2016. Dosage Form Optimization: Technology to Advance the Patient-Centric Drug-Development Process

Dosage Form Optimization:
Technology to Advance the
Patient-Centric Drug-Development Process
A Supplement to American Pharmaceutical Review SEPTEMBER/OCTOBER 2016
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Optimizing Drug Design for Patient Outcomes:
Challenges and Opportunities........................................................................4
CASE STUDY OptiForm® Solution Suite Accelerates Bioavailability
Enhancement for Early Phase Molecule...........................................................8
Early Phase Development Strategy for Better Drug Design.............................10
Patient-Centric Drug Design: A Clinical & Academic Perspective......................14
CASE STUDY Zydis® Fast DissolveTechnologies - Effective Dose
Forms for Pediatric Health............................................................................16
Faster to Market: Strategic Approaches in Manufacturing and
Clinical Supply.............................................................................................18
CASE STUDY Optimizing Small Batch Size to Solve Formulation Challenges......20
The Path to Create Optimal Dosage Forms.....................................................22
Contents
2
American Pharmaceutical Review | Dosage Form Development Supplement 2016
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South San Francisco, CA 94080
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Dosage Form Optimization:
TechnologytoAdvancethePatient-CentricDrug-DevelopmentProcess

3
For large and small pharmaceutical companies alike; developing a new drug is fraught with risk.
The time, money and resources devoted to drug development, clinical trials, manufacturing and marketing
are constantly growing. Current market forces are trending away from the blockbuster products of just a few
short years ago. Yet, there are strategies and technologies available now to minimize the risks of developing
new drugs and ensuring they are safe, well-tolerated and available to the widest possible patient populations.
Patient-centric drug development and optimization is both a tool and a trend for drug development. By
designing products with the patient in mind from the beginning of the process, pharmaceutical companies
minimize the many risks they encounter on the path to market.
Yet many in the industry are not aware of these benefits, what the available technologies are, and who to
partner with to ensure their products are patient-centric.
This supplement’s goal is to address those questions and provide the needed information for pharmaceutical
manufacturers to make informed decisions as they develop drugs with patient centricity in mind.
We sincerely hope you find the information, opinions and strategies in these pages helpful and use it as a
reference while developing your products.
Sincerely,
Mike Auerbach
Editor In Chief
A Note from the Editor

4
Mike Auerbach
Editor In Chief
American Pharmaceutical Review and
Pharmaceutical Outsourcing
Optimizing Drug Design for
Patient Outcomes:
Challenges and Opportunities
For every 100 prescriptions written for a chronic disease indication, the percentage of patients who
do not comply with the prescribed regimen rises from nearly 40% after 6 months to almost 70% after
12 months. Prescription non-adherence for chronic conditions is a leading reason for therapeutic
failure. It is estimated that the annual cost of non-adherence in the US is between $100 and $300
billion. These costs can be avoided if the underlying issues leading to non-adherence are addressed.
Multiple factors can impact a patient’s adherence to prescribed medication. Some factors are dosage
form related such as route of administration, pattern and frequency of dosing, ease of administration,
length of treatment, and drug side-effects. Other factors are patient related, such as age, gender,
cognitive status, and physical condition. Studies have shown that as the number of medications
taken per day increases, adherence begins to decrease. Recent FDA guidance for industry on the‘Size,
Shape, and Other Physical Attributes of GenericTablets and Capsules’provides more data and insight
into this problem, demonstrating a correlation between difficulty in swallowing certain dosage forms
or prescribed medication and a reduction in patient adherence and in some cases even complete
discontinuation of therapy.
DRUG DESIGN
Figure 1.

In light of these issues, the question arises as to whether the pharma
and biopharma industries can appreciate the role that intelligent drug
design of drug substances, drug products, and packaging can play in
patient adherence and outcomes. Increased industry investment in
adherence-supporting patient-oriented marketing suggests that industry
experts accept the value of improving adherence. Some companies have
embraced a more holistic approach, incorporating patient factors early in
development, including in designing a patient-friendly drug product. In the
Drug Delivery Landscape Survey conducted in 2015*, formulation scientists
and R&D managers from the pharma/biopharma industry responded that
patient adherence is an important factor in developing a drug formulation.
Interestingly, the survey data indicates that although the industry values
patient-centric drug design, it has not been very successful in applying
it. Target patient preference should be considered early in the process to
avoid costly changes at Phase II and later, but the survey results indicate
that changes in design tend to occur at these later stages as shown in Figure
1. Further, when the survey respondents were asked to rate the significant
factors in drug development, elements such as patient adherence, patient
dosing convenience, and impact on patient’s likely drug regimen all
received very low rankings. The sources for patient insight also highlight
the limited influence of patients in deciding the drug product design, with
direct patient input being used only 38% of the time to adapt the product,
and input from patient advocacy groups being used only 17% of the time.
There is a definite need for a drug delivery strategy that not only overcomes
formulation challenges but also meets patient demands. Fortunately, there
are advanced drug formulation and delivery technologies employed today
which can not only solve formulation challenges but also are likely to
generate better outcomes – for patients, payers, and innovators alike. Given
the demands placed on pharmaceutical companies to market drugs that
both deliver on their promise to treat/cure disease and to increase patient
adherence resulting in better outcomes, it is no wonder pharma companies
are turning to service providers with expertise, experience, and solutions to
address both challenges.
Implementing Patient-Centric Drug Development
Cornell Stamoran Ph.D., Vice President of Corporate Strategy at Catalent
Pharma Solutions, and Executive Director of Catalent’s Applied Drug
Delivery Institute, has been at the forefront of the industry’s drive to make
drugs more patient-centric.
“We believe that patient-centric design needs to be intentional, rather
than implicit, and other researchers have independently concurred,” says
Stamoran. “Importantly, we believe this starts with a clear understanding
of patient outcome-driving factors during medicinal chemistry, ensuring
the optimal form of the molecule progresses forward - finding the right
salt form, the right polymorph, etc. Based on a realistic assessment of the
gap between optimal patient-centered drug product design and current
molecule characteristics, the next step is in pre-formulation, identifying the
best formulation approach likely to bridge the gap. Once confirmed in target
animal models, that formulation can then be optimized, along with early
dose form selection, again always with a patient outcomes-enhancing view.”
Stamoran continues, “That initial optimized formulation should be taken
into Phase I, and then with the best dose form into Phase II studies. It may
be appropriate to structure a comparative Phase II study if there’s more
than one patient-focused dose form option. If a drug-device combination
is called for, there are already existing standards for human-factor testing
for the combination at these stages. Finally, following further optimization
of formulation and dose form, Phase III studies, structured appropriately
to also build evidence of advantaged patient-focus design for the product
versus comparator marketed products, comes patient-focused packaging
and labeling design.”
“Optionally, this can also include building in technologies to the dose
form, any related device, and packaging to enable future adherence/
usage monitoring, which would then integrate with downstream remote
monitoring and assessment technologies and applications.”
“Research conducted by the Institute indicates that few formulation sci-
entists receive patient-focused input to influence design choices made
during development, and often the information they do receive comes
during Phase III, too late to impact most drug substance and drug product
design decisions.”
Ralph Lipp, President and CEO of Lipp Life Sciences, having served as the
R&D leader at Eli Lilly and Co. and Schering AG, has a deep understanding
of patient-centric drug design and development, adds his thoughts
regarding current trends in patient-centric drug design; “Pediatric labeled
products for example have been produced for many years by the industry,
and yet, our understanding and addressing the unique formulation and
delivery needs of this important sub-population is still evolving as of today.
In addition significant advances have been made serving the needs of
geriatric patient populations more recently. In the area of cancer patient
needs, there is a growing recognition, that an enhanced focus on capturing
of patient reported outcomes in oncology trials will help to better design
and develop novel treatments for the affected patient groups, particularly
considering the extremely complex regimens these patients face.These are
just a few trend examples for very different patient groups, the underlying
principle, however, is the same, and transferable to further patient groups:
understand critical patient needs at the outset of your drug design activities
and use these specific insights along the value chain of developing new
medicines.”
Patient-Centric Drug Design Begins Early
As patient-centric drug development and design becomes more prevalent,
pharma companies are beginning to consider patient-friendly dosage
forms as early in the process as possible. Incorporating patient-centric
dosage form design is a smart business decision. But, as drug development
and clinical trial costs and complexities continue to grow, do pharma
companies have the resources needed to make the shift to patient-centric
drug design and development?
Stamoran offers his thoughts, “Although Catalent Institute’s research
indicates less than a quarter of companies regularly use patient input to
influence drug substance and drug product design decisions, there are
clearly some companies that do this well today. Without naming names,
I would highlight large regional or niche global players who focus on a
few therapeutic areas like diabetes, or specialty companies focused very
precisely on treating one disease or patient population. These companies
typically nurture very close relationships with patients, caregivers, and
advocacy groups in their area of disease focus, and look to understand the
patient’s whole treatment regimen, including concomitant diseases, and
put NMEs in development in the context of current competitive treatments
and other drugs that typical populations, or subpopulations, of patients
currently take. This information is shared comprehensively throughout the
development organization, and that deep and sustained awareness both
explicitly and implicitly influences day-to-day decisions made at the bench,
in the lab, in clinical trials, and by decision makers.”
DRUG DESIGN
5

