From Molecule

to Medicine.
Delivered.
 CONTENTS
 BIOLOGIC DRUG SUBSTANCE
4 Managing Demand Uncertainty in Biologics Production
8 Is Your In-House Strategy Ready for the Uncertainties of Biologic Drug Development?

 API DRUG SUBSTANCE

11 How Can You Avoid the Fallout from Incompatibility Between Your API and its Formulation?
13 Trends and Challenges in Outsourced Oral Solid Dosage Forms: A Q&A

 FORMULATION DEVELOPMENT
15 Characterizing Drug Substance Properties Early Can Optimize Drug Product Formulation

 PHARMACEUTICAL PROCESS DEVELOPMENT
18 Avoid the Do-Over: Why Early Investment in a Scalable Manufacturing Process Is Critical
22 Solving the OOS Problem with Continuous Manufacturing

 PATHEON ONESOURCE™
25 Single-Vendor CDMOs Bring Speed and Cost Savings to the Table
28 4 Perspectives on Single-Vendor Drug Development Models
28 Bringing the Single-Vendor Approach to the Pharma Industry
29 New Resource Saves Drug Developers Time and Money
31 A Single-Vendor CDMO Eases Communication Flow
32 Smaller Biotech Companies and the Single-Source CDMO

 CLINICAL SERVICES
34 Cold-Chain Fully Automated Assembly and Labeling of Pre-Filled Syringes for Clinical Trials

 COMMERCIAL MANUFACTURING AND TECHNOLOGY TRANSFER

36 Considerations in Selecting an Outsourced Solution
38 Technology Transfers: Reaping Rewards, Reducing Risks

 CLIENT SUCCESS STORIES

41 How Pacira Pharma is Working to Help Curb the Opioid Epidemic
43 Fighting the Opioid Epidemic: How Grünenthal’s Abuse-Deterrent Technology Contributes

2 www.patheon.com ● doingbusiness@patheon.com
 From the
President

Expanding Capabilities
Ongoing evolution in the industry
We need to look no further than recent headlines to see
evidence of the exponential changes and innovations happening
today in the pharmaceutical industry. The first gene therapy
was approved in July 2017 by the U.S. Food and Drug
Administration (FDA) following the approval of other gene
therapies for rare diseases in Europe. These targeted therapies
have the potential to significantly change the industry and most
importantly improve the lives of patients. Pharmaceutical and
biotechnology companies are constantly seeking to better
understand diseases and develop better therapies to meet the
growing needs of patients around the world.
These technological advances and novel compounds are
increasingly complex, requiring specialized resources, scientific
expertise and advanced manufacturing technologies to produce.
More and more companies are forging strategic relationships
with external partners to create customized solutions and deliver
technical expertise to accelerate delivery of new therapies to
market. Strong partnerships enable pharma and biotech
companies to focus on research and commercialization. As the
industry creates these new advances and approaches to treating
diseases, so too must the contract drug development and
manufacturing companies.
global reach in clinical trials packaging, labeling, distribution and
logistics services takes clients from drug formulation to clinical
trials support to commercial production seamlessly. The
combination also benefits biotech customers with the availability
of state-of-the-art bioproduction technologies and biologics
development and production expertise to shepherd new biologic
therapies throughout the development timeline.
It is an exciting time in the life sciences industry. The Thermo Fisher
and Patheon combination is well positioned to help clients
accelerate innovation, drive productivity and deliver on our mission
to enable our clients to make the world healthier, cleaner and safer.
”From Molecule to Medicine” is a compilation of insights and
perspectives from Patheon’s scientific, manufacturing and
engineering experts. We selected articles to provide a view
across the industry — from small and emerging biopharma
starting on the drug development journey to scale-up,
technology transfer, and commercialization. I hope you find its
contents valuable.

Combining resources to deliver value, from

molecule to medicine
With Thermo Fisher Scientific’s recent acquisition of Patheon,
the company is part of an organization dedicated to making the
world a healthier place. It brings an end-to-end solution designed Michel L agarde, President
to accelerate drug development and simplify our clients’ supply
chains. Patheon’s highly complementary capabilities in drug
substance, pharmaceutical development and drug product
manufacturing combined with Thermo Fisher’s expertise and

Patheon’s highly complementary capabilities in drug substance, pharmaceutical development and drug product
manufacturing combined with Thermo Fisher’s expertise and global reach in clinical trials packaging, labeling, distribution
and logistics services takes clients from drug formulation to clinical trials support to commercial production seamlessly.

www.patheon.com ● doingbusiness@patheon.com 3

Managing
Demand
Uncertainty
in Biologics
Production
Stephen Lam John Ward
Senior Vice President, Vice President,
Head of Biologics Engineering
When a biologics company prepares to launch a new product, it
must forecast the manufacturing capacity it will need. To create
this forecast, it must factor in its estimate of the size of future
sales, the timing of the launch, the dosage of the product, its
strategy for building its market and a host of other variables. Vari-
ations in any one of those factors can lead to drastically different
demand scenarios. If a company overestimates demand, it may
end up investing in too much capacity, and therefore find itself
paying more per unit of the product than it needs to, thus impact-
ing its margins. If it underestimates demand, it risks not being
able to satisfy demand, therefore losing revenue.
Forecasting demand is a complex endeavor. For instance, it’s
not unusual for the forecasted and actual dosage of a product
to vary by a factor of as much as three. Obviously, that makes a
big difference to a demand forecast. If a manufacturer has built
capacity in anticipation of a new product and its clinical trial is
delayed (for any number of reasons), that manufacturer’s capi-
tal is tied up in a fallow facility. For a small company for which
liquidity is critical, that can be catastrophic.
Why forecasting is so hard
When planning for capacity, a manufacturer must consider both
volume and scale. Both are important, the effect of scale being
4 www.patheon.com ● doingbusiness@patheon.com
Biologic
Drug Substance
to make costs non-linear with volume. For example, say a man-
ufacturer makes a 2,000-liter subculture batch, at a cost of
about $1.5 million to $2 million (including raw materials). For a
titer of 1 gram per liter, that’s about 1.6 kilos of active pharma-
ceutical ingredient (API), with yield losses, at a cost of $1,250 a
gram. A 20,000-liter batch, which would cost $4 million, would
yield about 16 kilos of product at $250 a gram. That’s 80% less
than the 2,000-liter batch. Much more cost effective.
However, at the 20,000-liter batch size, the sponsor could end
up with too much product, some of which may expire before it
can be sold. That’s a loss. Further, the commitment to large-
scale capacity is very expensive, whether in-house or via a
contract development and manufacturing organization (CDMO).
Large-scale plants cost hundreds of millions of dollars, and
many CDMOs require long-term commitments for large scale.
On the other hand, the manufacturer could run a batch only
every few years at large scale to guard against producing too
much product. However, that might create scheduling issues
and degrade the effectiveness of the manufacturing organiza-
tion; change overs in large-scale plants can be very expensive.
The manufacturer also risks losing inventory, not just due to
product expiration, but also due to latent defects, issues that
may only become apparent after several years. Plus, one would
still need three to five validation batches, which being large,
would be expensive.
It’s in the middle — between
Of course, at a smaller scale of production, each unit costs more.
small and large scale — where
Large or small, the approach one chooses will have a ripple things get more complicated.
effect throughout the business, affecting hiring decisions, cash
flow, schedule duration, available capacity, cost of goods and
them from meeting demand, and they lose revenue. Worse, it
on and on. And the scarcity of outsourceable capacity at cer-
can lead to a permanent loss of market share to competitors
tain scales (for example, 20,000-liters) further complicates the
whose products may not be covered by their patent.
process — all of which sometimes leads companies to choose
a solution that is suboptimal. The cost per gram of your API is a good place to start planning
your capacity as it tends to be forecast-independent. It’s pri-
marily dependent on the titer, which you will know early on.
An Rx for navigating complexity
Armed with that, you can determine your cost per gram of the
It is possible though to mitigate forecasting risk so long as you API and check that it fits the projected price. If it does, your next
start the process early in the product commercialization step is to choose the manufacturing scale.
lifecycle. Here is our approach:

