Global Head Device Development & Commercialization
Global Drug Development/Technical Research & Development
Novartis
48 SPECTROSCOPY
Low-Frequency Raman Mapping and Multivariate Image Analysis for Complex Drug Products
Daniel R. Willett, Huzeyfe Yilmaz, Anna M. Wokovich, Jason D. Rodriguez
Food and Drug Administration (FDA)/Center for Drug Evaluation and Research (CDER)/Office of Pharmaceutical Quality
(OPQ)/Office of Testing and Research (OTR)/Division of Pharmaceutical Analysis (DPA), St. Louis, MO
www.americanpharmaceuticalreview.com | | 3
IN THIS ISSUE »
12 MICROBIOLOGY 44 ROUNDTABLE
4 | | April 2019
A S S O C I AT E S O F C A P E C O D , I N C .
HORSESHOE CRAB
S U S TA I N A B I L I T Y P R O J E C T
Yo u c a n l e a r n m o re a b o u t t h i s e x c i t i n g
n e w p ro g r a m b y v i s i t i n g o u r w e b s i t e .
PR-18-035
» A Message from the Editor »
Collecting Data for Data’s Sake
Way back when, pre-Internet, the publishing company I worked for produced about 21 different magazines. All were new product tabloids
covering every imaginable industry. As a result, we had a large editorial department, since this was pre-internet, and pre-email, everything
was sent to us via regular mail. Editors had to sort through piles of mail, choose products that were appropriate to their markets and write
up new product reviews, oftentimes more than a hundred for each issue.
After an issue was complete, one of the tasks each editor had to do every month was to take a printed issue, and assign a code to every
product and every advertisement. This was a tedious task that involved looking through a massive printout of product categories, finding
the appropriate code, and writing that code on every piece of content in the issue. Depending on the size of the issue – this task could take
hours to complete.
Once finished, the marked-up issue was sent to Data Entry for processing. As Editors we all assumed this data was being used for some
purpose. When, finally, the inevitable happened, and someone asked what the data was being used for, the answer came back, “We aren’t
using it for anything, but keep doing it in case we need it, because we might.”
It wasn’t long after this, that we were allowed to end this task. To this day, I have no idea if that data collected was ever used for anything
worthwhile. Who knows, all this data could be sitting in a cloud somewhere.
I imagine the pharmaceutical industry has operated in this way for some time. Collect as much data as possible, store it, because who knows
someday it might be needed.
This is a wasteful, time-consuming and inefficient practice. As a traditionally conservative industry, you can sort of understand why it has
been this way for so long, but finally there are some initiatives taking hold that will hopefully transform the collection of data into truly
actionable information.
First is the promise of Big Data. With all of the data companies have been collecting, the time has finally come where this data can be used
for advancing programs and products. Without going into details leveraging Big Data is finding applications in advancing clinical trials,
increasing industry collaboration, streamlining sales and marketing, and developing apps for consumers.
On the heels of the Big Data push is the Pharm 4.0 initiative – which will essentially tie all resources - human, data, and physical machines –
in one virtual network.
Pharma 4.0 combines diverse technologies, including big data analytics and cloud computing. The ability to analyze the enormous amount
of data collected and then share insights will allow faster innovation and a quicker response to changing market dynamics.
It’s encouraging to see data used for a purpose, other than just for “in case”. Technology has advanced to the point where billions of pieces
of data can be collected and stored for every operation. It’s time that data was leveraged for good.
Mike Auerbach
Editor-In-Chief
mauerbach@comparenetworks.com
6 | | April 2019
the next
bioavailability
challenge...
Let’s solve it together.
Dissolution rate and solubility issues are With our deep knowledge, broad expertise, Visit pharma.lonza.com
increasingly common for drug candidates. and established track record we can find USA +1 800 706 8655
We can help you optimize the bioavailability the right solution to your specific challenge. Rest of world +44 (0)1 506 448080
of your compound through our comprehen- Email solutions@lonza.com
sive toolbox of enabling technologies. Our Advance your compound from concept to © 2019 Lonza. All rights reserved.
approaches include API crystal structure commercialization with one partner – Lonza.
design, particle size reduction, amorphous
dispersions, and lipid-based formulations.
» Editorial Advisory Board »
Shaukat Ali, PhD John Finkbohner, PhD Daniel L. Norwood, MSPH, PhD
Technical Support Manager Director, Regulatory Affairs Distinguished Research Fellow
BASF Corporation MedImmune Boehringer Ingelheim Pharmaceuticals, Inc.
Ghulam Shabir Arain, PhD, CSci, CChem, Adam S. Goldstein Mehul Patel
FRSC, FCQI Senior Manager, Clinical Purification, Operations/Development Global Marketing Director
Managing Director Genentech Endotoxin and Microbial Detection
DGS Pharma Consulting Ltd., UK Charles River
Davy Guillarme, PhD
Katherine Bakeev, PhD Senior Lecturer, School of Pharmaceutical Sciences David Radspinner
Director of Analytical Services and Support University of Geneva, University of Lausanne Director of Marketing and Applications Support for BioProcess
B&W Tek, Inc. Production
Chris Halling
Douglas J. Ball, MS Thermo Fisher Scientific
Senior Manager, Global Communications
Diplomate, American Board of Toxicology; Research Fellow, and European Marketing
Drug Safety Research & Development Aniruddha M. Railkar, PhD
Catalent Pharma Solutions
Pfizer Global Research & Development Director of CMC
Tarsa Therapeutics
Brian Lingfeng He
Suraj Baloda, PhD
Research Investigator Gary E. Ritchie
Founder and President
Bristol-Myers Squibb President
SARMICON, LLC.
Council For Near Infrared Spectroscopy
Ronald Iacocca, PhD
Rory Budihandojo
Senior Research Advisor, Product and Process Performance Rodolfo J. Romañach, PhD
Director, Quality Systems Audit
Eli Lilly & Co. Professor of Chemistry
Boehringer Ingelheim Shanghai Pharmaceuticals
Co., Ltd. University of Puerto Rico, Mayagüez Campus
Maik W. Jornitz
Vice President of Business Development Shouvik Roy, PhD
Harsh Chauhan, PhD
G-Con Manufacturing, LLC Principal Scientist, Organizational Unit Leader in
Assistant Professor
School of Pharmacy & Health Professions Hemant N. Joshi, PhD, MBA Drug Product Engineering
Creighton University Principal Amgen
Tara Innovations LLC Jim Rydzak
Robert V. Chimenti
Sr. Strategic Applications Engineer Ian Lewis, PhD Investigator, Strategic Technology Division
Innovative Photonic Solutions Director of Marketing GlaxoSmithKline
Adjunct Professor Kaiser Optical Systems, Inc. Ronak Savla
Rowan University
Ralph Lipp, PhD Fellow
Emil W. Ciurczak, PhD President and CEO Catalent Applied Drug Delivery Institute
Doramaxx Consulting Lipp Life Sciences LLC
Ken Seufert
Rick E. Cooley Jack Lysfjord Managing Director, North America
Retired Principal Consultant MEGGLE USA Inc.
Eli Lilly & Co., Inc. Lysfjord Consulting LLC
Jaleel Shujath
Weiguo Dai, PhD Steven R. Maple, PhD Industry Strategist, Life Sciences
Scientific Director, Janssen Fellow, Drug Product Development Head of Pharmaceutical Technology Development Dept. OpenText
Johnson and Johnson Lilly Research Laboratories, Eli Lilly & Co., Inc.
Donald C. Singer
Nila Das, PhD Jerold M. Martin GSK Senior Fellow, R&D
Senior Research Investigator Senior Vice President, Scientific Affairs GlaxoSmithKline
Bristol-Myers Squibb Pall Life Sciences
Onkar N. Singh, PhD, MBA
Vivek Dave, PhD John P. Mayer Director, Pharmaceutical Development at CONRAD
Assistant Professor, Pharmaceutical Sciences Senior Research Scientist Eastern Virginia Medical School
St. John Fisher College, Wegmans School of Pharmacy Indiana University
Allen Templeton, PhD
Michael Dong, PhD Michael J. Miller, PhD Associate Vice President
Consultant President Formulation Sciences Merck Research Laboratories
MWD Consulting Microbiology Consultants, LLC
Zhenyu Wang, PhD
Dr. Thomas Dürig Ronald W. Miller, PhD, MBA Associate Principle Scientist and Group Leader
Sr. R&D Director, Pharmaceutical and Food Ingredients President , Technology Consultant Respiratory Product Development
Ashland Inc. Miller Pharmaceutical Merck & Co.
8 | | April 2019
Find your perfect fit
with excipients tailored
to exacting quality and
regulatory standards
Dana-Farber
ASCO @DanaFarber
@ASCO
“By the year 2030, colon cancer is estimated to rise 90% and
"We need to shorten the time it takes from idea to rectal cancer to rise by a staggering 124% in these young
discovery and from discovery to application at the point patients,” said the director of the Young-Onset Colorectal
where lives are saved." Dr. Raymond Osarogiagbon on Cancer Center, Kimmie Ng, MD, MPH. Learn more about our
why he's passionate about NCI funding. Why do you new center: http://ms.spr.ly/6010T12G6
#LiveToConquerCancer?
Bayer US
Johnson & Johnson @BayerUS
@JNJCares
Leaps by Bayer and Khloris Biosciences have joined forces
to develop novel, first-in-class anti-cancer vaccines with the
Some 20% of people diagnosed with #lungcancer have
potential to address one of today’s biggest issues in human
never smoked. Scientists who've dedicated their research
health: to prevent and cure cancer. Read more:
to defeating the disease share why early detection is key—
http://bit.ly/2WJNNBt
and what you can do to protect yourself:
https://goo.gl/r1XC7Z
Celgene Corporation
Memorial Sloan Kettering @Celgene
Cancer Center
@sloan_kettering #NEWS: #Celgene and @AcceleronPharma announce
submission of a Biologics License Application to the U.S. FDA
Researchers have redesigned CAR T cells in hopes of in both #MDS & Beta-Thalassemia for an investigational agent.
improving immunotherapy treatment for multiple myeloma. #thalassemia http://bit.ly/2uNaQ27
https://t.co/pQsM9Y2yFx
facebook.com/AmericanPharmaceuticalReview
twitter.com/ampharmrev
linkedin.com/groups/American-Pharmaceutical-
Review-3889659
10 | | April 2019
CNPerspectives
American Pharmaceutical Review is one of several outstanding publications available from CompareNetworks, Inc.
Here is a look at the insightful content our readers may enjoy from four of our sister publications: Pharmaceutical Outsourcing,
Labcompare, American Laboratory and Biocompare.
Preclinical research provides a great deal of insight into a new treatment’s safety, but clinical studies are vital to determining how a drug will affect
the human body, enabling researchers to gauge toxicity and overall efficacy of the treatment to achieve the desired patient outcome. While there
is always risk associated with a clinical trial, there are elements that give the study its best possible chance of success. Paramount among these
factors is the storage and handling of clinical compounds at each clinical trial site. Segregation and control of clinical compounds from approved
drugs can be a heavy burden at the trial sites, especially considering the increasing volume of approved temperature-sensitive drugs.
https://bit.ly/2I6w57Y
One of the challenges in providing human mesenchymal stem cells (hMSCs) for curative use is the production of large quantities of cells in a
robust manner. Whatever the tissue source, the number of hMSCs extracted will not be sufficient for clinical use; hMSCs have to be expanded
following isolation. Besides providing the needed cell quantities, hMSC production must also comply with the manufacturing process regulations
required of a fully controlled production system. hMSC expansion in stirred-tank bioreactors can be monitored and is scalable, and hence can
fulfill these requirements, from experimental quantities to production.
https://bit.ly/2thktph
The manufacture of therapeutic proteins, particularly monoclonal antibodies, has evolved into reliable, robust protocols characterized by
platform processes and standardized unit operations. These production methods, and their attendant efficiencies, have been disruptive in the
traditional sense but took decades before they were universally accepted. For example, single-use processing took years to reach its current
status, and has perhaps reached an adoption steady state. Similarly, the roughly tenfold improvement in titers for fed-batch CHO (Chinese
hamster ovary) cell cultures—a significant driver for disposable manufacturing—has been transformative, but took decades to achieve.
https://bit.ly/2uVoZKG
www.americanpharmaceuticalreview.com | | 11
» MICROBIOLOGY »
Operator: Reducing that the air handling system is functioning as designed, that water
systems are low in bioburden and are not leaking, and there is good
control of in-coming materials, will derive from people. It follows
Facility Environmental that an effective contamination control strategy will focus on the
control of operators. Control extends to behaviors, gowning and
having the correct equipment, and this will be supported by periodic
12 | | April 2019
TruCLEAN -
Cleaning with Confidence
TruCLEAN
Pro XL Cart Wringer TruCLEAN Mop Frame
Customer Service:
1-800-848-8483
» MICROBIOLOGY »
In terms of walkthroughs of the facility, examples of the types of • Is shoe disinfection regularly undertaken?
things that plant microbiologists or quality assurance staff should be • Are interlocks in place between the cleanroom and the
looking for in relation to personnel are presented below. As well as the process area?