“Therearestillmanyopportunitiestoimprove,evenforthesehighlyfocused
companies. There is a great deal of published research focusing on drivers
of patient treatment, discontinuation, and adherence, often not funded by
industry, published each year. One of our goals through the institute is to
marshal existing published evidence into databases and other more usable
vehicles and analyses that can enable clear understanding of design factors
significant to different patient populations, and a clear understanding of
the evidence therefore.”
“The development of in silico predictive tools and algorithms for patient
focused design decisions also is an important area of focus. While many
strides have been made in in silico basic formulation prediction in recent
years, virtually none of this is oriented to design factors linked to patient
outcomes. Since much of drug substance optimization and drug product
design activity today is done experimentally, it creates inefficiency and cost
barriers as well as development time challenges for companies who wish
to be more patient focused in design. Catalent has recently developed a
scientifically driven, structured approach to both molecule optimization
and optimal formulation state selection, to drive progress in this area.”
“Clearly, many companies today are focused on differentiating, at times
even patient outcomes- enhancing, commercial packaging, and there is
some body of published evidence demonstrating some success in this area.
However, this, along with most of the other adherence-related spend from
innovator companies, is most often related to single product adherence
and outcomes enhancement, rather than for the patient’s full typical
regimen of treatments.”
“As companies begin to embrace patient-focused drug design, we believe
it will likely lead to increased usage of external outsourcing partners who
understand the principals of patient-focused design, have proven history
of success generally, and can implement them in the specific disease area
needed. Also, given budgetary constraints, larger companies focusing in
many diverse therapeutic areas may be challenged to implement these
concepts quickly across their diverse portfolios, another way where patient-
focused design CDMOs can play an important role.”
Lipp adds his thoughts regarding patient specific drug development
and the value it can add, “In order to maximize the value obtainable by
the application of patient-centric drug design, pharma companies will
benefit from a mixed approach. In-house understanding of the criticality
and the vital elements of the approach, not only at the management
level, but particularly at the drug development team level, is crucial. Also,
establishing a drug development process which allows for the optimal use
of patient need insights internally is important. However, in many cases
certain aspects of patient-centric drug design can be executed better with
the help of experienced external service and technology providers. In order
to make these collaborations between pharma and external partners most
useful, it is important to stay focused on patient needs and use individual
technologies as a means to an end. From that perspective, working with an
external partner who provides multiple technologies to select from when
addressing a specific patient need can be more attractive then working
with a single-technology provider, since any potential technology bias can
be easily minimized.”
Good For Patients – Good For Pharma Companies
All pharmaceutical companies strive to provide the best products to treat
the most patients safely and effectively, but they also seek to make the drug
development process as quick, efficient, and economical as possible. This
leads to a possible conundrum: can patient-centric drug development be
mutually beneficial to patients and pharmaceutical companies?
“While it is obvious, that the ultimate goal of any drug development
needs to be the creation of better patient outcomes, pharmaceutical
companies need also to generate a return on their R&D investment in
order to be able to continuously develop and provide novel treatments,”
says Lipp. “In order to generate a return on investment commensurate to
the value provided to patients, market access and reimbursement often
are critical factors for novel medicines. In general, utilization of patient-
centric approaches in drug development offers the opportunity to
deliver better products which come with demonstrated patient benefits.
These demonstrated patient benefits will likely be valued by patients,
providers, and payers. Consequently the chances for adequate market
access, reimbursement, and return on investment should be higher for
pharmaceutical companies investing in patient-centric approaches.”
“Patient-focused drug design brings product developers and markets
real and tangible benefits,” says Stamoran. “First, improving the odds
of initial Phase II success, carrying forward to better odds of increased
product approvals. Second, if developers build proper real-world, patient-
focused evidence during Phase III, research from the Institute with both
US insurers and international single payer representatives indicates
formulary decision makers want, and will consider such as one factor in
formulary coverage and/or benefit tiering. Third, in some cases we have
found that optimizing the formulation leads to a substantial reduction in
(often costly) API while achieving equivalent efficacy. Plus, this can lead
to a strong foundation for adherence-differentiated professional medical
marketing/communications, and possible integration into future patient-
driven adherence apps/monitoring programs.”
Stamoran concludes, “In short, potential benefits mean more approvals,
better market access/reimbursement positioning, more differentiated
products, and possibly a lower cost.”
Meeting Patient-Centric Goals
So, let’s suppose you are currently developing a drug. It shows promise.
You are already into testing and you need to make sure your new drug is
meeting therapeutic targets and in a patient-centric dose form. Are there
ways to quickly and effectively enhance or change a product’s design to
meet these goals?
“First, and most importantly, companies should not settle for drug
substance or product characteristics that are widely known to impact
patient outcomes – by limiting patient compliance, increasing safety risk
or side effects, or underserving a specific sub-population of patients,” says
Stamoran. “For example, there are many approaches that companies can
use to improve drug formulations to reduce or eliminate the food effect –
undesired variability in bioavailability when a medication is administered
with food. Yet critically important products, like certain oral oncology
products, are still being approved with “take with/without food” labeling,
which most research shows is not typically followed by the average patient.
Another example of settling is to expect a rheumatoid arthritis patient, who
has substantial joint dexterity issues and pain, to be able to inject a solution
into a vial containing a lyophilized drug, then once reconstituted to draw it
back into a syringe, then self-inject.”
Stamoran continues, “Second, drug developers need to ensure that target
therapeutic profiles are grounded based not just on key opinion leader
input, but on direct feedback from patients, caregivers, and disease/
patient advocacy groups – including their needs, challenges with current
treatments, their normal regimen complexity, etc. And further, to ensure
DRUG DESIGN
6

visibility of this input to anyone in development whose work can impact
product design.”
“Finally, for many pre-filing drugs the window of opportunity to deploy
patient-focused design is mostly closed pre-launch, with Phase III trials
already ongoing or even finished. However, it’s exactly the right time
to begin planning a line extension – one which can improve “real world”
outcomes. And if there are bandwidth challenges to doing so – bring in a
partner like Catalent!”
Designing drugs to be patient-centric leads to another, perhaps obvious,
question: are patient-centric drugs one step on the path leading to truly
personalized medicines? Lipp offers his thoughts, “Personalized medicine
holds a strong promise in certain disease areas where addressing individual
patient needs – potentially based on specific genetic characteristics - and
preferences is crucial to create meaningful patient outcomes. However,
many of the diseases known today do not require a highly sophisticated
tailoring to generate the desired patient outcomes. In certain cases
straightforward dose adjustment of a specific medical entity will be
sufficient to offer valuable treatment options to rather large patient groups.
Over time, we will likely see personalized medicine approaches grow
beyond the area of niche players. From my perspective, patient-centricity
considerations will be of high importance to both areas, personalized
medicines and treatment approaches for broader patient populations.”
Finding Experienced Help
With increasing demands being placed on pharma companies to deliver
patient-centric drugs as quickly as possible, many have turned to service
providers who have the experience and capability to advance drug
candidates through the development cycle.
Stamoran explains, “Contract development and manufacturing organi-
zations, or CDMOs, can play a very important role in increasing both the
speed of development and the transition of development to commercial
launch and beyond. First, being able to integrate core disciplines at one site,
and scaling up from clinical to commercial at that same site, often can make
a difference in achieving accelerated development programs for fast-track
or break-through products. The likelihood of successful scale up within a
site is significant, and minimizes failures and risks attendant to site-to-site
scale up during late development.”
“Additionally, the larger CDMOs, like Catalent, launch hundreds of products
a year on behalf of customers and thus have significant experience at
ensuring things go as smoothly as possible, and equally importantly
decades of experience at solving things that arise which could jeopardize
launch timings or potentially regulatory approvals. And if the product is
using an advanced technology for formulation or dose form, even if the
sponsor has some experience in formulation for that formulation or dose
form type, the technology providing firm is likely to have far deeper and
broader experience in formulating, filing, and scaling up that technology.“
“Consideration of flexible scale for launching products is also important,
and larger outsourcing providers typically bring substantial capacity
that can be available to support surges in launch uptake, new country
reimbursement approvals, and other variables that can drive variation
from original volume plants. Finally, getting the formulation right to
optimize both clinical impact and manufacturability is key, and can impact
virtually every step downstream - clinical optimization, transition speed,
process and performance reliability, improved launch odds, and post-
launch scale and reliable supply - all of which create substantial value for
sponsors,”he concludes.
Future Outlook And Advice
Taken as a whole, the benefits to innovator companies who include patient-
centric drug development as a key factor in their clinical trials, scale-up and
manufacturing plans, are numerous. Early adopters of this strategy will
see many benefits to this approach now and into the future. They will also
be ready to take advantage of future technologies and processes as they
become available and use them to their benefit.
Regarding future advances, Lipp offers his outlook. “On the process
side, I see the emergence of holistic approaches to patient-centric drug
development – spanning all design phases from early concept to final
market product and beyond (looking at market feedback and life cycle
management opportunities) - being developed by the industry. In order
to execute these processes in an optimal fashion all members of the
respective drug development teams need to base their scientific and
technological decision making on a sound knowledge of the patient needs
for the intended product.”
“On the technology side, there are continuous advances being made.
Examples which come to mind stem from the area of advanced drug
delivery systems providing patient benefits in domains like better handling
(devices), higher bioavailability and /or less inter- and intra-patient variance
in dose delivered (oral delivery technologies), longer application intervals
(s.c. depot systems, transdermal systems), less invasive ways of application
(pulmonary and nasal delivery of biomolecules) etc. It is important to look
at the potential advantages that these evolving technologies provide in full
appreciation of well understood patient needs to maximize their impact on
the respective drug design challenge at hand.”
Stamoran adds his thoughts on future benefits realized by adopting a
patient-centric drug development philosophy, “For current early-to-mid
development opportunities, the first benefits will likely be realized by
increased market access and/or more favorable reimbursement, as long
as the product is accompanied by sufficient evidence of differentiated
performance,”says Stamoran.
He continues, “For later stage development and early marketed products
– a rapid assessment of short-term enhancement opportunities, perhaps
with adherence-enhancing packaging and labelling content, could be
accompanied by a full patient-focused life cycle plan.”
“Further focus by Catalent and other external partners on predictive
in silico tools integrating chemical and clinical/patient aspects of drug
substance and drug product design will enable more rapid, efficient and
effective patient-focused design of drug substance and formulation.
Continuing dose form and device innovation – such as oral peptide delivery
, noninvasive delivery of large molecules, and shifts from infused to non-
infused biologics – will create new opportunities to improve finished dose
aspects of drug product.”
“Finally the Catalent Applied Drug Delivery Institute is beginning a multi-
year patient focused design research collaboration with industry, academic
and patient/disease focused organizations, to help support and hopefully
accelerate the adoption of patient-focused drug design. We’re pleased to
invite others who share our passion and vision to join us in making patient-
focused drug design a reality,”Stamoran concludes.
*The 3rd annual Drug Delivery Landscape Survey was sponsored by
Catalent Applied Drug Delivery Institute. For more information, visit www.
drugdeliveryinstitute.com
DRUG DESIGN
7