2. Choose the manufacturing scale

1. Determine a target cost per gram for the API
Too often, this conversation does not happen until it is too late.
Companies fearful of overproducing often launch without
enough capacity. Then, post-launch, they must scale up, and
they get caught in a long pre-approval process. That precludes
If you are a large manufacturer, you’ll generally have the option
to be in the $100 to $150 per gram band (See Exhibit 1), and
you can use capacity you already have for large-molecule pro-
duction. This will enable you to maintain a low cost and manage
your risk. For a large company with a broad product portfolio,

Client Cost ($/g)

700

600

500

400

300

200

100

0
42 105 210 315 420 525 1260 2520 3780 kg/Year
10 25 50 75 100 125 300 600 900 2000 L Batches
10 20 30 40 50 120 240 360 5000 L Batches
13 17 40 80 120 15000 L Batches

2-6 2000 L Own ($/g) 2000 L Outsource ($/g) 2 x 5000 L Own ($/g) 5000 L Outsource ($/g)

6 x 5000 L Own ($/g) 6 x 15000 L Own ($/g) 6 x 15000 L Outsource ($/g)

Exhibit 1: Scale, utilization and throughput have a significant impact on cost (based on a titer of 3g/l @ 75% yield)

www.patheon.com ● doingbusiness@patheon.com 5
 Client Cost ($MM/Yr)
1400 Need big tanks

1200

1000
Differential
800
Many options are creates
viable in the “middle” driver for
change
600

400
2000 L scale
200
very viable

0
42 105 210 315 420 525 1260 2520 3780 kg/Year
10 25 50 75 100 125 300 600 900 2000 L Batches
10 20 30 40 50 120 240 360 5000 L Batches
13 17 40 80 120 15000 L Batches

2-6 2000 L Own ($/g) 2000 L Outsource ($/g) 2 x 5000 L Own ($/g) 5000 L Outsource ($/g)

6 x 5000 L Own ($/g) 6 x 15000 L Own ($/g) 6 x 15000 L Outsource ($/g)

Exhibit 2: Total cost expended identifies driving force for change

dedicated capacity allows it to flex to accommodate demand
variations across the portfolio and to build its expertise in large-
molecule production.
For smaller production volumes, you will be on the left of the
Manufacturing Scale chart, and the cost will be about $350 per
gram if you outsource two to three 2,000-liter bioreactors.
process, or both. You can always improve the process in paral-
lel and implement the new one when it’s ready.
In Exhibit 2, the vertical gap between the lines is the financial
driver for change. For instance, at 1,000 kilos per year, that’s
about a $300 million incentive to switch from 2,000-liter out-
source to 15,000-liter outsource.

It’s in the middle, between small and large, where things get
more complicated. 3. Determine campaign size and frequency
For example, at 100 kilos per year, the cost would be about Plan the campaign to meet the expected annual demand and make
$35 million for an outsourced 2,000-liter process, versus about sure this will scale up at launch to meet peak projected sales. If the
$17 million for self-built. So, the answer could be to self-build. campaign volume is in the range, but your cost per unit is not, con-
sider how you might improve the yield. Conversely, if the volume is
Alternatively, the solution might be to develop the process to
improve the yield. That might cost say $20 million with all the too small, then consider a smaller scale for product launch, and
development work and regulatory refiling required. Improving either how to scale up post-launch or how to improve the yield.
the process often makes sense once the volume is in the range
of 20-50 batches per year. Then the lower API cost can often
pay back the initial investment within a few years while releas-
We recommend a
ing capacity for other products. Process development is often a
lot less expensive than building a plant, although the outcome
manufacturing strategy that can
is less certain. accommodate a forecast range
Or the right answer might be to outsource at first and then, if the and that you can adapt as
volume meets or exceeds expectations, look at the cost-benefit
of changing from outsourced to insourced, or of improving the better data becomes available.
6 www.patheon.com ● doingbusiness@patheon.com
4. Build flexibility into the scale
Clone Selection
One way to achieve flexibility is through multiplexing. For exam- 5 Clones
Selection based on growth, productivity, stability and product
ple, one company recently validated its process in 2,000 liters
stainless. It intends to obtain full approval for a multiplexed ar-
Process Development
rangement of six times 2,000 liters via a license variation. Parameters Studied: pH, temperature, perfusion rate, etc.

Another way to acquire flexibility is to combine solutions. For

Media Evaluation
example, you could outsource to a CDMO while working on Custom Media Optimization

improving the process or combine outsourcing with production

from your own large tanks. In fact, in the early stages, it is
Process Characterization & Scale-Up
sometimes a good idea to make capacity variable (with, for
example, several 2,000-liter tanks), and then consolidate as
forecasts become more certain. Combining multiplexing with a
Titer
future increase in downstream scale may simplify future tech-
nology transfers and regulatory strategies. By engaging in
these discussions earlier in the commercialization timeline, you
can develop multiple scenarios and test them against financial,
regulatory and commercial success factors. You can also use Clone
this time to discuss your potential strategies with regulatory Development

agencies during the clinical development process. Media

Scale-Up

5. Improve the yield

There are various new ways to improve API yield. One client
asked Patheon to conduct a full perfusion development pro-
gram on a complex recombinant protein to lower their cost of
Exhibit 3: Improvement in titer due process development
production. We went back to the cloning step and selected the
best of five options. We then tested 20 media combinations and
created an inexpensive custom medium. And then we scaled
and process yield. That means you can think about what cost
up the process. The result was a 6-fold improvement in titer and
band is optimal for each demand scenario and how best to
a 10-fold improvement in volumetric reactor productivity. You
maximize margins while reducing risks.
can see the improvement due to each step in Exhibit 3.
The best advice is to start early, build options into your process,
understand the lead times to make the changes and continue to
The early planner contains the uncertainty
evaluate your strategy during the commercialization process. In
Ask any planner, and they will tell you that the only thing they this way, you can reduce the uncertainty in your plans. ■
know for sure about the forecast is that it will be wrong. The
question is by how much. We recommend that you create a
manufacturing strategy that can accommodate a forecast range
and that you can adapt as better data becomes available.

Biologics manufacturers have many potential paths to accom-

modate demand forecast uncertainty, but once one is chosen,
it can be difficult (and expensive) to switch. The earlier you start
to plan, the more time you have to arrive at an option that’s best
for your company. Even outsourcing can have lengthy lead
times, even longer if the process is complex and the desired
volumes are high.

There is no reason not to begin planning early. By the end of

Phase I, a company will have a good idea of the dosing range

www.patheon.com ● doingbusiness@patheon.com 7
 Biologic
Drug Substance

Is Your In-House
Strategy Ready
for the
Uncertainties of
Biologic Drug
Development?

John Ward
Vice President,
Engineering

The pharmaceutical industry’s past reliance on blockbuster drugs
has evolved to include a focus on developing drugs that treat the
unmet needs of smaller patient populations. These niche drugs
most often come in the form of biologics, which are an increasing-
ly larger share of new drug approvals in the past decade, from a
low of 10% to a high of 27%.1 By 2022, 50% of the value of the top
100 products is expected to come from biologics.2
This proliferating number of targets has had a profound effect on
the complexity and cost of drug development, which can take up
to 15 years to complete and, as outlined in recent estimates, can
cost up to $2.6 billion.3 Yet, despite the time and resources invest-
ed, only about 12% of the drug candidates that make it into Phase I
1 BioWorld, Biologics Share Of Medicine Chest Grows, And So Do Pricing
Concerns — http://www. bioworld.com/content/biologics-share-medicine-
chest-grows-and-so-do-pricing-concerns
2 EvaluatePharma, World Preview 2016, Outlook to 2022 — http://info.
evaluategroup.com/rs/607-YGS-364/images/wp16.pdf
3 Tufts Center for the Study of Drug Development, Tufts CSDD Assessment of
Cost to Develop and Win Marketing Approval for a New Drug Now Published
— http://csdd.tufts.edu/news/complete_ story/tufts_csdd_rd_cost_study_
now_published
testing are approved by the FDA.4 This is because drug develop-
ment is complex and unpredictable, especially for biologics, which
are developed by growing “live” cells in a bioreactor. Depending on
the conditions, the results can vary with each batch. These char-
acteristics make large-molecule drugs much more challenging to
bring to market than small-molecule drugs. It also makes them
more exciting, as the knowledge and expertise industry stands to
gain from this new frontier could potentially change the face of
medicine; however, a company has to be able to withstand the
highs and lows of biologics development.
Is it possible to achieve
efficiency and flexibility within
a drug developer’s own
walls, or is outsourcing
pharma’s best not-so-secret
weapon against today’s

development uncertainties?
4 PhRMA, 2015 Profile, Biopharmaceutical Research Industry — http://www.
phrma.org/sites/default/files/pdf/2015_phrma_profile.pdf