14 | | April 2019
When finding nothing means everything.
When it comes to patient safety, should close determines your product’s sterility by providing
enough ever be good enough? In an industry a definitive yes or no result for the most critical
that relies on cutting edge technology to stay of decisions. Through reagent-catalyzed amplified
compliant, a subjective, visual final sterility ATP-bioluminescence detection, even the lowest
confirmation is no longer acceptable. levels of microbial ATP can be rapidly intensified
Celsis® rapid microbial detection to detectable levels.
16 | | April 2019
« MICROBIOLOGY »
(and status indicators for departments); through training courses; and reduce the impact upon the cleanroom environment.
through short and targeted coaching sessions (such as at the time of a
The approach outlined in this article, centered on education, audit
shift handover). Comparing the performance of different departments
and changing the culture can prove to be effective, not only in driving
through the use of metrics is also a possibility, if competition is deemed
changes to behavior but also in providing examples so that training
to be something that helps to drive improvement.
systems can be updated and procedures relating to gowning and
As an example, a poster campaign could center on improving glove
practices can be improved.
management and hand sanitization. This could be supported by visual
boards; creating training videos; adding photographs to procedures;
and a renewed training program. A training program should be rolled
out to all personnel with access to the manufacturing area to educate References
personnel on the importance of hand-washing and hand hygiene
1. EudraLex. The Rules Governing Medicinal Products in the European Union, Volume 4 - EU
Such key messages should also be incorporated into site induction Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary
programs and as part of the training package delivered to new starters, Use, Annex 1, Manufacture of Sterile Medicinal Products, Brussels, Belgium, 2009: https://
prior to going through gowning qualification. The training can also be ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2008_11_25_gmp-an1_
re-delivered should any operator be excluded from a cleanroom and en.pdf
be required to requalify. 2. FDA. Guidance for Industry Sterile Drug Products Produced by Aseptic Processing —
Current Good Manufacturing Practice, U.S. Department of Health and Human Services,
The effectiveness of updates to procedures, alterations to induction
2004: https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf
processes, and training can be measured through the incident rate
3. Hannigan, G.D. and Grice, E.A. Microbial ecology of the skin in the era of metagenomics
of glove plate microbial excursions, with the expectation that the
and molecular microbiology, Cold Spring Harb Perspect Med. 2013 Dec 1;3(12):a015362
incidence rate will decrease.
4. Kooken, J.M., Fox, K.F., and Fox, A. Characterization of Micrococcus strains isolated from
indoor air, Mol Cell Probes. 2012 ;26(1):1-5
Summary 5. Sandle, T. A Review of Cleanroom Microflora: Types, Trends, and Patterns, PDA Journal of
Pharmaceutical Science and Technology, 2011, 65 (4): 392-403
While the GMP expectations concerning control of microbial 6. Mackintosh, C.A. , Lidwell, O.M., Towers, A.G., and Marples, R.R. The dimensions of skin
contamination have generally remained constant over the past fragments dispersed into the air during activity, The Journal of Hygiene. 1978, 81(3)471-
decade, the number of warning letters and audit observations 479
pertaining to operator related microbial contamination in cleanrooms 7. Whyte, W. and Hejab, M. European Journal of Parenteral and Pharmaceutical Sciences,
appear to have increased over the last number of years. This trend 2007, 12 (2). pp. 39-46
suggests that need for greater vigilance on operator behavior so to 8. Eudy J. Human Contamination. A2C2 Magazine. April 2003
www.americanpharmaceuticalreview.com | | 17
» FORMULATION & DEVELOPMENT »
In regards to oral bioavailability, much research and discussion have groups susceptible to metabolism (such as phenols) could be
been levied against two issues: solubility and permeability. Depending concealed through ester formation, as in some prodrug approaches.
on the drug molecule, its dose, and its application, release from the oral The structure of the molecule could also be redesigned to avoid the
dosage form, dissolution into gastrointestinal fluids, and avoidance susceptible group followed by additional activity testing. However,
of precipitation may each require significant formulation efforts and both of these approaches require the generation of new molecules
strategies. Permeability is also a considerable problem for highly and would necessitate expensive toxicology testing in addition to
hydrophilic or highly hydrophobic molecules (i.e. logP values <1.5 or clinical studies. The advantage of our patented approach5 is that with
>5). To handle these issues better, several systems have been devised a relatively small amount of preclinical and formulation work, the
to guide drug developers. The first common one was Lipinski’s “Rule approach can be tested clinically.
of 5”,1 followed by Amidon’s “Biopharmaceutical Classification System” This article will discuss the approach as applied to three different types
(widely known as BCS),2 Benet’s “Biopharmaceutical Biopharmaceutics of compounds.
Drug Disposition Classification System” (BDDCS),3 and most recently a
“refined Developability Classification System” (rDCS).4 Although these
frameworks vary in purposes and methods, their common theme is to
understand the limiting factors determining oral drug bioavailability.
Application 1: Buprenorphine
Overall, absolute oral bioavailability (Fpo) may be estimated by Several buprenorphine products are marketed in the US to treat
multiplying the fraction absorbed (Fa), the intestinal availability (Fg), the epidemic of opioid use disorder, including sublingual or buccal
and the hepatic availability (Fh), as shown in Equation 1 below. For products, and a monthly depot injectable formulation. However,
many pharmaceuticals, considerations of solubility and permeability there has been no orally swallowed formulation of buprenorphine
(determinants of Fa) may suffice for bioavailability estimations and itself. Recently, an ester prodrug of buprenorphine (buprenorphine
comparisons, if Fg and Fh are close to 1. However, on their way to hemiadipate) was under development for oral dosing, but failed
systemic blood circulation, some drugs are extensively metabolized in Phase 1 clinical trials.6 Buprenorphine itself has very low
in the intestine and the liver. This presystemic metabolism can oral bioavailability7,8 despite good solubility and permeability.8
deliver a “one, two punch” resulting in low and variable oral absolute Buprenorphine has a high intrinsic hepatic clearance suggesting a
bioavailability. Thus, oral bioavailability could be maximized by high hepatic extraction ratio, thus a low hepatic availability (Fh), which
improving Fa, Fg, and Fh. we estimated to be 0.29.8,9 Additionally, the intestinal metabolism
of buprenorphine is also extensive, resulting in a low intestinal
Equation 1: Fpo = Fa*Fg*Fh
availability (Fg), which we estimated as 0.04.8,9 Even granting a fraction
One common approach to overcoming rapid presystemic metabolism absorbed (Fa) of 1, the absolute oral bioavailability of buprenorphine
is through structural modification of the active compound. Functional in humans is estimated between 1 and 3%.8-10 Therefore, the very low
18 | | April 2019
| Your molecule
Our mission
Drug substance | Drug product | Analytical services
Vincent Taiani
Mechanic, Packaging
www.cambrex.com
» FORMULATION & DEVELOPMENT »
20 | | April 2019
« FORMULATION & DEVELOPMENT »
Meanwhile, clinical studies have shown 6. Indivior. Result of Phase 1 trial of RBP-6300
mixed results in the use of dietary com- References: Buprenorphine Hemiadipate. Investor Information
2016; http://www.indivior.com/investor-news/
pounds for bioavailability enhancement. For
1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. result-phase-1-trial-rbp-6300-buprenorphine-
example, piperine (from black pepper) in-
Experimental and computational approaches to hemiadipate/. Accessed 2019/03/28, 2019.
hibits human P-glycoprotein and CYP3A4,23
estimate solubility and permeability in drug discovery 7. Jeffcoat AR, Cook CE, Perez-Reyes M, et al. Human
and enhances the oral bioavailability of the-
and development settings. Adv Drug Del Rev disposition of intravenous, oral and sublingual [3H]
ophylline and propranolol as demonstrated 2001;46(1–3):3-26. buprenorphine. In: Harris L, ed. Problems of Drug
in humans.24 In animal models, piperine in-
2. Amidon GL, Lennernas H, Shah VP, Crison JR. Dependence, 1992: Proceeding of the 54th Annual
creases the oral bioavailability of curcumin, Scientific Meeting The College on Problems of Drug
A theoretical basis for a biopharmaceutic drug
resveratrol,epigallocatechin gallate, and classification: The correlation of in vitro drug product Dependence, Inc. Vol 132. Keystone, CO: US Department
amoxicillin.25-28 Additionally, curcumin has dissolution and in vivo bioavailability. Pharm Res. of Health and Human Services; 1992.
also been shown to inhibit numerous en- 1995;12(3):413-420. 8. Maharao NV, Joshi AA, Gerk PM. Inhibition of
zymes involved in presystemic elimination.29 3. Wu CY, Benet LZ. Predicting drug disposition via glucuronidation and oxidative metabolism of
However, in a clinical study with healthy application of BCS: transport/absorption/ elimination buprenorphine using GRAS compounds or dietary
volunteers, piperine and curcumin at fairly interplay and development of a biopharmaceutics constituents/supplements: in vitro proof of concept.
high doses failed to change the AUC values drug disposition classification system. Pharm Res. Biopharm Drug Dispos. 2017;38(2):139-154.
for acetaminophen, midazolam, or flurbi- 2005;22(1):11-23. 9. Cubitt HE, Houston JB, Galetin A. Relative importance
profen, but modestly increased Cmax for 4. Rosenberger J, Butler J, Dressman J. A refined of intestinal and hepatic glucuronidation-impact
acetaminophen.30 As noted in the study, developability classification system. J Pharm Sci. on the prediction of drug clearance. Pharm Res.
2018;107(8):2020-2032. 2009;26(5):1073-1083.
circulating plasma concentrations of uncon-
jugated piperine or curcumin were unde- 5. Gerk PM, Barr WH, Ritter JK, Inventors; Virginia 10. Maharao N, Venitz J, Gerk PM. Use of generally
tectable (<0.6μM or < 0.05μM, respectively) Commonwealth University, assignee. Selective recognized as safe or dietary compounds to inhibit
metabolic approach to increasing oral bioavailability buprenorphine metabolism: potential to improve
despite the high doses, but conjugated me-
of phenylephrine and other phenolic bioactivities. US buprenorphine oral bioavailability. Biopharm Drug
tabolites were abundant. Therefore, to make patent 9,616,0332017. Dispos. 2019;40(1):18-31.
an oral bioavailability enhancement strategy
clinically successful, one would need to pay
careful attention to the biopharmaceutics
and disposition of the enhancers as well as
the active compounds. Particularly, it would
be best to maximize the exposure of the in-
testinal and hepatic enzymes to the enzyme
inhibitors during the absorption phase of
the active ingredient.
Conclusion
Despite the wealth of available literature
regarding solubility and permeability en-
hancement approaches, relatively little is
established regarding bioavailability en-
hancement by inhibition of presystemic me-
tabolism. Our patented approach works to
address the issues discussed above by using
RELIABLE
combinations of enzyme inhibitors directed
toward multiple metabolic pathways.5 This
DOMESTIC Your Integrated Drug
Substance Partner
approach would be well-suited for com-
pounds with rapid intestinal and/or hepatic
SUPPLY Meet us at
metabolism resulting in low and variable More than 40 Years of Experience CPhI North America,
oral bioavailability, especially for older drug April 30 - May 2, 2019
molecules like buprenorphine and phen- Chicago, IL
ylephrine and nutraceutical compounds. Booth 207
Hopefully, more partnerships between in-
www.ALBcustom.com
dustry and academia will help to bring many
new products to market.
www.americanpharmaceuticalreview.com | | 21
» FORMULATION & DEVELOPMENT »
11. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism study of buprenorphine: 24. Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC. Effect of piperine on bioavailability
evidence for new metabolic pathways. Drug Metab Dispos. 2005;33(5):689-695. and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin
12. Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P. Contribution of the different Pharmacol. 1991;41(6):615-617.
UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine 25. Barve K, Ruparel, K. Effect of bioenhancers on amoxicillin bioavailability. ADMET & DMPK.
metabolism and relationship with the main UGT polymorphisms in a bank of human liver 2015;3(1):45-50.
microsomes. Drug Metab Dispos. 2010;38(1):40-45.
