Drug Development and Delivery - March 2011
Drug Development and Delivery - March 2011
Drug Development and Delivery - March 2011
IN THIS
ISSUE
INTERVIEW WITH
CETERO RESEARCH’S CEO
Coating Film
Permeability 20
Jinghua Yuan, PhD
Combination
Products 27
Leah R. Kendall
Prefilled
Syringes 48
Cindy H. Dubin
Lifecycle
Management 55
Graham Reynolds
Technology &
Services
Showcase 64
Retinal
The science & business of drug development in specialty pharma, biotechnology, and drug delivery Disease 70
Noah Beerman
Stephen From
Joseph James Susan
Beaurline Cunningham, Banbury, PhD
The Use of Surface- PhD Fast-Dispersing
Modified Nanoparticles Dosage Forms for
Tackling the
to Facilitate the the Pediatric Market
Challenge of
Processing of Oral
Nucleic Acid
Solid Dosage
Delivery: Progress
Forms
& New Approaches
Drug Delivery Ad 4-10.qxp:Innercap Ad FINAL 3/25/10 10:31 AM Page 1
the
a d va n tag e s
of multi-phase, multi-compartment capsules are clear
For more information contact us at the telephone number and email address below: United States Patent No. 7,670,612
US and International Patents Pending
9216 Palm River Road, Suite 203 • Tampa, FL 33619 USA • (813) 837-0796 • www.innercap.com • [email protected]
© 2003–2010 INNERCAP Technologies, Inc. all rights reserved.
2-4 DDT March 2011 front pages _DDT Frntmttr apr06 06.2-4.qx 2/25/11 11:42 AM Page 2
2-4 DDT March 2011 front pages _DDT Frntmttr apr06 06.2-4.qx 2/25/11 3:00 PM Page 3
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Corporate/Editorial Office
219 Changebridge Road, Montville, NJ 07045
Tel: (973)299-1200
Fax: (973) 299-7937
www.drug-dev.com
West Coast
Warren De Graff
Western Regional Manager
818 5th Avenue, Suite 301
San Rafael, CA 94901
Tel: (415) 721-0644
Fax: (415) 721-0665
E-mail: [email protected]
Prefilled
Syringes
55 Lifecycle Management & Differentiation
“And the market numbers concur. In
Through Injectable Delivery Systems
2009, an estimated 2 billion prefilled Graham Reynolds believes the inter-dependence of the
packaging and delivery system needs to be carefully
syringe units were sold, and the market
considered at an early stage, and a thorough understanding
for the technology was estimated to be of both is key to ensuring a successful drug/delivery system
combination.
worth up to $2.5 billion. The biologics
sector is being credited with having the 60 Cetero Research: Addressing Today’s
most influence on the prefilled syringe Challenges in Drug Development
Drug Development Executive: Dr. Troy W. McCall, Cetero’s CEO,
market, as there is an increasing need
focuses on innovative advancements to address drug
for self-administration of these drugs for development challenges and how CROs must build capabilities
and expertise to offer value to sponsors in a constantly
chronic conditions.”
evolving, yet uncertain, industry environment.
DEPARTMENTS
Drug Development & Delivery March 2011 Vol 11 No 2
Excipient Update . . . . . . . . . . . . . . . . . . . . . . . . . 20
Permeability Study on the Coating Film Consisting
of CA-398-10 NF/EP & CA- 320S NF/EP
Combination Update . . . . . . . . . . . . . . . . . . . . . . 27
FDA Regulatory Update: Top 10 Policy Development
Issues for 2011 & What May Stand in the Way of
Advancing Them
Dan Marino,
MSc
Executive Editorial
Director
Drug Delivery
Technology
article Sciences, Inc., a leading pharmaceutical CRO, recently trained to use the instruments to their fullest capability.”
P announced the establishment of a strategic alliance with “Particle Sciences is committed to remaining one of the premier
HORIBA Instruments of Irvine, CA, which is the US sales and drug delivery development services providers,” added Dr. Lee. “We
marketing division of HORIBA Limited of Kyoto, Japan. This offer a broad array of drug delivery technologies and routinely work
alliance ensures that both client bases are provided with a total on atypical dosage forms. It’s critical that our analytic and
solution, combining the most up-to-date physical characterization characterization capabilities keep pace with our formulation
tools with operational expertise in a fully GLP/GMP compliant expertise. Additionally, as our clients scale to clinical and ultimately
setting. Under the arrangement, the full array of HORIBA commercial processes, we need to ensure the methods we develop
characterization tools will be available at Particle Sciences. are phase appropriate and based on readily available techniques.
“The need for particle size analysis and physical HORIBA is the world’s largest instrument manufacturer with the
characterization in general is growing rapidly within this highly most complete product offering and can now provide the level of
regulated environment,” said Dr. Robert Lee, Vice President of security our clients deserve.”
Pharmaceutical Development at Particle Sciences. “Particle Sciences “Many pharmaceutical customers are located along the East
is a world leader in particulate formulations and drug/device Coast,” said Dr. Pohl. “The combination of our Edison, NJ,
combination products. We looked for a partner that shared the same headquarters plus the Bethlehem, PA, location of Particle Sciences,
commitment to quality and innovation, and HORIBA fit the bill.” Inc., gives HORIBA a strong one-two punch to support these
With this in place, HORIBA clients will have a resource that customers. Services ranging from sample analysis, customer support,
can both develop and perform characterization under cGLPs and and full consulting services will now be readily accessible to our
Drug Development & Delivery March 2011 Vol 11 No 2
cGMPs. “Our client base ranges from start-ups to the largest customers.”
multinational Pharma and Biotech companies,” said Dr. Mike Pohl, Particle Sciences is an integrated provider of drug development
HORIBA’s Vice President. “For a variety of reasons, we are often services with deep expertise in micro- and nano-particulate drug
asked if we can recommend a site familiar with pharmaceutical delivery technologies and drug/device combination products with
development at which they could have work performed. We have additional specialized capabilities in topical and mucosal drug
worked with Particle Sciences for some time and have been products. Through a full range of formulation, analytic, and
impressed with their facility and their team. By entering into this manufacturing services, Particle Sciences provides pharmaceutical
relationship, we can ensure that our clients not only gain access to companies with a complete and seamless development solution that
the most advanced technology, but also that the operators are highly minimizes the time and risk between discovery and the clinic.
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pharmaceutical partners with an enhanced choice of drug delivery treatments across a broad range of applications, including central
technologies to improve the performance of their treatments,” said Ian nervous system drugs, allergy medications, and dosage forms for
Muir, PhD, President, Modified Release Technologies for Catalent. pediatric and geriatric populations. Additionally, Lyopan technology
“The Lyopan technology is ideally suited to deliver a wide dose range lends itself easily to the development of both prescription and OTC
of APIs in a fast-dissolve tablet. These are key considerations for products.
situations in which patient adherence, ease of swallowing, and a lack “With its long history of developing lyophilized fast-dissolve
of access to water are important issues to address.” products, Catalent is the ideal partner to launch our innovative Lyopan
Lyopan is a proprietary technology for the development and technology,” commented Hans Peter Rohrer, Chairman of Pantec.
manufacture of fast-dissolve lyophilized tablets, including OTC The acquisition of Lyopan technology also has clear synergies
products, such as allergy treatments or travel medications. Lyopan also with several of Catalent’s existing technologies, such as Zydis fast-
requires significantly less water than existing technology, an dissolve, a unique, freeze-dried oral solid dosage form that disperses
advantage that helps reduce energy consumption, sublimation, and instantly in the mouth without requiring water.
drying time. As a result of these advanced characteristics, Lyopan
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with moderate-to-severe chronic lower back pain. The primary remains positioned as the first potential single-entity, controlled-
efficacy endpoint is the mean change in average daily pain intensity release hydrocodone product,” said Stephen J. Farr, PhD, President and
scores between ZX002 and placebo. Chief Operating Officer. “Because it does not contain acetaminophen
Initial top-line data from Study 801 and an open-label Phase III and allows for convenient twice-daily dosing, ZX002 may fulfill a
safety study (Study 802) are anticipated to be available during the beneficial treatment option for both patients using immediate-release
second half of 2011. As previously announced, Zogenix has completed hydrocodone combination products on a chronic basis and an
enrollment of Study 802 to evaluate overall safety of ZX002 in alternative for patients already using extended-release opioids for the
patients for up to 1 year. management of their moderate-to-severe pain. We look forward to
Pending positive Phase III clinical results, Zogenix expects to obtaining top-line safety data from Study 802 and efficacy and safety
submit an NDA for ZX002 with the US FDA by early 2012. If data from Study 801 during the second half of this year to support a
approved, ZX002 has the potential to be the first controlled-release potential NDA submission by early-2012."
version of hydrocodone and also the first hydrocodone product that is 15
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(GSK). The technology uses injection-molding processes to The FlexTab technology allows for a variety of fill materials,
produce unique capsule-shaped dosage forms that offer a new including powders, pellets, liquids, micro-tablets and tablets, and
platform for formulating a wide range of new pharmaceutical and can even deliver separate liquid and powder APIs in one dose. This
consumer health products. The deal between Capsugel and GSK innovation opens the door to novel product designs and
was brokered by SR One, GSK’s corporate venture fund. customization options. It extends Capsugel’s capsule technology
“Capsugel is very excited to have this innovative technology beyond the well-established dip-molding process used today,
as part of our suite of offerings”, said Keith Hutchison, Vice expanding into higher value segments and offering enhanced value
President of Research and Development at Capsugel. “We believe for customers.
the FlexTab technology’s unique performance characteristics and Capsugel is moving forward immediately to bring the
novel presentation will enable us to formulate the next generation technology and assets in-house with plans of making the new
of pharmaceutical and biotech products for our customers. With dosage form available to customers as soon as possible.
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M
erck Serono, a division of Merck KGaA, Darmstadt, Merck Serono. “This partnership with Domain Therapeutics
Germany, recently announced an exclusive development reflects our long-term commitment to develop new treatments for
and licensing agreement with Domain Therapeutics, Strasbourg, neurodegenerative diseases.”
France, to develop metabotropic glutamate receptor 4 (mGluR4) “This agreement is a validation of Domain Therapeutics’
Positive Allosteric Modulator (PAM) drugs targeting Parkinson’s business model of addressing difficult GPCRs and partnering
disease and other neurodegenerative diseases. compounds, with a significant deal, at an early stage of Drug Development & Delivery March 2011 Vol 11 No 2
Domain Therapeutics will contribute optimized compounds development,” said Pascal Neuville, CEO, Domain Therapeutics.
that have been developed from their proprietary chemical series. “Merck Serono is known to set very high standards for the
Under the terms of the agreement, the company will receive EUR compounds they are licensing, and this deal is a demonstration of
2 million in up-front payment and research funding and is eligible the quality of our work. We anticipate that this agreement will
for up to EUR 132 million in milestones for the first two products, enable us to sign further deals of this kind.” mGluR4 is a
as well as undisclosed royalties. glutamate receptor, member of the G-Protein Coupled Receptor
“We are pleased to have the opportunity to work with Domain (GPCR) family, and is believed to be a potential therapeutic target
Therapeutics, which has developed great expertise in the G- for Parkinson’s disease.
Protein Coupled Receptor area,” said Bernhard Kirschbaum, Allosteric modulation of mGluR4 receptors is thought to
Executive Vice President for Global Research and Development at exert regulatory activity on glutamate-mediated neurotransmission.
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INTRODUCTION
Cellulose esters form the most suitable semi-permeable membranes for osmotic drug delivery systems. Eastman produces
several types of cellulose esters, in which CA-398-10 NF/EP and CA-320S NF/EP are the most commonly used for the
application. CA-398-10 NF/EP and CA-320S NF/EP could be used alone or combined to form the membrane.1-4 CA-398-10 NF/EP
and CA-320S NF/EP have different acetyl content (CA-398-10 NF/EP, 39.8% vs. CA-320S NF/EP, 32.0%) and physical
properties.5 These differences in properties result in different permeability of the coating films. One would expect that the
permeability of the coating films could be tailored by adjusting the ratio of two polymers in the coating solution to fit
particular needs.