8 www.patheon.com ● doingbusiness@patheon.com
To avoid costly mistakes and wasted efforts, a company must
prepare for any surprises along the drug development pathway.
One way to accomplish this is to diversify its strategies rather
than develop only a single-pronged attack for launching a prod-
uct. This flexibility creates the opportunity to incorporate multi-
ple solutions if necessary. By adopting an operational approach
that minimizes risk and optimizes drug development, a drug
developer can successfully manage its product portfolio and
reach its commercial goals. But is it possible to achieve effi-
ciency and flexibility within a drug developer’s own walls, or is
outsourcing pharma’s best not-so-secret weapon against to-
day’s development uncertainties?
Below are two main areas where a drug developer can face
significant obstacles during biologics development. By evaluat-
ing these capabilities, a drug developer can answer the critical
question of whether its in-house strategy is ready for the uncer-
tainties of drug development.
Capacity: Is your facility prepared for the
demands of today’s biologics pipeline?
As part of pharma’s evolution, the demand for capacity in bio-
pharma is changing. An increased focus on process technology
improvements in pharma over the last 20 years has resulted in
much higher yields, enabling pharma to reduce its programs and
products to smaller capacities. These new production processes
and capabilities, such as perfusion and continuous processing,
are driven not just by the need for smaller batches but also by the
complexity and instability of biologics. Other operational capabil-
ities like single-use technology (SUT) and online buffer
conditioning offer additional major benefits, such as simplified
logistics. While these technologies have become more sophisti-
cated, they can still be difficult to apply in production. Until these
technologies further advance, pharma manufacturers must
come up with a more feasible plan to achieve flexibility and effi-
ciency in this new manufacturing landscape. This is especially
important, as a recent study by the American Pharmaceutical
Review shows that half of all products projected in the future can
likely be met with a 5,000-liter bioreactor or smaller per product.5
Fortunately, the emergence of SUT has brought promise to man-
ufacturers that need to quickly expand capacity and have the
resources to invest into this transition. SUT offers the flexibility
needed for bio’s future, and with facilities taking 12 to 18 months
to build (as opposed to the timeline for stainless-steel facilities of
five to six years for large-scale), it is an attractive solution to a
growing need for capacity in a shorter period of time.
Nevertheless, a manufacturer cannot take full advantage of the
benefits of any facility type if the demand forecast it relies on is
inaccurate. In lower-throughput scenarios, SUT is often a more
www.patheon.com ● doingbusiness@patheon.com
sensible route. As your throughput increases, the economics
start to shift to stainless steel, as the cost of SUT components
can be expensive in a high-demand scenario. Without the abil-
ity to accurately predict demand, though, there is no way to re-
ally know which facility type is best for your product.
Considering the substantial costs of producing and storing bio-
logics, the implications of an inaccurate forecast can be
far-reaching. When demand is overestimated, companies are
left with unused product and the likelihood of a significant loss
in unproductive investments. This affects the company, its em-
ployees and its stakeholders. If it is underestimated, a manu-
facturer is left scrambling to come up with enough product to
meet demand and creates new opportunities for its competi-
tion. As it attempts to come up with the needed capacity, the
upfront costs of building infrastructure, hiring personnel and
installing the necessary systems begin to mount. Meanwhile,
patients in need of lifesaving drugs are left waiting for their
medication. Still, the final product must be delivered quickly, at
a reasonable cost and at the highest quality possible.
Experience: “The better you putt,
the bolder you play.”
American golfer Don January once said the quote above to de-
scribe the risks a golfer is willing to take with their shot if they
know they have the skills to face — and prevail over — a com-
plicated situation on the green. Putting is difficult, and improving
at it requires a lot of practice. The same can be said for devel-
oping biologics. A drug developer that is confident its team has
the necessary skills to overcome the challenges of biologics
development is more likely to keep its business in-house. But a
small to midsize innovator company usually does not have the
5 American Pharmaceutical Review, Global Biomanufacturing Trends,
Capacity, and Technology Drivers: Industry Biomanufacturing Capacity
Overview — http://www. americanpharmaceuticalreview.com/Featured-
Articles/188840-Global-Biomanufacturing-Trends-Capacity-and-
Technology-Drivers-Industry-Biomanufacturing-Capacity-Overview
9
resources to staff a large team of experts. Therefore, it be-
comes unlikely they have the resources and experience not
only to foresee potential issues but also to quickly come up with
a solution that does not have a long-term impact on a product’s
timeline and development costs.
For example, technology transfers are a critical step and nec-
essary even in an in-house scenario, as multiple sites separating
process development and manufacturing can exist. According
to the ICH Q10 guidance6, “The goal of technology transfer ac-
tivities is to transfer product and process knowledge between
development and manufacturing, and within or between manu-
facturing sites to achieve product realization. This knowledge
forms the basis for the manufacturing process, control strategy,
process validation approach and ongoing continual improve-
ment.” In other words, it is passing on the “recipe” for your prod-
uct, and there is no room for error. For platform processes,
such as a standard 2,000-liter fed batch, there is not much
change in the standard operating procedures (SOPs) and batch
records used from one process to the next. If a process is de-
signed to the platform, and it works at a small scale, a company
mitigates the risks at scale-up. However, for custom processes,
particularly with biologics, it can be much more difficult to main-
tain the integrity of a drug’s formulation. If the integrity is not
maintained, that manufacturer suddenly finds itself in a situa-
tion downstream where unexpected variables, such as extrane-
ous protein or unpredicted scale-up issues, have a negative
impact on the final product.
There is much to be said about the advantages of the technical
knowledge that can be gained from running a variety of campaign
types using multiple types of processes, such as in the tech trans-
fer example above. The experience of analyzing and solving a
wide range of process and product issues creates a much stron-
ger skill set than only having to address a handful of problems with
one product type each year. This strategic advantage translates to
a higher level of expertise in both operations and development. A
drug developer must consider how much practice its team has “on
the green,” and if they are prepared with the boldness manufactur-
ing biologics requires. If the decision is to not enter into a partner-
ship, a company is placing itself into a silo and potentially at risk of
As a manufacturer attempts to
come up with needed capacity,
the upfront costs of building
infrastructure, hiring personnel,
and installing the necessary
systems begin to mount.
10 www.patheon.com ● doingbusiness@patheon.com
not having access to necessary expertise. This makes it impera-
tive its team has the know-how to work with biologics.
That expertise also extends to the regulatory side. More pro-
cesses moving through a plant results in more agency inspec-
tions. This builds a stronger, broader understanding of the
regulatory framework as well as a familiarity of the agency with
the company itself, which can facilitate and even expedite a prod-
uct’s speed to market. In addition, a drug developer must be able
to recognize the impact of changes that can occur during devel-
opment and how this affects the final formulation (and, thus, its
approval). For example, what happens when a drug’s intended
delivery system is initially an auto injector, but the concentration
ultimately requires a dose higher than the 3-milliliter max of that
system? The in-house team must have the knowledge not only to
recognize any modifications it needs to make to manufacturing
plans but also to understand how it might change the regulatory
pathway originally intended for that product.
Summary
Overall, the decision to stay in-house or to outsource is not
easy, but it is quite possibly the most important one you will
make as you begin your journey into the production of biolog-
ics.7 A company venturing into this market might have a promis-
ing and potentially life-changing target; yet, it may not have the
tools to successfully bring it to market. Partnering with a CDMO
that offers flexible development and manufacturing solutions
can help reduce the variability biopharma organizations often
encounter during the drug development process; it also creates
an ability to customize a solution that accounts for the ebb and
flow of demand and capacity needs. Rather than relying on a
strategy that claims to solve forecasting issues, a flexible solu-
tion allows a manufacturer to adjust to changes as they occur.
If a company determines capacity and expertise gaps exist in its
strategy, the advantages of an experienced and flexible CDMO
can be invaluable. Having the resources necessary helps miti-
gate the risks of drug development while creating an opportunity
to achieve necessary speed-to-market milestones in a highly
competitive market. By accessing pharma’s best weapon against
development uncertainties, a manufacturer reaps the benefits of
a cost effective solution that also provides the technical and busi-
ness capabilities needed for commercial success. ■
6 International Conference on Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use, Guidance for Industry Q10 Pharmaceutical
Quality System — https://www.fda. gov/downloads/Drugs/.../Guidances/
ucm073517.pdf
7 Lam, Stephen, Managing Demand Uncertainty in Biologics Production
— http://go.patheon.com/rs/910-ISZ-451/images/Whitepaper_FBM_
ManagingDemandUncertainty.pdf