26. Johnson JJ, Nihal M, Siddiqui IA, et al. Enhancing the bioavailability of resveratrol by
13. Hendeles L, Hatton RC. Oral phenylephrine: an ineffective replacement for
combining it with piperine. Mol Nutr Food Res. 2011;55(8):1169-1176.
pseudoephedrine? J Allergy Clin Immunol. 2006;118(1):279-280.
14. Eccles R. Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An 27. Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS. Piperine enhances the bioavailability of
illogical way to control methamphetamine abuse. British journal of clinical pharmacology. the tea polyphenol (-)-epigallocatechin-3-gallate in mice. J Nutr. 2004;134(8):1948-1952.
2007;63(1):10-14. 28. Zeng X, Cai D, Zeng Q, et al. Selective reduction in the expression of UGTs and SULTs, a
15. Hengstmann JH, Goronzy J. Pharmacokinetics of 3H-phenylephrine in man. Eur J Clin novel mechanism by which piperine enhances the bioavailability of curcumin in rat.
Pharmacol. 1982;21(4):335-341. biopharmaceutics & drug disposition. 2017;38(1):3-19.
16. McEnvoy GK, ed AHFS Drug Information. 1999 ed. Bethesda: American Society of Health- 29. Volak LP, Ghirmai S, Cashman JR, Court MH. Curcuminoids inhibit multiple human
System Pharmacists, Inc.; 1999. cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas
17. Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral decongestants. Pharmacotherapy. piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos. 2008;36(8):1594-
1993;13(6 Pt 2):116S-128S; discussion 143S-146S. 1605.
18. Lexi-Comp. Phenylephrine. Lexi-Comp Online; 2015: https://online.lexi.com/lco/action/ 30. Volak LP, Hanley MJ, Masse G, et al. Effect of a herbal extract containing curcumin and
doc/retrieve/docid/patch_f/1799564. Accessed 4/3/2015. piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics
19. Zhang Z, Gerk PM. Effects of generally recognized as safe (GRAS) and dietary compounds in healthy volunteers. Br J Clin Pharmacol. 2013;75(2):450-462.
on phenylephrine metabolism in LS180 human intestinal cells. Biopharm Drug Dispos.
2018;39(9):443-447.
20. Statista. Total U.S. dietary supplements market size from 2016 to 2024 (in billion U.S.
dollars). The Statistics Portal 2019; https://www.statista.com/statistics/828481/total-
About the Author:
dietary-supplements-market-size-in-the-us/. Accessed 2019/03/28, 2019.
Phillip M. Gerk received his Doctor of Pharmacy
21. Jaisamut P, Wiwattanawongsa K, Graidist P, Sangsen Y, Wiwattanapatapee R. Enhanced
oral bioavailability of curcumin using a supersaturatable self-microemulsifying (Pharm.D.) degree at the University of Illinois at
system incorporating a hydrophilic polymer; in vitro and in vivo investigations. AAPS Chicago, then did a clinical research fellowship at
PharmSciTech. 2018;19(2):730-740. Auburn University. He then attended the University
22. Lu P, Tong Q, Jiang F, et al. Preparation of curcumin prodrugs and their in vitro anti-tumor of Kentucky where he received his Ph.D. and
activities. Journal of Huazhong University of Science and Technology Medical Sciences.
stayed to perform postdoctoral research. He has been a faculty
2005;25(6):668-670,678.
member at Virginia Commonwealth University in the Department of
23. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. Piperine, a major
constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Pharmaceutics since 2004, where he performs his research on drug
Ther. 2002;302(2):645-650. metabolism, transport, and oral bioavailability.
22 | | April 2019
» BIOPHARM PROCESSING »
Single-use bioprocessing equipment has made considerable progress in 5 to 10 years to about 70-75% stainless and 25-30% single-use. This
in the past 10 years. An estimated 10% of current total worldwide includes growth in the SUS market of up to 300% and market share
bioprocessing capacity, or about 1.7 million liters, involves primarily growing to ~25-30%. These data reflect downstream applications
single-use system (SUS) process lines. The market has grown from a remaining limited over the next 5 years, with some increased
few legacy products, such as plastic serum and media storage bags, adoption of SUS continuous chromatography and increased use
tubing, and filter membranes, to the current situation where single-use for commercial manufacturing. These projections also reflect likely
technologies represent the majority of non-commercial applications market growth from many new players entering bioprocessing,
in bioprocessing. This includes a wide variety of products and novel including in developing countries and biosimilar developers.
technologies currently available and in development.
BioPlan’s 15th Annual Report and Survey of Biopharmaceutical
Manufacturing, 2018,1 which included responses from 222 biopharma- Market for Single-Use Equipment
ceutical manufacturers and CMOs in 22 countries and 130 bioprocess-
ing suppliers or vendors, shows that single-use equipment is domi- The most dramatic growth will be for commercial-scale GMP manufac-
nating small- and mid-scale bioprocessing and is being adopted for turing. The single-use market for commercial applications is projected
larger-scale commercial manufacturing. to grow to over $1 billion/year in the next five years. This will be driven
by products currently in development using single-use systems receiv-
With advancing technology, knowledge, and experience, future ing approval and graduating to commercial-scale manufacturing. New
progress and market expansion are expected. In addition, the products will continue to mostly be monoclonal antibodies, which will
expansions and adaptations now being implemented in mainstream generally continue to require manufacture of 100 kilograms or more.
biologics production are also being seen in adjacent sectors, including This will increasingly involve parallel tracks, continuous bioprocessing,
cell and gene therapy, and even in the production of cosmetics and and/or multiple facilities worldwide anchored by 500-2,000 L SUS bio-
food derived from plant cell and tissue cultures, which are now being reactors. But even with this growth, fixed stainless steel systems will
produced at manufacturing scales. still dominate GMP/commercial and thus the overall market.
Single-use equipment is generally made of plastic parts that are The BioPlan annual survey and other sources confirm that among the
sterilized by gamma irradiation, then used once and discarded. facilities surveyed, mostly in the U.S. and Europe, average purchases of
More than a decade of combined industry experience has shown single-use equipment are over $1 million/year. Bioprocessing profes-
the benefits of single-use versus fixed stainless steel, including lower sionals realize that SUS has improved bioprocessing. Over two-thirds
capital investment and operational costs, as well as flexibility. SUS (68.8%) of survey respondents cited SUS as providing “some” or “sig-
enable rapid setup of bioprocessing and progressive manufacture nificant” improvement in their bioprocessing within the past year.
of multiple products at multiple scales in the same areas. Single-use
But end users recognize that they are often using first-generation
product lines have expanded from basic storage bags to complex
or other less than optimal equipment. Our survey indicates that
bioreactors. Now, essentially all bioprocessing, particularly upstream,
over the past five years, end users have continued to express a de-
can be done with single-use systems.
sire for improved single-use systems. As with most emerging tech-
Less than 20 years ago, just a few single-use systems were available, nology, once new and better products and systems are introduced
generally limited in size to 100 liters. Now single-use bioreactors and and become the norm, demand for further improvement continues
mixers are available at ≤2,000 L scale. Due to engineering limitations, until a general level of satisfaction is reached. In the bioprocess-
systems above 2,000 L are generally not practical or cost-effective. ing industry, end users are apparently concerned that innovation in
Currently, 1,000 L bioreactors are on track to be become the industry single-use bioprocessing supplies has been slow in coming. This is
standard for new product large-scale and much commercial-scale fully expected and normal in such a highly regulated environment,
manufacturing, with a growing number of companies offering an and demand for better products continues.
increasing range of product options.
Single-use products with the highest rate of use at any stage/scale
In terms of revenue, stainless steel facilities currently account for are shown in Figure 1. The most commonly used products are simpler
~85% of the market and single-use ~15%. This is projected to change devices, such as bags and connectors. But it is significant that more
24 | | April 2019
Biocompatibility
Redefined.
www.sartorius.com/single-use-redefined
» BIOPHARM PROCESSING »
than 70% of facilities use major bioprocessing using stainless steel. As such, stainless steel
systems, including bioreactors, mixers, and Concerns Over SUS will continue to dominate bioprocessing in
tangential flow filtration, and are more likely terms of capacity and number of large-scale
to be fully dedicated to using SUS. As use of SUS increases, concerns about cost and commercial facilities.
can be expected to increase, particularly
Among the reasons for adopting single- A number of individualized biologics and
as more bioprocessing professionals only
use described as “very important,” 46.2% personalized medicines are in active develop-
familiar with stainless steel equipment
of respondents said it decreases the risk of ment, including patient-specific cellular and
purchase SUS. However, from other survey
cross-product contamination, 41.2% said it gene therapies, cultured tissues and organs,
research, we found that price is not a
and cancer and other therapeutic vaccines.
eliminates cleaning requirements, 44.1% said primary concern among purchasers of any
With their one-off nature and need for sterility,
it reduces the time to get a facility up and bioprocessing equipment. End users prefer
these products can be expected to be manu-
running, and 40.4% said it reduces capital to purchase the best equipment they can get
factured using single-use equipment. BioPlan
investments in facilities and equipment. With and are willing to pay more, as long as the
has projected significant growth in cellular and
regard to concerns or potential problems, premium is not excessive.
gene therapy capacity and facilities, despite a
five were mentioned by more than 50% of Single-use systems manufacturing will current shortage that will become an actual
respondents: “Breakage of bags and loss of advance and continue to proliferate, with capacity crunch in coming years.
production material,” 75.0%; “Leachables and more diverse technologies and products
We are already seeing another trend: modular
extractables,” 73.3%; “High cost of dispos- becoming available. However, in terms of
facilities, with processes housed in connectable,
ables,” 68.8%; and “Material incompatibility capacity, most of the largest facilities are
portable clean rooms or isolator units, and
with process fluids” and “We do not want to likely to remain in use. New capacity will
whole portable manufacturing facilities that
become vendor-dependent (single-source is- be added at smaller scales, with most new
can be constructed and operational in a
sues),” 56.7% (tie). commercial manufacturing facilities still
matter of months or even weeks. With modular
systems using SUS equipment and providing
much the same advantages as single-use,
the market is expected to grow dramatically.
This includes “plug-and-play” factories, with
whole production lines and facilities fully
clonable. With an increasing demand for
domestic biopharmaceutical manufacture,
modular facilities will become more common
in developing countries, particularly China and
India, in the next decade.
Besides inherent conservatism in this highly
regulated industry, an issue restricting
progress in the expansion of single-use
systems is vendors’ hesitancy and end users’
distress over incremental improvements and
other changes in established product lines.
This is because any changes in bioprocessing
products already in use can require extensive
validation studies, more regulatory filings,
costly testing, new SOPs, etc. Innovations
in single-use equipment will more likely
originate from small companies or new major
suppliers and developers less attached to
aging technologies. New technologies in this
industry are generally implemented by totally
new facilities and process lines, not retrofitting.
26 | | April 2019
« BIOPHARM PROCESSING »
W
NE
888-884-6986
Distributors Worldwide
www.americanpharmaceuticalreview.com | | 27
» MICROBIOLOGY »
Some fungi are used directly as food, e.g., mushrooms, as they are high Even hazardous wastes can be remediated using fungi in contaminated
in protein and low in calories. (Dhande, 2019) soils. (Dhande, 2019)
28 | | April 2019
UNPRECEDENTED ACCURACY.
RELIABLE CONSISTENCY.
©2019 bioMérieux, Inc.· BIOMERIEUX, the BIOMERIEUX logo and BIOBALL are used pending and/or registered trademarks belonging to
bioMérieux, or one of its subsidiaries, or one of its companies · Patents: www.biomerieux-usa.com/patents • PRN 18-0069-01
Effective for a wide range of testing applications – including growth promotion, sterility
assurance testing, and antimicrobial effectiveness testing. Talk to our microbiology experts today
to see how BIOBALL and BIOBALL Custom Services can unlock value in your lab.
biomerieux-usa.com
» MICROBIOLOGY »
Fungal Metabolites
A single-cell protein (SCP) is a protein which has been derived from Literature Cited
a culture of single-celled organisms, frequently used as a food
supplement. Several species of fungi (both yeasts and molds) have Anonymous (2019) New England Compounding Center Meningitis Outbreak. Wikipedia. Downloaded
from: https://en.wikipedia.org/wiki/New_England_Compounding_Center_meningitis_outbreak
been used as single-cell proteins. SCPs can be used to increase the
on March 27, 2019.
nutritional value of foods, e.g., adding vitamins, amino acids, and
Dhande, R. (2019) Potential Applications of Fungi; A Biotechnological Approach. Street Directory.
lipids. (Godani, 2019 and Dhande, 2019)
Downloaded from: https://www.streetdirectory.com/travel_guide/119227/science/potential_
applications_of_fungi_a_biotechnological_aproach.html on March 27, 2019.