case study
OptiForm‰
Solution Suite Accelerates
Bioavailability Enhancement
for Early Phase Molecule
Executive Summary
A biotech company developed an extremely poorly soluble new molecule
in pre-clinical phase. Catalent provided a structured approach with its new
offering OptiForm‰
Solution Suite, to help select the most suitable formulation
technology to enhance the molecule’s bioavailability. In just 12 weeks, experts
at Catalent conducted a thorough assessment of the molecule’s characteristics,
evaluated multiple bioavailability enhancement technologies in parallel, and
finally delivered the optimal formulation. This integrated service efficiently
and rapidly helped the molecule progressing to animal PK studies, and the
enhanced bioavailability enabled the single ascending dose studies in phase I.
The Challenges
The Catalent Solution
Catalent’s scientists offered the customer with an integrated solution OptiForm‰
Solution Suite that has a 3-step approach: assess, enhance and deliver.
assess The team conducted a thorough assessment of the molecule’s physical and
chemical properties. The molecule characterization data confirmed that the molecule
belongs to DCS IIb1
, according to the Solubility Limited Absorbable Dose (SLAD)
model shown below. The classification also explains the food effect by measuring the
solubility in different biorelevant dissolution media, including FaSSIF2
and FeSSIF3
.
DEVELOPMENT DELIVERY SUPPLY
molecule
properties
A typical BCSII molecule
• Poorly soluble: aqueous solubility < 0.08 µg/mL
• Highly permeable: estimated permeability (Peff) is 6.62x10-4
cm/s
target
bioavailability
Minimal dose exposure of 1,400mg for single ascending dose studies in
phase I
challenges Poorly bioavailable molecule (<2%) in a standard oral solid dose formulation
prohibiting phase I entry
• Milling technology failed to improve its bioavailability
• Strong food effect - 4 fold increase in exposure yet bioavailability remained <10%
• Prodrug can enhance solubility to ~2mg/mL but unstable
case study
OptiForm
Bioavailability Enhancement
for Early Phase Molecule
Executive Summary
A biotech company developed an extremely poorly soluble new molecule
in pre-clinical phase. Catalent provided a structured approach with its new
offering OptiForm
technology to enhance the molecule’s bioavailability. In just 12 weeks, experts
at Catalent conducted a thorough assessment of the molecule’s characteristics,
evaluated multiple bioavailability enhancement technologies in parallel, and

OptiForm is a registered trademark of Catalent Pharma Solutions
˝ Copyright 2015 Catalent Pharma Solutions, Inc. All rights reserved. ca/of/cs1 (10/15)
more products.
better treatments.
reliably supplied.™
Discover more solutions at www.catalent.com/optiform
global + 1 888 SOLUTION (765-8846)
eu + 800 88 55 6178
solutions@catalent.com
enhance Based upon the extensive data that Catalent had gathered from
hundreds of actual molecules studied, the scientists established a formulation
scenario for the molecule. Potential enabling technologies were shortlisted as
below, and technical studies were conducted in parallel to evaluate all.
1 lipid system Studies showed that the molecule is fully compatible and soluble in some lipid excipients
2 solid dispersion Studies showed that the molecule is not miscible
and compatible with most common polymers
3 particle size reduction Studies showed that the optimal particle size is 37 µm for
maximum 75mg dose exposure. The formulation failed to meet the bioavailability
requirement of 1,400mg exposure for the phase I single ascending dose study
Based on the study outcomes, Catalent scientists selected lipid systems delivered in
softgels. The lipid excipients were screened to ensure optimal solubility and precipitation
resistance upon dispersion in biorelevant dissolution media. The prototype lipid systems
exhibited good stability data after more than 2 weeks of stability stress study.
deliver Catalent delivered the recommendations for two lipid formulation
candidates, as well as a positive chemical physical stability risk profile. The
proposed formulations enhanced the molecule’s bioavailability which in turn
enabled dose escalation beyond the targeted range (1,400mg/dose).
The OptiForm‰
Solution Suite program was completed in 12 weeks. Animal PK studies
were soon conducted using the materials that Catalent provided, and showed similar
exposure to the pro-drug and drug solutions in DMSO4
, close to complete absorption.
Catalent further developed the formulation candidates with RP Scherer softgel
technology to successfully move the molecule from preclinical to phase I studies.
Conclusion
Catalent’s OptiForm‰
Solution Suite offered a structured approach with parallel
formulation feasibility assessment for this novel molecule. The rigorous scientific
data indicated lipid systems as the most suitable formulation to enhance the
bioavailability of the molecule. With Catalent, the molecule quickly progressed
from preclinical to animal PK study, and soon reached phase I human study.
1. DCS: Developmental Classification System
2. FaSSIF (Fasted state simulated intestinal fluid): Intestine without food
3. FeSSIF (Fed state simulated intestinal fluid): Intestine with food
4. DMSO: Dimethyl sulfoxide. It is a polar aprotic solvent that dissolves both polar and nonpolar
molecules and is miscible in a wide range of organic solvents as well as water
predictedpeffinhumanscm/secx10-4
dose/solubility ratio 1000500250
10
1
0.1
5000
I
good solubility
& permeability
II
good permeability
& poor solubility
IIb
(solubility limited)
IIa
(dissolution rate
limited)
IV
poor solubility
& permeability
III
good solubility,
poor permeability
10000 100000
prodrug food effect nce
bcs/dcs plot with human jejunal permeability &
aqueous dose solubility ratio as axes
BCS
DCS
slad

10
Early Phase Development
Strategy for Better Drug Design
Introduction
TheTufts Center for the Study of Drug Development (CSDD)
estimates the cost of bringing a drug to market at $1.4
billion.1
Time and opportunity costs nearly double that
figure, to $2.6 billion, and sponsors spend an additional
$312 million on post-approval R&D. This represents a 145%
increase over CSDD’s 2003 estimate.
Catalent has created the Applied Drug Delivery Institute
with the sole purpose of bringing together pharmaceutical
innovators, organizations, and academia to improve clinical
outcomes, medication delivery profiles, patient adherence
and treatment efficacy. The institute has identified the
top challenges facing the pharmaceutical industry as:
formulation, drug delivery, and lengthy development
cycles and high costs.2
Soaring drug development costs
resulting from the greater complexity of clinical trials, a
renewed focus on chronic and degenerative diseases, and
the need for comparative drug effectiveness data, have all
contributed to a greater need to look at the science behind
drug delivery and make a concerted effort to improve drug
delivery and patient compliance. 3
Currently, approximately 70% of new chemical entities
fall into the Biopharmaceutics Classification System (BCS)
classification 2,4
where poor solubility is the major hurdle
preventing complete bioavailability. BCS categorizes APIs
according to solubility and permeability, which are key
attributes related to drug development.5
Safety, efficacy,
and stability remain perennial challenges for BCS category
2 molecules.
Each solid-state form of an API has unique physicochemical
propertiesthatcanhaveaprofoundimpactonbioavailability,
stability,andmanufacturability.Identificationoftheoptimal
solid-state form for development relies on several factors:
• A clear understanding of the target attributes of
the API and drug product
• Design and execution of an appropriate screen to
produce solid-state forms of importance
• Detailed evaluation of relevant solid-state forms
• Assessment of the risk-benefit profile of the
candidate solid-state forms against the
target attributes.
Catalent’s OptiForm® API - a solid-form screening service
address all of these objectives and has provided stable
crystalline form for more than 500 compounds till date.
Factors not addressed in early development phases often
surface during clinical stages, where high attrition rates
contribute disproportionately to development costs.
Approximately 60% of molecules in Phase I are promoted
to Phase II. The Phase II to Phase III success rate is 36%;
56% of Phase III drugs are eventually approved. Combined,
these failure rates translate to just one approval for every
12 molecules entering human studies.6
Addressing these concerns early in development, through
scientifically rigorous and data-driven design and
development strategies is crucial to overcoming the innate
shortcomings of many therapeutic molecules.
A single approach cannot solve all these challenges, nor
do existing resources permit application of all potential
solutions to every potential drug. A rational strategy
involves examination of the API’s physicochemical and
biopharmaceutical characteristics, and carefully selecting
technologies that are a good fit. In silico screening is a
technique that can help narrow down options without
consuming drug material. In addition, early formulation
studies with high throughput and rapid screening
techniques based on a minimum amount of API can
streamline development and lower overall costs.
These tools, combined with a rational approach to
molecule form selection and formulation selection, could
help reduce the number of molecules that fail during early
development. An efficient approach should include:
• High throughput screening for drug form
and formulation
• Collaborative, inter-disciplinary drug development
• Early drug delivery feasibility studies
• Selection of proven drug delivery technologies
Developability
The Developability Classification System (DCS)7
is an
improvement on BCS, but with emphasis on the ability to
be able to incorporate the molecule into a drug delivery
system. DCS focuses on key early product development
issues that need to be overcome to improve absorption.8
A preponderance of drugs fall into DCS quadrant II, with poor
solubility but adequate permeability. Quadrant II may be
further subdivided into categories for which molecules are
either dissolution rate-limited in the gastrointestinal tract
(classification IIa) or solubility-limited (IIb), as delineated by
the Solubility-Limited Absorbable Dose Rule (see diagonal
line in graph).
EARLY PHASE DEVELOPMENT STRATEGY
Stephen Tindal,
Director, Science &
Technology, Catalent
Pharma Solutions has
30 years of experience
in formulation
Sciences. He has
wide expertise in
commercializing many
Rx, Gx, OTC and VMS
products. Stephen
specializes in root
cause investigation,
technology
innovation,
gelatin innovation,
customer liaison and
supporting business
development.
David Igo, PhD,
Director, Product
Development and
Manufacturing,
Catalent Pharma
Solutions combines
novel automation
tools and solid-
state workflows to
support the discovery
and evaluation of
crystalline forms, salts,
and co-crystals. He has
co-invented a variety
of high-throughput
technologies utilized
in solid-state screening
along with a range of
unique crystalline salts
and solid-state forms.