How Can You Avoid
the Fallout from
Incompatibility
Between Your
API and its
Formulation?
Matthew J. Jones, Ph.D.
Crystallization Expert
In drug development, designing a formulation for a drug product (a
tablet, for example) calls for careful attention to both the physical
and chemical properties of the active pharmaceutical ingredient
(API or drug substance). It also requires awareness that certain
physical attributes, such as particle size distribution of the drug sub-
stance, can change with processing conditions and changes in the
synthesis route that is employed. The formulation, which includes all
of the excipients used to make the tablet, ensures the active ingre-
dient is released in such a way as to not only provide the best effica-
cy for the patient but also protect the drug substance. If the drug
substance has unfavorable interactions with any of the excipients, it
can have a negative effect on the shelf life and performance of the
drug product and can potentially cause harm to the patient.
For these reasons, it is critical the experts creating the formulation
are aware of any reactions that can occur between an API and a
tablet’s excipients. This enables the correct choice of excipients,
avoids unpleasant surprises at a later stage and allows the focus to
remain upon the manufacturing scale-up of both the drug substance
and the formulated product. So what can a pharmaceutical company
do to recognize both unfavorable drug substance properties and in-
compatibility between an API and its formulation? Finding the answer
to this question early allows a drug manufacturer to avoid potential
risks to the patient as well as costly interruptions during development.
www.patheon.com ● doingbusiness@patheon.com
API
Drug
Substance
The API characteristics your
formulator can’t ignore
One difficulty in developing a new drug product is matching the time-
line for a drug substance manufacturing development with a drug
product formulation. In most cases, the chemists and engineers will
have almost completed development of a manufacturing process
when the formulators begin developing the final commercial formu-
lation. More often than not, chemists and engineers finish develop-
ment under the assumption that their role is complete — an efficient
process to manufacture the drug substance to a purity specification
has been developed — leaving the formulator to contend with a drug
substance that is less than optimal for product development.
This separation, as well as the lack of overlap in processes, can lead
to critical knowledge gaps between the chemists and formulators
about powder properties. If these drug substance properties are
characterized early, it helps to identify and flag any potential issues
that may lead to problems in formulation development. This is be-
cause the physical and chemical properties of the drug substance
have a direct impact upon the formulation requirements for the drug
product. For example, solubility and particle size, both physical
properties, control the dissolution rate and therefore the availability
of the drug substance in the body. Chemical properties can lead to
unwanted reactions with other components in the product, resulting
in undesired impurities and loss in efficacy or even harmful side ef-
fects to the patient. Without an open line of communication between
each team, the development chemists are not fully aware of those
factors that have an impact on formulation development; converse-
ly, formulators may not fully appreciate the limits imposed by the
manufacturing process on manipulating drug substance properties.
11
In addition to a lack of communication, organizational barriers can
also create challenges. Frequently, chemical development and
pharmaceutical (product) development are separate organizational
units, and good communication is required to minimize the impact of
this mismatch in the development timelines.
The following list highlights the importance of a drug substance’s
physical and chemical characteristics:
●● Solubility: The solubility of a drug substance in physiolog-
ical fluids — gastric juice or intestinal fluids — is important
as it represents the upper concentration limit for the drug in
that environment.
●● Dissolution rate: If the material does not dissolve fast
enough in the body, it simply passes through with no thera-
peutic effect on the patient. On the other hand, if the material
dissolves too quickly, it can become toxic, creating serious
safety issues. Achieving optimal absorption of a drug is de-
pendent on the particle properties combined with the formu-
lation it is in.
●● Powder properties: Mean particle size and size distribution
are particularly important because they determine the disso-
lution rate, which, in combination with the substance’s solubil-
ity, controls the drug’s availability for uptake by the body.
They also influence the flow properties of a powder.
●● Flow properties: Whether a drug substance is free-flowing,
like coarse table sugar, or has poor flow properties, like con-
fectioner’s sugar, it can have consequences on both the
manufacturing process and the product. “Sticky” powders
may result in reduced drug substance amounts in the product
due to losses in the processing equipment. Poor flow proper-
ties of the drug substance-excipient mixtures might lead to
segregation of the components and insufficient content uni-
formity in the individual dose.
While it may seem like, in the case of incompatibility of physical at-
tributes, the easiest solution is to redevelop the final isolation to fit
the formulation, extensive changes to a process would likely require
additional clinical studies to demonstrate equivalence of the product
for approval. Even minor modifications are not feasible once the API
manufacturing process has been locked and even registered with
the regulatory authorities. For a small company pursuing a new
drug, there may not be funding for additional clinical trials. This
could also cause considerable delays in the development timeline,
which is something pharmaceutical companies often cannot afford.
With a typical time to market of 12 years, any delay reduces the al-
ready short time for recovery of investment once the product is com-
mercialized. Decreasing development timelines by generating the
right type of information early in the development process not only
expedites a company’s ROI, but also, and more importantly, gets
the medicine to the patients faster. One measure to prevent the
fallout of incompatibility or unsuitable API properties, and thereby
timeline delays, is to align the development of the synthesis and final
12 www.patheon.com ● doingbusiness@patheon.com
isolation of the drug substance with the formulation development.
Doing so can reduce the need for the two teams to go back and
forth to optimize the drug substance properties and improve the
formulation. Yet, many companies struggle to make this transition
due to organizational silos that have become common in the indus-
try. Nonetheless, if a company can remove these perceived walls to
communication, it can generate necessary collaboration between
two groups whose roles are crucial to successful drug development.
Communication and collaboration:
A solution forward
While some may be reluctant to align the processes of API synthe-
sis and formulation because of the perceived risks and costs asso-
ciated with front-loading development work, it can be argued that
the modest cost of gaining good insight into critical formulation-en-
abling knowledge early is worth the risk. This is especially true when
considering that the vast majority of candidates typically fail to make
it to market. According to a recent BIO Industry Analysis study, “the
overall likelihood of approval (LOA) from Phase I for all developmen-
tal candidates was 9.6% and 11.9% for all indications in oncology.”1
Therefore, a company can potentially face added costs even if it
does not create a more aligned approach to API synthesis and for-
mulation, and the cost of a failed drug is sometimes too significant
for some companies to overcome.
A simple way to approach this realignment is to create awareness
and understanding as well as communication channels between
organizational units. Once these channels are open, it is likely the
benefits of a more aligned relationship will quickly become appar-
ent. The formulator can now build a substantial base of knowledge
from the development chemist or engineer during the design of the
final isolation process for the drug substance. The formulator will
also become more aware of what factors have an impact on formu-
lation development. At the same time, the development chemist will
have a deeper understanding of the chemical properties of the API,
which helps identify possible chemical interactions with the excipi-
ents the formulator intends to use. The alignment ends up becoming
a small step toward implementing procedures that can be critical to
the overall process. As a result, this communication of information
becomes a key to identifying potential issues and working together
to resolve them.
Implementing significant changes such as these to a company’s
procedures can be difficult, and without the money and expertise,
it can even be impossible. An alternative is to seek a partner that
has already considered and addressed this issue. Working with an
experienced partner obviates the need for time-consuming and po-
tentially disruptive organizational changes. It also allows rapid gain
of understanding and time by making full use of your partner’s
knowledge and experience when defining the best strategy for a
seamless development from drug substance to drug product. ■
1 Biotechnology Innovation Organization (BIO), Clinical Development Success
Rates 2006-2015 — https://www.bio.org/sites/default/files/Clinical%20
Development%20Success%20Rates%202006-2015%20-%20BIO,%20
Biomedtracker,%20Amplion%202016.pdf