Godani, K. (2019) Top 6 Fungal Products Obtained from Fungal Biotechnology. Biology Discussion.
Conclusion Downloaded from: http://www.biologydiscussion.com/biotechnology/fungal-biotechnology/top-6-
fungal-products-obtained-from-fungal-biotechnology/8530 on March 27, 2019.
This partial listing of some of the real and potential uses of fungi barely Idnurm, A. and Meyer, V. (2014) Welcome to Fungal Biology and Biotechnology. Fungal Biology
touch the surface of the possibilities. The research in fungi applications and Biotechnology 1:8-9. Downloaded from: https://fungalbiolbiotech.biomedcentral.com/track/
has the potential to totally change how we live in the world. The pdf/10.1186/s40694-014-0008-5 on March 27, 2019.
Various Names Saprophytic fungi Aid in the decay of dead animals and plants
Amino Acids
Antibiotics
Bakeries
Breweries
Cheese Production
Enzymes
30 | | April 2019
« MICROBIOLOGY »
Epidermal Growth Factor Pichia pastoris Transition Therapeutic’s treatment for diabetes
Hepatitis-B Sacchromyces cerevisiase Glaxo Smith Kline’s Ambrix and Pharma’s HBVAXPRO
Hepatitis-B Surface Antigen Pichia pastoris Glaxo Smith Kline’s treatment for serum hepatitis
Insulin-like growth factor 1 Pichia pastoris Cdphalon’s product for insulin-like growth factor 1 deficiencies
Organic Acids
Citric Acid Aspergillus niger Food preservation, powerful cleaning agent, and in cosmetic products
Fumaric Acid Rhizopus nigricans Used in food and beverage products, oral pharmaceutical formulations
Gluconic Acid Aspergillus niger Acidity regulator for food additives, cleaning products
Prepare acrylic fibers and rubbers, reinforced glass fiber, water treatment
Itaconic Acid Aspergillus terreus
systems, artificial diamonds and lenses
Perfumes
Recycling
Whole recombinant S. cerevisiae- Treatment of cancer and viral diseases together with cytotoxic drugs to
Saccharomyces cerevisiae
based method increase clinical responses.
Vitamins
Glycolipid mannosylerythritotol
Ustilago scitaminea NBRC 32730 Biosurfactant
lipids
www.americanpharmaceuticalreview.com | | 31
» FORMULATION AND DEVELOPMENT »
Polymeric Particles as
Vaccines have been successful at preventing a range of diseases
including diphtheria, polio, whooping cough, measles and tetanus;
whereby incidences of such diseases are now rare in developed
32 | | April 2019
Expect the expected.
Faster Cell Banking In-depth Regulatory 32-35 day turnaround time More than 80 years of Comprehensive Biologic
scheduling, extensive Cell Guidance from experts for Lot Release Testing. combined Viral Clearance Raw Materials Testing,
Bank Characterization, who guide the regulatory and Viral Safety including development
and expansive LN2 capacity updates. experience. and validation for unique
for Cell Bank Storage. methods.
» FORMULATION AND DEVELOPMENT »
34 | | April 2019
Clinical Trial Supply
Organized By
This year we will be looking at those issues which are affecting companies in the Bay Area. Such as, but
not limited to: harnessing tried and tested technologies which can improve accuracy, reduce wastage
and improve efficiency, exploring ways clinical supplies and quality assurance teams can work together
to ensure trials run on time. All while learning from others and what cross-industry technologies will
future clinical trials be utilizing.
vaccine to promote tumor antigen-specific the local draining lymph node, smaller which include: emulsification, such as single
cytotoxic T lymphocyte responses.28,29 The particles (< 100-200 nm) can potentially and double emulsion solvent-evaporation
most widely investigated adjuvants are traffic independently to the draining lymph methods, and nanoprecipitation (also
Toll-like receptor (TLR) ligands and include; node where they can be taken up by the known as solvent displacement method)
polyinosinic:polycytidylic acid (a TLR3 resident dendritic cells, which are present (Figure 3). Adjusting the parameters of
agonist), monophosphoryl lipid A (a TLR4 at high densities and may more efficiently the fabrication process can determine the
agonist), pentaerythritol lipid A (a TLR4 process and present antigen than migrating properties of particles, such as size, size
agonist), and CpG oligodeoxynucleotides dendritic cells.34,35 The same researchers also distribution, encapsulation efficiency, and
(CpG ODN: a TLR9 agonist). These ligands, also investigated the effect of surface charge and the yield. There are a variety of polymers
known as pathogen-associated molecular hydrophobicity on the capacity of particles that can be used to fabricate particles,
patterns (PAMPs), are capable of stimulating to drain independently to the lymph node however those polymers that offer desirable
dendritic cell maturation by binding to TLRs and found an inverse correlation between characteristics when considering them for
and initiating a signaling cascade resulting in hydrophobicity and lymph node targeting; use as cancer vaccine delivery systems are
up-regulation of surface antigens (e.g. CD80 and a direct relationship between anionic preferred. Specifically, polymers should be
and CD86) and cytokines (e.g. interleukin-12) charge density and lymph node targeting biodegradable and biocompatible where
that promote effector T lymphocyte of particles.34 the degraded by-products are readily
responses. Polymeric particles possess the
Several techniques have been used to metabolized and non-toxic.36 Examples of
capability to efficiently encapsulate and
fabricate polymeric particles, examples of such polymers are poly(lactic-co-glycolic
deliver the tumor antigen and immunological
adjuvant (either co-loaded or separately
encapsulated) to dendritic cells.19-21 Finally,
the ability of polymeric particles to be tuned
or functionalized provides the opportunity to
target the particles to dendritic cells, thereby
promoting more efficient uptake and this is
discussed in more detail below.
Aside from the many advantages listed
above, polymeric delivery systems are
considered to be promising candidates
for vaccine delivery because they possess
pathogen-mimicking properties in terms Figure 2. Electron photomicrographs of polymeric particles. (A) PLGA particles; (B) PA
particles; and (C) PSN particles. Scale bar represents 1 μm.
of shape, size and morphology (Figure
2); and they can deliver the antigen in a
similar fashion to how it would be delivered
during a natural infection.30,31 The size of the
particles delivering vaccine components
is considered to be a determining factor in
terms of the endocytic pathway used by
dendritic cells for uptake. In general, larger
particles are engulfed by phagocytosis
while smaller particles are taken up by
pinocytosis.32 A comparison of antigen-
loaded particles of different sizes (300, 1000,
7000, and 17000 nm diameter) showed
that smaller-sized particles were readily
taken up by bone-marrow derived dendritic
cells and consequently they were more
efficient at stimulating antigen-specific
effector immune responses in vivo in a
murine model.33 Other groups have shown
that, while larger particles (> 100-200 nm
Figure 3. Fabrication process of polymeric particles (emulsification and
diameter) generally remain at the site of
nanoprecipitation techniques).
vaccination and require uptake by migratory
dendritic cells in order to be delivered to
36 | | April 2019
« FORMULATION AND DEVELOPMENT »
acid) (PLGA), poly(anhydrides) (PA), poly(sulfenamides) (PSN), and intratumorally to manipulate the tumor microenvironment. A recently
poly(phosphazenes) (PPZ). These polymers have been well-studied reported example is in situ immunization against B cell lymphoma
and are the most widely explored polymers for particle fabrication and with PLGA particles co-encapsulating CpG ODN and doxorubicin, a
use in vaccine applications. Particle-based formulations fabricated chemotherapeutic compound inducing immunogenic apoptosis. The
with certain types of polymer can function not only as delivery vehicles, principle of this strategy is that dying tumor cells provide a source of
but also as immunological adjuvants. PA and PPZ particles have antigen for dendritic cells in the tumor microenvironment while CpG
been reported to have an adjuvant effect in that they can stimulate ODN functions as an immunological adjuvant to enhance dendritic
dendritic cells through binding to TLRs.22,37,38 Another important cell maturation and therefore antitumor immune responses.40,41 Also,
characteristic of many polymer-based systems is that the degradation heterologous (diversified) prime-boost vaccination strategies where
rate of the particles can be tailored according to polymer composition. different versions of cancer vaccine formulations are administered
To explain, varying the molar ratio of PA monomers during the hold the promise of inducing more effective cytotoxic T lymphocyte
copolymerization process can tune the degradation rate and therefore immune responses.8 This could be of particular importance for
control the release kinetics of the cargo from polymeric particles immunogen-encoded viral vectors where homologous prime-boost
(Figure 4).22,38,39 A number of studies have indicated that varying the vaccinations could be problematic due to high immunogenicity
molar composition of copolymers can also have a significant effect on and limited effectiveness owing to the production of viral-specific
the properties of particles.38 One major factor is hydrophobicity which neutralizing antibodies.42 One such example to address this issue is the
plays a key role in the opsonization and cellular uptake of particles. diversified prime-boost vaccination using antigen-loaded polymeric
For example, increasing the molar ratio of the carboxyphenoxy particles (as a prime vaccine) and attenuated adenoviral vector
hexane (CPH) monomer in a PA copolymer composition resulted in encoding antigen (as a booster).43
a significant increase in the hydrophobicity of particles and, in turn,
Another attractive characteristic of polymeric particles is that their
stimulated more potent antitumor immune responses and improved
surface is amenable to chemical modifications, allowing researchers
their in vivo performance.38 The effect of hydrophobicity, however, may
to improve targeting and refine the ability of the delivery system to
vary depending on the size of the particles used.34
interact specifically with the host’s immune system, hence, generating
One of the critical factors affecting cancer vaccine efficacy is the number robust tumor-specific immune responses.44 The surface chemistry
and timing of vaccinations. Many vaccines are required to be given as a of polymeric particles is of crucial importance in determining their
prime-boost involving multiple doses to achieve desirable outcomes. cellular uptake, biodistribution, targeting, and therapeutic effects.
Reducing the number of vaccinations required to achieve an optimal Although polymeric particles are generally easily recognized and
immune response would be desirable from the perspective of patient ingested by dendritic cells (Figure 5), appropriate surface modulation
compliance. Interestingly, preclinical studies showed that vaccination can afford them an enhanced capacity to bind to specific targets or
with a single subcutaneous dose of PA-based particles encapsulating penetrate through biological barriers; therefore, further enhancing
a tumor model antigen was found to induce enduring tumor antigen- the performance of the cancer vaccine formulation.45 For example,
specific cytotoxic T lymphocytes and generate long-term protection mannose and carbohydrate grafted onto polymeric particles
against lethal tumor challenge, and this was as effective as a prime- were found to enhance active targeting to dendritic cells and
boost regimen.22 Other novel immunization strategies involving macrophages.46,47 In addition, coupling of polymeric particle surfaces
polymeric particles are currently being studied. For example, in situ to specific proteins such as antibodies offers the opportunity for active
vaccination, is a promising strategy where particles are injected immunological targeting.24,48 As an example, a recent study used a
novel targeting approach involving ICI-functionalized particles to
www.americanpharmaceuticalreview.com | | 37
» FORMULATION AND DEVELOPMENT »
target PD-1 on dendritic cells and demonstrated that these polymeric 18. Abbas AO, Donovan MD, Salem AK. Formulating poly(lactide-co-glycolide) particles for
particles could enhance the efficacy of ICI.49 The surface charge of plasmid DNA delivery. J Pharm Sci. 2008;97(7):2448-2461.
particles also plays a crucial role in determining the fate of particles 19. Geary SM, Hu Q, Joshi VB, Bowden NB, Salem AK. Diaminosulfide based polymer microparticles
within the cell. Once particles have been taken up, or endocytosed, by as cancer vaccine delivery systems. J Control Release. 2015;220(Pt B):682-690.
dendritic cells, they need to escape the endosome in order to deliver 20. Joshi VB, Geary SM, Carrillo-Conde BR, Narasimhan B, Salem AK. Characterizing the
antitumor response in mice treated with antigen-loaded polyanhydride microparticles.
their cargo to the cytoplasm. Switching the surface charge of particles
Acta Biomater. 2013;9(3):5583-5589.
from negative to positive by using cationic polymers or dendrimers
21. Ahmed KK, Geary SM, Salem AK. Development and Evaluation of Biodegradable Particles
such as chitosan, poly(amidoamine), and poly(propyleneimine) can Coloaded With Antigen and the Toll-Like Receptor Agonist, Pentaerythritol Lipid A, as a
promote endosomal escape through a mechanism known as the Cancer Vaccine. J Pharm Sci. 2016;105(3):1173-1179.
proton sponge effect.36,50 The ease of designing polymeric particles 22. Wafa EI, Geary SM, Ross KA, Goodman JT, Narasimhan B, Salem AK. Single dose of
with multifunctional and versatile platforms has made them attractive polyanhydride particle-based vaccine generates potent antigen-specific antitumor
candidates for cancer vaccine delivery. Collectively, many of the immune responses. J Pharmacol Exp Ther. 2018.
favorable traits of polymeric particle-based platforms discussed above 23. D’Mello SR, Yoo J, Bowden NB, Salem AK. Microparticles prepared from sulfenamide-based
have culminated into the successful implementation preclinically, and polymers. J Microencapsul. 2014;31(2):137-146.
many of them are under active and intense investigation for cancer 24. Walk RM, Elliott ST, Blanco FC, et al. T-cell activation is enhanced by targeting IL-10
vaccine applications. cytokine production in toll-like receptor-stimulated macrophages. Immunotargets Ther.