For molecules falling under the IIa classification, the dose is expected to
dissolve completely during the ~3 hour transit through the small intestine
– provided that more of the undissolved molecule dissolves to replace
it. Molecules in the IIB quadrant do not completely dissolve within the
available time. This is of particular importance in dose-escalation studies
where the second and subsequent dose will never dissolve and the end
point of the study cannot be reached.
DCS Classification provides insight into appropriate early-development
technologies for overcoming pK and pD issues: DCS I molecules are
typically formulated as conventional solid dosage forms. Molecules in
categories IIa often exist in micronized form or as solutions. Molecules
in the IIb category require lipid-based solutions or amorphous solid
dispersions. Molecules under category III are challenging, and often benefit
from permeation enhancement such as Catalent’s Optigel™ Bio technology
which can provide a pathway for an IV to oral delivery conversion, resulting
in enhanced therapies for patients. Molecules in category IV are extremely
challenging, often requiring individualized treatment.
Accelerated Development Programs
Accelerated regulatory pathways, including Fast Track and Breakthrough
designations, shorten the approval process for drugs for treating rare or
life-threatening diseases, or that alleviate unmet medical needs. Taking
full advantage of accelerated regulatory timelines involves adopting a
structured development approach at the very earliest stages.
Many sponsors of NCEs lack the internal support and infrastructure for
some or all of the development activities needed to take full advantage of
expedited designations.
Catalent, through its development and analytical services, offers Integrated
Solutions to serve the needs of accelerated development. Expedited
development is supported by Catalent’s proven expertise in:
• Analytical development, validation, release and stability testing
• Pre-formulation and formulation development
• Clinical trial manufacturing, supply, packaging, labeling, and
distribution support
• Scale-up, registration and process validation batch manufacture
• Commercial manufacturing
Companies seeking expedited pathways must assure that other
development activities support their program. Considerations include
analytical method validation, drug substance performance and process
qualifications, market image and packaging, prior approval inspections,
and business considerations.
Communication with the FDA is critical for expedited programs to
succeed. Moreover drug quality may not be compromised for speed,
and all development activities must occur at the same level as for non-
expedited products.
Very Early Development
Catalent utilizes early in silico analytical assessment to help predict a
molecule’s DCS classification, and to help determine whether a molecule’s
bioavailability will be solubility- or permeability-limited.
Early development should focus on understanding the extent to which
drugs enter the bloodstream and the properties that enable this. Solubility
screening for these characteristics typically occurs during early development.
Also key is understanding the drug’s solubility/stability in simulated
biological fluids, which approximates performance in the GI tract. Rapid
stability screening helps developers understand the drug’s decomposition
characteristics in simulated biological systems, and provides clues regarding
appropriate delivery vehicles.
Understanding these factors through solid state analytical tools is a proven
strategy. Catalent employs microscopy and x-ray powder diffraction to
characterize a drug particle’s morphology and crystallinity. Calorimetry
measures melting onset and heat of fusion, which provide indications of
thermal stability and the overall quality of the solid state dosage form.
Absorption provides information on the hygroscopicity.
Drug discovery focuses primarily on activity in specific assays and often
selects only one molecule from related structures to move forward. Since
discovery may have identified several candidates with comparable activity, the
process for evaluating the developability of candidate drug is far easier if the
delivery platform is known in advance. But without concrete developability
assessments, candidates may be selected by activity alone. Therefore, early
analytical data could help guide discovery strategies toward candidates with
an appropriate balance of activity, solubility, permeability and stability.
OptiForm® Solution Suite
Catalent’s OptiForm® Solution Suite is a newly launched formulation
screeninganddevelopmentservicethatidentifiesappropriateformulations
for early-phase molecules.
OptiForm® Solution Suite consists of a three-step approach:
• Assess involves understanding the molecule’s physicochemical
properties with an eye towards formulation. During this stage
Catalent employs the solubility limited absorbable dose
(SLAD) model and in silico DCS classification to create an early
formulation screening protocol for evaluating technologies that
overcome the molecule’s limitations.
• Enhance applies parallel screening of appropriate delivery
technologies depending on the molecule’s DCS category and any
other considerations evolving from the data or from a customer’s
preferred strategy.
• Deliver provides vials of material to be used in an animal pK
study and recommends a path to first-in-man studies to provide
exposure and dose escalation.
Figure 1.
11