Trends and
Challenges in
Outsourced
Oral Solid
Dosage Forms:
A Q&A
Anil Kane, Ph.D., MBA
Global Head of Technical and Scientific Affairs,
Formulation
Combination drugs, ingestible sensors, and targeted deliv-
ery are the future of pharma.
As drug companies have fewer and fewer new compounds
entering their R&D pipelines, outsourcing of development
and manufacturing activities for oral solid dosage forms and
sterile forms is on the rise. In a recent podcast, Anil Kane,
Ph.D., MBA, Global Head of Technical and Scientific Affairs
of Formulation at Patheon, discussed trends and significant
changes in outsourcing the manufacture and development
of solid oral dosage forms.
Q: What have been the most significant
changes in outsourced oral solid dosage
forms over the past decade? What are the
current trends?
Kane: The shrinking new drug discovery pipeline has led to
significant changes in dosage form development and manufac-
turing strategies. Existing molecules are being evaluated for
newer indications in the same or different therapeutic catego-
ries. Fixed-dose combinations of new drug entities combined
with off-patent drug candidates for synergistic effects or other
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API
Drug
Substance
clinical benefits are also under evaluation. And, pediatric-friend-
ly formats such as sprinkles, mini-tablets, and orally disintegrat-
ing tablets are gaining popularity.
In addition, the demand for lifecycle management strategies
such as pediatrics, controlled-release dosage forms, fixed-
dose combinations, and formats such as multi-layer tablets or
multiparticulate capsules is increasing.
Due to more stringent regulatory requirements, developers
need to apply a much higher level of product and process un-
derstanding and robustness justification by using systematic
scientific- and risk-based approaches as well as the principles
of quality by design (QbD).
Additionally, increased use of highly potent compounds has led
to the need for full containment, process automation, closed-
loop product transfers between processes, barrier isolators,
and equipment with clean-in-place and wash-in-place capabili-
ties. Moreover, early-stage investment in and adoption of con-
tinuous manufacturing is gaining popularity. Finally, there is a
need to address data integrity requirements, resulting in more
automation, data capture, documentation control, and training
to imbibe the culture of quality.
13
Q: Can you highlight any changes you have
seen in lifecycle management strategies?
Kane: Some of the most widely used lifecycle manage-
ment strategies are pediatric, controlled-release dosage
forms, and fixed-dose combinations. Pediatric formulations,
particularly in terms of palatable powder for reconstitution,
sprinkles, dissolvable tablets or mini-tablets, and chewable
soft gels, are becoming increasingly popular.
Controlled-release technologies are a frequently applied
lifecycle management extension strategy. These technolo-
gies have apparent benefits in delivering drugs over an ex-
tended period of time, reducing the frequency of dosing and
improving patient compliance. Another lifecycle manage-
ment strategy is solubility enhancement, thereby potentially
lowering the dose of existing drugs.
Q: What trends has Patheon seen in
controlled-release dosage form development?
Kane: In the last three to five years, we have experienced
an increase in the demand for dosage forms that exhibit an
enteric release followed by an immediate-release portion
and then a slow release of the drug over a specified period
of time. These delivery systems could be for the treatment of
irritable bowel syndrome, ulcerative colitis, Crohn’s disease,
or certain types of cancers in the lower part of the GI tract.
The benefits of these oral drug delivery systems are that drugs
can act locally as well as systemically by getting partially or
completely absorbed at the site of action, thus improving ther-
apeutic effect. Dosage forms that have been formulated to
deliver such drug candidates include enteric-coated con-
trolled-release tablets, or pulsatile-release beads in the form
of extruded beads, pellets, and capsules.
Q: What is the effect of mergers,
acquisitions, and licensing deals on an
outsource partner?
Kane: The mergers and acquisitions as well as in- and out-
licensing activity in the pharmaceutical industry continue to
grow. As more clinical candidates are outsourced, Patheon
has seen that clinical candidates and the drug products are
licensed out by small or emerging companies to large com-
panies or biotech companies, and then get acquired by other
pharma companies. But, the programs stay with us despite
change of ownership. In the past three to five years, we have
seen more than 55 programs licensed out between Phase I
14 www.patheon.com ● doingbusiness@patheon.com
The industry will
slowly embrace the
long-term benefits of
continuous manufacturing
and will invest in this model
to develop clinical and
commercial products.
to Phase III, but these programs have continued at Patheon
and we continue supporting these programs from clinical
through registration and then commercial launch, and resup-
ply. This ensures continuity of supply, as well as avoids loss
of know-how and product knowledge.
Q: What are future trends you expect in the
pharma industry?
Kane: I believe there will be more emphasis on continuous
manufacturing of solid oral dosage forms. The industry will
slowly embrace the long-term benefits of continuous manu-
facturing and will invest in this model to develop clinical and
commercial products.
●● There will be emphasis on patient-friendly dosage forms,
reducing pill burden, addressing the problem of polyphar-
macy, and improving patient compliance.
●● Combinations of drugs and devices will bring several
benefits to patients.
●● Drugs targeted to specific sites of activity or absorption
will enhance the therapeutic effect use of biodegradable
sensors, imaging techniques, and application of medical
and pharmaceutical electronics to deliver drugs accurate-
ly and at a pre-determined rate for enhanced efficacy.
●● Ingestible sensors could monitor the compliance of drug
administration and drug misuse.
●● Technological advances can help personalized therapy
and delivery of the right drugs for improving therapy. ■