2012;1:13-23.
25. Song C, Noh YW, Lim YT. Polymer nanoparticles for cross-presentation of exogenous
antigens and enhanced cytotoxic T-lymphocyte immune response. Int J Nanomedicine.
References 2016;11:3753-3764.
26. Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol.
1. Xu J, Murphy SL, Kochanek KD, Bastian B, Arias E. Deaths: Final Data for 2016. Natl Vital 2013;31:443-473.
Stat Rep. 2018;67(5):1-76.
27. Andersen MH, Schrama D, Thor Straten P, Becker JC. Cytotoxic T cells. J Invest Dermatol.
2. Weeks JC, Catalano PJ, Cronin A, et al. Patients’ expectations about effects of chemotherapy 2006;126(1):32-41.
for advanced cancer. N Engl J Med. 2012;367(17):1616-1625.
28. de Barros CM, Wafa EI, Chitphet K, Ahmed K, Geary SM, Salem AK. Production of
3. Paci A, Veal G, Bardin C, et al. Review of therapeutic drug monitoring of anticancer drugs Adjuvant-Loaded Biodegradable Particles for Use in Cancer Vaccines. Methods Mol Biol.
part 1--cytotoxics. Eur J Cancer. 2014;50(12):2010-2019. 2017;1494:201-213.
4. Banchereau J, Palucka K. Immunotherapy: Cancer vaccines on the move. Nat Rev Clin Oncol. 29. Goforth R, Salem AK, Zhu X, et al. Immune stimulatory antigen loaded particles combined
2018;15(1):9-10. with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse
5. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for model of melanoma. Cancer Immunol Immunother. 2009;58(4):517-530.
PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833. 30. Gregory AE, Titball R, Williamson D. Vaccine delivery using nanoparticles. Front Cell Infect
6. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator Microbiol. 2013;3:13.
approach to cancer therapy. Cancer Cell. 2015;27(4):450-461. 31. Ulery BD, Petersen LK, Phanse Y, et al. Rational design of pathogen-mimicking amphiphilic
7. Grenier JM, Yeung ST, Khanna KM. Combination Immunotherapy: Taking Cancer Vaccines to materials as nanoadjuvants. Sci Rep. 2011;1:198.
the Next Level. Front Immunol. 2018;9:610. 32. Champion JA, Walker A, Mitragotri S. Role of particle size in phagocytosis of polymeric
microspheres. Pharm Res. 2008;25(8):1815-1821.
8. Ahmed KK, Geary SM, Salem AK. Surface engineering tumor cells with adjuvant-loaded
particles for use as cancer vaccines. J Control Release. 2017;248:1-9. 33. Joshi VB, Geary SM, Salem AK. Biodegradable particles as vaccine delivery systems: size
matters. AAPS J. 2013;15(1):85-94.
9. Rosalia RA, Cruz LJ, van Duikeren S, et al. CD40-targeted dendritic cell delivery of PLGA-
nanoparticle vaccines induce potent anti-tumor responses. Biomaterials. 2015;40:88-97. 34. Rao DA, Forrest ML, Alani AW, Kwon GS, Robinson JR. Biodegradable PLGA based nanoparticles
for sustained regional lymphatic drug delivery. J Pharm Sci. 2010;99(4):2018-2031.
10. Chen Q, Xu L, Liang C, Wang C, Peng R, Liu Z. Photothermal therapy with immune-adjuvant
nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat 35. Reddy ST, van der Vlies AJ, Simeoni E, et al. Exploiting lymphatic transport and complement
Commun. 2016;7:13193. activation in nanoparticle vaccines. Nature Biotechnology. 2007;25:1159.
11. Ahmed KK, Geary SM, Salem AK. Applying biodegradable particles to enhance cancer 36. Ross KA, Brenza TM, Binnebose AM, et al. Nano-enabled delivery of diverse payloads across
vaccine efficacy. Immunol Res. 2014;59(1-3):220-228. complex biological barriers. Journal of Controlled Release. 2015;219:548-559.
12. Salem AK. Nanoparticles in vaccine delivery. AAPS J. 2015;17(2):289-291. 37. Andrianov AK, Marin A, Fuerst TR. Molecular-Level Interactions of Polyphosphazene
Immunoadjuvants and Their Potential Role in Antigen Presentation and Cell Stimulation.
13. Geary SM, Salem AK. Exploiting the tumor phenotype using biodegradable submicron Biomacromolecules. 2016;17(11):3732-3742.
carriers of chemotherapeutic drugs. Crit Rev Oncog. 2014;19(3-4):269-280.
38. Wafa EI, Geary SM, Goodman JT, Narasimhan B, Salem AK. The effect of polyanhydride
14. Joshi VB, Geary SM, Salem AK. Biodegradable particles as vaccine antigen delivery systems chemistry in particle-based cancer vaccines on the magnitude of the anti-tumor immune
for stimulating cellular immune responses. Hum Vaccin Immunother. 2013;9(12):2584- response. Acta Biomater. 2017;50:417-427.
2590.
39. Torres MP, Vogel BM, Narasimhan B, Mallapragada SK. Synthesis and characterization
15. Gross BP, Wongrakpanich A, Francis MB, Salem AK, Norian LA. A therapeutic microparticle- of novel polyanhydrides with tailored erosion mechanisms. J Biomed Mater Res A.
based tumor lysate vaccine reduces spontaneous metastases in murine breast cancer. AAPS 2006;76(1):102-110.
J. 2014;16(6):1194-1203.
40. Makkouk A, Joshi VB, Lemke CD, et al. Three steps to breaking immune tolerance to
16. Joshi VB, Geary SM, Gross BP, Wongrakpanich A, Norian LA, Salem AK. Tumor lysate-loaded lymphoma: a microparticle approach. Cancer Immunol Res. 2015;3(4):389-398.
biodegradable microparticles as cancer vaccines. Expert Rev Vaccines. 2014;13(1):9-15.
41. Makkouk A, Joshi VB, Wongrakpanich A, et al. Biodegradable microparticles loaded
17. Geary SM, Lemke CD, Lubaroff DM, Salem AK. Proposed mechanisms of action for prostate with doxorubicin and CpG ODN for in situ immunization against cancer. AAPS J.
cancer vaccines. Nat Rev Urol. 2013;10(3):149-160. 2015;17(1):184-193.
38 | | April 2019
« FORMULATION AND DEVELOPMENT »
42. Siemens DR, Elzey BD, Lubaroff DM, et al. Cutting edge: restoration of the ability to interested in studying biodistribution and pharmacokinetics of polymeric
generate CTL in mice immune to adenovirus by delivery of virus in a collagen-based matrix. nanoparticles for drug delivery.
J Immunol. 2001;166(2):731-735.
43. Lemke CD, Geary SM, Joshi VB, Salem AK. Antigen-coated poly alpha-hydroxy acid based Emad I. Wafa is currently a graduate student in the Ph.D.
microparticles for heterologous prime-boost adenovirus based vaccinations. Biomaterials. program at the College of Pharmacy, University of Iowa.
2013;34(10):2524-2529.
Prior to joining the University of Iowa, Emad earned
44. Morris AS, Wongrakpanich A, Geary SM, Salem AK. Chapter Nine - Microparticles and
his bachelor’s degree in Pharmaceutical Sciences from
Nanoparticles for Cancer-Targeting Vaccines. In: Skwarczynski M, Toth I, eds. Micro and
Nanotechnology in Vaccine Development. William Andrew Publishing; 2017:171-183. Misurata University, Libya. His research primarily deals with designing
45. Morris AS, Salem AK. Surface Engineered Nanoparticles: Considerations for Biomedical and developing cancer vaccines using biodegradable polymeric particles.
Applications. Advanced Engineering Materials. 2017;19(11):1700302. He is also interested in improving transfection of antigen-presenting cells
46. Kim N, Jiang D, Jacobi AM, et al. Synthesis and characterization of mannosylated pegylated using polymeric nanovectors.
polyethylenimine as a carrier for siRNA. Int J Pharm. 2012;427(1):123-133.
Dr. Sean Geary is an assistant research scientist who
47. Vela-Ramirez JE, Goodman JT, Boggiatto PM, et al. Safety and biocompatibility of
carbohydrate-functionalized polyanhydride nanoparticles. AAPS J. 2015;17(1):256-267. obtained his PhD in Tumor Immunology from the University
48. Nobs L, Buchegger F, Gurny R, Allemann E. Poly(lactic acid) nanoparticles labeled of Adelaide, Australia. For the past decade, he has been
with biologically active Neutravidin for active targeting. Eur J Pharm Biopharm. intensively involved in the development and testing of a
2004;58(3):483-490. range of particle based and viral cancer vaccines in preclinical settings,
49. Ordikhani F, Uehara M, Kasinath V, et al. Targeting antigen-presenting cells by anti-PD-1 resulting in many publications in peer-reviewed journals.
nanoparticles augments antitumor immunity. JCI Insight. 2018;3(20).
50. Kou L, Sun J, Zhai Y, He Z. The endocytosis and intracellular fate of nanomedicines: Aliasger K. Salem is the Bighley Chair and Professor of
Implication for rational design. Asian Journal of Pharmaceutical Sciences. 2013;8(1):1-10. Pharmaceutical Sciences and Head of the Division of
Pharmaceutics and Translational Therapeutics at the
University of Iowa College of Pharmacy. Aliasger Salem
About the Authors is also currently the leader of the Experimental Therapeutics program
at the Holden Comprehensive Cancer Center and co-director of the
Suhaila O. Suliman is a graduate student in the Ph.D. Nanotoxicology Core at the Environmental Health Sciences Research
program in Pharmaceutics at the University of Iowa. As Center. Prior to joining the University of Iowa in 2004, he was a postdoctoral
part of her Ph.D. studies, she focuses on enhancing cancer fellow at the Johns Hopkins School of Medicine and completed his PhD at
vaccine efficacy and stimulating robust tumor-specific the School of Pharmacy and Pharmaceutical Sciences at the University of
immune responses using particle-based formulations. She is also Nottingham in the UK.
www.americanpharmaceuticalreview.com | | 39
» BIOPHARM DEVELOPMENT »
40 | | April 2019
« BIOPHARM DEVELOPMENT »
The main objectives of risk management are to investigate the risk and
the underlying root cause to minimize risk and to finally determine the
impact of the risk management initiatives taken.
For risk management all interactions of the user with the device need
to be evaluated in depth.
Topics like:
Figure 1. Risk management process as defined in ISO 14971 • Ambiguous, unclear device status
LD
HV
Leaders in
Pharmaceutical Package
Testing Equipment
uu
m
De
cay
Your Container Closure
c
Va
Integrity Experts
c
iPa
Ver
www.americanpharmaceuticalreview.com | | 41
» BIOPHARM DEVELOPMENT »
Current guidelines do not prescribe which tools to use. In most cases this at least involves sensitivity, cytotoxicity, and skin irritation. Risk
FMEA (Failure Mode and Effects Analysis) is being used for evaluation management tools are used to evaluate the overall impact considering
of medical devices and combination products. This tool is being used the cumulated exposure time, location of exposure, release of potential
to evaluate the design, usability, process (e.g. assembly, packaging, toxins, etc.
shipping), and biocompatibility.