Catalent’s Optiform® Solutions Suite received
the prestigious “Editor’s Choice” award at the
2016 Interphex Conference.
Parallel Drug Development
Due to their physicochemical liabilities, many
molecules enter Phase I studies with little
knowledge of their solubility, resulting in a sub-
optimal formulation and poor bioavailability.
Large pharmaceutical companies are equipped
to conduct parallel formulation screening. But
resources such as automated liquid handling,
solidmetering,automationexpertise,androbotics
software programming lie outside the capabilities
of small or even average-sized drug sponsors.
Moreover, study material is often scarce during
early development. Without sophisticated
screening resources, companies are limited
in the number and types of tests that are
practically available. These limitations apply to
physicochemicalanalyses,biochemicalassays,and
small animal experiments.
By accurately handling very small quantities
of a compound per test, high-throughput
screening allows drug developers to investigate
as many dosage forms and formulations as are
appropriate for a compound’s DSC category.
The deeper the formulation testing advances,
the more likely a drug will fulfill the patient-
centric goals of the development program.
This is where expertise in interpreting data and
extrapolating it to scale becomes critical by
combining miniaturization of analysis methods
without foregoing the power of experiment.
Confidence in experimental results is greater at
large scale than at smaller scale, but the beauty
of small-scale HTS is the ability to conduct many
morestudiestobroadenthedevelopmentpicture.
Developersmaynot know as accurately the results
of any one test, but they may cover a broader
design space.
In theory, parallel screening considers all
reasonable and available dosage forms, but
most sponsors have already decided on oral,
injection, topical, or inhalation delivery. Given,
say, the preference for an oral dosage form, the
next decision is how the molecule is processed
to overcome potential bioavailability issues.
Depending on the delivery vehicle, this might
entail grinding, micronizing, or nano-sizing.
Molecules in DSC categories II, III and IV may also
require solubility and/or permeation enhancers.
Catalentlaunchesapproximately160newproducts
and works on thousands of molecules each year,
approximately half of which are promoted to the
next development stage. At Catalent, HTS is a very
early piece of the development continuum that
guides decision-making on which molecules to
develop further.
Many development partners claim extensive
dosage form and delivery capabilities, but few
can carry projects through to approval. Switching
service providers entails substantial costs and
delays associated with technology transfer.
Note that some discovery companies are only
interested in “proof of principle” compounds that
they can sell or license to a larger developer. In
these instances, having conducted thorough,
preliminary development work will make the
product more attractive to potential buyers, but
cannot guarantee that the technology can be
reproduced in another facility.
Macromolecules
Developing peptide and protein drugs presents
unique challenges. Delivery of biologicals is
limited by the molecule’s degradation in the
gastrointestinal tract. Bioavailability is in many
cases too low to achieve therapeutic systemic
concentrations. Traditionally these medicines are
delivered by injection or infusion, which raises
compliance issues, particularly for biologics
requiring frequent administration.
Catalent’s OptiGel™ Bio delivery platform is based
on technologies similar to those successfully
employed for marketed large-molecule drugs. By
overcoming adverse stability and permeability,
OptiGelBioenablesoraldeliveryofsomepeptides
and proteins. It prevents gastric proteolysis of
API and provides targeted delivery through
enteric coating while improving permeability of
high molecular weight compounds. Additional
modifications can improve API absorption in
the small intestine, while permeation enhancers
improve transport through the tight junctions of
the lumen.
Catalent has devised preformulation and
formulation screening protocols for determining
the suitability of peptides and proteins for OptiGel
Bio formulation. When successfully applied,
OptiGel Bio transforms macromolecules unsuited
to oral delivery into self-administered drug
products with improved compliance.
In addition to OptiGel, Catalent offers Zydis®,
a unique, freeze-dried oral solid dosage form
that disperses instantly in the mouth. Zydis
tablets can enhance pharmacokinetics through
pre-gastric absorption. It can also improve
patients compliance due to its quick dissolving
properties and elimination of the need for water
for drug delivery.
To help users evaluate Zydis tablets for their
products,Catalentofferssolubilityassessmentand
prototype screening services.
Conclusion
Pharmaceutical development is costly, lengthy,
and fraught with uncertainty. The sheer number
andbreadthofcompetenciesinvolvedliesbeyond
the capability of many drug sponsors. Molecules
falling into the DSC quadrant II, particularly IIb,
present persistent challenges for formulation and,
eventually, for drug delivery. When conducted
early on, developability assessments can pay
rich dividends by promoting “fast to human, fast
to fail.” Similarly, formulation testing to improve
bioavailability of poorly soluble/permeable
molecules can guide every facet of mid- to
late-stage development by providing close
approximations of what would be expected to be
the final, approved drug product. Together, these
activities comprise a structured, rational approach
based on proven, industry leading expertise in
solving complex bioavailability challenges.
Since the components of best-in-class early
development fall outside the expertise of many
small to mid-sized companies, sponsors should
consider a development partner whose success
depends on their success, and which can take
a project from the discovery stage through
commercialization.
References
1. Tufts Center for the Study of Drug Development.
Briefing delivered Nov. 18, 2014. Accessed at
http://csdd.tufts.edu/files/uploads/Tufts_
CSDD_briefing_on_RD_cost_study_-_Nov_
18,_2014..pdf
2. Finding optimal form. The Medicine Maker. Accessed at:
http://bit.ly/1U2CQpF.
3. Mullin R. Costs to develop new pharmaceutical drug
now exceeds $2.5 billion. Chemical & Engineering News,
November24,2014.Accessedat:http://bit.ly/1U2zfrx.
4. Bioavailability and solubility: a demand for enhanced
technologies & materials is spurring innovation.
Drug Development & Delivery. Accessed at: http://bit.
ly/1U2BxXI.
5. U.S.FoodandDrugAdministration.Thebiopharmaceutics
classification system (BCS) guidance. Accessed at:
http://1.usa.gov/1U2yxL5.
6. Tufts Center for the Study of Drug Development.
Briefing delivered Nov. 18, 2014. Accessed at:
http://csdd.tufts.edu/files/uploads/Tufts_
CSDD_briefing_on_RD_cost_study_-_Nov_
18,_2014..pdf
7. J.Butler.Theoptimaluseofbiorelevantmediaandsample
modeling.ControlledReleaseSociety,2008,NewYork.
8. Presentation: The optimal use of biorelevant media
and simple modeling for the prediction of in-vivo oral
behavior. James Butler, GlaxoSmithKline. Accessed at
http://www.apsgb.co.uk/Events/PastEvents/20110609/
James%20Butler.pdf.
12

14
Patient-Centric Drug Design:
A Clinical & Academic Perspective
Towards a Renaissance of Pediatric Pharmaceutical Development
Successful drug delivery to pediatric patients depends on overcoming basic differences between
children and adults. Pharmacokinetic and pharmacodynamic differences can make developing drugs
very challenging for young patients. One can think of pediatric medicines as one of the last uncharted
frontiers in patient-centric drug development.
Oral dosage forms, the preferred administration route, may not always be palatable or available in
doses appropriate for children. Thus pills and tablets are often manipulated in ways that are not ideal
for delivering safe, effective, and consistent doses. Compounding pharmacies can help but their
results are not always reproducible. Parents often resort to dividing doses, crushing and dissolving
them in liquids, and administering drugs in quantities that have not been adequately tested.
Alternative delivery vehicles are similarly problematic. Rectal dosage forms provide consistent dosing
but are not patient-friendly. Younger children in particular have problems with nebulization masks
that do not fit their face properly or cause them distress. Achieving reliably metered therapeutic
dosages is complicated when small gaps exist between the mask and the patient’s face.1
Most issues in pediatric drug development arise from the fact that drugs are traditionally developed
for adults and not children. However, many improvements in pediatric drug development have
occurred during the last 15 years.
Development-Stage Incentives
Several regulatory changes have resulted in the recent development of close to 600 drugs supported
by new pediatric studies. Relevant laws include:
• Best Pharmaceuticals for Children Act (BCPA). The 2002 law established a program for
pediatric drug development, provided mechanisms for studying on- and off-patent drugs in
children, and offered an additional 6 months of exclusivity for on-patent pediatric drugs.
• Pediatric Research Equity Act (PREA). Passed in 2003, PREA requires sponsors to test new
drugs in children under certain circumstances. Testing must occur with the same drug and
for the same indication for which the drug was approved in adults.
BCPA and PREA have a sound scientific basis. The occurrence of suicidal thoughts in children taking
the antidepressant Paxil® was not uncovered until FDA ordered sponsor GlaxoSmithKline to conduct
pediatric studies. The result was an FDA warning, in 2008, for prescribers to consider the risks of
prescribing Paxil to patients younger than 18.
Before BCPA and PREA were enacted, as many as 80 percent of drugs prescribed to children were
untested in that patient population. By 2008 between 50 and 60 percent of such medications had
been studied at some level in children. Nevertheless, children have been described as the “orphans”
of drug development.2
A bioavailability classification system (BCS) is not yet available for classifying the suitability of
biopharmaceuticals for pediatric administration. However, preliminary investigations suggest that
such a system may be available within a few years.3
DRUG DESIGN
Rachel Meyers, Pharm.D, BCPS, BCPPS is the
clinical associate professor at Ernest Mario
School of Pharmacy, Rutgers, NJ. Dr. Myers
specializes in pediatrics and pediatric critical
care. She is a member of several professional
organizations including the American
Pharmacists Association, the American
Association of Colleges of Pharmacy, the
American College of Clinical Pharmacy, and
the New Jersey Pharmacists Association. Dr.
Meyers is a member of the Pediatric Pharmacy
Advocacy Group, and serves as the chair for
the local chapter, the Garden State Pediatric
Pharmacy Advocacy Group.

Delivery Hurdles
Many shortcomings of pediatric-administered medicines arise from less-
than-perfect dosage forms and delivery mechanisms. Improvements in
these areas could be achieved with minimal regulatory risk.
Unpleasant taste is a perennial issue for many drugs administered to chil-
dren. Clindamycin, an antibiotic for treating Gram positive and anaerobic
infections, has a particularly bitter taste and unpleasant smell. Dosing is fre-
quent and of long duration. Moreover the drug is available only as a dilute
suspension requiring large administration volumes, which for young pa-
tients amplifies its negatives and complicates administration of therapeutic
doses. Other antibiotics routinely administered to pediatric patients have
similar issues.
Sabril® (vigabatrin; Lundbeck LLC), which is prescribed for infantile
seizures, is a classic case of a drug that has not been ideally formulated for
its intended patient population. Sabril is available as a 500 mg tablet or a
500 mg packet. The tablet is too large for very young children to swallow.
Parents must suspend the packet contents in relatively large volumes of
water, which introduces issues previously mentioned. It also requires
caregivers to perform a multi-step process in order to mix and measure the
prescribed dose. 4
Infant acetaminophen, available in several liquid formulations, comes with
no directions for parents. While a dosing syringe is provided, there is no
indicated dose for the age-group for which this product is intended.
Otherimportantmedicationscommonlyprescribedforchildrenalsorequire
liquid compounding. These include Lamotrigine, Topiramate, Tacrolimus,
Metronidazole, Lansoprazole, Spironolactone, and many others. As always,
compounding carries inherent risks in preparation and administration such
as inadequate shaking and errors in calculations and measurements.
Measuring volumes of liquid pediatric medicines is critical for delivery of
safe, effective doses.5
Available metering devices include cups, syringes,
droppers, and vials, and the ubiquitous teaspoon. Only 12.8% of pediatric
oral prescription liquid products come with measuring devices, and
pharmacists only occasionally provide them. Even when available, the
devices’inherent inconsistencies can result in under- or over-dosing.6
Improvement on the Way?
Thanks to regulatory and market incentives, more drug developers than
ever are tapping into the potentially lucrative and medical need-fulfilling
pediatric drug market.
The Michigan Pediatric Safety Collaboration was founded to address the
lack of standardization for oral compounded liquid pediatric medicines.
The state-wide, FDA-funded pilot program maintains a database of more
than 100 recipes for pharmacies to refer to, ensuring consistency in
compounded formulations in the state.
Drug developers are doing their part as well. The benzodiazepine
Midazolam, for example, was approved as a rectal formulation in 1997 but
presented the usual problems.The drug is administered to children who are
experiencing seizures. An intranasal form of Midazolam, delivered through
an atomization mister, was found to be as effective as the rectal dose and
much easier to administer, however a commercially available product is
still needed.
For drugs most suitable for administration by tablet or capsule, orally
disintegrating tablets have shown benefit. Lansoprazole, prednisolone,
and ondansetron are now available in this format, providing an attractive
alternative dosage form for these pediatric-relevant products.
Conclusion
Even with dedicated development programs, pediatric drugs present
numerous obstacles. Pharmacokinetic and pharmacodynamic studies
performed within ideal clinical settings may not reflect real-world results.
Additionally,dosageformanddeliveryplatformsrequirecloseconsideration
in children. Industry and regulators recognize these facts, and are working
harder than ever to introduce safer, more effective pediatric medicines to
address specific patient-centric issues.
References
1. LinH.etal.RespiratoryCare.2007;52(8)1021-26.
2. GrantB.Arethekidsalright?TheScientist,March2012.
3. Shawana R. Pediatric biopharmaceutical classification system: using age-appropriate initial
gastricvolume.AAPSJ.2016May;18(3):728-36.
4. HowtogiveSabriltoyourbaby.Accessedat:http://sabril.net/infants/giving_sabril/
5. SobhaniPetal.AnnPharmacother.2008;42:46-52.
6. Johnson A, Meyers R. Evaluation of measuring devices packaged with prescription oral liquid
medications.JPediatrPharmacolTher.2016Jan-Feb;21(1):75–80.
7. Holsti M et al. Intranasal midazolam vs rectal diazepam for the home treatment of
acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med. 2010
Aug;164(8):747-53.
DRUG DESIGN
15