The objectives of this study were to investigate the effects of the ratio of CA-398-10 NF /EP to CA-320S NF/EP on the
permeability of the coating films, to investigate the effects of plasticizer level and molecular weight on the permeability of
the coating films, and to address the effect of acetyl content variation in CA-398-10 NF/EP polymer on the permeability of
the coating films.
MATERIALS Barnstead, Van Nuys, CA) were used as the NF/EP and low acetyl content of CA-398-
To determine the permeability of solvent systems. All of the materials were 10 NF/EP with PEG 400 as the plasticizer.
coating films, the designed coating solution used as received. The table is color coded so that one color
was coated on model tablets. The model region has the same ratio of CA-398-10
tablets consisted of POLYOX water-soluble METHODS NF/EP to CA-320S NF/EP with changing
resins with a molecular weight of 5,000,000 plasticizer concentration. Group 2 is the
(Dow Chemical, Midland, MI), colorant Experimental Design of Coating formulations having CA-320S NF/EP and
(Sensient Technologies Corp., St. Louis, Formulation low acetyl content of CA-398-10 NF/EP
MO), and magnesium stearate Four groups of coating formulations with PEG 3350 as the plasticizer. The water
(Mallinckrodt Baker Inc., Phillipsburg, NJ). were designed. Table 1 lists one group concentration is kept at 10% in the total
For coating solutions, CA-398-10 NF/EP (Group 1) of formulations having CA-320S solution for all formulations. The other two
with an acetyl content at 39.4% (CA-NF,
Drug Development & Delivery March 2011 Vol 11 No 2
groups of formulations were the same faster water uptake rate indicates the film is slower around the first 5 minutes during a
compositions as Groups 1 and 2, except high more permeable. It was observed that the water uptake experiment. The shift in uptake
acetyl content of CA-398-10 TG was used to water uptake rate changed from fast to slightly rate may be due to the change in mechanism
replace the low acetyl content CA. There were
36 formulations in total. FIGURE 1
of water transporting through the film. In the statistical tools. Design Expert® software developed for four groups of formulations.
beginning of the testing, by capillary action, (Design Expert V7., Stat-Ease, Inc., The models are displayed in Table 2.
water will occupy the pores or small channels Minneapolis, MN) was employed to establish
formed during coating; after that water will models to predict water uptake rates. Because The Ratio of CA-398-10 NF/EP to
penetrate through the membrane by diffusion. water uptake rates changed during the course CA-320S NF/EP Effect on the
40.3
39.4
40.3
39.4
CA_NF: CA-398-10 NF/EP; CA_TG: CA-398-10 TG
CA-398-10 (%)
Acetyl Content of
PEG3350
PEG 3350
PEG 400
PEG 400
Plasticizer
-4.09833E-06* CA_TG * PEG
-1.02092E-06* CA320S * PEG
-1.07434E-06 * CA320S * CA_TG
+0.000376468* PEG
+2.02306E-05 * CA_TG
+6.82472E-05* CA320S
0.001820165
To 5 Minutes
-2.50565E-06* CA_TG * PEG
+5.34942E-07* CA320S * CA_TG
+0.000201294* PEG
+1.73484E-06* CA_TG
-7.68814E-06* CA320S
0.000617775
Beyond 5 Minutes
0.001326205
0.000617775
+5.89555E-05* CA320S desired rate of water uptake in an osmotic
-7.68814E-06 * CA320S
+1.71733E-05 * CA_NF
+1.73484E-06* CA_NF
39.4 PEG 3350 +0.000373997 * PEG
+0.00023638 * PEG drug delivery system by selecting the
-1.07434E-06* CA320S * CA_NF
+5.34942E-07 * CA320S * CA_NF
-2.15027E-06 * CA320S * PEG
-2.50565E-06* CA_NF * PEG
-4.09833E-06 * CA_NF * PEG appropriate ratio of CA-398-10 NF/EP to
CA-320S NF/EP to use in the coating
formulation. Thus, one can control the rate at
0.001820165 which a drug is released from an osmotic
+6.82472E-05* CA320S 0.000617775
+2.02306E-05 * CA_TG -7.68814E-06* CA320S
40.3 PEG3350 +0.000376468* PEG +1.73484E-06* CA_TG tablet by controlling the rate of internal
-1.07434E-06 * CA320S * CA_TG +0.000201294* PEG
-1.02092E-06* CA320S * PEG +5.34942E-07* CA320S * CA_TG osmotic pressure build-up, which is a direct
-4.09833E-06* CA_TG * PEG -2.50565E-06* CA_TG * PEG
function of the rate of water uptake by the
CA_NF: CA-398-10 NF/EP; CA_TG: CA-398-10 TG tablet. Indeed this concept is already used
23
20-26-DDD March 2011-Excipient Update_Layout 1 2/25/11 11:51 AM Page 24
Effect of PEG Level & PEG level and PEG molecular weight on the water PEG molecular weight has little, if any,
Molecular Weight on the Water uptake of coating films. impact on the rate of water uptake. However,
Uptake of the Coating Films Figure 2 displays the effect of PEG level PEG level has a significant effect as is seen
PEG 400 and PEG 3350 at 0%, 11.1%, and PEG molecular weight on the water from the eight-fold increase in the water
and 25% relative to total CA polymer weight uptake, while the ratio of CA-398-10 NF/EP uptake when the PEG is increased from 0 to
were studied to investigate the effect of PEG to CA-320S NF/EP was maintained at 25% of the total CA polymer weight. Based
50/50%. The results of this study show that on past research with cast films, it is expected
FIGURE 3 A, B & C
A B
C
Drug Development & Delivery March 2011 Vol 11 No 2
Predicted water uptakes at 30 minutes to show the effects of PEG level and PEG molecular weight, and acetyl variation in CA-398-10 polymer on the water
uptake of the coating films. (3A) CA-398-10/CA320S = 50/50, left lines: low acetyl CA-398-10 was used; right lines: high acetyl CA-398-10 was used. (3B)
CA-398-10/CA320S = 75/25, left lines: low acetyl CA-398-10 was used; right lines: high acetyl CA-398-10 was used. (3C) CA-398-10/CA320S = 90/10, left
lines: low acetyl CA-398-10 was used; right lines: high acetyl CA-398-10 was used.
24
20-26-DDD March 2011-Excipient Update_Layout 1 2/25/11 11:51 AM Page 25
PEG400
PEG was present in the formulations, lower
11 0.0636 0.0534 16.0
1. Mishra B, Makesh BK, Sankar C. Oral push-pull osmotic years experience in formulation and drug delivery. Ms. Clipse
pumps of pentazocine hydrochloride: development and attended East Tennessee State University in 1968 and 1982.
evaluation. Ind J Pharmaceut Sci. 2006;68(1):85-87.
2. Prabakaran D, Singh P, Kanaujia P, Jaganathan KS, Rawat
A, Vyas SP. Modified push-pull osmotic system for
simultaneous delivery of theophylline and salbutamol:
development and in vitro characterization. Int J
Pharmaceutics. 2004; 284:95-108.
3. Yuan J, Shang PP, Wu SH. Effects of polyethylene glycol Dr. Ray Newton is retired and was the Group Leader of the
on morphology, thermomechanical properties, and water
Formulation Products Lab. His career at Eastman included a wide
vapor permeability of cellulose acetate- free films. Pharm
Drug Development & Delivery March 2011 Vol 11 No 2
T
he FDA’s Office of Combination Products (OCP) has for focus primarily on its regulatory responsibilities, which the Office
many years engaged on policy issues and how best to continues to perform timely and efficiently. Of late, policy-making
serve patient needs with respect to drug delivery and has had to take a back seat. Although the OCP has initiated work
other combination product products in a thoughtful and patient- on several guidance documents and other policy issues, many of
focused manner. However, it seems that in recent years, the these await the next step of publication, finalization, response to
significant increases in the OCP’s workload have created a need for industry comments, and the like. We have considered what the
additional resources specifically devoted to supporting the OCP most significant issues are and indentified the 10 most critical to
and combination product policy development, while at the same drug delivery regulation.
time preserving the OCP’s other functions, including the informal
dialogue in which the OCP engages with industry and the public. (1) GOOD MANUFACTURING PRACTICES
This discussion will summarize that resource quandary, and then (GMPS)FOR COMBINATION PRODUCTS
will turn to highlighting the top 10 policy issues percolating in the
drug delivery and combination product area. We ranked this issue at the top of the list for several reasons.
Drug delivery and other combination products - products that In September 2009, the OCP published a proposed rule on GMPs
involve the convergence of two or more different types of FDA- for combination products. As described in the March 2010
regulated articles (drugs, medical devices, and biological products) Combination Update in Drug Delivery Technology, many issues
- represent promising advances in patient care. Patients suffering implicit in these rules impact drug delivery products and the
from serious diseases and conditions have already benefited from entities that manufacture them. As such, drug delivery product
innovative drug delivery technologies, and many more are developers and manufacturers are anxious to understand the final
currently being researched and developed. Industry estimates content of these rules. Recently, the Agency has publicly predicted
reflect this growth and development. that the proposed rules will not be finalized until the end of 2011.
In turn, as Agency data demonstrate, increases in the The Agency announced its intent to publish rules on combination
development and marketing of combination products have product GMPs in early 2006; however, prior to the proposed rule
significantly impacted the OCP’s workload, leading to more things published earlier this year, the only interpretation offered by the
like Requests for Designation, inter-agency consultations, and Agency was a draft guidance document issued in September 2004.
Drug Development & Delivery March 2011 Vol 11 No 2
individual requests from industry for Agency meetings. The OCP Waiting until the end of 2011 continues to put a strain on
has done a great job rising to the occasion, executing these manufacturers that need to move forward with new technologies to
regulatory responsibilities in a timely and thoughtful manner. improve patient care, and the wait also leaves critical regulatory
At the same time, though, in spite of the tremendous industry issues in a state of ambiguity and flux.
growth and consequent impact on the Agency, the resources the
FDA has been able to devote to combination products has (2) POST-MARKET SAFETY REPORTING
remained nearly static. Indeed, the first annual report of the OCP
reported that the Office was staffed by 6 individuals, with one As with GMPs, we understand the Agency is predicting the
vacancy. At that time, the eventual projected staff was 10 proposed rule on post-marketing safety reporting for combination
individuals. Today, 7 years later, there is just 1 more staff member. products will not be finalized until the end of 2011. Although most
As a consequence of the growth in this field (and without developers and manufacturers probably would agree that the GMP
corresponding growth in its staff), the OCP increasingly has had to regulations should have a higher level of priority, the post-market 27
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safety reporting requirements nevertheless are an important priority. response to those comments, the OCP has explained in public
Ideally, finalizing these rules also would be accomplished prior to forums that they are working on a second, companion autoinjector
the end of next year. guidance that should clarify the numerous ambiguities in the draft
guidance published nearly 2 years ago. Many members of the drug
(3) IMPLEMENTING GUIDANCE DOCUMENTS delivery technology industry are anxious to obtain clarification on
ON COMBINATION PRODUCT GMPS & the issues raised by the first guidance and with respect to
POST-MARKET SAFETY REPORTING autoinjector issues generally.