Characterizing
DS Properties
Early Can
Optimize DP
Formulation
Anil Kane, Ph.D., MBA
Global Head of Technical and Scientific Affairs,
Formulation
Early on, the drug substance (DS) manufacturer will provide a
wealth of preliminary characterization data. And if the drug is
active in early nonclinical and preclinical testing, a larger quantity
of the DS will be prepared for more comprehensive animal safety
and pharmacokinetics studies. These studies may require up to
several hundreds of grams (sometimes a kilo) of purified DS with
low levels of impurities and residual solvents that meet global
regulatory standards.
But changes in the DS process as it scales up can affect the drug
product (DP). As processes change, many properties of the DS
can also change: its purity, potency, by-products, particle size
distribution, morphology (crystal shape and structure), and rate
and extent of dissolution. Therefore, as DS manufacturers evalu-
ate and optimize the synthetic route, process conditions, crystal-
lization solvents, etc., they must understand and track these
changes, and discuss them with DP formulators to anticipate
challenges in formulation.
DS characterization is critical to DP formulation but characteriza-
tion and formulation are often not integrated during drug devel-
opment. This creates needless difficulties because if DS chem-
ists and DP formulators collaborate on a formulation development
strategy for early Phase I first in-human clinical studies, they can
save time, money, and avoid rework.
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Formulation
Development
Siloed development is neither
efficient nor effective
Traditionally, DS and DP have related but distinct deliverables. The
end-product for a DS development team is a pure chemical sub-
stance produced in 5-to-12 synthetic steps; the end-product for a
DP development team is a patient-friendly drug. For DP formula-
tors, the DS team’s end-product is their starting point.
Typically, the industry has been conservative in characterizing the
full properties of the starting material for the DS: A minimum num-
ber of tests are conducted to suit the requirement of the immediate
next step, such as preclinical toxicity or animal exposure studies.
This is unfortunate. As molecules become more difficult to formu-
late, this sequential, compartmentalized development model is no
longer adequate.
DS and DP functions must collaborate on a
sound formulation strategy
Early stage, pure DS is ideally suited for characterization tests
which can catch problems early by identifying properties that could
dictate future formulation choices. Yet developers routinely assume
15
the preclinical period is too soon to consider formulation, reasoning
that “We are not formulating yet; we are just identifying challenges
before we trip over them.”
A systematic DS characterization should include a series of critical
formulation-enabling tests, and establish a thorough understand-
ing of a molecule’s properties to flag issues that can be addressed
early in the clinical stages. A detailed DS profile can help DP formu-
lators craft a strategy to make sure, for example, that the DS will not
get degraded in the GI tract. A forced degradation study can ensure
a molecule is protected via its formulation.
For example, recently a company produced a DP formulation in par-
allel with the human Phase I clinical study, based on a truncated DS
characterization effort (shortened to reduce overall development
time). The resulting formulation was a DS blend in a capsule, packed
in blisters for stability. However, after one-month stability data
showed that the DP had degraded, a thorough investigation and root
cause analysis revealed that the DS was degrading due to alkaline
conditions, and in response to exposure to a specific range of light.
Due to the rushed timeline and incomplete characterization effort,
there were no baseline characterization data available that demon-
strated the stability of the DS in different pH conditions, or in the
presence of different intensities of light. This was an avoidable mis-
take that required reformulating the DP and slowed development.
Systematic testing could have prevented it.
Data from forced degradation studies enable chemists and formula-
tors to understand if a DS is stable under acidic or alkaline pH buf-
fers, as well as in accelerated conditions of light, heat, humidity, and
exposure to oxygen. If a systematic forced degradation study on the
DS and DP had been carried out early on, the formulators could
have designed the DP with excipients to stabilize the DS in an alka-
line environment. And if a DS were sensitive to light, it could be for-
mulated in a capsule with light protection, or in a tablet with an
opaque coating. It may need to be manufactured under specific light-
ing conditions. For example, a recent case study of a DS revealed
that it was stable under red light but not yellow. As a result, handling
the DS in the lab, as well as during manufacturing, was only done
under red light to maintain DS stability in the DP, and to avoid any
degradation and the formation of photo-catalyzed impurities.
Here are some crucial DS properties that can inform and improve
formulation strategies, but only if the testing is done in a timely
fashion and results are communicated.
Properties critical to formulation that are
not often available early (but should be)
●● Aqueous And pH Solubility: Solubility of the material in
acidic, neutral, or alkaline pH buffers helps DP formulators
16 www.patheon.com ● doingbusiness@patheon.com
know whether the molecule is stable at the pH ranges prevail-
ing at its intended site of release, absorption, or permeation.
A formulator can use this information to modify the pH of the
microenvironment to improve solubility of the DS, or prevent
precipitation in biological fluids of certain pH ranges.
●● pH Stability: The stability of a DS under various pH conditions
is as important as its solubility. Formulators can add acidifiers or
alkalizers to stabilize the DS in the relevant dosage form.
●● Partition Coefficient (log P, log D): This tells the formulator if
the molecule will dissolve better in a lipid or an emulsion. For
poorly soluble lipophilic compounds, formulators can develop a
lipid-based formulation, using surfactant, self-emulsifying sys-
tems, or other techniques. If a compound has better solubility in
lipids than it does in aqueous buffered solutions, formulators
can perform a systematic lipid vehicle screening test using
phase diagrams to understand its solubility in mono, binary, or
tertiary solvent mixtures, and then formulate a dosage form bet-
ter suited to deliver the drug without precipitation. A systematic
lipid digestion screen can ensure solubilization/emulsification of
the drug in biological fluids on administration.
●● Ionization Constant (pKa): The pKa of a drug influences many
biopharmaceutical characteristics such as lipophilicity, solubility,
protein binding, and permeability. These in turn directly affect
pharmacokinetic characteristics such as absorption, distribution,
metabolism, and excretion. For instance, a molecule can be
modified to link to a certain protein, such as complexation, or
salts such as chloride or maleate. Knowing the pKa is important
for salt screening, an early step in determining which candidate
to advance (or terminate). And it helps formulators optimize drug
delivery. Different salts of a free base may have different solubili-
zation, absorption, and stabilization properties. A systematic salt
screening of a DS in early stage is key to identifying the right salt
to use to take development to the next steps.
Other physico-chemical properties
critical to formulation
●● Particle Size And Morphology: The size and shape of parti-
cles determines their surface area and density, which in turns
influences the flow of powders. While the shape of many crys-
talline substances changes due to the conditions of crystalliza-
tion, crystal size is primarily a function of the rate of cooling.
Limiting size to a narrow range can ensure uniform blending
with excipients in the formulation. Particle size also affects sol-
ubility; micronization is a common first tool to apply to
poorly-soluble substances. The dose of the drug and the drug
loading both impact formulation. For example, a low-dose drug
or a highly potent drug administered at a very low concentration
are both examples of drug candidates at high risk for problems
in blend uniformity, “content uniformity,” and segregation/
non-uniformity in the finished product. A high-dose formulation
or a high loading dose formulation present fewer challenges in
terms of blend uniformity, but increase the risks of product pro-
cessing and compressibility problems. Particle size distribution
becomes more important as the DS is formulated into the DP.
●● Stability Under Forced Degradation: The stability of the
DS under accelerated conditions of acidity, alkalinity, light,
humidity, and temperature is important to formulation of the
dosage form. Knowing it helps the formulator select the right
ingredients and excipients, as well as the process conditions
that will ensure stability of the product during manufacture.
●● Long-term Stability: The stability of the DS under ICH condi-
tions over a longer period also helps formulators select excip-
ients and process conditions that maintain the stability of the
product during manufacture, and in subsequent storage.
●● Hygroscopicity And Water Sorption: If the drug substance ab-
sorbs moisture under ambient and plant conditions, it will need to
be protected from normal humidity. It is also important to know the
degree of moisture pick up, and if it is prone to convert to hydrates,
solvates, or to other polymorphs. Different solvates, hydrates, or
polymorphs of the same parent drug can have different solubility,
rate of absorption, or stability profile characteristics. A dynamic
vapor sorption (DVS) study can help understand the molecule’s
sorption and desorption properties under various humidity levels.
●● Flow properties: Bulk and tapped density are important for for-
mulators because they indicate the flow of powder into the dies
of a high-speed tablets press, the potential of the blend to seg-
regate, and to have compressibility challenges. When a DS ex-
hibits poor flow characteristics, formulators can select excipients
that improve flowability (e.g., Fast Flo lactose/MCC), or reduce
the inter-particulate forces with colloidal silica, among other sub-
stances. They can select process steps that adjust the particle
size of the blend, such as wet or dry granulation. Flow properties
become more important as you scale-up manufacturing.
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●● Compressibility: It is useful to understand the behavior of the
DS under compression. For example, do the particles fracture?
Do they deform? Is the material ductile, fragile, and does the
blend have sufficient elastic or plastic properties? Based on the
answers to these questions, a formulator can add suitable excipi-
ents such as cellulose derivatives, dicalcium phosphate, and/or
various grades of lactose or mannitol to optimize the compress-
ible behavior of the finished blend for a tablet formulation.
Properties that DS chemists routinely
provide (and are not likely to change)
●● Melting Point: A low melting point substance may need to
be handled differently by the formulators during dosage
form development.
●● Organic Solvent Solubility: Important to understand for
specific cases such as if the compound must be spray dried
by dissolving it in an organic solvent, or if a solvent-based
drug layering or polymer coating is to be applied.
DS chemists and DP formulators must
communicate early and often
To succeed in an increasingly complex environment, companies
need a more holistic approach to crafting their formulation develop-
ment strategy. Ideally, DS chemists investigate properties in paral-
lel with DP formulators, and characterize things that will not change
(e.g., log P, log D, solubility, MP, pKa, etc.). Meanwhile, DP formula-
tors determine the best solution for formulation, and tell the DS
chemists what properties they are looking for, such as direct com-
pression, limits on particle size distribution, and polymorphs.
As development proceeds, strong lines of clear and frequent com-
munication can screen out risks because DS chemists can inform
DP formulators if something critical has changed. The two disci-
plines also can collaborate by agreeing on high-risk areas, commit-
ting to a sound set of characterization tests, and bracketing the DP
characteristics needed or preferred.
Molecules continue to get more challenging from the perspective of
solubility, bioavailability, and exposure. Advances in formulation
technologies continue to provide more solutions. Necessity is the
mother of invention, but recent inventions have drawn companies
into developing more difficult molecules.
It’s time to establish effective communications between DS
chemists and DP formulators if we are to manage the risks and
maximize the rewards of transforming less soluble and less bio-
available molecules into effective new drugs. ■
17