Process risk analysis is evaluating the impact of all process steps on
the quality of the device. During this step not only the device, but
Which Information Needs to Go into the combination product itself needs to be evaluated. All process
steps need to be considered such as filling of the drug product or
the Risk Management File? biologics into primary packaging, assembly of the drug constituent
For all marketing applications and marketed products risk part with the device constituent part(s). Filling of drug products is
management needs to be documented properly. For the US this will fairly straightforward, if state of the art methods for aseptic filling are
be part of the Design History File (DHF) and for EU it will be part of the being used. In case the drug constituent part is biologic, this might
Technical File (TF) following the requirements of the medical device complicate the matter. For example, a number of pump types can’t
regulation (MDR) Annex I. be used because of shear forces they create. A significant portion
The following topics need to covered and documented accordingly of large biologic products are susceptible to this problem. For this
during the risk evaluation: reason, the correct type of pumps has to be chosen or filling speeds
have to be reduced to an acceptable level. This property of biologics,
• Risk Management Plan
susceptibility to shear forces, also needs to be considered in the
• Hazard Identification
design of the device, as very thin needles, which clearly is a current
• Use related Risk Analysis trend, would also exhibit this problem. Furthermore, packaging
• Design Risk Analysis and shipping need to be evaluated thoroughly, as they typically
• Process Risk Analyses bear some surprises. During all processing steps the heat exposure
of any biologics have to be controlled. This is especially true for
• Risk Management Report
the compounding, filling, and packaging step. To consider and
Following this main structure, a significant number of additional implement a temperature control during compounding and filling
evaluations need to take place. is very straightforward, however during packaging the heat-sealing
Typically, the risk management plan describes the roles and respon- process is easily forgotten.
sibilities of contributing team members. It contains the risk accep-
Finally, the risk management report should summarize the overall risk/
tance matrix and lists all definitions related to the product evaluated.
benefit analysis and also point out the residual risks.
For example, during the hazard identification step the potential haz-
ards themselves as well as hazardous situations need to be evaluated
and discussed. The sequence of events and potential harm to the user
need to be taken into consideration. Why are We Implementing Risk
During the use related risk analysis, all use steps have to be Management Tools for Combination
evaluated thoroughly using tools of human factors or usability. Of
course, the instructions for use are at the center of this evaluation.
Product Development?
Also, reasonably foreseeable misuse has to be evaluated in depth.
Clearly, the proper implementation of a risk management process can
For all topics above a well thought through ergonomic design will
be a win-win for both, the patient and the company.
help to alleviate a significant number of the problems. Especially for
combination products, during this step it is of utmost importance It is an expectation that the patient has a product in his hand, which
to consider the indication of the drug product or biologic. Based on is easy to use and has been designed properly. It is important to
the indication the patient population will be defined. For example, realize for combination products, at least for the device constituent
when developing a treatment for arthritic patients the ergonomic part, there is a similarly high expectation as for consumer products.
design might have to be completely different compared to the
As a patient, I can’t make a judgement on the quality of the drug or
needs of young adults. Starting use related risk analyses early in
biologic, but I can draw a lot of conclusions on the functionality and
the development process allows designers to address use failures
design of the device.
by optimizing the device design which is the most effective risk
mitigation. In turn, for any company being able to create inspiring, reliable devices
During the design risk analysis, the ISO 10993 standard needs to be easing the treatment for the patient there is a huge competitive
applied additionally, in order to evaluate biocompatibility. In most advantage especially in the field of generics and biosimilars, where
cases, for devices with skin contact (intact skin or damaged skin) there is by definition no difference in the drug part.
42 | | April 2019
June 3-6, 2019
Philadelphia, PA
JOIN US #BIO2019
FOR BI0 2 19
IN PHILADELPHIA
As the world’s largest global biotechnology partnering event, the BIO International
Convention (#BIO2019) is the one event where you can access 16,000+ attendees
from 67 countries, network and set up meetings via BIO One-on-One Partnering™,
and attend 150+ education sessions. Discover the next generation of cutting-edge
products, therapies, and cures all week long.
Paula Peacos
Senior Consultant
ValSource, Inc
2. In my opinion, the industry in general is still learning how Keeping track of data is also a challenge. With large facilities in particular,
to appropriately apply QRM to their operations. QRM assessing microbial and particulate trends remains important so
is quickly being incorporated, but not all programs are that appropriate actions can be taken promptly. Furthermore, it is
well-designed or sufficiently robust. For example, some important to understand when the process is leaning out of control,
risk assessments are still justifying current practice as to enable personnel to be alerted to a potential change in the process.
opposed to identifying potential contamination risks. This
To aid microbiologists, there are a number of powerful databases on
is a particular problem where specific regulatory guidance
the market which provide graphical illustration of trends and which
or requirements are lacking.
meet data integrity requirements.
3. Lack of new microbiological monitoring methods.
Jeanne Moldenhauer, Vice-President, Excellent Pharma Consulting:
Detecting/recovering microbial contamination is still done
using antiquated methods that are known to be relatively 1. Some of the control problems result from the establishment
inefficient, highly variable, and extremely limited. A very of unrealistic limits for types of contamination, e.g., setting a
well designed and robust EM and trending program helps zero-tolerance level for molds.
44 | | April 2019
« ROUNDTABLE »
2. Another concern with contamination control is the replace the need for humans for carry out operations, as with the use
reluctance of companies to use/implement newer of robotics. An advantage with automation is that processes can be
technologies that actually prevent microbial growth. stopped if there has been a shift in environmental conditions, such as
an increase in particle counts.
Technologies which help to show that tasks are being conducted
Looking at the latest in contamination control correctly are important, such as glove stations which can indicate how
products and solutions, can you tell us about often and for how long hands have been sanitized for, and tracking
some new technologies and/or processes that are technologies that indicate that cleanrooms are being disinfected
available now that you are excited about? for the appropriate time periods are useful for helping to address
personnel related contamination control issues.
Cundell: With all aseptic processes, removing human interventions
is a key design and operation strategy for improving contamination Other technologies of interest are the spectrophotometric particle
control. Automation will continue to be emphasized. Equipment like counters, which can be used to differentiate between inert particles
depyrogenation tunnels, multiple-container filling and stoppering and those which are biologic. Although there are still some factors to
stations, vision systems for defect detection, online container-closure overcome in terms of screening for false positives, taking samples over
integrity testing, and robotic lyophilizer loading and unloading are a sufficiently long time period provides useful data for benchmarking.
now commonplace in sterile product manufacturing facilities. Such data can then be used to assess changes in a facility, such as
the impact of maintenance work or to assess the impact of increased
The ability to exclude people from aseptic processing has a hierarchy of
numbers of personnel in an area.
risk: laminar flow hood > biological safety cabinets > restricted assess
barrier systems > open isolator systems > closed isolator systems with A further area that’s receiving increased coverage is with air
gloves > gloveless isolator systems. Robotic systems are uniquely decontamination units with HEPA filters. These offer an additional
suitable for inclusion in barrier systems like gloveless isolators. technology to destroy a a range of airborne microorganisms.
Remember, robotic systems will automate standard manipulations,
Moldenhauer:
exclude people from critical aseptic processing areas, and do not look
or move like humans. 1. There are many new water-based technologies that are
antimicrobials, e.g., increased oxygens (ozonated) and
Peacos:
electrostatically charged hydrogens. These products have
1. I am a huge fan of single use/disposable technologies sporicidal properties without leaving residues and without
that minimize the amount of product exposure to human damage to stainless steel surfaces or employees.
intervention because they are very effective and relatively
2. There is also an increased focus on products that prevent
easy and inexpensive to implement. A firm can greatly
growth, both in building materials, coatings, paints and the
reduce their risk of contamination in a short amount of
like. For example, nanotechnology infused products.
time through the use of these technologies as opposed to
having to do new construction or retrofitting. Examples
include the use of sampling apparatus that can be sterilized
in place, pre-assembled and/or pre-sterilized parts and In the past few years have regulatory expectations
components, welded connections etc. These can go a long from the FDA and other global agencies resulted
way to aid in contamination control for small firms that in more scrutiny placed on contamination control
simply don’t have the capital to convert their operations to, efforts? Can you elaborate? Do inconsistent or
for example, isolator technologies.
different global regulations place a regulatory
2. Technologies such as the Growth Direct, which decrease strain on pharmaceutical companies?
the turnaround time for obtaining microbiological
data (colony counts). Environmental excursions and Cundell: Contamination control during aseptic processing has always
contamination risks are often not detected until 3-7 been scrutinized by regulatory agencies. From 2014 through 2017,
days after sample collection using traditional processing 48% of the U.S. sterile drug recalls were for visible particles, 31% for
methods. Meanwhile, manufacturing operations are lack of sterility assurance, 8% for labeling issues, 3% for container
continuing. Furthermore, this method is nondestructive, defects and 10% for other reasons (Johns et al, 2018). The biggest
meaning microbiologists can culture and identify the disruption presently is the publication of the revision to the EU Good
organisms to allow for appropriate investigation. Some Manufacturing Practice, Annex 1 that contains rules that differs from
rapid detection methods destroy the organisms or do not current industry practice and the 2004 FDA Sterile Drug Products
allow for recovery, which in my opinion significantly lowers Produced by Aseptic Processing — Current Good Manufacturing
their value. Practice. Gap analysis will reveal many procedural changes and capital
Sandle: With aseptic processing, ideal technologies are those that improvements that may be necessary when the revision becomes
separate people from products, such as isolators, and which can official. This will consume many resources.
www.americanpharmaceuticalreview.com | | 45
» ROUNDTABLE »
46 | | April 2019
« ROUNDTABLE »
the program itself and supporting risk assessments and accessible to patients will be better manufacturing processes”, Peter
procedures etc. need to be revisited and reassessed on a Marks, Director of FDA’s Center for Biologics Evaluation and Research
relatively frequent basis and updated or supplemented as (CBER), told attendees at the Galien Forum in New York City on Oct.
needed. This is especially critical for new processes, new 25, 2018, in a panel discussion on gene therapy. “At this point, the
facilities and new technologies which are still evolving. FDA has approved one directly-administered and two cell-based
Sandle: gene therapies”, Marks said, “but the Agency has received over 700
investigational new drug (IND) applications in the gene therapy field”.
1. Contamination control requires an understanding As the FDA points out, there is a large gap between R&D, clinical
of the microbial entry points and the various routes supplies, and routine commercial production. Perhaps the biggest
that can be taken to arrive where they are undesired. challenge in gene and cell therapies is cell viability, but the best
Hazard identification is key and then assessing how the approaches to microbial contamination monitoring and control have
contamination might end up impacting on a process. This
not been established.
involves understanding the sources of contamination
and how contamination can be transferred. The risks The revisions to 21 CFR 610.12 Sterility to allow for more flexibility
associated with the different sources of contamination in sterility testing biologics was helpful. The proposed USP general
and the potential impact should be assessed, in terms of informational chapter <1071> Microbial contamination detection/
the severity of contamination (should it occur) and the sterility testing of short life products: A risk-based approach may
likelihood of a contamination event occurring (probability). contribute to the discussion in the industry.
This enables an organization to focus on risk mitigation Peacos:
and then to put in place appropriate detection systems to
1. I see a general push in the industry for firms to more
ensure that the contamination risks remain within a level
quickly incorporate available contamination control
of control.
strategies such as the use of isolator technology,
2. Extending the principles of quality risk management to automation, single use/disposable technologies and
microbiological sampling is also important, to ensure that closed systems to replace traditional aseptic processing
the samples taken are meaningful and relate to the primary lines. These technologies reduce the amount of human
contamination risks. The use of HACCP (Hazard Analysis intervention required, which is the main source of
and Critical Control Points) can be employed to determine microbial contamination. New construction should ideally
microbiological environmental monitoring locations. have these technologies built in as part of the design. A lot
3. There also needs to be a greater focus on the training of firms are still using the old traditional methods where
of cleanroom personnel and implementation of more better technology is available and has been for some time.
robust training programs defining aseptic technique, 2. I also see a shift from “standard industry practice” to risk-
pharmaceutical microbiology and so on. based controls specifically tailored to the product and
4. Keeping track of process variations is important. If the processes in question. New technologies are emerging
process is as validated, then the standard sample set will be faster than the regulatory bodies can issue specific
sufficient. However, if the process is different, such as having requirements. The current lack of specific guidance for
a longer process hold, then additional samples should be so-called “low bioburden processes”, which have elements
considered to assess bioburden and endotoxin risk. of both aseptic processing and nonsterile manufacturing is
a good example of this. This basically put the onus on the
5. Having less paperwork in cleanrooms sounds simple,
industry, and will require firms to have very strong, science-
but this minimizes contamination and leads to better
based and holistic QRM programs.
control over processes and samples. With this, electronic
systems offer a number of advantages for environmental Sandle: It is interesting that compendia appear to be removing
monitoring and for completing batch records limits, such as recommended levels of bioburden and endotoxin
for excipients and raw materials, and placing the need for an
Moldenhauer: The biggest recommendation is to know what is
assessment with manufacturers to assess the risk in relation to their
causing your contamination issues, i.e., identify the contaminants and
learn all you can about these organisms to try and find the root cause. own processes. There is a similar expectation with ‘objectionable
microorganisms’; things have shifted from prescribed lists to the need
for pharmaceutical manufacturers to deploy scientific decision making
What do you see as the major industry critical as to which microorganisms, potentially present in the manufacturing
environment, present a risk to a product (which involves understanding
issues over the next five years in regards to
the physicochemical properties of the product) and to the patient
contamination control? population for which the product is intended.