The Agency has acknowledged that implementing guidance will (6) NUMBER OF MARKETING SUBMISSIONS
be critical to ensure a successful and timely implementation of both
of the aforementioned proposed rules. Publishing these guidance The Agency published a Concept Paper on the number of
documents, at least in draft form, prior to issuing the final rules marketing submissions required for a combination product in 2005.
would be extremely helpful to ensure stakeholders can comply with The Agency has not produced a guidance document or responses to
the final requirements within the effective date of the rules. These the comments raised in the industry comments. Incidentally, we are
guidance documents will undoubtedly be complex and will require a also not aware that a docket was established for this issue, so the
fair amount of Agency manpower in order to issue them in a timely public is unable to access any comments submitted. Hopefully, the
manner. Agency will be able to make some progress on a guidance document
or a Concept Paper revised in response to comments at some point
(4) REPORTING MANUFACTURING & DESIGN this year.
CHANGES TO MARKETING APPLICATIONS
(7) REGISTRATION & LISTING
The FDA has reported they have been working on a guidance
document on this topic since 2006. This is an extremely complex Currently, there is no published guidance on registration and
issue that no doubt requires a significant amount of Agency listing requirements for combination product manufacturers. We
resources, both from OCP and the Centers. It is also a topic on understand the OCP has been working on a draft guidance document
which industry has an acute need for guidance. In an industry survey for quite some time, and that registration and listing questions are
conducted a few years ago, post-market modification issues were among the most frequently asked of OCP.
among the topics industry rated highest as needing Agency
guidance. Along with the proposed rules on GMPs and adverse event (8) CLINICAL STUDY REQUIREMENTS Drug Development & Delivery March 2011 Vol 11 No 2
reporting, rules or guidance on the reporting of design and
manufacturing changes to marketing applications should be one of In recent times, drug delivery and other combination product
the highest ranking priorities in terms of combination product policy developers also have ranked clinical trial requirements for
development. combination products very highly among current guidance document
needs. These clinical trial issues may include such topics as
(5) AUTOINJECTOR GUIDANCE bioequivalence studies for autoinjectors, human factors as part of
Phase III studies, patient numbers required to demonstrate device
The Agency issued a draft guidance on Technical effectiveness, clinical trial designs for combination products, and
Considerations for Pen, Jet, and Related Injectors Intended for Use number of clinical studies required for medical devices. The Agency
with Drugs and Biological Products in April 2009. The September has not issued guidance on these issues since the high level guidance
2009 Combinaton Update in Drug Delivery Technology discussed on Early Development Considerations for Innovative Combination
and analyzed this draft guidance. As you may remember, industry Products in September 2006.
29
had a number of concerns with this draft guidance. Partly in
27-31 DD&D March 2011-Combination Update - _Layout 1 2/25/11 11:52 AM Page 30
(9) CHEMICAL ACTION additional personnel devoted to the policy-making function and who
are formally tasked with ensuring the advancement of regulatory
This is another topic on which we understand the Agency has policy concerning combination products.
been developing a guidance document for quite some time; however, These top 10 issues are at the heart of advancing drug delivery
the Agency has not yet published a draft for comment. Although it’s and other combination product policy development and regulation, as
difficult to offer a prediction without better understanding what the moving policy development forward will help provide the clarity and
Agency has in mind, the content of this guidance could be fairly far- regulatory predictability that is needed to provide patients with safer
reaching across the combination product spectrum and could well and more effective healthcare. We eagerly await progress on these
impact drug delivery technologies. issues and hope the Agency finds a way to support them in the
coming year. u
(10) CONTRAST IMAGING AGENT
Designation, consulting with other Agency personnel who are Epstein Becker & Green’s
responsible for marketing submissions, and participating in industry Washington, DC, office. She advises
meetings. Importantly, the OCP also engages regularly with members clients on the regulatory
requirements of the FDA and on
of industry to discuss questions concerning individual combination
reimbursement issues. Ms. Kendall
products.
also serves as Counsel to the
With these significant issues on the horizon, the time is right for Combination Products Coalition and
the FDA to review the Agency’s prioritization of and resources develops and advocates for FDA
allocated for combination product issues. The Agency needs to policy and rule-making on issues impacting combination
consider how it can support the advancement of combination product products. She earned her BS in Chemistry and graduated first
in her class from law school.
policy development without jeopardizing the OCP’s other functions
and the current level of informal discussions with the industry on
individual product issues. At minimum, the OCP seems to need
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D E L I V E R Y
PEDIATRIC
PEDIATRIC
D E L I V E R Y
Fast-Dispersing Dosage Forms for the Pediatric
Market
By: Susan Banbury, PhD; Karen MacGregor, PhD
INTRODUCTION
Recent recognition and industry acceptance of the unique therapeutic needs of pediatric patients has led to regulatory
activity and development programs that are re-defining this market segment. The result has been a push by developers and
formulators emphasizing pediatric drug delivery–the creation of formulations engineered and packaged specifically for children
to meet the needs of pediatric patient populations.1 Several factors are driving the growth of the pediatric drug delivery as a
business strategy. The pediatric sector is forecast to be one of the fastest growing drug markets throughout the next decade,
according to Greystone Research Associates.1 The growing availability of drugs targeted for childhood illnesses is focusing
efforts on child-friendly delivery methods.
Throughout the past few years, the pharmaceutical industry has seen patent expiries for major blockbuster drugs,
resulting in losses worth billions. More blockbuster drugs are about to lose patent protection in the coming years. In such a
situation, pharmaceutical companies are increasingly adopting various drug delivery systems to enhance their product efficacy
and patient compliance, and extend patent protection through innovative repositioning and reformulations of existing drugs.
This has resulted in recent significant growth in the drug delivery market.
The oral drug delivery market, in particular, remains the largest segment of the overall drug delivery market, presently
valued at $49 billion, and is expected to reach $92 billion by 2016.2 Growth in the oral drug delivery market is being driven in
part by innovative oral formulations like orally disintegrating tablets (ODTs) and fast-dissolving oral thin films (OTFs), which
offer the stability, dose accuracy, and convenience of solid oral dosage forms with the dosing ease of a liquid to facilitate
patient compliance, an important consideration in pediatric drug delivery.
COMPARING THE chewing or drinking liquids. The 2008 conventional tableting technology and
FAST-DISPERSING FAMILY FDA Guidelines on ODTs recommend a achieve the rapid disintegration by varying
disintegration time of 30 seconds or less degrees of compaction in combination
(in vitro) and maximum tablet weight of with water-soluble excipients and/or super
ODTs and OTFs have continued to
500 mg. Recent market studies indicate
Drug Delivery Technology March 2011 Vol 11 No 2
PEDIATRIC
D E LI V E R Y
Dose Size
Mouthfeel
Dispersion Speed
Feature
Yes
< 60 mg (Soluble)
< 400 mg (Insoluble)
Smooth
~3 Seconds
Technology
Zydis Fast-Dissolve
Yes
< 500 mg
Gritty
15-60 Seconds
Compressed
Loosely
OTF delivery technologies, leading the Dispersion Speed ~3 Seconds 15-60 Seconds
research to forecast the market for drug
products in OTF formulations to have Mouthfeel Smooth Gritty
33
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Dosage Form
Fast-Dispersing
Platform
Technology
Technology
Proprietary
Company
Technology
Products (API)
Examples of Commercial
PEDIATRIC
D E LI V E R Y
TA B L E 2 PACKAGING
Fast-Dispersing Technology Proprietary Technology Examples of Commercial Special packaging requirements are often
Dosage Form Platform Technology Company Products (API)
®
Claritin Reditabs (loratadine)
®
®
necessary for ODTs because of their relative
® Zyprexa (olanzepine)
Zydis Catalent Pharma Solutions ®
Lyophilized
Zofran (ondansetron)
®
Minirin Melt (desmopressin)
fragility. In the case of the Zydis ODT
Lopéramide-Lyoc (loperamide)
Lyoc CIMA Labs Paralyoc (acetaminaphen)
technology, the blister pack is an integral part
Spasfon-Lyoc (phloroglucinol)
®
®
Lamictal ODT (lamotrigine)
of the product, forming the molds for the
AdvaTab Eurand ®
Orally Disintegrating Tablets Unisom® SleepMelts (diphenhydramine HCl)
® ®
Clarinex Reditabs (desloratidine)
individual unit doses. The size, shape, and
® ®
Orasolv CIMA Labs Orapred ODT (prednisolone)
®
Tempra FirsTabs (acetaminophen) depth of the blister mold can be changed,
Compressed Tablets ®
® Alavert (loratidine)
Durasolv CIMA Labs ®
NuLev (hyoscyamine) depending on dose and weight requirements.
®
® Nurofen Meltlets (ibuprofen)
Flashtab Ethypharm
Calpol
TM
Fast-Melts (acetaminophen) Blister pockets can also be debossed with
® TM
Frosta Akina FortéCal (calcium carbonate)
Dissolvable Film
®
TheraFlu Thin Strips (cough/cold ingredients) letters, numbers, or simple logos, which are
®
ARx Triaminic Thin Strips (cough/cold ingredients)
Technology ®
Gas-X Thin Strips Anti-gas (simethicone)
®
then re-created on the base of the Zydis units
Sudafed PE (phenylephrine)
Buccal Wafers
LTS Lohman
Therapie-Systeme
®
Benadryl Allergy (diphenhydramine)
®
Listerine PocketPaks (breath-freshening wafers)
for unique identification and brand
Oral Thin Films ®
Listerine Whitening
combination with the fast dispersion and tablets may no longer be the dominant form
dissolution of excipients, typically results in a for dosing such moieties.5 However, PEDIATRIC ODT FORMULATIONS
smooth “melt” sensation in the mouth. development of enhanced oral protein
delivery technology using ODTs, with the The portability of ODTs and ease of
potential to release these drugs in the oral administration to children make these a
ODTS & LARGE MOLECULES cavity for transmucosal absorption, is very potentially valuable aid to children’s health,
promising for the delivery of high molecular and the European Medicines Agency’s
In addition to conventional small weight protein and peptides. Committee for Medicinal Products for Human
molecules, the Zydis lyophilization process Use (CHMP) described orally dispersing
has also been shown to be suitable for the dosage forms as having “great promise for
formulation of peptide and protein drug children.”6
molecules. Protein and peptide molecules are
34
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PEDIATRIC
D E LI V E R Y
NUCLEIC ACID
D E L I V E R Y
Tackling the Challenge of Nucleic Acid Delivery:
Progress & New Approaches
By: James J. Cunningham, PhD; Louis S. Crocker, PhD; Anthony Leone, PhD
INTRODUCTION
It is broadly accepted that nucleic acid delivery, particularly targeted intracellular delivery following systemic
administration, remains one of the most difficult challenges facing pharmaceutical scientists today. Nucleic acids are large,
hydrophilic, charged molecules, and as such, are not easily transported across the cell membrane. Add to this the poor
stability of unmodified nucleic acids in circulation, and the desire to direct delivery to specific cell types in specific tissues,
and the complexity multiplies. Efforts to achieve such delivery have enjoyed a resurgence of interest following the discovery of
RNA interference (RNAi) in mammalian cells, which has the potential to revolutionize drug discovery and development and
provide an entirely new therapeutic modality.1,2 Despite the significant challenges facing this endeavor, major progress has
been made throughout the past several years, and the following aims to highlight some of the most promising approaches.