Avoid the Do-Over:
Why Early
Investment
in a Scalable
Manufacturing
Process is Critical
Title Goes Here
Enrico Corona
Director,
Pharmaceutics & Process Technology
The road to take a drug compound from discovery to commer-
cialization is long, expensive and often fraught with unforeseen
challenges. While every project will undoubtedly face some
bumps along its path, far too many programs hit insurmount-
able obstacles that require innovators to backtrack and correct
their course before proceeding, further extending timelines and
adding costs.
The failure of drug compounds in mid- to late-stage develop-
ment is far more common than anyone would like it to be. Only
about 30% of drug compounds successfully transition from
Phase II to Phase III, and just 54% of the remaining programs
ever advance beyond Phase III.1,2 Reasons for Phase III failure
span the gamut from safety challenges to poor efficacy to com-
mercial complications. In addition, some firms learn late in the
process — during Phase III or IV, when they should be focused
on evaluating drug safety and efficacy — that fundamental
problems in process design must also be addressed, resulting
in a repeat of drug product development activities.
How can developers avoid these costly delays? Investing in a
scalable manufacturing process early-on can make the differ-
ence between advancing through drug development in a pro-
ductive, step-wise fashion and having to redo early-phase work
to correct problems.
18 www.patheon.com ● doingbusiness@patheon.com
Pharmaceutical
Process
Development
Jonathan Sutch
Senior Manager,
Formulation Development
The problem with shortcuts
Small companies often hesitate to invest in a full analysis of
their molecule’s physical and chemical properties in early stag-
es for a variety of reasons. Unfortunately, this delay can create
roadblocks as the compound matures.
Most small biopharmaceutical companies, for instance, function
with accelerated development timelines and limited resources.
This environment pushes them to race to the next development
milestone that’s linked to funding. In addition, many biopharma
companies simply may not have enough API available in Phases I
and IIa to run all the necessary process characterization studies.
Companies are often working on life-saving treatments, generics
or biosimilars, which adds great pressure to advance molecules
to market as quickly as possible.
In the end, smaller companies often trade investment in a prop-
1 J. Paul, “Reducing the Risk of Late-Phase Failures,” Pharma R&D, July 5,
2016, https://pharma.elsevier.com/ pharma-rd/reducing-the-risk-of-late-
phase-failures.
2 T.J. Hwang et al., “Failure of Investigational Drugs in Late-Stage Clinical
Development and Publication of Trial Results,” JAMA Intern Med.
176(12):1826-1833 (2016), http://jamanetwork.com/journals/
jamainternalmedicine/article-abstract/2565686.
erly characterized molecule for a “quick and dirty” approach to
their API. We’ve seen such firms use very conservative pro-
cess parameters during development, which generates a limit-
ed pool of data. Such narrow process parameters may provide
fast answers that scratch the surface of process information,
but will not collect the richer data that is needed for adequate
characterization and prediction of success during scale-up.
A major problem with this strategy is that drug developers ab-
solutely need a great deal of information about their molecule
for it to be successful in later stage work. Indeed, the key com-
ponent in any drug product is the drug substance. Not under-
standing its stability, crystallinity, solubility, hygroscopicity and
other parameters will only spell trouble during process scale-up
down the road.
To put this into perspective, a company that takes what may
be its first or second batch of material into development could
very well be working with an unfavorable polymorph or salt
form that stands no chance of clinical (or commercial) suc-
cess down the road.
In addition, not thinking about a molecule’s future from a pro-
cess design standpoint means that the next batch created
could have a completely different set of characteristics from the
one already in development. Such characteristics may include
a different particle size or shape, solubility variations, or even
different polymorphic forms, which undoubtedly will affect drug
safety and efficacy.
The only way to move forward at this point is to spend time
and money to redevelop the formulation. While very ear-
ly-phase redevelopment is not a problem, if companies are
moving into later development without having done proper
characterization studies, they essentially have the wrong drug
in their formulation.
Such a lack of preparedness could pose a variety of potential
issues and consequences. We’ve had Phase II projects trans-
ferred into Patheon with the hopes of starting Phase III produc-
tion immediately. Sometimes, at this point, even a small but
necessary change requires us to go back and conduct rounds
of formulation work, which delays the timeline by several
months and costs of hundreds of thousands of dollars. If a for-
mulation vulnerability were to be identified at an even later
stage, it would cost much more to rectify.
Even products already on the market are not safe from po-
tential manufacturing problems if the process is not robust
enough to handle common alterations like a change in the
supply chain. When changes require a product to come off
the market, it will cause a significant loss in revenue and
consumer confidence. Ritonavir (Norvir, Abbott) is a well-
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It is critical to ensure that
process development is robust
and manufacturing scale-up is
embedded in from the
beginning ... [and] weigh the
short-term benefits against the
potential long-term risks —
especially to patients.
known example of conformational polymorphism from the
mid-1990s. The API changed polymorph while it was in com-
mercial production and the life-saving HIV treatment was
forced to be withdrawn from the market until developers
could solve the problem.
Drug makers must learn lessons from situations like these;
when they’re developing products, it is critical to ensure that
process development is robust and manufacturing scale-up is
embedded in from the beginning. Any firm considering the path
of delayed process development work should strongly weigh
the short-term benefits against the potential long-term risks —
especially to patients.
Phase III: Still work to be done
Big Pharma companies, with reduced budget constraints, usu-
ally allocate resources to performing sufficient process charac-
terization studies that allow for better process design beginning
in early-stage work. Some drug developers even use a platform
approach that allows them to standardize solubility, compound-
ing, lyophilization and various critical parameters across a
range of compounds.
Even if such groundwork has been laid by an in-house team, it
is still possible for an experienced partner to determine further
areas for improvement through risk assessments during late-
stage tech transfer to a CDMO. We feel it is important during
this critical juncture to ensure a compound will both be suc-
cessful as a commercial product and has the necessary data to
satisfy the regulators — another area where time can be lost.
This is where the principles of quality by design (QbD) really
come into play. Regulators are now expecting to see an en-
hanced level of product knowledge to ensure robustness —
19
and Phase III is a good time to do that with the help of a manu-
facturing partner.
If you perform QbD work and evaluation during Phase III, then
chemistry, manufacturing and controls work will not be a
rate-limiting step when the clinical program is ready to seek
regulatory approval.
Real-world failures and successes
Compounds and process design cannot be created for the mo-
ment; they must be developed with the future in mind. When
firms develop a compound — no matter how early-stage the
project may be — they must do so with an eye on the informa-
tion required for successful commercialization.
The following real-world scenarios demonstrate how the choice
to invest (or not to invest) in a scalability strategy in early devel-
opment has significant long-term effects on the project.
Choosing speed over process development:
Repeating early-stage work.
Close to commercialization, Company A transferred a product
to Patheon while simultaneously switching their drug sub-
stance provider. This supplier change had huge repercus-
sions on the API that the developer was unable to foresee
because of its very light early development work. Rather than
starting late-stage production as the client had hoped,
Patheon had to perform re-formulation work to better under-
stand the API and make sure the formulation was more robust
before moving forward.
This delay could have been avoided by applying the principles
of QbD to the drug product and the drug substance. A product
that is developed using QbD principles is naturally going to be
When firms develop a
compound — no matter how
early-stage the project may
be — they must do so with
an eye on the information
required for successful
commercialization.
20 www.patheon.com ● doingbusiness@patheon.com
more robust as it scales up and better able to handle changes
such as those in supply. Engaging QbD approaches — such
as the use of risk assessments, experiments of design, and a
good control strategy — early in the process will help ensure
that all the stages of scale-up can be managed throughout a
product’s lifecycle.
Waiting to understand key product
attributes: Costly reformulation.
During a transfer, we learned that Company B was working with
a formulation it already knew had dissolution challenges. The
client felt it was not worth investigating the problem until later
phases to avoid development delays. We helped the company
trace the problem back to a fundamental issue with their formu-
lation. If left unaddressed, the product would not have passed
regulatory scrutiny, so the only path forward was reformulation.
If Company B had not ignored the dissolution issues and invest-
ed earlier in the right level of science, this backtracking could
have been avoided.
Implementing QbD with FMEA:
Successful scale-up.
As Company C moved through the development process, QbD
was an important priority. Not only does a QbD-type submission
give regulators confidence in the submission’s ability to handle fu-
ture changes, but it also gives manufacturers confidence that their
process is robust. Robustness is a central part of successful
scale-up and using appropriate QbD strategies enabled Company
C to fully understand its product as it scaled through development.
One particularly effective tool in the QbD toolbox is failure mode
and effects analysis (FMEA), the gold standard in risk assess-
ments for understanding any possible design failures. A well-exe-
cuted FMEA approach should be interdisciplinary, tapping into the
knowledge of experts from development and commercial teams.
Checkpoints of assessment during formulation development may
involve numerous process parameters and the effects they could
have on clinical quality attributes like safety, quality and efficacy.
Step-wise and gated
Step-wise and gated assessments help companies build quality
and science into process design; they have broad knowledge of
assessments help
how API changes may affect quality attributes, for instance, or if a companies build quality
change in excipient grade will affect the end-product.
and science into
Given all the areas involved in an effective FMEA, working with a
knowledgeable CDMO can be advantageous. Remember, a process design.
small company may have access to just three or four molecules
over the course of several years, but a CDMO like Patheon will
The single-source option enables the CDMO’s drug product
see hundreds of different molecules in the same period. This
team to provide feedback to its drug substance team about
makes us adept at handling challenges, knowing which potential
what worked well and what did not with the API. Company E, for
problem areas to look out for during risk assessments and lever-
instance, might benefit from addressing some powder flow is-
aging more diverse information for better process development. sues at the Phase II juncture and still ultimately achieve the
desired end-point (i.e., high yield and a pure drug substance)
along with deep knowledge about key product attributes. Con-
Failure to consider commercial equipment:
trast this situation to an API delivered from a third party. If flow-
Development delays. ability problems surfaced in this scenario, it would take much
more time to investigate the source of the issue and adjust the
Company D used its in-house team to develop a lyophilized
process design appropriately. Without this kind of network, a
formula. The firm’s long lyophilization cycle was fit for purpose
CDMO might simply just take whatever drug substance it re-
at the early stage, but became economically unreasonable as
ceives and work with that material — one that may have red
the process was scaled up. Additional development work was
flags it would not find without a deeper investigation.
needed to rethink the lyophilization process.
In the end, being able to influence the type of drug substance
The firm missed out on the fact that having full knowledge of and drug product through a single network of experts can
equipment trains — and the capability of full scalability between make the development and scale-up path much more effi-
laboratory and production lyophilization units — would lead to cient and, with deeper knowledge, a more robust process
better development of freeze-drying cycle parameters as well will be developed.
as cost savings. By understanding the full breadth of equipment
required from batch through commercialization in early stages,
companies may spend a little more time developing the right Summary
process at small-scale, but scale-up will be far easier later on
In an effort to move through the drug process quickly, some
with potentially reduced cycle times.
companies spend less time doing proper development work.
This scenario applies beyond lyophilization as well. We’ve seen The compound may arrive at the tech transfer commercializa-
first-hand that deep knowledge of various equipment trains and tion scale with a dossier that appears scientifically sound. But
the different parts that connect them — as well as access to a when the system is put under a stress it has not encountered
full breadth of tools and techniques, starting from benchtop to before, the process may experience significant problems if it is
not robust. Patheon believes this situation can be avoided by
clinical manufacturing and up to commercial manufacturing —
partnering with an experienced development team and ad-
will greatly contribute to the success of nearly all molecules.
dressing scalability and process design early in development,
and building on this work through to commercialization. This
Using a single-source vendor through investment will pay dividends as one takes a compound into
late-stage commercialization with a good understanding of the
scale-up: Time and cost savings.
compound and process. ■
Company E had developed its first GMP batch of API and success-
fully used it for the first batch of clinical supply. The firm, ready to
begin Phase II trials, had an opportunity to build in additional under-
standing by working with a CDMO provider that aligns drug substance
and drug product units (such as the Patheon OneSource™ program).