Cundell: Clearly major issues surround gene and cell therapies and Moldenhauer: I see the industry working towards a climate of
the following quote illustrates this. “The key to making gene therapy prevention of contamination rather than reaction to contamination.
www.americanpharmaceuticalreview.com | | 47
» SPECTROSCOPY »
This article reflects the views of the authors and should not be construed This article focuses on low-frequency Raman spectroscopic analysis
to represent the Food and Drug Administration’s views or policies. using a commercially available low-frequency Raman laser/filter
coupled with a Raman microscope to perform pharmaceutical
mapping measurements. In addition, multivariant statistical analysis
Introduction techniques are utilized to highlight the unique and wide range of
information that can be obtained from low-frequency Raman mapping
Confocal Raman mapping provides a robust means of characterization of pharmaceuticals.
that can non-destructively provide both chemical and structural Here we provide three examples of using low-frequency Raman
information for a wide range of pharmaceutical dosage forms.1-3 A mapping for analysis and characterization of a wide range of
literature review of Raman mapping for pharmaceuticals shows the pharmaceutical drug types. First, we demonstrate the capability of low-
spectral ranges used in studies is primarily limited to Stokes signals that frequency Raman mapping for determining the active pharmaceutical
are 200 to 4000 cm-1 away from the excitation laser line. This region is ingredient (API) distributions and crystal sizes in an over-the-counter
accessible with most commercial instruments and allows extracting (OTC) oral dosage form. The mapping analysis of the OTC product
valuable fingerprint information about molecules such as aromatics, Excedrin® was performed on a tablet core. Using multivariate analysis
carbonates, sulphates, silicates, oxides and hydroxides within the 500- of Excedrin®, three major components were observed in the low-
1500 cm-1 range, and hydrogen interactions with carbon, nitrogen and frequency spectral region, all of which were similar to the reference
oxygen at around 3000 cm-1.4 By contrast, the low-frequency Raman spectra of the three declared APIs in the drug product (i.e., caffeine,
region (<10 cm-1 to 200 cm-1) has not been readily available in the past, acetaminophen and aspirin). In the second example, low-frequency
even though Raman in this frequency range provides access to lattice Raman mapping was utilized for the identification of polymorph
vibrations of molecular crystals and has the potential to more directly conversions in transdermal drug delivery systems (TDDSs). A principal
probe intermolecular interactions in solids such as pharmaceutical component analysis (PCA) of the Raman map revealed unintended
dosage forms. Specifically, low-frequency Raman spectroscopy provides polymorph formation within the TDDS. Finally, a topical cream
an avenue to probe polymorph detection of pharmaceutical systems as (Zovirax®) was mapped via the low-frequency spectral region. The
well as drug identification and quantitation for crystalline materials, multivariate analysis of this Raman map demonstrated an additional
both of which are critical quality attributes that need to be assessed and capability of low-frequency Raman spectroscopy; probing crystal
monitored during or after manufacturing.5-6 The low frequency Raman orientation. The spectral variance within the low-frequency Raman
region for measurements of lattice phonons in pharmaceuticals has map was used to identify various crystal orientations. Orientation
become more accessible in recent years with advances in precise optical identifications can be useful, as spectral variances in crystalline APIs
filters and narrow linewidth lasers. Therefore, low-frequency region can be misinterpreted as polymorphs. Overall, the potential of low-
investigations in pharmaceutical products has started to transition frequency Raman mapping combined with multivariate statistical
from the academic laboratory with customized laboratory set-ups to analysis is demonstrated here through analysis of a variety of drug
pharmaceutical labs and production lines.7-10 products. We show that low-frequency mapping is a complementary
48 | | April 2019
« SPECTROSCOPY »
tool to fingerprint region Raman mapping for rapid and sensitive ~4.5 times those in the fingerprint region, allowing for faster mapping to
identification of APIs, polymorphs and other crystal information that be performed to obtain the same signal-to-noise ratios.
is obtained from lattice phonons only. The data set obtained on the Excedrin tablet was comprised of
approximately 220k unique spectra taken across the entire tablet
surface (Figure 1A). Traditional, spectra by spectra comparison
Materials and Methods across the 220k set of spectra is prohibitively time consuming.
However, multivariant image analysis can be applied to rapidly
Pharmaceutical products were characterized by StreamHRTM Raman interpret the Raman data. In multivariate methods, spectral
imaging using a Renishaw InVia confocal Raman microscope features are utilized fully by revealing the variance within a spectral
coupled with a TR-Micro Thz-Raman System from Ondax Inc. which map and, simultaneously, dimensionally reducing the dataset.
provided the filter/laser combo needed to access the low-frequency Typically, unsupervised methods such as PCA are used for chemical
region down to ~5 cm-1 in both stokes and anti-stokes regions. imaging and performs the task via eigen decomposition of the
An 808 nm laser excitation source from the Ondax system, -70°C covariance of the spectral dataset. However, eigenvectors that are
thermoelectrically cooled charge-coupled device (CCD) camera and used in the dimensionality reduction are not true representatives of
a Leica DM2500 microscope were used for the Raman acquisition. A the Raman spectra, rather, they represent the contribution of a mixture
1200/mm grating was used to disperse the light through a spectral of the Raman signatures (peaks) to the spectral variance. To allow for
range of -400 cm-1 to 900 cm-1. The objective and step size used for the easily visualized data sets that can be quickly compared to a library
low-frequency Raman mapping varied to best fit the product being of reference spectra, a better suited method is Multivariate Curve
analyzed, but in general an optical montage was first obtained to Resolution-Alternating Least Squares (MCR-ALS). For the analysis of
allow for a representative region to be selected and mapped. Cosmic the Excedrin® tablet, MCR-ALS was applied to the Raman microscopy
ray removal was done in WiRE 4.4 software using the width of feature mapping with the assumption of a three-component system due to
and nearest-neighbor methods. Preprocessing and MCR/PCA analysis the 3 APIs expected in the system. Spectral pre-processing included
of the data was then carried out in Matlab R2017a using PLS Toolbox + standard normal variant (SNV) followed by Savitzky-Golay smoothing
MIA (Eigenvector Research, Inc., Version 8.6.2). (0 order, 7 point) and then a baseline correction with a Whittaker filter
(asymmetry=0.001, lambda=100). Since the data obtained is resulting
Sample preparation for the products selected for analysis were as
from Raman mapping, the components can not only be extracted,
follows: The Excedrin® tablet was prepared by splitting it in half with
but also visualized spatially to reveal the location of each individual
a razor blade and placing it on the microscope stage. The release liner
component across the tablet surface (Figure 1B).
of the transdermal delivery system (TDDS) was removed and the TDDS
was placed backing side down on a gold coated microscope slide The MCR-ALS analysis neatly highlights three unique components
and placed on the microscope stage. The Zovirax® cream was thinly which can be compared to reference library spectra (Figure 1C). When
spread on a gold coated microscope slide and placed on the these MCR loadings are overlaid with expected spectra for the APIs that
microscope stage. was obtained from the USP reference standards, all three components
can be readily identified. With component 1 shown in red on the MCR
scores image resulting from the acetaminophen and component 2
shown in green resulting from caffeine in very good agreement with
Result and Discussion
API Mapping
To investigate the feasibility of low-frequency Raman mapping for
characterization of pharmaceutical products, an over-the-counter
(OTC) tablet consisting of three active pharmaceutical ingredients
(APIs) was selected for analysis. This OTC product (Excedrin®),
is a combination drug for the treatment of pain comprised of
acetaminophen (250 mg), aspirin (250 mg), and caffeine (65 mg) as
the active ingredients, all of which have well defined peaks in the low-
frequency Raman region.
The Ondax system with an 808 nm laser/filter set coupled with the
Renishaw InVia Raman microscope was used to obtain the low- Figure 1. Low-frequency Raman mapping of Excedrin®
frequency Raman mapping data from the Excedrin® tablet. The strength tablet. A: Optical montage (bottom left: photo of tablet
of the Raman signal in the low-frequency region from ~ 5 cm-1 to prior to splitting) B: MCR 3 component composite
200 cm-1 allowed for data to be acquired with the fastest (100 millisecond) scores image. C1-3: MCR component loadings alongside
acquisition times allowed by the Raman system. Raman signals in corresponding reference spectra for API of interest.
the low-frequency region generally have signal intensities of up to
www.americanpharmaceuticalreview.com | | 49
» SPECTROSCOPY »
the USP reference spectra for those two APIs. Component 3 shown in
blue indicates a good agreement with aspirin, however an additional
shoulder is observed at ~140 cm-1 that isn’t present in the reference
spectra for aspirin. This additional peak is likely due to an excipient
present in the Excedrin® tablet that isn’t included in the model that
was built since the limitations were set to three components. These
labeled excipients include benzoic acid, carnauba wax, FD&C blue No.
1, hydroxypropylcellulose, hypromellose, microcrystalline cellulose,
mineral oil, polysorbate 20, povidone, propylene glycol, simethicone
emulsion, sorbitan monolaurate, stearic acid and titanium dioxide.
However, due to the expected amorphous nature of the majority of
these excipients, they are unlikely to contribute well defined features
in the low-frequency region, as opposed to the forest of spectral
signatures that would be expected in the traditional fingerprint
region. Thus, this helps to highlight the ability of low-frequency
Raman mapping to provide API distributions across the tablet surface
with minimal interference from the excipients present.
Polymorph Identification
In addition to rapidly identifying and mapping API location across
the surface of a pharmaceutical product, low-frequency Raman is Figure 2. Low-frequency Raman mapping of two crystals
capable of identifying changes that may occur in the API due to observed in a TDDS. A: 20x optical montage (insert: 100x
montage of mapped area). B: PCA scores image for PC1.
polymorphism or co-crystallization which may negatively affect the
C: Average spectra that had positive PC1 scores labeled as
product performance. The low-frequency Raman region is a sensitive “red” crystal and average spectra corresponding to negative
screen for polymorph changes due to the impact of changes in the on PC1 labeled as “blue” crystal along with the reference
lattice vibrations on the low frequency spectra. spectra for the API used to manufacture the TDDS.
50 | | April 2019
« SPECTROSCOPY »
Acknowledgements
This project was supported, in part, by an appointment (H.Y.) to the
Research Participation Program at the Center for Drug Evaluation
and Research administered by the Oak Ridge Institute for Science
and Education through an interagency agreement between the U.S.
Figure 3. Low-frequency Raman mapping of two crystals Department of Energy and the U.S. Food and Drug Administration.
observed in Zovirax®. A: Optical montage B1: MCR
scores image for 2 component MCR. B2: MCR loadings We would also like to acknowledge Dr. Anjan Roy from Ondax, Inc.
for component 1 and 2, and acyclovir reference spectra. for his valuable insight in discussions related to this project and Dr.
C1: MCR scores image for 4 component MCR (showing
components 1 and 4). C2: MCR loadings for components Ahmed Zidan from FDA/CDER/OPQ/OTR/ Division of Product Quality
1 and 4 colored according to MCR image. Research (DPQR) for his assistance with the transdermal studies.
the two crystals with two distinct spectra. The MCR scores image for References
components 1 (green) and 4 (blue) show two distinct crystals (Figure
1. Ewing, A. V.; Kazarian, S. G., Recent advances in the applications of vibrational
3C1) with the primary differences in the MCR loadings being attributed
spectroscopic imaging and mapping to pharmaceutical formulations. Spectrochimica Acta
to a peak at 37 cm-1 for the “blue” crystal and a shoulder at 90 cm-1 for
Part A: Molecular and Biomolecular Spectroscopy 2018, 197, 10-29.
the “green” crystal (Figure 3C2).
2. Gordon, K. C.; McGoverin, C. M., Raman mapping of pharmaceuticals. International Journal
Upon initial investigation, these changes were attributed to a of Pharmaceutics 2011, 417 (1), 151-162.
polymorphic difference between the two crystals, however further 3. Smith, G. P. S.; McGoverin, C. M.; Fraser, S. J.; Gordon, K. C., Raman imaging of drug delivery
analysis of multiple crystals revealed that this difference was due to systems. Advanced Drug Delivery Reviews 2015, 89, 21-41.
the orientation of the crystals. Because of the directional and polarized
4. Socrates, G., Infrared and Raman characteristic group frequencies: tables and charts. John
nature of the laser beam used for excitation and the rectangular shape Wiley & Sons: 2004.
of the acyclovir crystals, excitation was being obtained either along
5. Otaki, T.; Tanabe, Y.; Kojima, T.; Miura, M.; Ikeda, Y.; Koide, T.; Fukami, T., In situ monitoring
the horizontal or vertical axis resulting in distinct low-frequency
of cocrystals in formulation development using low-frequency Raman spectroscopy.