NUCLEIC ACID THERAPEUTICS the delivery of plasmid DNA to express without a delivery vector.9 Ocular delivery
& MODALITIES antigens, comprise another area of active is perhaps the best example of this:
8
investigation. Fomivirisen and Pegaptanib are both
In specific circumstances, such as delivered via intraocular injection, and
Therapeutic interest in nucleic acid
local delivery, where direct administration numerous siRNA therapeutics have been
delivery now spans many decades, dating
to the site of action is feasible and a evaluated preclinically and clinically for
back to the advent of gene therapy, as
localized effect is desired, nucleic acids indications such as age-related macular
investigators began to explore viruses,
can be successfully delivered naked, degeneration, choroidal
calcium phosphate, and other methods to
deliver DNA to restore missing or
FIGURE 1
deficient gene function.3 The field
continued to expand with the discovery
that short, single-stranded synthetic
Drug Development & Delivery March 2011 Vol 11 No 2
administration of siRNA therapeutics. must be overcome.17 These challenges are Lipofection with cationic lipids has
summarized in Figure 2. Interaction of the been in common use for many years to
siRNA or delivery vehicle with whole blood transfect cells in vitro. Cationic lipid-based
SIRNA MECHANISM & UTILITY components can result in inflammatory systems were later developed for plasmid
responses, such as cytokine elevation or DNA delivery in vivo and have since been
RNA interference (RNAi) is a highly complement activation. These responses can adapted to siRNA delivery, making them the
Drug Development & Delivery March 2011 Vol 11 No 2
conserved cellular mechanism for regulating serve both to alter the biodistribution of the most mature of the non-viral technologies
gene expression. RNAi utilizes small siRNA and result in dose-limiting toxicity. currently used for systemic in vivo nucleic
interfering RNA (siRNA), which are short Interaction with other whole blood acid delivery.18,19 The SNALP technology
(approximately 21 base pairs) double- components, such as fibrinogen, transferrin, developed by Tekmira (formerly Protiva)
stranded RNA molecules, to induce specific lipoproteins, or nucleases, can also affect demonstrated robust silencing of ApoB
degradation of messenger RNA (mRNA). potency by manipulation of the delivery mRNA in non-human primates and has since
siRNAs are produced via the Dicer pathway, vehicle and/or components. These been evaluated in three clinical trials (ApoB
or are introduced therapeutically into the interactions and alterations may heavily SNALP, ALN-VSP, ALN-TTR01).20 Another
cell. Once in the cytosol, an siRNA molecule influence biodistribution or degrade the lipid nanoparticle technology, the AtuPlex
interacts with Argonaute and other proteins delivery vehicle (eg, nuclease activity). platform from Silence Therapeutics, is also
to form the RNA-induced silencing complex Chemical modifications of oligonucleotides, currently in clinical development for solid
(RISC), and the complex then catalytically such as 2' O-methylation, can be effective at tumors, and the lipid nanoparticle approach
cleaves the complementary mRNA. dampening immune stimulation as well as is used in much of our work at 37
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40
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F O R M S
SOLID DOSAGE
SOLID DOSAGE
F O R M S
INTRODUCTION
Surface-modified silica nanoparticles (SMNs) are a non-aggregated form of colloidal silicon dioxide (CSD) that have
been found to enhance physical attributes associated with the processing of powder blend formulations used for making oral
solid dosage forms (OSDFs). The core material, amorphous silica, has been a standard for processing pharmaceutical powder
blends to manufacture OSDFs. The SMNs can be dry-blended and readily distributed, transferring from particle to particle
during mixing with minimal energy. Counter to typical flow modifiers, these materials can simultaneously enhance flow
ability and increase tap/bulk density by as much as 50% in blends and raw materials. Improvements have been seen in many
pharmaceutical operations, including but not limited to stability on storage, powder transfer operations, solids blending,
tableting, capsule fill, and cleaning. Other excipients have been used in attempts to address these processing challenges,
yet rarely are multiple benefits simultaneously seen (eg, the typical trade-off of increased flowability at the expense of
increased bulk density). As a result, a reduction of processing steps, reduced capital equipment costs, increased rate of
tablet/capsule production due to increased tablet flow, and a reduction in unit weight variability will reduce manufacturing
costs.1 The ease of mixing and more uniform response of materials using SMNs is also anticipated to improve process
robustness.
CHARACTERIZATION OF with similar results using ibuprofen as the (TGA) was performed on SMNs to obtain
MODEL APIS & SMNS API, but due to space limitations, those sample weight loss versus time and
results are not presented here. The effects temperature. The powder sample was run
The initial objective of this work was described herein are not due to the on the TGA with the following parameters:
to investigate and characterize how surface chemical composition of the nanoparticles equilibrate at 30°C, ramp at 10°C/min to
Drug Development & Delivery March 2011 Vol 11 No 2
SMNs affect the physical attributes of a themselves. Similar effects have been 105°C, isothermal at 105°C for 10 minutes
typical pharmaceutical blend, both with and shown using metal oxide nanoparticles, and ramp at 10°C/min to 700°C. The
without the presence of a model active metal nanoparticles, phosphate-based weight loss pattern shows negligible losses
pharmaceutical ingredient (API). The nanoparticles, and the like. For comparison until temperatures greater than 400°C are
blends were then used to demonstrate the purposes to CSD, the most commonly used reached. This indicates the ligands are
improved physical processing attributes due flow aid in the industry, amorphous surface strongly attached to the core particle.
to the SMNs. Acetaminophen (APAP) was modified silica nanoparticles, were used in
chosen for specific reasons: first, its poor the studies below.
flow properties are well documented and DETERMINING DEGREE OF
lead to many difficult manufacturing issues CRYSTALLINITY OF APAP
for both tablet and capsule formulation; THERMOGRAVIMETRIC & SMNS BY X-RAY
second, it is present in relatively high ANALYSIS (TGA) OF SMNS DIFFRACTION (XRD)
proportion in a typical OSDF and; third,
because it is still a commercially important The binding strength of the surface XRD of APAP was performed to
pharmaceutical product in today’s modification to the nanoparticle core is an evaluate the form and degree of
42
marketplace. This work has been replicated important factor in estimating the stability crystallinity of the APAP in comparison to
of the SMNs. Thermogravimetric analysis established reference patterns. Different
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Sample Preparation
Samples were tested after gently milling
to reduce the size of clumps present in the “as
received” powder. Samples were placed on
glass inserts as dry powders.
SMNs - 0.25% & 0.5% on Acetaminophen (5K zoomed image)
Data Collection APAP crystals were imaged and are were weighed before and after thermal
Reflection geometry data were collected
essentially smooth and featureless, showing analysis to confirm that no change in weight
in the form of a survey scan by use of a
none of the fine particle matter observed for occurred. Results are summarized in Table 1.
Bruker D8 Advance diffractometer (Bruker
the SMN-treated material. The SMNs in The concentration of SMNs on the surface of
AXS, Madison WI), copper K radiation, and
Figures 1 and 2 are clearly present and appear APAP has no significant effect on the
Vantec detector registry of the scattered
to be uniformly dispersed over the surface of duration of the melt event with 0.25% and 1%
radiation. The diffractometer is fitted with
APAP following dry blending, without any loadings yielding traces virtually identical to
variable incident beam slits and fixed
preferential localized deposition on edges, those of the native APAP. The melt onset and
diffracted beam slits. The survey scan was
cavities, crevices, etc. There appears to be a maximum temperatures and enthalpies were
conducted using a coupled continuous mode
mixture of primary and aggregated also not appreciably changed upon addition of
from 5° to 55° (2q) using a 0.015° step size
nanoparticles. Increasing the concentration of SMNs.
and 6-second dwell time. X-ray generator
SMNs from 0.25% to 0.5% appears to
settings of 40 kV and 40 mA were employed.
proportionately increase the coverage of
The powder XRD patterns of the APAP
SMNs over the surface of APAP in a uniform POWDER FLOW & DENSITY
show it to be highly crystalline and in
fashion. ENHANCEMENT
conformance to reported reference patterns,
with peak intensity differences attributed to
Differential Scanning The APAP/SMN blends and the
preferred orientation effects. The powder
Calorimetry (DSC) APAP/CSD (Aerosil 200, Evonik/DeGussa
XRD pattern of the SMNs indicates a
DSC of APAP/SMNs blends could give Corp., Parsippany, NJ) blends were added to a
noncrystalline amorphous form.
an indication of possible interaction between 4-quart planetary mixing bowl in separate
the APAP and SMNs such as degradation experiments; each was blended for 3 minutes
reactions. APAP was dry blended with SMNs at 60 rpm. The blend was passed though a 60-
ANALYTICAL at concentrations of 0.25% and 1%, and the mesh screen and returned to the mixer and
CHARACTERIZATION OF blends were analyzed by DSC. Mixing was blended for an additional 2 minutes at 60 rpm.
POWDER BLENDS CONTAINING done with a planetary mixer (1 min at 60 Powder flow and bulk density
SURFACE MODIFIED SILICA rpm/sieve mixture through 60 mesh measurements were performed on blends of
NANOPARTICLE & screen/mix again for 1 min at 60 rpm). Pure APAP with varying concentrations of SMNs
ACETAMINOPHEN APAP and SMNs were also measured, and CSD as a comparator on a model PTGS-3
respectively. Approximately 3 mg of each Flow Tester (Pharma Test, Hainburg,
Scanning Electron Microscopy sample were heated from 20°C to 250°C at a Germany) instrument. Five measurements
(SEM) rate of 10°C/min on a TA Q1000 (TA were made for each blend and used to Drug Development & Delivery March 2011 Vol 11 No 2
SEM images of the SMNs blended with
Instruments, New Castle, DE). Sample pans determine an average flow rate. Bars are used
APAP can give some indication of the
resulting distribution and a measure of the
ability to dry blend SMNs. Changes in FIGURE 2A&B
distribution of SMNs on the APAP surfaces
with changing SMNs concentration can also
be evaluated. APAP was dry blended with the
SMNs at two concentrations of SMNs
(0.25%, 0.5%). Mixing was done with a
planetary mixer (1 min at 60 rpm/sieve
mixture through 60 mesh screen/mix again for
1 min at 60 rpm). Samples were prepared for
imaging by sprinkling/dusting on carbon paint
applied to the sample holder (aluminum disc).
The instrument used was a Hitachi S-4800
SMNs - 0.25% & 0.5% on Acetaminophen (50K zoomed image) 43
UHR Field Emission SEM. The untreated
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CAPSULE-FILLING TRIALS
result was that added to the dry blend and mixed for 10
FIGURE 4 Formulations A and minutes on a planetary mixer. The lubricant
B exhibited reduced was added as a pre-mix to the formulation
ejection forces even and mixed for 3 minutes on the planetary
as machine speed mixer. A similar formulation using 1% (w/w
increased. to the formulation) CSD was prepared for
Fill weight was comparison. When CSD was used in place of
measured from SMNs, a tablet could not be made because the
capsules made at a mixture had insufficient flow to fill the die.
bed height of 40 mm The samples were compressed on a 16 station
and a machine speed Manesty Beta Press (Thomas Eng.) running at
of 40 rpm. The three speeds (40, 50, and 60 rpm); for these
results are shown studies, all 16 punch and die sets were used.
below in Table 3. The fill weight settings were not changed as
Formulations A and the speed of the press was adjusted in order to
B stand out as show the nature of the flow properties. The
having a higher tooling type (Natoli Eng. Co., St. Charles,
Comparison of Tapped Densities of APAP/SMNs or CSD Blends average fill weight MO) is described as 5/16” standard concave
with progressively with tapered dies. Tablet breaking strength
cavity to the body of the hard gelatin capsule. lower % RSD with increasing compression was measured using a KEY HT-300 hardness
To study the effect of compression force (CF) force at a fraction of the concentration tester (Englishtown, NJ). For this study, 25
on fill weight and ejection force, the machine compared to Formulation C. tablets were compressed and tested for
was run at three compression forces (50, 100, hardness at each speed. Unfortunately, the
and 150 N) at 40 rpm. transducer used to measure compressional
To study the effect of machine speed on DIRECT-COMPRESSION force was not operable at the time of this trial.
fill weight and ejection force, the machine TABLETING TRIALS The tableting results for a non-optimized
was run at three machine speeds (40, 60, and direct compression formulation of APAP are
70 rpm) at 100-N compression force. The fine The objective of this study was to assess shown in Table 4.
powder APAP (Spectrum Chem.) was blended the compaction behavior of APAP Based on the tablet trial results, it can be
with SMNs at two levels, 0.08% and 0.25% formulations by measuring breaking strength concluded that the tablets exhibited acceptable
and with CSD at 0.5%. The flow and density and weight variation. A non-optimized direct hardness. The weight variation also met USP
properties of the APAP alone did not make compression formulation containing APAP standards for content variation (USP 32-NF
the encapsulation process viable without powder, a binder, disintegrant, lubricant, and 27, <905> Uniformity of Dosage Units, pp.
blending with SMNs or CSD. Although a SMNs for process enhancements was 382). Note that for high dose drugs, the USP
capsule formulation will typically contain prepared for these trials. The SMN states that content uniformity can be
other components to ensure adequate plug concentration chosen for these tests was 1% measured by weight variation. APAP content
formation and minimize plug ejection forces, w/w with respect to the formulation. This is uniformity was measured at 147.4 mg ± 1.9
this study was intended to evaluate the filling higher than the levels used previously to show (1.3%), or 62.7% ± 1.1 (1.7%) of the
characteristics of this binary mixture in density and flow characteristics because the formulation using a drug content assay
typical capsule filling equipment and to purpose of this study was to indicate whether method similar to the USP monograph for
determine if the SMNs are capable of the presence of the SMNs would have a APAP tablets.
imparting favorable characteristics to this deleterious effect on the properties of the
process. The effects of compression force and tablets produced. Presumably lower
machine speed on the plug ejection force are concentrations of SMNs would have no more CONCLUSION
shown in Table 2.