case study
Zydis‰
Fast Dissolve
Technologies - Effective Dose
Forms for Pediatric Health
The Patient Compliance Challenge
Patient compliance with medication is a complex problem and can be especially
challenging for pediatric populations. In fact, compliance rates in children are as low
as 11%, with formulation and palatability shown to be major contributing factors.1
Zydis‰
fast dissolve formulations are an effective solution through extremely
rapid dispersion in the mouth and the smooth, pleasant taste. Patient acceptance
of Zydis‰
formulations is especially high in pediatric populations, demonstrated
by 50% of medications currently formulated in Zydis‰
Orally Disintegrating
Tablets (ODT) being specifically indicated for use with children.
ODT Formulations Reduce Overall Cost of Care2
Vomiting limits the success of oral rehydration in children with gastroenteritis,
which may necessitate intravenous rehydration and extended hospital stays.
A patient tailored ODT formulation of the effective antiemetic Ondansetron
was developed to be taken without water. In an independent study, this
was found to quickly reduce vomiting, allowing more successful oral
rehydration in children and significantly improving patient outcomes:
· Less vomiting, increased oral hydration, reduced need for intravenous rehydration
· Economic value assessed through cost savings from reduced length of hospital stay
“The tablet is easy to administer, has few side effects, and is safe and effective.”2
Study Outcome Measure ODT Anti-emetic
No. (%)
ODT Placebo
No. (%)
P Value
Patients with Zero vomiting episodes 92 (86) 70 (65) <0.001
Vomited during oral rehydration 15 (14) 37 (35) <0.001
Patients requiring intravenous rehydration 15 (14) 33 (31) 0.003
table 1: outcome measures of single odt dose of ondansetron versus placebo2

ODT Formulation Improve Therapeutic Outcomes3
Primary nocturnal enuresis (bed-wetting) is a prevalent childhood condition and
a distressing problem that affects up to 10% of 7 year old children and 3% of
adolescents, where symptoms can persist through to adulthood. Desmopressin is an
effective treatment, but compliance in pediatric populations can be a challenge.
Transition to Fast Dissolve Formulation
Increases Patient Response
An independent study showed: “that the probability of having a reduction in
bed-wetting episodes is increased by a factor of two for patients
receiving Desmopressin ODT compared to Desmopressin tablet.”3
“Given the huge impact on self-esteem, quality of sleep, performance at school
and social and familial life, prompt and successful treatment is mandatory.”3
Zydis‰
Formulations Improve Outcomes for
Pediatric Patients and Healthcare Providers
Zydis‰
fast dissolve formulations are an excellent solutions for improving
pediatric medication and are proven to enhance product performance and
patient outcomes. In a recent United States FDA Advisory Committee, the
superior dispersion speed of a sub-lingual Zydis‰
formulation was deemed
especially suitable for children due to ease of administration.4
1. Assessing the palatability of medications in children; Matsui D; PPDT, 2007:8 (2)
2. Oral Ondansetron for Gastroenteritis in a Paediatric emergency Department; Freedman et al; New Engl J Med 354; 16 2006
3. Desmopressin melt improves response and compliance compared with tablet in treatment of primary
monosymptomatic nocturnal enuresis, Juul et al, Eur J Paediatr (2013) 172:1235-1242
4. 26th
Meeting of The Allergenic Products Advisory Committee, December 12,
2013. Meeting transcripts accessed March 2014 www.fda.gov
˝ 2016 Catalent Pharma Solutions. All Rights Reserved. mrt/zydisped/cs (07/16)
Outcome Period 1 (2 weeks)
Solid Oral Dose
Period 2 (2 weeks) ODT
Full Responder 3 23
Responder 2 0
Partial Responder 17 14
Non Responders 84 66
table 2: reduced bed-wetting episodes when treated with odt
formulation versus standard desmopressin
®
more products.
better treatments.
Discover more solutions at www.catalent.com/zydis
us + 1 888 SOLUTION (765-8846)
eu + 800 88 55 6178

18
Faster to Market: Strategic
Approaches in Manufacturing
and Clinical Supply
The path to successfully launch a therapy to market requires more than an innovative approach
for drug discovery and development. With the changing landscape of the industry, a continuously
evolving manufacturing strategy and ensuring the patients’ needs are met during clinical trials and
beyond have become vital. This article explores key trends and strategies in manufacturing and
clinical trial studies, which can pave the way for faster launches of therapies to the market.
Key Considerations for Scale-Up Strategy
This section is based on an interview with Matthew Mollan, RPh, PhD. Matt is an industry veteran and is
expert in advanced drug delivery and manufacturing technologies. He is currently the General Manager,
Development and Analytical Solutions; Advanced Delivery Technologies at Catalent Pharma Solutions.
One of the overriding and increasing trends that has occurred in the last seven years is the number
of clinical trial programs going forward with a narrower and more focused indication for approval.
This trend allows new and often life-saving products to be launched into the market faster and has
contributed to a fairly dramatic increase in the number of products approved by the FDA; 45 approvals
in 2015 versus 24 approvals in 2008. Another trend is the shift away from the classical “blockbuster”
strategy which required very large Phase III trials with the goal of covering multiple indications and
the potential to very quickly develop products with over $1 billion in sales and hundreds of millions
of dosage forms after approval. The trend to increase the chances of approval has shifted to target
a narrow indication to help the drug get to market as quickly as possible and then continue with
post-approval clinical trials to expand the drug’s indications. This often results in the product being
re-launched every year or two, with a new indication or expansion of an indication to increase the
product’s market penetration and the patient population it is approved to treat.
The net effect of this strategy is that today, scale-up is seen as a continuum that will be driven by
additional indications and market share rather than by a singular event occurring during a very late
stage of the approval process. This fundamental shift now affects how scale-up is considered, with
the assumption that scale-up may occur a few times during a product’s lifecycle.
As a result of this strategy, the currently trending scale-up step percentage is quite smaller than
that traditionally seen (i.e., a 2x scale-up vs a traditional 10x scale-up). It was common in the 1990’s
and 2000’s that companies would launch products at a 1000 -1500 kilograms batch size. Today, you
see many companies with plans to launch products that have batch sizes of 200 to 600 kilograms.
This reduction in quantity reduces the need to increase production capacity to facilitate scale-
up from Phase III clinical batch sizes to commercial scale. Companies are focused on minimizing
risks due to scale-up and are proceeding as quickly as possible by keeping a similar batch size as
the historical data supports, and then viewing scale-up as something that will occur in multiple
iterations post-approval.
At Catalent, we have an NPI (New Product Introduction) Process. It is a stage-gate program that
looks at the different types of issues that a client should be concerned about as their product moves
through clinical trial stages, validation, and eventually into commercialization. The NPI process gates
are a series of defined steps during which we assess all of the information known by the client as
MANUFACTURING AND CLINICAL SUPPLY
Matthew Mollan, RPh, PhD is the General
Manager, Development and Analytical
Solutions for advanced delivery technologies
at Catalent Pharma Solutions. He is an industry
veteran and an expert in advanced drug
delivery and manufacturing technologies.
Esther Sadler-Williams, M.Sc. MRPharmS is
the Global Director, Strategic Development
and Innovation at Catalent Pharma Solution.
She is the lead author for the ISPE’s guidance
document on NIMPs and delivery of IMP’s
direct to patients’ homes.