Raman peaks from horizontal or vertical crystal orientation. While International Journal of Pharmaceutics 2018, 542 (1), 56-65.
crystal orientation will not change the performance of the API, the
6. Mah, P. T.; Fraser, S. J.; Reish, M. E.; Rades, T.; Gordon, K. C.; Strachan, C. J., Use of low-
knowledge of the impact of orientation is important to note to avoid frequency Raman spectroscopy and chemometrics for the quantification of crystallinity in
false assumptions of presence of polymorph when none are present. amorphous griseofulvin tablets. Vibrational Spectroscopy 2015, 77, 10-16.
Importantly, the orientation sensitivity can be avoided entirely if the
7. Hisada, H.; Inoue, M.; Koide, T.; Carriere, J.; Heyler, R.; Fukami, T., Direct high-resolution
laser beam is depolarized prior to being focused on the sample. imaging of crystalline components in pharmaceutical dosage forms using low-frequency
raman spectroscopy. Organic Process Research & Development 2015, 19 (11), 1796-1798.
8. Larkin, P. J.; Dabros, M.; Sarsfield, B.; Chan, E.; Carriere, J. T.; Smith, B. C., Polymorph
Conclusions characterization of active pharmaceutical ingredients (APIs) using low-frequency raman
spectroscopy. Applied Spectroscopy 2014, 68 (7), 758-776.
In summary, the capabilities of low-frequency Raman mapping in
9. Walker, G.; Römann, P.; Poller, B.; Löbmann, K.; Grohganz, H.; Rooney, J. S.; Huff, G. S.; Smith,
the characterization of APIs in a variety of pharmaceutical products G. P. S.; Rades, T.; Gordon, K. C.; Strachan, C. J.; Fraser-Miller, S. J., Probing pharmaceutical
was demonstrated in three case studies. By utilizing the strong low- mixtures during milling: The potency of low-frequency raman spectroscopy in identifying
frequency Raman signatures that arise from crystalline API, rapid disorder. Molecular Pharmaceutics 2017, 14 (12), 4675-4684.
data acquisition and high selectivity of the low-frequency region for 10. Wang, H.; Boraey, M. A.; Williams, L.; Lechuga-Ballesteros, D.; Vehring, R., Low-frequency
the API over excipients (which tend to be more amorphous in nature shift dispersive Raman spectroscopy for the analysis of respirable dosage forms.
resulting in weaker low-frequency Raman signatures), identification, International Journal of Pharmaceutics 2014, 469 (1), 197-205.
www.americanpharmaceuticalreview.com | | 51
» ROUNDTABLE »
In your opinion what are the most important As the pharmaceutical market moves toward
properties raw materials/functional excipients can more specialized treatments, what benefits can
give to finished pharmaceutical products? Why? raw materials and functional excipients provide to
these new types of drugs?
Bikash Chatterjee, President and Chief Science Officer, Pharmatech
Associates: The contribution of functional excipients has greatly in- Chatterjee: One area of innovation we see now involves excipients
creased over the last decade. The key impacts made by functional ex- that are co-processed as part of the API manufacturing process,
cipients in finished products include solubility and range in some cases resulting in API formulations that can be more easily manufactured.
from drug efficacy to masking taste and extending product shelf life. One significant area where the impact of functional excipients is seen
Susan Burke, PhD, Director Process Development - Materials is in biologic drug and vaccine development. Biologics are susceptible
Science; Jackie Milne, PhD, Principal Scientist; Ron Kelly, PhD, to degradation from both storage and processing conditions. Newer
Principal Scientist; Ting Wang, PhD, Senior Engineer; Patrick functional excipients can stabilize these products that are prone to
Gammell, PhD, Executive Director Process Development, Amgen: destabilization from a variety of mechanisms.
Amgen is an attribute led, patient-centric organization. We design Burke, Milne, Kelly, Wang, Gamell: Raw materials, both non-
for the patient; therefore, our excipients are important for ensuring compendial and compendial excipients, will continue serve as
we can to deliver to our target product profile. Excipients serve enablers for ensuring stability and delivery of therapies for patients, as
many important roles in the production of finished pharmaceutical these components are essential for the development of such products.
products. They are selected for the specific functionality they afford However, for novel non-compendial materials, a paradigm change is
to the formulation such as providing the right osmolality or protection required to be able to meet the needs of specialized medicines. A shift
of the therapeutic molecule from shear stresses. The excipients must to a more attribute-focused approach for materials is warranted. Like
be inert to avoid impact to the stability and the pharmaceutical profile the Quality Target Product Profile (QTPP), a Material Target Attribute
appropriate for the intended use of the finished drug product. In Profile (MTAP) can serve as a framework for capturing information on
addition, compendial compliance ensures that the excipients meet raw material performance requirements, relevant material attributes,
the quality standards for use in pharmaceutical products. Consistent impact on process and product performance, target attribute ranges,
performance and quality of the excipients is important for optimal and control strategies. This approach provides a better understanding
efficacy at the time of administration of the finished drug product. of the influence of raw material variation for enhanced reliability in
Adhering to those standards supports our ability to delivery patient- manufacturing and product quality. An attribute-centric approach
centric products to the market. to raw materials ensures that the attributes important for the
52 | | April 2019
« ROUNDTABLE »
development of specialized medicines are identified and controlled, appreciative of their roles. A pharmaceutical company must be
which will support patient-centric outcomes. knowledgeable about their raw material supply with traceability
throughout each level of supply chain, as far as is necessary. This is
critical to both ensuring supply continuity in the event of a local
What are some important attributes a supplier of disaster and supply-chain integrity in the event of a deliberate attempt
raw materials/functional ingredients must have at adulteration.
in order to meet the product demands of the Transparency leads to increased predictability. Information about
marketplace? changes introduced to a material allow for an understanding of the
primary sources of variation, thus enabling us to predict the outcome
Mark Mitchell, Principal Engineer, Pharmatech Associates: As the of pharmaceutical manufacturing. Communicating such changes
pharmaceutical industry embraces Quality by Design, a key element clearly allows for better understanding and control over potential
of process understanding is how raw material variability impacts drug downstream impacts.
product quality. Providing a raw material that simply “meets spec” is
not sufficient in this new paradigm. A supplier should have intimate The pharmaceutical industry is adopting best practices, such as
knowledge of their product (i.e., raw material/functional ingredient) developing robust supplier-relationship and detailed technical
in terms of its process control and capability relative to its quality engagement, to enhance raw materials reliability. Another important
attributes. By providing this data to drug product manufacturers element for advancing knowledge of raw materials is the transfer and
during product design and development, the criticality of that analysis of suppliers’ data. A standard guide for electronic data transfer
raw material/functional excipient to finished drug product can be (ASTM E-3077-17) from supplier to pharmaceutical manufacturers
appropriately evaluated by either design of experiments or risk has been established in 2017. Data analytics can facilitate enhanced
assessment. Knowledge of raw material variability when moving from engagement between the pharmaceutical industry and suppliers,
small-scale to commercial scale processes allows for more predictable through the sharing of the analysis to suppliers for mutual learning
drug quality as product quality issues due to unexpected changes in and improvement. The enhanced collaboration requires improved
raw materials can be avoided. standardization in key areas such as terminology, units, SKUs etc.
Burke, Milne, Kelly, Wang, Gamell: To keep pace with the increasing
demands of the pharmaceutical industry, raw material suppliers must
place emphasis on ensuring they develop strong partnerships with
Looking at the future, what role will suppliers
pharmaceutical manufacturers and actively engage in seeking the of raw materials/functional ingredient have as
voice of customer. It is imperative they understand the requirements drug development becomes more complex and
for raw materials to be used in a regulated environment. To deliver on more specialized?
the needs of the pharmaceutical industry, suppliers must have a strong
quality management system and a philosophy of transparency as their Chatterjee: We will see more drug development companies looking to
foundation. It has become increasingly important for suppliers to partner with key functional excipient suppliers to produce consistent
implement robust monitoring programs including statistical process and ready-to-process APIs. Continuous manufacturing itself is hugely
control strategies and the capability to readily transfer raw material API dependent and demands a steady and reproducible product to
data to their customers. This must be supported by depth and breadth realize the long-term benefits of such new innovative approaches to
of technical knowledge, testing capabilities, and engagement with drug production.
their supply chain partners. Burke, Milne, Kelly, Wang, Gamell: As drug development continues
to evolve, so too must the relationship with raw material suppliers.
Strong partnerships built on trust and a commitment to transparent
As the globalization of the pharmaceutical industry communication are a must for keeping pace with advancements in the
continues – what must ingredient suppliers do pharmaceutical industry. With the globalization of supply chains and
to ensure the quality of their products and the increasing complex distribution channels throughout the world, raw
availability of same? material suppliers must enhance the resilience of their organizations
by building robust business continuity strategies that take into
Chatterjee: Over the last decade the emerging markets in particular consideration the potential for unforeseen challenges such as natural
have stumbled badly in terms of ensuring excipient purity, disasters. In addition, suppliers must continue to strengthen their
consistency, and functionality. To be competitive, investing in process supply chains, control strategies, and reliability of their materials. The
understanding will become essential, especially as the complexity and increased complexity of drug development a deep understanding
sophistication of new drug delivery forms continues to escalate. of raw material variation is of great importance. Suppliers that
Burke, Milne, Kelly, Wang, Gamell: Supply-chain transparency is employ advanced data analytics to monitor their material attributes,
of vital importance in an age of increasing globalization. The parties in combination with robust process control strategies, will be well
representing each link of the supply chain need to be open and equipped to support their customers in the pharmaceutical industry.
www.americanpharmaceuticalreview.com | | 53
» »
SECTION TITLE
Pharmaceutical
P .N.
P.I N Suspensions of Cyclosporin A Form 2;
Points
Points
Patent Innovation News
A.V. Gore, P.S. Mohanty, and
E.Q. Farnes; Allergan, Inc., USA;
U.S. Patent # 10,206,971, February 19, 2019.
Cyclosporin A is available in the market as an ophthalmic emulsion
under the brand name Restasis. It is indicated to increase tear
production in the treatment of dry eyes. Due to cyclosporine A’s poor
water solubility, it is currently formulated by dissolving it in oil or by
The purpose of this column is to highlight using high levels of surfactants and solubilizers. The former leads
Article Title
to forming an emulsion and the later forms an aqueous solution
and summarize recent key patents in the
pharmaceutical arena issued by the US
Introduction
of cyclosporine. The inventors of the present invention discloses a
nanosuspension formulation of cyclosporine A using its crystalline
Patent Office in February 2019. Paragrapgh
polymorph.TextThis invention may provide a better dosage form of
cyclosporine A. The inventors claim that the nanosuspension may
have advantages such as higher bioavailability, longer retention
Anvit Vasavada, MS, Sunny Christian, MS (RA), time in eye, improved tolerability etc. over the current formulations.
Neelam Sharma, MS and
Hemant N. Joshi, PhD, MBA*
Tara Innovations, LLC
www.tarainnovations.com
*hemantjoshi@tarainnovations.com
54 | | April
November/December
2019 2011
« SECTION TITLE »
www.americanpharmaceuticalreview.com | | 55
» ADVERTISER'S INDEX »
ON-DEMAND WEBINAR
SPEAKER
Luca
Lyophilized Drug Product Development Ogunleye
Wolfe Laboratories
The contact directory is for information purposes only. While every effort has been made to ensure it is accurate and complete, any errors or omissions are not the responsibility of the publisher.
56 | | April 2019
A HEALTHY WORLD
WITH AJINOMOTO BIO-PHARMA SERVICES,
YOU HAVE THE POWER TO MAKE.
You have the power to make a difference by delivering
therapeutics that improve quality of life and inspire a healthier
world. You need a manufacturing partner who has the power
to make your every challenge their own and who shares your
unwavering tenacity and dedication from clinical studies through
commercial success. Together, we have The Power To Make.
CDMO SERVICES:
Small & Large Molecules
Process Development
WHAT DO YOU
WANT TO MAKE?
www.AjiBio-Pharma.com
DRUG DEVELOPMENT IS SCIENCE.
CRAFTING SUCCESSFUL TREATMENTS IS ART.
Successful treatments with better outcomes for patients are built on science, superior formulation
technologies and the art of drug design.
Catalent’s passion and expertise guiding thousands of molecules into clinic is there to help you turn
your science into reality. Catalent, where science meets art.
us + 1 888 SOLUTION (765-8846) eu 00800 8855 6178 catalent.com/art © 2019 Catalent Pharma Solutions. All rights reserved.