Drug Development & Delivery March 2011 Vol 11 No 2
pronounced effects on the tablet performance.
Compression force studies showed a The formulation was prepared by adding 1% These experiments have proven that
significant decrease in ejection force values by wt SMNs to the APAP and mixing for 5 surface-modified nanoparticles enhance
by incorporating SMNs instead of CSD in all minutes on a planetary mixer. The remainder powder processing as characterized by
cases. Best performance was observed with of the excipients, except the lubricant, were improved flow and increased bulk/tapped
Formulation A with 0.25% SMN loading at
each compression force and machine speed, TA B L E 4
although the improvement over Formulation B
with three times less SMN loading was not
substantial. The limiting concentration of
SMNs required to optimize the flow effect
will no doubt depend on morphology and
particle size of the bulk materials, and
rigorous prediction of this effect is beyond the
scope of this paper. A particularly interesting Tablet Properties of APAP/1% SMN Direct-Compression Formulation at Three Press Speeds
45
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ACKNOWLEDGEMENTS
REFERENCES
46
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48-54DDT March 2011-rd 1-DDT Special Feature_Layout 1 2/28/11 11:51 AM Page 48
Special Feature
prefilled Syringes pinpoint
Stability, compatibility & Safety
By: Cindy H. Dubin, Contributor
Drug Delivery Technology March 2011 Vol 11 No 2
48
48-54DDT March 2011-rd 1-DDT Special Feature_Layout 1 2/28/11 11:52 AM Page 49
P
refilled syringes and injection devices
FIGURE 2
continue to grow in importance as West Pharmaceutical Services. Despite their
means of improving administration, varied approaches to prefilled syringe
compliance, safety, costs, and accuracy of development, they all concur the market is one
drug delivery. The market for prefilled of the strongest growing segments inside the
syringes has achieved significant progression pharmaceutical primary packaging market,
in recent years. The pharmaceutical industry and the systems are an ongoing success story
accepts prefilled drug technology as a proven whose benefits will ensure commercial
format of choice for many parentally opportunities in the future.
administered drugs. Because a product’s
delivery system can affect patient compliance,
easier-to-use devices have been linked to BAXTER BIOPHARMA
higher sales and market share. SOLUTIONS–TAILORED
And the market numbers concur. In MANUFACTURING CAPABILITIES
2009, an estimated 2 billion prefilled syringe
units were sold, and the market for the
technology was estimated to be worth up to As pharmaceutical companies search for
$2.5 billion.1 The biologics sector is being increased efficiency through manufacturing
credited with having the most influence on the service collaborations, there is a greater need
prefilled syringe market, as there is an for sustainable partnerships. To this end, BD Medical offers the HypakTM family of glass
increasing need for self-administration of Baxter BioPharma Solutions, a business unit prefilled syringes.
these drugs for chronic conditions. Prefilled of Baxter, is investing in prefilled syringe
syringes offer numerous advantages here: manufacturing capabilities. Just last year,
Ease of administration, dosing accuracy, BioPharma Solutions business won the 2010
patient compliance, safety, and reduced pain. Vaccine Industry Excellence (ViE) Best
Contract Manufacturing Organization Award, According to Ms. Zinselmeier, the
However, protein-based drugs have
which recognized the company’s range of benefits of prefilled syringes to the healthcare
introduced a challenge to the prefilled syringe
services in niche and core therapeutic areas, as system are driving this method of drug
market, eg, certain vials can have a diluting
well as its client relationships. delivery development. From an end-user
affect on a drug’s potency. Both contract
“Our organizational ability to manage perspective, a prefilled syringe provides ease
manufacturers and syringe developers are
complex projects is particularly relevant to of administration and compliance benefits;
investing dollars and manpower to advance
prefilled syringes,” says Kristie Zinselmeier, from a pharmacy perspective, prefilled
construction materials.
Director of Marketing, BioPharma Solutions. syringes offer a reduction in the potential for
Some of these companies are featured in
“As we see the increased desire for, and admixture-related medication errors and
this exclusive, annual Drug Development &
relevance of, an enhanced delivery system, it contamination; and from the pharmaceutical
Delivery report. They include: Baxter
becomes even more critical to execute on company’s perspective, increased competition
BioPharma Solutions; BD Medical,
commitments, allowing the pharmaceutical for scarce economic resources within global
Pharmaceutical Solutions; Catalent Pharma
company to capitalize on opportunities that healthcare systems drives the desire to provide
Solutions; Cook Pharmica; Gerresheimer
may present themselves in this dynamic additional delivery enhancements to increase
FIGURE 1 market.” the likelihood that a product’s
In the area of prefilled syringe contract commercialization objectives will be achieved.
manufacturing, BioPharma Solutions offers “Many of our pharmaceutical partners
Drug Delivery Technology March 2011 Vol 11 No 2
instead of seasonal vaccine; seasonal vaccine through its recently opened Brussels, Belgium,
FIGURE 3
given instead of H1N1) had been reported in facility, which was built specifically to provide
nearby towns.3 While the underlying causes of high-volume, prefilled syringe filling. With
such incidents vary, the potential danger of more than 25 years of experience in filling
predrawn and unlabeled vaccine syringes vaccines, low-molecular weight heparins, and
residing in the refrigerator at a busy clinic, diluents, Catalent has expanded its focus to
side by side with other syringes is clear. include biologics and therapeutic vaccines
BD has been investing time and money to based on its customers’ pipeline needs.
better understand the differences between PFS According to Sheila Dell, PhD, Vice
and MDVs. The company recently funded President Business Development for Catalent
research conducted by John’s Hopkins Pharma Solutions, several of the company’s
University, Bloomberg School of Public customers have their pipeline products
Health, to understand the efficiency, targeted for drug/device combinations,
economic, and clinical best practice especially if the therapeutic area is for a
implications comparing PFS versus vials. In chronic ailment that requires frequent
this study, several deviations from best medication. The prefilled syringe with
practices were noted in the preparation for autoinjector is meeting those therapeutic
Catalent has the ability to handle both glass
injection, including: 1) predrawing vaccine needs.
and plastic syringes to meet the changing
needs of customers.
from vials into unmarked syringes; 2) using “In the next 3 to 5 years, we expect to see
the same alcohol swab to repeatedly sterilize more syringe products filled in specific
vials; 3) pooling vaccine remainders from drug/device combinations,” she says. “This
multiple spent vials to assemble a full dose; will improve the quality of patient care and
BD MEDICAL–PHARMACEUTICAL
SYSTEMS–ENHANCING PATIENT and 4) saving leftover vaccine doses that were medication compliance in addition to reducing
OUTCOMES & OPTIMIZING predrawn from vials for the following day. medication errors.”
INJECTION EFFICIENCY With respect to the impact of Changing trends in the syringe market
time/efficiency/economy of different vaccine enabled Catalent to enter collaborative
The US predominantly uses MDVs, but packaging, the John’s Hopkins study agreements with customers to provide them
PFSs have gained market share throughout the concluded that the additional time needed for access to a range of value-added technologies
past few years. It is estimated that currently, multi-dose vaccine preparation has an impact for injectables, including the ASITM
PFSs hold approximately 30% of the market on clinic efficiency. Assuming medical autoinjector and the ProtectorTM syringe safety
for influenza vaccines.2 There are many factors assistant labor costs of approximately shield.
that continue to drive the adoption of PFS in $14/hour, for example, the extra staff time “Last year, Catalent provided support for
the US, such as the preparation of injectable required to administer 1,000 doses of MDV more than a dozen companies on more than
medications, the opportunity to extend vaccine versus PFS would add about $147 to two dozen vaccines, providing advanced
medication or vaccine supply due to the clinic costs. solutions to accelerate product development,
reduced overfill requirements (vs. vials), and “A complete cost analysis would need to to speed up time-to-market, ensure adequate
the opportunity for pharma to differentiate its factor in not only acquisition costs of the product supply, and provide new ways of
products. However, one additional factor vaccines and syringes, but the opportunity cost delivering vaccines to patients,” explains Dr.
influencing the growth of PFS is the of lost clinician or pharmacist time and, in the Dell. “Due to our substantial surge capacity
stubbornly high incidence of bloodborne event of a safety mishap, any potential costs and our vast experience at handling large-scale
pathogen transmission due to unsafe injection related to those events,” says Brian Lynch,
Drug Delivery Technology March 2011 Vol 11 No 2
practices, and the potential opportunity for Marketing Manager for BD Prefilled Syringes. FIGURE 4
unit-dose, ready-to-administer formats, such as As a result of its own research, BD
prefilled syringes to reduce this. Human factor Medical is confident that any parenteral
errors in the administration of parenteral drugs medication can benefit from the use of a
can contribute to outbreaks due to primary prefilled syringe as it offers greater simplicity
breaches in infection control practices. in use versus alternative packaging forms.
Although not as commonly reported,
accidental administration of the wrong
injectable medication/vaccines occurs, as in a CATALENT PHARMA
2010 Wellesley, MA, incident involving a SOLUTIONS–KEEPING
school nurse giving insulin instead of H1N1
PACE WITH CUSTOMER NEEDS Cook Pharmica’s “one source-one location
vaccine to the school staff. It was revealed that model” offers comprehensive parenteral CMO
Catalent Pharma Solutions provides services at a single location, including this high-
similar injection mix-ups (eg, insulin given
50 prefilled syringe fill/finish manufacturing speed syringe line under barrier isolation.