well as our own findings and collate it so we understand where there are
gaps. It involves working collaboratively with our client to develop a plan
to address the gaps during scale-up activities.
One concept that has not changed, even with Fast Track programs,
is the expectation from regulators to implement a Quality by Design
(QbD) approach as well as to understand the Critical Quality Attributes
(CQA) and Critical Process Parameters (CPP). It is essential to consider
regulatory requirements for a product that will be globally distributed,
and ICH guidelines are useful, in addition to FDA and EMA guidance, for
scale up considerations.
A methodology to help minimize risks for scale-up is to focus on
technologies that work in a continuous manner, such as roller compaction
technology. One positive attribute about using continuous technology for
as many unit operations as possible is that the batch size at each step is
determined by time (i.e., 30 minutes makes 100 Kg, so 90 minutes makes
300 Kg), thus minimizing scale-up risk. Another consideration for scale-
up is focusing efforts on using very similar, if not the same, equipment
manufacturers to eliminate small differences between manufacturing
equipment vendors that potentially add unknown risk to the scale-up. The
final key focus for scale-up of a drug product is that it should ideally occur
after scale-up of an API is completed. This will ensure that any changes to
the characteristics of the API during its scale-up do not impact the validity
of the scale up of the drug product.
Meeting Patients’Needs in Clinical Studies
This section is based on an interview with Esther Sadler-Williams, M.Sc.
MRPharmS. She is the lead author for the ISPE’s guidance document on NIMPs
and Delivery of IMP’s Direct to Patients’ Homes. Esther is currently the Global
Director, Strategic Development and Innovation at Catalent Pharma Solution.
Patient-centricity is certainly a buzz word in the industry. We are very aware
that in clinical trials, there is a lot of interest in ensuring that the trial meets
patients’needs.The real problem that the industry is experiencing in clinical
research is a reduction in patient recruitment. Most importantly, patient
retention rates in clinical trials are dropping with some reported figures as
low as 23%. Thus, the problem is getting the patient into the clinical trial
and keeping them there. If that patient is lost, the cost could be upwards of
$40,000 to replace that patient. However, a more serious consequence may
be that it could be difficult to complete the clinical trial on schedule, which
can impact getting innovative products to market on time. Ethically, we all
want to design a clinical supply chain that meets the patient’s needs and
improves the likelihood that the patient remains in the study.
Although at Catalent we support our clients in delivering the complete
clinical supply chain, we felt that we had a role to play to ensure, along
with our sponsors, that the clinical trial supplies are patient and clinical site
‘friendly’. This led to the initiation of our Patient- and Site-centric program.
Thefirstthingwedidwastoholdinternalbriefingsessionsonthechallenges
faced by clinical sites and patients with clinical supply medication. Then we
established a global patient-centric team involving individuals across the
world from all aspects of our business. For example, we included individuals
who design the labels and the packaging as well as those who write the
batch records or ship the clinical supplies to the hospital. Thus, across our
eight sites, we have a lot of representatives to identify the actions we need
to take to provide harmonized, global guidance to our sites as well as to
our clients.
We then wanted each of our eight Catalent Clinical Supply Services (CSS)
sites to understand firsthand the challenges experienced by their local
clinical sites in managing clinical trials so we established relationships with
various clinical trial sites around the world. Our teams can then visit the
clinical site and, in return, the clinical trial pharmacists can appreciate the
processes involved in manufacturing clinical supplies through visiting our
facilities. This creates opportunities where we can exchange views on how
we can improve packaging design and hone our processes associated with
the clinical supply chain.
Based on the feedback from patients and pharmacists, as a team we have
decided to focus, initially, on key parameters to improve label layout for
patients and clinical sites as well as supporting the clinical sites by letting
them know the status of the product being shipped to them.
Enhancing patient safety is the most important aspect of the patient and
site centricity program. As part of this program, based on our observations
at clinical sites, we have just launched a new label format that we call the
Peel-ID™ label. This label provides the site with an integral peel off section
repeating the key numerical kit identification information - information
that can then be affixed to any surface of the kit providing the hospital
pharmacy with options in storage of the material. This means the clinical
site does not have to handwrite the kit identification number on another
face of a box if they want to store the kit in another orientation, a practice
which is quite common and can result in transcription errors. This Peel-ID™
label helps to ensure that the right kit gets to the right patient.
Another aspect to be considered in a patient-centric program is the dose
form itself. What our sponsors are looking for is a means to ensure that
the medication is something that can be managed by the patient. If the
patients are provided with a capsule that is too large to swallow easily,
then they may not be able to comply with the clinical trial. Similarly if the
product tastes terrible, then there is a risk that the patients are not going to
continue with the clinical trial. To that end, we have been working with one
of our clients who wanted us to support them in the design of a survey that
they could use with patients just before they started their Phase II programs.
The goal was to ensure that the design of the dosage form itself, and how
it is packaged for the subsequent clinical phases, enhances the ability of
the patients to comply. This included exploring packaging concepts that
supported dosing compliance. As an example, some patients really like
blister cards which can be pre-printed with days of the week or calendar
dates whereas if medication is presented in bottles, these may not be as
easy for the patient to remember when they need to take their medication.
To summarize some of the conclusions drawn from our patient and site
centricity program, it is important that the information supplied and the
design of the clinical medication (kit) supports the ability of the patient
to comply with the dosing schedule of the clinical trial protocol. If we can
make our supply chain more patient- and site-centric, then sponsors are
more likely to recruit and retain those patients and the clinical site might be
more willing to participate in the study in the first place.
MANUFACTURING AND CLINICAL SUPPLY
19

technical note
Optimizing Small Batch Size To
Solve Formulation Challenges
Executive Summary
It is common to have a limited amount of API in the early phase of drug development,
which impedes the rapid progression of drug development. Catalent has developed
a new approach that enables the use of industrial scale machines from the very
beginning and can result in manufacturing cGMP batches with good yields.
The Challenges
Currently, use of a minimal amount of API poses major challenges in developing
a formulation. If lab scale equipment is used during development, it leads to
• A required subsequent scale-up of the manufacturing step
which is an expensive and time-consuming process
• Resulting drug products potentially not being suitable for regulatory or clinical
trials as most of the lab scale equipment does not reside in cGMP facilities
If current manufacturing practices are followed to handle small batches of API on
industrial size machines, it results in handling difficulties and lower product yield.
The Catalent Solution
Catalent optimized the small batch size manufacturing
process on industrial machines, which resulted in
• Manufacturing under cGMP conditions
• Higher yields ranging from 83.6 % to 96.6 %
• Faster development by setting Quality Process Parameters
from the beginning of the project
• Flexibility to accommodate a wide range of capsule shapes and sizes
As a case study, a brand new tooling developed by Catalent was used with specific dies
and wedges. Three capsule sizes were selected to evaluate the adapted process and
equipment (Table 1, Row 1). Three formulations were tested to evaluate the impact of
this parameter on the yield of the batch produced (Table 1, column 1). Three batches
were manufactured, one per size. Each batch was divided in fractions, 2 fractions per
rp scherer softgel

formulation and the yield of each batch was evaluated. Before the first trial, a pre-setting
of the machine was performed. The duplicates were performed in a single campaign,
and a machine setting was done for each fraction. Like all production, in-process control
was performed during manufacturing to control the quality of the produced capsules.
Product losses were quantified during each step of manufacturing (Table 2), and it
was identified that product losses were mainly due to the machine set-up and could
be minimized. The product loss values were used to calculate the global reconciliation
of the fractions (Table 1). With the special tooling and setting developed, the yields
were over 80% in all cases, compared with 20%-30% for conventional equipment.
The formulation has no impact on the results since no specific trends were identified.
Conclusion
The new approach enables the formulation development of a drug molecule
in softgels on industrial scale machines, with as little as 500ml of fill
material. Catalent’s approach to modify the process parameters, equipment,
and tooling fabrication has resulted in high quality output for cGMP
processes, and optimized the yield of small batch size production.
˝ Copyright 2015 Catalent Pharma Solutions, Inc. All rights reserved. ot/sg/tn3 (10/15)
more products.
better treatments.
Discover more solutions at www.catalent.com
global + 1 888 SOLUTION (765-8846)
eu + 800 88 55 6178
formulation type capsule format (fill weight)
2 oval
(100mg)
7.5 oval
(400mg)
20 Oblong
(1000mg)
Medium chain triglycerides (Hydrophobic) 90.6% 96.6% 93.3%
Semi-solid lipophilic system (Hydrophobic) 93.9% 87.0% 83.6%
Macrogol 400 (Hydrophilic) 88.4% 91.9% 94.4%
step fraction
Medium chain
triglycerides
(Hydrophobic)
Semi-solid
lipophilic system
(Hydrophobic)
Macrogol 400
(Hydrophilic)
1 (%) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%)
Transfer in hopper 1.1 0.4 0.0 0.0 1.4 1.8
Machine set-up 2.9 1.5 2.3 1.3 1.9 3.2
Encapsulation IPCs 0.4 0.2 0.2 0.2 0.3 0.3
Drying IPCs 0.1 0.1 0.1 0.1 0.1 0.1
Inspection step 0.4 0.0 0.0 0.0 0.0 0.1
Packaging step 0.0 0.0 0.0 0.0 0.0 0.0
Total Measurable Losses 4.9 2.2 2.6 1.6 3.7 5.5
table 1 Mean yield obtained from encapsulation of 500g and 1000g fill mix batches
using different formulation types and softgel capsule sizes and formats
table 2 Identification and quantification of measurable losses performed on one batch
global reconciliation Global reconciliation (%) = [Quantity of packaged capsules + product losses (capsules)]/
[Theoretical batch size (quantity of capsules)] x100

The Path to Create Optimal
Dosage Forms
Optimizing pharmaceutical formulations offers numerous benefits that help differentiate products
by delivery route, dosage form, improvements in safety and efficacy, and most importantly, to
meet patient needs. Thus the “patient voice” becomes a value driver during the early-stages of
formulation development rather than an after-thought in late-stage formulation development.
There are many factors and options to consider during early drug formulation and dosage form
development. A scientifically based approach which focuses on the drug’s ability to treat diseases
through enhancements in bioavailability and to better address patient-specific needs such as ease
of administration, food effects, and less frequent dosing, is the ultimate goal for a patient-centric
approach to formulation development. Fortunately, there are many products, technologies, and
insights available to make the drug development journey a more cost-effective and efficient
process.
Even with the advanced technologies available today for drug development there are still
challenges to be overcome. Drugs with poor solubility, or poor permeability, or both, leading to
poor bioavailability can be developed into effective medicines for large and diverse populations,
and enhance patient compliance. There are multiple formulation strategies employed during
the drug development process based on the target product profile (disease state, physiology,
route of administration, etc.) and properties of the drug. Currently three of the most widely used
strategies for improving dosage forms are particle size reduction, amorphous solid dispersion,
and lipid based technologies.
Particle Size Reduction is a technology used for small molecule drugs in various types of dosage
forms. It’s beneficial in improving an API (active pharmaceutical ingredient) content uniformity
for commercial tablet manufacturing, suspension stability and/or texture of oral, topical, or
ocular formulations, and is still a conventional technology for enhancing the oral and pulmonary
bioavailability of small molecules. Hot Melt Extrusion (HME) is another technology that is proving
to be very valuable to the pharmaceutical industry due to its ability to generate physically stable
and processable solid dispersions of amorphous APIs. Relative to crystalline APIs, amorphous
solid dispersions improve bioavailability in more than 80 percent of cases where it is employed.
HME processing systems disperse APIs in the polymer matrix at the molecular level to form solid
dispersions or solid solutions.
Lipid-based formulation technologies can be employed to solve complex formulation and
development challenges, including improvement of solubility, permeability, or both to enhance
bioavailability. Each of these enabling technologies can be employed to improve the bioavailability
of many poorly soluble drugs, and in the case of lipid-based formulations, poorly permeable drugs
as well. Advancing these challenging drugs through development to the market is critical to
provide options for patients with unmet medical needs to have their illnesses treated.
The Drug Classification System (DCS) provides insight into appropriate early development
technologies that may be employed to overcome PK (pharmacokinetic) issues in enhancing drug
solubility, adsorption, and permeability in the gastrointestinal tract. For example, DCS I molecules
are typically presented as conventional solid dosage forms. Molecules in categories DCS IIa may
be formulated with micronized or nanosized active pharmaceutical ingredients (APIs). Molecules
in the DCS IIb category require lipid-based formulations or amorphous solid dispersions as
solubility-enhancing technologies, sometimes along with particle size reduction for those cases
where the API is dispersed (or suspended) as solid particulates in a lipid-based suspension or
solid dispersion HME, for effective formulation development of a poorly soluble drug.
OPTIMAL DOSAGE FORMS
Elanor Pinto-Cocozza, PhD, Technical
Specialist, Science & Technology, Catalent
Pharma Solutions has over 7 years of scientific
and technical expertise in preformulation
and formulation development in controlled
release, solubilization, and immediate
release technologies for oral, parenteral, and
immediate release drug delivery. She is an
active member of AAPS and was the 2015 Chair
for the Modified Release Focus Group.
Jeffrey E. Browne, PhD, Director,
Science & Technology, Catalent Pharma
Solutions has extensive expertise in in
pharmaceutical manufacturing & technical
services, as well as drug delivery R&D, with
a focus on topical, transdermal, inhalation,
and oral liquid dosage forms. He is an active
member of AAPS and has served on several
focus group committees and frequently presents
at regional and national AAPS meetings.
Sampada B Upadhye, PhD, is the technology
platform leader for bioavailability
enhancement & OptiMelt™ at Catalent Pharma
Solutions. She has extensive experience
in the area of solubilization of pre-clinical
NCEs, formulation design of amorphous solid
dispersion technologies of hot melt extrusion
as well as spray drying. Her research expertise
include formulation design and process
development of extruded formulations with
twin screw technology.
22

Most APIs (70%) in current development fall into DCS quadrant II1
, with
poor solubility but acceptable permeability. Quadrant II may be further
subdivided into categories for which molecules are either dissolution rate-
limited in the gastrointestinal tract (classification IA) or solubility-limited
(IIB), as delineated by the Solubility-Limited Absorbable Dose Rule.
The DCS groups drugs in these categories:
Class I - high permeability, high solubility
These compounds are well absorbed and their absorption rate is usually
higher than excretion.
Class II - high permeability, low solubility
The bioavailability of these products is limited by their solvation rate. A
correlation between the in vivo bioavailability and the in vitro solvation can
be found.
Class III - low permeability, high solubility
The absorption is limited by the permeation rate but the drug is solvated
very quickly.
Class IV - low permeability, low solubility
Those compounds have a poor bioavailability. Usually they are not well
absorbed over the intestinal mucosa and a high variability is expected.
Particle Size Reduction: A Straight-forward
Solution for Oral Bioavailability Enhancement
For molecules falling under the DCS IIA classification, the dose is expected
to dissolve completely during the ~3 hour transit through the small
intestine provided the drug particle size is less than the calculated target
particle size based on the Drug Classification System.
Particle size reduction works by increasing the surface area of the drug
that is exposed to fluids in the gastrointestinal tract, thereby increasing
the dissolution rate of the drug. Drugs that dissolve rapidly are naturally
more quickly absorbed. However particle size reduction does not affect a
drug’s intrinsic solubility. Numerous drugs’ oral bioavailability have been
improved by micronizing or wet-milling (nanosizing). These include DCS
category IIa drugs (nitrendipine, carvedilol), and category IIb drugs that lay
close to the Solubility-Limited Absorbable Dose Rule line.
In looking at the patient-centric approach to formulation development,
the particle size of the drug is critical when understanding the effect of
food consumption on bioavailability of the drug compound. Danocrine,
which treats pelvic pain and infertility in women, shows a six-fold food
effect (fed vs. fasting), which was eliminated by formulating the drug
as a nanocrystalline suspension.1
Drugs in the DSC IIa classification,
with poor solubility but adequate permeability, tend to have a higher
AUC and Cmax when administered with food. The positive impact of
nanoparticle formulations is believed to arise due to increased contact
area between nanosized drug particles and biological membranes.2
By reducing food effects, nanosizing also enhances dose tolerance,
compliance, safety and efficacy.3
Tricor® from Abbvie Inc. is an example of a drug for which particle size
engineering provided differentiation and follow-on approvals. Tricor-1,
a non-micronized product approved in 2001 for lowering triglycerides,
had a substantial food effect. This was followed by FDA approval in 2003
of Tricor-2, a micronized, lower-dose formulation also with a food effect,
for the broader indication of lowering low-density lipoprotein. The third
iteration of this drug, the nanomilled Tricor-3 approved in 2004, did not
show a food effect.
Lipid-based Formulation Encapsulated in
Soft Capsules: An Oral Delivery Option for
Enhanced Bioavailability
Softgels are an ideal option to deliver lipid-based formulations developed
for improving bioavailability and better patient compliance. Through the
use of material sparing techniques, feasibility studies can be performed to
develop prototype lipid fill formulations when API quantities are scarce.
Laboratory-scale encapsulation of these fills provides small batches of soft
capsules that can be used for in-vitro testing as well as in-vivo animal PK
studies. Lipid-based formulations in soft capsules are readily scalable from
laboratory-scale to pilot-scale to production-scale thereby allowing for
reduction in overall product development cycle times.4
One of the fastest-
growing segments of the pharmaceutical industry is the development
highly potent drug products.5
Unlike tablets that involve powder-
generating production steps, lipid-based formulations which are liquid
or semisolid in nature, followed by their encapsulation in soft capsules,
do not present issues such as dust generation, and as a result the risks
of employee exposure and product cross-contamination are minimized.
Lipid formulations in soft capsules are often the delivery option of choice
for high-potency APIs, not only for the safety and contamination concerns
mentioned previously, but for also achieving excellent dose uniformity
even for drugs dosed at microgram levels.
More recently it has been shown that lipid-based formulations and enteric
coated soft capsules enable the oral delivery of peptides and proteins, for
example through Catalent’s OptiGel™ Bio technology.
By using lipid-based formulations, whose end products of digestion serve
as permeation enhancers to open up tight junctions between cells, enteric
coated soft capsules offer an excellent means of delivering these lipid
formulations containing peptides and proteins to their site of absorption.
Importantly, this technology protects the API from degradation while
providing high local concentrations of intact API and permeation enhancer
to maximize the potential for absorption Conventional soft capsules
use gelatin as the film-forming polymer in the capsule shell, which can
successfully be used for a wide range of API’s and lipid-based formulations.
However, there are instances, where a gelatin-based soft capsule cannot be
OPTIMAL DOSAGE FORMS
23
1. Y.WuandL.Z.Benetetal.,Bull.TechniqueGattefosse99,9–16(2006).

2016. Dosage Form Optimization: Technology to Advance the Patient-Centric Drug-Development Process

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