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single location can minimize wasted time, ready-to-fill processing. UNILIFE CORP.–A NEW
redundancy, and information loss. We are also To address end-user safety needs, APPROACH TO BRAND
able to minimize the number of relationships prefilled syringe suppliers, like Gerresheimer, DIFFERENTIATION
and practices a sponsor has to manage. Finally, have developed advanced syringe closure
the model allows us to help sponsors better solutions like the TELC (Tamper Evident Unilife Medical Solutions may be the new
deliver life-enhancing products to patients, in Luerlock Closure) systems. This enables kid on the block in the pharmaceutical market
a more timely manner,” he says. syringe manufacturers to mount just one for prefilled syringes, but the company has
The one source-one location model was integrated component on syringes–adapter, invested significant resources in building the
also designed to bridge a separation between closure, and tamper-evident seal. operational capabilities to make Unilife a
packaging and filling. Generally speaking, Gerresheimer has also focused on the reliable supplier of drug delivery devices that
says Mr. Hawkins, outsourcing teams tend to sensitivity of protein-based products. meet the quality assurance expectations of the
be in different departments within According to Ms. Petersen, medical-grade customer. With production of the Unifill
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Obtaining special access to our devices Reynolds, West’s Vice President, Marketing,
FIGURE 6
within target therapeutic areas, as sanofi- and Innovation, Pharmaceutical Delivery
aventis has already done for vaccines and Systems. He attributes this to the company’s
anti-thrombotics, offers pharmaceutical FluroTec® barrier film for plungers, which act
companies the opportunity to generate to minimize interactions between the piston
powerful brand differentiation against their and the drug.
competition. Many drugs are packaged in a syringe
“They are a primary drug container that with a fixed needle and can be used in
can be integrated into fill-finish lines and combination with devices, such as
have USP-compliant materials inside the autoinjectors and safety systems. Recalls of
Unifill’s ready-to-fill syringe integrates safety fluid path for biocompatibility. Yet, they are drugs packaged in glass vials and syringes,
into the glass barrel and meets needlestick not a commodity item. Obtaining special and issues of functionality between glass
prevention mandates. access to our device within target therapeutic syringes and autoinjectors are leading
areas, as Sanofi-Aventis has already done for companies to seek improved alternatives to
syringe about to commence at a new facility in
the Unifill syringe, offers pharmaceutical glass syringes, including polymeric syringes.
York, PA, Stephen Allan, Vice President,
companies the opportunity to generate brand West’s range of plastic prefillable
Marketing and Communications for Unilife,
differentiation in competitive therapeutic drug syringes use Daikyo Crystal Zenith®
which expects 2011 to be a big year for the
classes,” he says. technology, which includes the recently
company.
Sanofi-Aventis retained the rights to introduced 1-mL long insert needle syringe
“The initial production and launch this
negotiate the exclusive purchase of the Unifill system. This cyclic olefin polymer system
year of the Unifill ready-to-fill syringe is the
syringe within therapeutic classes, including offers customers a solution for packaging
start of a new generation of innovative devices
antithrombotic agents and vaccines until June drugs in a clean, high-quality syringe system
from Unilife that will help empower
2014. without the issues caused by silicone oil,
pharmaceutical companies to harness the true
One characteristic that attracts pharma aggregation, and breakage. Biologic therapies
competitive potential of their injectable drug
companies, like Sanofi-Aventis, is the for chronic conditions, such as the various
products,” says Mr. Allan.
prospect for brand differentiation without autoimmune diseases, will be the key focus
Fully passive safety features have been
industrial disruption, explains Mr. Allan. for West’s Daikyo Crystal Zenith systems.
fully integrated within the glass barrel of the
It is this brand differentiation that will “We expect the Daikyo Crystal Zenith to
syringe to virtually eliminate the risk of
help pharma compete, he adds. become the future of prefillable syringes for
operators being exposed to blood-borne
“There is a new arms race developing in biologic drugs,” says Mr. Reynolds. “The
pathogens via potential transmission modes
the pharmaceutical market for prefilled trend toward plastic, prefillable systems that
including needlestick injuries or splatter.
syringes. It’s no longer just about just having a overcome the limitations of glass will enable
Our Unifill ready to fill syringes can
new and improved drug. It’s about how that more novel package/device combinations to
function as a safe and secure primary
drug interacts with healthcare workers and be developed and introduced, which will lead
container for injectable drugs and vaccines.
their patients to enhance the overall provision to more innovative delivery solutions for
Unilife syringes are designed for integration
of healthcare. The pharmaceutical company injectable drugs.”
into the fill-finish systems used for equivalent
that has access to the best device that is Combining a syringe with a mechanical
standard prefilled syringes. All materials
different and truly meets the needs of the device, such as an autoinjector, creates
inside the fluid path are also USP-compliant
patient will beat the competition.” additional challenges of functionality. West
materials to facilitate biocompatibility.
can help customers overcome such issues
However unlike other prefilled syringes, this
through options such as the ConfiDose®
is not a commodity item. Unifill syringes are WEST PHARMACEUTICAL autoinjector system, which has been designed
unique and available only from Unilife. SERVICES, INC.–
Drug Delivery Technology March 2011 Vol 11 No 2
INJECTABLE
D E L I V E R Y
Lifecycle Management & Differentiation Through
Injectable Delivery Systems
By: Graham Reynolds
INTRODUCTION
When pharmaceutical and biotech companies begin to develop a drug, the delivery system is often far from top of mind.
The growth of sensitive biologics and the plethora of recent drug product recalls, however, have encouraged drug
manufacturers to start thinking about container closure systems and delivery systems early in the development process. Issues
such as breakage, glass delamination, and particulate contamination have also forced the industry to rethink glass as a
standard and consider novel materials, including plastics, that offer stronger, safer, and more efficient packaging options.
Ideally, drugs will be stored first in bulk containers, then move to a standard system of vial, stopper, and seal during
clinical testing. As the drug moves to market, additional containment and delivery systems, including prefillable syringe
systems, may be developed. Some drugs, including biologics, may require a delivery device or injection system. For each new
containment system, testing is required and can often be time-consuming and costly. The development of novel materials,
such as cyclic olefin polymers, can provide ideal lifecycle management solutions. Such materials, which are typically break-
resistant and inert, can be used in a variety of containers, devices, and systems due to flexibility in molding. In addition to
standard vials and prefillable syringes, the ability to develop a custom container in the same basic materials has significant
advantages when considering an integrated system.
As the industry trends toward the use of devices or delivery systems to aid with the increased need for injection in the
healthcare and home settings, the link between packaging and delivery system manufacturers and pharmaceutical
manufacturers must be strong and start early. The inter-dependence of the packaging and delivery system needs to be carefully
considered at an early stage, and a thorough understanding of both is key to ensuring a successful drug/delivery system
combination.
AN ENVIRONMENT FOR if not all of these products are delivered established market area where devices are
INJECTABLE GROWTH through injection. These trends are driving commonly used (such as in the treatment
the need for prefillable syringe systems of various autoimmune diseases) or who
and drug delivery devices and systems that often need to enter the market directly
Growth in injectable therapies, driven
can be used in either a clinical or home- with a competitive delivery system to
by increased incidence of chronic Drug Development & Delivery March 2011 Vol 11 No 2
care setting. ensure competitive parity or additional
conditions, such as diabetes and
Because biologics are often large patient benefits. Such differentiation is
autoimmune diseases (including multiple
molecule products that do not transport key to competing with established
sclerosis and rheumatoid arthritis), has
well through non-injectable delivery
resulted in the development and launch of
methods, delivery devices such as auto- FIGURE 1
an increasing number of new biologics
injectors are often the best choice for
designed to treat these conditions. Most of
administration. While different
these products require regular injectable
technologies, such as inhalation and
delivery, often by the patient or caregiver.
transdermal patches, have been attempted,
Evidence shows there is continued
in many therapeutic areas, injection has
growth in biological products, and that
proven to be the most effective method of
most of these require delivery by injection.
delivery. Device requirements are driven
An analysis of the top 20 biologics on the
either as a means of product lifecycle
market by revenue demonstrates that most West’s ConfiDose® Auto-Injector System
management or by companies entering an 55
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INJECTABLE
D E L I V E R Y
products, and partnering with a manufacturer incomplete delivery of the drug. Each of
FIGURE 2
to provide novel technology should be an these recalls may have a significant financial
important part of the product’s launch plan. impact on the pharmaceutical or biotech
A specific example could be the company.
planned launch of a drug for the treatment of Early decisions regarding containment
autoimmune disease, in which the selection materials and delivery systems may help
of a system composed of a prefillable ensure compliance and increase safety once
syringe and an auto-injector (usually the product reaches the market. In some
disposable) requires careful consideration of cases, the earliest entry of a drug to the
the primary container and the delivery market may be facilitated by the use of a
system, and the performance of the two in traditional container closure system, such as
combination with the specific drug product. a vial, with some form of reconstitution
system if the product is lyophilized. This
system is used for convenience and may not
THE NEED FOR EARLY be the final or best delivery system for the
PARTNERSHIPS drug. Many drugs move to prefilled syringe
The Daikyo Family of Products
systems that may later be used within a
Recent US FDA recalls relating to device, such as an auto-injector. The drug
potential risks with glass prefilled syringes and systems once the product hits the
molecule is the same, but the delivery
in auto-injectors highlight the need for market.
system has changed, which may require
vigilance when considering the interaction Working closely together,
costly testing to ensure the new container
between device and container in the pharmaceutical and packaging
closure system does not react with the drug.
development process. In addition, manufacturers can look for ways to
There are many examples of this type of
documented sensitivity of certain biologics differentiate a product through the packaging
lifecycle management with established
to silicone oil, tungsten, and other materials and delivery systems. There are several
products, as well as examples of newer drugs
is driving the need to select systems reasons the relationship should start early.
whereby the company may choose to launch
carefully at an early stage of development. First is to ensure that packaging is right for
in a more sophisticated system, rather than
The recalls highlight several issues that the drug product. Packaging can be a huge
in a vial format.
may occur when glass is used within a factor in the success of a drug product
In many cases, and particularly when
prefillable system. Breakage, delamination, getting through the regulatory approval
large molecule biologics are concerned, the
and particulate have resulted in a significant process smoothly and to the market quickly.
prefilled syringe system may not be an
increase in costly recalls of drug product. In How the product is going to be delivered Drug Development & Delivery March 2011 Vol 11 No 2
adequate match for the delivery device,
2011, lots of dexamathasone sodium should be determined based on the clinical
which can lead to safety issues, such as
phosphate and sodium bicarbonate were application. This will help the company
breakage when using glass syringes or
recalled after the drug manufacturer detected understand what type of primary packaging
incomplete delivery of highly viscous
glass particulate within the vials. Particulate is needed, and how that packaging will fit
products. Here, early planning and a stronger
contamination was also cited in the recall of with the delivery system. Ideally, the same
focus on the lifecycle management of the
lots of liver injury treatment in 2010. Glass material should be used for containment
containment system can be key to ensuring
delamination, which produces siliceous from research through to commercialization.
the earliest product launch with lower risk,
flakes, was the cause of a massive recall of Proper packaging can have an effect on
no matter what format is selected by the
certain lots of anemia drugs. In 2006, certain successful development and registration.
drug company. By ensuring a good fit early
lots of a drug product delivered by an auto- While the focus of the regulatory bodies may
in the development process, pharmaceutical
injector that contained a glass prefilled be on the drug itself, the reality is that when
companies can essentially build increased
syringe were recalled in several European that drug hits the market, it arrives inside a
compliance and ease of transition to devices
countries because of problems with slow or container closure system. Selecting the right
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INJECTABLE
D E L I V E R Y
system early in the process can help those with dexterity issues. Such devices may can be an area of concern for caregivers,
manufacturers not only differentiate their have both sight and sound signals to aid end family members, and downstream disposal
product in a crowded market, but also users who may have trouble determining and safety. Much of the focus for self-
increase the chances of a successful move to when the dose has been given fully, thus injection devices has been on reducing
market. aiding in compliance. Recent innovations in anxiety for the patient through improved
Often, the goal is to move from a devices have also incorporated electronics as needle technology and injection devices that
vial/stopper system to a prefilled syringe a means of providing instant user instructions, can reduce needle phobia by hiding the
system. Here again, early consideration to in cases of rarely used emergency treatments, needle both before and after injection (such as
container closure and drug delivery systems or as a means of aiding compliance. West’s ConfiDose® auto-injector system).
can mitigate risk. Use of a consistent material Diabetic insulin is available in multiple Other areas of treatment require needle-
throughout the drug’s lifecycle can minimize formats, including syringes, pens, and pumps. free systems. For example, when treating
risk. For example, cyclic olefin polymers, As these devices become more complex, hemophilia, needle-free systems and devices
such as Daikyo Crystal Zenith® packaging many utilize electronic feedback to ensure have been used extensively to eliminate
systems, provide a break-resistant, silicone- patient compliance. Information about the needles during the reconstitution process. Use
free solution that can be molded in a variety medication can be downloaded from the pen of vial adapters, needleless transfer devices,
of shapes and sizes. Already well established or pump directly to the caregiver. A physician and diluent-filled Luer lock syringes have
in the global market as a primary container can then determine quickly and easily if the helped to eliminate dangerous needles from
for approved drug products, Daikyo Crystal patient has been following his or her the reconstitution process and create a safer
Zenith packaging systems provide an medication schedule. Linking diagnosis to environment for those suffering from
excellent alternative to glass that can be used treatment, in conditions such as diabetes, is hemophilia.
throughout the drug’s lifecycle. Having the also becoming a more active area in terms of
same material for bulk storage, vials, and device development.
prefillable syringe systems provides SOLUTIONS THROUGH NEW
consistent functionality and minimizes the TECHNOLOGY
material contamination risk as the drug moves SAFER FOR CAREGIVERS
from research to clinical trials to & END USERS New technologies and novel materials,
commercialization. This is especially such as Daikyo Crystal Zenith, are helping to
important for biopharmaceuticals, which may Devices can be designed to aid not only make delivery system decisions easier and
react with particulate from silicone-oil and in patient compliance, but also patient and more effective for both the pharmaceutical
tungsten contamination. provider safety. In recent years, there has manufacturer and the end user. By developing
been an increased focus on needlestick safety. a thorough understanding of the drug’s
According to the National Institute for intended use and the patient’s needs,
Drug Development & Delivery March 2011 Vol 11 No 2
DESIGNED FOR INCREASED Occupational Safety and Health (NIOSH), packaging manufacturers can lend their
PATIENT COMPLIANCE & SAFETY approximately 600,000 to 800,000 needlestick expertise to pharmaceutical manufacturers to
injuries occur annually in the US. These develop a package that differentiates the drug
Many pharmaceutical companies have injuries carry the risk of serious infection in the market and helps to ensure that the
advanced devices capable of increasing from diseases, such as HIV and hepatitis. patient’s needs are met. The key goal remains
patient compliance. Treatment for diseases, New technologies include passive the safety and effectiveness of the drug
such as diabetes and multiple sclerosis, are systems, such as West’s NovaGuardTM safety product, and a thorough knowledge of
prime for device use. In many cases, a range needle and the erisTM safety syringe system*, potential interactions with packaging,
of device options is available to support a that allow for safer injection without altering combined with an intimate knowledge of the
single drug. the caregiver’s administration technique in the regulatory and quality environment, is key in
For example, a single drug used to treat hospital and clinical setting. this area.
multiple sclerosis may be available in a ready- In the home care setting, although When designing a delivery solution,
to-use, pre-measured, prefilled syringe. In needlestick prevention has not been a pharmaceutical companies must consider the
addition, an auto-injector may be available for significant issue for self-injecting patients, it end user. This is increasingly important as
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INJECTABLE
D E L I V E R Y
devices are designed to be safe and effective, or other device. The insert-needle version
but also easy-to-use for those patients who also is produced without the use of adhesives BIOGRAPHY
may have limited dexterity, and who may not or tungsten, and a high level of built-in
be medically trained. For example, West has quality through novel manufacturing
created an internal group that focuses on techniques supported by multiple in-line
early stage concept development that works inspections, thereby ensuring the optimum
closely with outside partner Insight Product container for sensitive biologic products,
Development, a group of industrial designers particularly when used with an injection
who help determine a product’s external look device, such as an auto-injector.
and feel and fully understand the needs of the In addition, cyclic olefin polymers, such
patient and administrator (often the same as Daikyo Crystal Zenith, offer customers the
person). Creative concepts can be impractical benefits of low extractables, break-resistance,
if they are not combined with a fundamental and high quality in a vial or syringe system.
knowledge of how a device can be Daikyo Crystal Zenith material can be
engineered, produced, assembled, and linked molded into complex shapes, an advantage
to the primary container. West provides a over glass. Pharmaceutical companies can
fully integrated process from initial patient select a Daikyo Crystal Zenith containment
Mr. Graham Reynolds joined West in 1980 as
needs through to manufacture, always with a solution for the lifecycle of their drug, from
thorough knowledge of the requirements of development through to commercialization. a Polymer Technologist, and throughout his
the drug product, which we believe is critical When coupled with an auto-injector, such as career with West, has held a range of
to ensuring that drug products can be West’s ConfiDose auto-injector system, positions with increasing responsibility. In his
launched effectively with an optimum which works well with all syringes and high- current role as Vice President, Innovation
packaging and delivery system. viscosity drugs, pharmaceutical companies
Strategic Marketing, Mr. Reynolds works
A range of new technologies is now have a unique, easy-to-use product that is
within the Delivery Systems business
available to meet the many challenges of the safe for patients.
pharmaceutical market. In the area of By working with a packaging provider segment, where he leads initiatives and
prefillable syringe systems, West offers the who has an intimate knowledge of the develops strategies for future growth,
first silicone-oil-free product on the market, regulatory and quality requirements of the including the acquisition and development of
the ready-to-use Daikyo Crystal Zenith medical field, pharmaceutical manufacturers new technologies that enhance the West
prefillable syringe system. One of the reasons will increase their ability to create a novel
portfolio. His activities include work on key
customers choose the Daikyo Crystal Zenith device that establishes the drug product as a
strategic areas involving injection devices,
syringe system is because it offers much less leader in the market. Differentiation through
safety and administration systems, auto-
Drug Development & Delivery March 2011 Vol 11 No 2
variability in functionality than traditional delivery system technology, as well as advice
glass systems. Coupled with a plunger with from a partner with experience and injectors, and prefillable syringes. In 2005,
Daikyo Flurotec® barrier film, the Crystal understanding of the drug packaging industry Mr. Reynolds relocated to the US from Europe,
Zenith syringe system does not require and end-user needs will not only aid in where he was responsible for European
siliconization, which leads to variability and product compliance, but also may help get Marketing and led the integration of the
can affect the gliding performance of the products to market faster.
acquired technologies from West subsidiary,
plunger. With a prefillable syringe system, *The erisTM safety syringe system is not currently available in the US.
MediMop. His experience within the core West
gliding performance can have a major impact All trademarks and registered trademarks are the property of West
when you place the system into a device, Pharmaceutical Services, Inc., in the United States and other business has been complemented by several
jurisdictions, unless otherwise noted.
such as an auto-injector, which relies on the years of work in the field of devices and
Daikyo Crystal Zenith® and Daikyo Flurotec® are registered
complete delivery of a drug from a syringe. trademarks of Daikyo Seiko, Ltd.
delivery systems. Mr. Reynolds holds a degree
Gliding force, drug viscosity, and in Polymer Technology from Trowbridge
Crystal Zenith and Flurotec technologies are licensed from Daikyo
siliconization consistency can be factors in Seiko, Ltd.
College, UK.
ensuring reliable dosing from an auto-injector
59
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development. Part of patent expirations, and diminishing sales of by investing more wisely in early-phase clinical
these changes include development, which is the most efficient stage
drugs. These challenges are forcing companies
an increase in R&D
to work outside the traditional paradigms of to determine viability. More robust trial designs
outsourcing to drive
greater productivity in a drug discovery and development. Part of these at this stage can significantly improve the speed
shorter period of time changes includes an increase in R&D and cost of the entire development process by
with fewer internal outsourcing to drive greater productivity in a more efficiently answering questions about the
resources.” viability of a drug candidate. Efficient study
shorter period of time with fewer internal
resources. conduct combined with advanced scientific
60
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techniques can provide better Using an experienced CRO can ascending dose (MAD), preliminary
decision-making and reduce the expedite a drug candidate through the drug-drug interaction and patient
probability of costly later-stage drug development process, gaining proof-of-concept into one study. This
failures. the necessary information needed to can reduce the time it takes to gain
make key go/no-go decisions. While proof-of-concept in half and reduce
this is particularly true for smaller study costs by more than 10 percent.
companies that may have limited
Q: What can Contract
resources and expertise, even large TIMELINES NEEDED TO ACHIEVE
Research Organizations
companies have seen clear and FIRST-TO-FILE: The rate-limiting step
(CROs) do to be better
measurable advantages in outsourcing of first-to-file applications for a
partners?
clinical trials to CRO partners. An generic product is the bioequivalence
experienced CRO can help streamline studies that must be completed for
A: CROs have become an integral
a sponsor’s program, allowing most products. The typical timeline
part of drug development as sponsors
multiple studies to be completed in a for the bioequivalence studies ranges
cut their internal capabilities to better
shorter timeline. from 56 to 63 days from dosing to
control costs and improve overall
CROs need to think beyond the final reports. Using a suite of
R&D productivity. CROs frequently
traditional fee-for-service approach services, dedicated lab capacity,
have a much wider range of scientific
and collaborate with their clients to enhanced project management, and
expertise from conducting thousands
develop innovative study designs, clinic resources that are bundled
of studies, and thus can often
development approaches, and together and strategically prioritized,
recommend and develop protocols
contracting agreements that help Cetero has developed a process that
that accomplish sponsors’ multiple
speed development and facilitate can condense the standard timeline to
goals and objectives. This improves
decision-making and timelines for 28 days or less. We recently began
efficiency and brings innovation to
key milestones in product offering this timeline as a premium
the clinical trial process.
development. A few brief scenarios of service offering for clients with first-
Like any good partnership,
how contracting and design to-file market opportunities.
finding the right match between the
innovation can accelerate critical
sponsor and CRO is important. Every
timelines include the following:
Vol 11 No 2
EXPLORATORY DEVELOPMENT:
CRO has its own unique strengths
Contracting flexibility and scientific
and weaknesses. It is important for
ACCELERATED PROOF-OF-CONCEPT: collaboration in areas where
sponsor companies to properly
Drug Development & Delivery March 2011
America to meet the growing demand recent Cetero project involving a availability of studies requiring
for more diverse study volunteer vaccine has spanned more than one weekday, multi-day, or weekend
Drug Development & Delivery March 2011
populations as well as inclusion and year based upon the novel study stays. Study-specific advertising
exclusion requirements. Across the design. Up-front work focused on targets specific groups of people
industry, CROs and sponsors are biomarker measurement, control of with a brief message about the
seeking to broaden their access to sample integrity, and testing of the purpose of the study, age groups,
patients through collaborations with intended clinical response. and/or gender requirements.
medical centers, patient organizations, Also important is integrated Advertising for special populations,
and specialty clinics. These efforts can program planning – determining ways such as the elderly or post-
be supported through maintenance of to reach the goal faster through an menopausal women will involve
an active research database of potential integrated development approach, targeted media and/or select
62
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community placements. Working includes explaining the function of have a lower systemic exposure than a
with local investigator sites and the Principal Investigator and tablet taken orally, but the local
physician networks to recruit and Institutional Review Board, and concentration within the nasal mucosa
screen patients, but with the study monitoring procedures in place will be higher. Therefore, the safety
conduct within one central clinical during the conduct of a study. measure for a nasal spray will be more
site. Community outreach is another Risks and benefits. All focused on the local effects rather than
method. Offering free health investigational and approved drug systemic effects. Also, because a nasal
screenings provides an opportunity products have risks. This includes a spray will be administered to healthy
for potential participants to learn full explanation of potential side subjects as well as those with
more about clinical research and effects or adverse events, even if congestion, regulators often ask for the
specific study opportunities. temporary in nature, needs to be pharmacokinetics to be examined in
One of the keys to recruiting and communicated clearly. volunteers with and without nasal
retaining participants is the ability In each of Cetero’s locations, we congestion.
to set expectations at the beginning make community-based efforts to Transdermal delivery systems, such
of a study. Participants must be help increase public awareness and as patches, are designed to remain on
clearly informed about what understanding of clinical trials. the skin for an extended period of time.
happens during a clinical study and Due to the potential for irritation or
what to expect in terms of their sensitization from this long-term
involvement. The more details that Q: Do certain dosage contact, specific studies are required to
are given, the better prepared the forms (i.e., nasal sprays, demonstrate whether this will happen
participant will be, but the study patches, injections) present with the experimental dosage form.
administration team has to ensure any special challenges (or As one of the drawbacks for vaccine is
the participant comprehends the the requirement for subcutaneous
advantages) for clinical
details given. The key topics to injections, many companies are looking
trial testing?
cover include duration of the study at sublingual dosing alternatives. These
and follow-up, how long the study studies present a variety of challenges,
A: Nearly all dosage forms present
will last, the timing of the visits and including the duration of the study. Just
their own challenges for running
flexibility, if any, in the timing and as a vaccine is intended to lead to years
Vol 11 No 2
Aveva has a number of products for license from its development BD Medical - Pharmaceutical Systems provides high-quality, customized,
pipeline along with a full complement of R&D capabilities to produce clinically proven drug delivery systems and self-injection technologies to
transdermal drug delivery systems that fortify pipelines and maximize help pharmaceutical and biotechnology customers’ injectable drugs reach
product life cycles. Aveva Drug Delivery Systems is one of the world’s their full potential. BD has over 100 years of experience in manufacturing
largest manufacturers of, and a pioneer in, transdermal drug delivery and processing technology for parenteral drug delivery systems and has
systems with a rich history of providing pharmaceutical partners with developed an in-depth understanding of the pharmaceutical industry’s
fully integrated, controlled-release transdermal products that fulfill requirements. BD has leveraged this experience when developing
unmet market needs. Products for licensing include Sufentanil, advanced drug delivery systems that span from small-scale clinical
Fentanyl, Clonidine, and Nicotine. For more information, contact Robert through large-scale commercial programs. With a broad range of
Bloder, VP of Business Development, at (954) 624-1374 or visit innovative systems and services, BD Medical - Pharmaceutical Systems
www.avevadds.com. provides pharmaceutical companies with support and resources to help
them achieve their goals. For more information, contact BD at (800) 225-
64
3310 or visit www.bd.com/pharmaceuticals.
64-69 DDD March 2011-Tech Showcase_Layout 1 2/25/11 12:11 PM Page 65
86,000-sq-ft
New Jersey facility for tablet and capsule production. High Shear Wet
and Fluid Bed Granulating/Drying, Tablet Compression and Pan
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Partnership Spotlight
RXi & EyeGate Set Their Sights
on the Retinal Disease Market
By: Cindy H. Dubin, Contributor
Mr. Noah Beerman Mr. Stephen From
President & CEO President & CEO
RXi Pharmaceuticals EyeGate Pharma
O
phthalmic drugs constitute a prominent segment of the Dr. Craig Mello, and the company’s intellectual property position in
global pharmaceutical market, with sales of more than $14 RNAi chemistry and delivery.
billion in 2009, according to a new report, World And, Mr. From highlighted the fact that EyeGate Pharma is the
Ophthalmic Pharmaceutical Market 2010-2025. Eye diseases are only company to have successfully used iontophoresis to safely and
common worldwide and range from relatively mild conditions like effectively deliver medication to both the anterior and posterior
allergic conjunctivitis to vision-threatening conditions, such as segments of the human eye.
macular degeneration. A large prevalence rate, combined with a high
unmet medical need for many sight-threatening ocular diseases, Q: What are the unmet needs of the ophthalmic
provides major opportunities in this sector as seen with the recent market, and how will your collaboration meet
success of Genentech’s Lucentis for macular degeneration. these needs?
According to the report, beginning in 2010, novel drugs from
small-molecule anti-infectives to complex biological molecules will Mr. Beerman: There are significant opportunities in the
appear. These treatments will harness a range of drug delivery ocular market, particularly in retinal disease, for breakthrough
systems. Expected future benefits include restoration of vision and products. We have the potential to develop next-generation
the cessation of vision loss, with high potential gains for developers. treatments and/or improve upon existing therapies, and this
Success in the market will be characterized by products with superior collaboration with EyeGate will help us explore a route of
efficacy, safety, and tolerability. Emerging technologies that increase administration that satisfies the needs of the doctor and the needs of
clinical effectiveness and/or patient compliance will be particularly the patient. Our work in RNA interference, for which our founder
important therapeutically and commercially. won the Nobel Prize, is a natural mechanism where short, double-
RXi Pharmaceuticals is a leader in RNAi-based therapeutic stranded RNA molecules interfere with the expression of genes in
discovery and development with a therapeutic platform that includes living cells.
both RNA interference (RNAi) compounds and delivery methods. Many drugs on the market today are repositioned drugs not
The company is leveraging this broad and integrated RNAi specifically developed for ophthalmic diseases. We are developing a
therapeutic platform to build a pipeline of RNAi therapeutics for new class of therapy that has the potential to be broadly applicable to
Drug Development & Delivery March 2011 Vol 11 No 2
treating several disease areas, including retinal disorders. RXi multiple therapeutic areas, including diseases of the eye.
recently partnered with EyeGate Pharma to evaluate administration
of its RNAi compounds via the EyeGate drug delivery system, which Mr. From: There have been very few drugs approved in the
is based on iontophoresis. This is an active method of drug delivery area of retinal disease, and Lucentis is one. We want to give patients
in which an electrical field created by a low-level of electrical and doctors a treatment tool that as yet does not exist for retinal
current is applied to an ionizable substance or drug particle in order disease. Despite material advances in ophthalmic medicine in recent
to increase its mobility across a biological membrane. decades, there remains significant opportunity to improve patient
In a recent interview with Drug Development & Delivery, Mr. care, lower cost of services, and treat sizable unmet medical needs.
Noah Beerman, President and CEO of RXi Pharmaceuticals, and Mr. As life expectancy increases, so does the incidence of ophthalmic
Stephen From, President and CEO of EyeGate Pharma, discussed disease, such as glaucoma, macular degeneration, and diabetic
why they believe their companies are well positioned to compete retinopathy.
successfully in the ophthalmologic market. Mr. Beerman cited RXi’s The collaboration with RXi will explore the use of our
next-generation therapeutic platform, experienced management team, iontophoresis technology to deliver RXi’s “self-delivering” rxRNATM
70 accomplished Scientific Advisory Board, including Nobel Laureate, (or sd-rxRNATM) compounds to the eye in preclinical models.
70-71-DD&D March 2011-Partnership Spotlight_Layout 1 2/25/11 12:13 PM Page 71
Iontophoresis delivers a drug across a (transmitted across the sclera, or white length of the therapeutic effect, we have seen
biological barrier, such as the ocular surface protective outer membrane of the eye) effective target silencing in the retina with
into the eye. Once inside the eye, we believe iontophoresis delivery platform, the sd-rxRNA compounds for several weeks.
the sd-rxRNA compounds will access retinal EyeGate® II Delivery System, was designed This critical result demonstrates that the
cells, and by virtue of their self-delivering by engineers and ophthalmologists and is ability of sd-rxRNAs to enter cells in the
properties, will enter these cells and silence based on more than 10 years of research and retina is significantly improved over
disease-causing genes. development, providing a strong body of conventional siRNAs. The use of sd-rxRNAs
scientific and proof-of-concept data. may change the landscape of ocular
Q: What segment of the retinal The system consists of two parts: A oligonucleotide-based therapeutics, enabling
disease market are your efforts reusable battery-powered generator and a rapid discovery and validation of a range of
being focused? disposable applicator that contains the drug. novel therapeutic targets and creating the
EyeGate’s iontophoresis technology is potential for next-generation therapeutics for
Mr. From: We are focused on wet and coulomb-controlled, which means that it the treatment of serious retinal disorders.
dry age-related macular degeneration, regulates each unit of drug used for There is also opportunity to improve on
diabetic retinopathy, and diabetic macular treatment. The annular design and electrode existing therapies, for example, extending the
edema, which together affect tens of millions composition allows for safe and effective time required between doses and using more
of people in the US. Macular degeneration transcleral delivery. The treatment is needle- effective or patient-friendly models of
affects 20 million people in the US. Two free and requires only topical anesthesia administration for delivery to the eye. The
types exist: atrophic (dry form) and administration. company intends to select a development
exudative (wet form). Wet-AMD is candidate in a retinal disorder in 2011.
responsible for 90% of blindness and affects Q: What data can you share
approximately 2 million people. The high about your individual trials so Mr. From: EyeGate Pharma’s lead
prevalence of these diseases has created far? internal clinical candidate, EGP-437
significant opportunities for companies to (dexamethasone phosphate formulated for
develop innovative medicines and technology Mr. Beerman: To date, we have iontophoresis), is currently being developed
that improve patient diagnosis and care. At seen a robust uptake of our compounds into to treat dry eye, uveitis, scleritis, and other
the core of our approach is the understanding the retina after intravitreal dosing in animal inflammatory conditions. We have completed
that for medicine to be effective, it needs to models. Most, if not all, cells take up sd- two Phase II studies (one uveitis and one dry
be able to get to the anatomy of the eye that rxRNA within minutes of exposure. eye), and we are currently enrolling for a
is responsible for the disease. Intravitreal administration of sd-rxRNA Phase III dry eye pivotal study. Results of the
shows efficient distribution and uptake of sd- Phase II dry eye study showed findings in
Q: Why is it so difficult to deliver rxRNA compounds to essentially all cell multiple symptoms and signs, and had a
drug to the eye to treat these types with complete penetration through all rapid onset of action. The EyeGate II
diseases and how does layers of the retina, including retinal pigment delivery system and EGP-437 have been
iontophoresis overcome those epithelial cells. This broad cellular studied in more than 300 subjects with more
difficulties? distribution profile allows the technology to than 1,300 treatments performed.
be applied to inhibit a wide range of ocular
Mr. From: Due to natural barriers, gene targets for different therapeutic Q: As you move forward with
topical (eye drops) instillations and systemic indications. preclinical trials and your Drug Development & Delivery March 2011 Vol 11 No 2
delivery of therapeutics to the back of the In addition to robust uptake by retinal partnership, what will be your
eye are inefficient. To overcome the low cells, target gene silencing has been observed primary objective?
bioavailability issue associated with these with sd-rxRNAs targeting two different genes
delivery modalities, more aggressive following administration to the eye Mr. From: There are 25,000
treatments like intravitreal injections are (MAP4K4 and PPIB). At 48 hours, 50% ophthalmologists in the US and approximately
performed. But as you can imagine, this is gene silencing was observed for both sd- 2,000 of them specialize in retinal disease
not ideal and comes with potential rxRNAs. When compared to more cases. They need another tool for treating
complications, such as retinal detachment, conventional, chemically stabilized siRNAs, these diseases, and we must continue to
hemorrhaging, and endophthalmitis. The confocal microscopy shows efficient sd- address their needs, as well as those of their
challenge has been to get compounds to the rxRNA retention throughout the retina, while patients. We look forward to working with
back of the eye less invasively. conventional compounds are not retained by RXi to accomplish these goals. u
EyeGate Pharma’s trans-scleral retinal cells. While we don’t yet know the
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Avantor 3 www.avantormaterials.com/macron-drugdevelopment
BIO 47 www.convention.bio.org
BD 13 800-225-3310 www.bdpharma.com
Catalent 76 www.catalent.com
INTERPHEX www.INTERPHEX.com
RDD 69 www.rddonline.com/rddeurope2011
Unilife 51 www.unilife.com