www.patheon.com ● doingbusiness@patheon.com 21

Solving the
OOS Problem
with
Continuous
Manufacturing
Eric Jayjock
Director,
Continuous Manufacturing
The goal of Pharmaceutical Process design has long been to
implement a fixed process that can produce on-spec materials,
which can be confirmed by quality testing.
However, there is variability in everything. In the manufacturing
world, variability can be produced by environmental conditions
(such as seasonal changes), the way a particular piece of
equipment performs through its lifecycle, or even the properties
of the incoming materials (their density, or flowability). Conse-
quently, the combination of a fixed manufacturing process and
normal variations in environment, equipment, and material
properties can, and often do, produce products that will fall out
of spec (OOS).
Fortunately, the data-rich nature of the continuous manufactur-
ing process potentially can greatly reduce or even eliminate
OOS events.
The complexity of the product lifecycle
Strategies exist for managing the variables introduced by envi-
ronmental factors, and by equipment, but they usually do not ex-
tend to dealing with variations in material properties. Moreover,
the interactions between normal variations, be they environmen-
22 www.patheon.com ● doingbusiness@patheon.com
Pharmaceutical
Process
Development
tal, equipment or material-based, is practically never investigat-
ed. To understand the impact of those on the manufacturing pro-
cess, and the challenge they present, it is important to have a
clear view of how a product moves through its lifecycle.
The standard mode of drug manufacture is to begin by produc-
ing batches in the 1kg to 10kg range, and then scale up by a
factor of 10 for pilot scale experimentation, and another factor
of 10 for commercial scale production, which typically ends up
somewhere between 150kg to 800kg.
At each step up the scale, batches are produced over a relative-
ly short period (when compared to the full production lifecycle),
often with API material that is still undergoing process changes.
When the manufacturing process is scaled for commercial pro-
duction of 150kg to 800kg batches, there is very little chance to
understand the impact of the variability introduced by incoming
materials; it is both logistically difficult and cost prohibitive to
interrogate the process with batches of that size. Once the pro-
cess has been validated, it is essentially fixed, making it difficult
to determine why batch failures happen. And in those cases
where the cause of a failure can be identified, it is often prohib-
itively complicated to roll the accumulated product knowledge
back into the manufacturing process.
That is why OOS is an inevitable outcome of a fixed manufac-
turing process. Any variation in material properties not investi-
gated during development can lead to batches of OOS material,
with its attendant waste and costs.
Two reasons why continuous
manufacturing makes every kind of sense
Continuous manufacturing for oral solid-dose (OSD) products
in particular (and pharmaceutical manufacturing in general) can
make manufacturing more reliable, and less wasteful and cost-
ly than the batch method for two reasons:
1. Continuous manufacturing de-couples batch size from
the amount of material needed to examine the integrity of
the process, allowing commercial production to be stud-
ied in more depth with much less material.
2. Steady-state unit operations (feeding, blending, compac-
tion, and so on) make it much simpler to characterize a
process as it does not vary over time. This makes it easier
to relate material attributes to process conditions and
product attributes.
The consequence of these two effects is that quality by design
(QbD) process understanding can be built on a scale more typ-
ically associated with pilot scale quantities than with manufac-
turing-scale production, with a concomitantly lower investment
in time and money.
Six steps to implementing
continuous manufacturing
The conventional approach to pharmaceutical manufacturing is
largely a trial-and-error process that identifies an acceptable
range of process parameters that will deliver the expected
product attributes. Continuous manufacturing allows one to in-
vestigate product and process performance, incorporating from
three to seven factors (with 20 to 50 conditions), using about as
much product as a single conventional batch produced by the
conventional process.
For example, with a typical direct compaction tableting set-
up, the transit time on the line might be a little less than
10 minutes, at a throughput around 50kg an hour. With a
continuous solid-dose manufacturing process — integrating
feeders, mills, blenders, and a tablet press — it is possible to
change one or more aspects of the process line, wait until
the time for the transition, and then collect a sample. In ef-
fect, 30 independent experiments can be performed with
about 300kg of product.
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Here’s how it would integrate into a process development study:
1. Perform a risk analysis (FMEA or a similar method) for the
product under investigation using any and all available
date to estimate the intended process knowledge space.
2. Use one run of about 300kg where a different set of ex-
perimental conditions is established once every 10 min-
utes or so (this time will be dependent on the amount of
back mixing within the process).
3. Assimilate the results of changing about 30 conditions to
get the big picture of how they act individually, or in com-
bination to affect the output.
4. From that, refine the knowledge space and define a control
strategy that will keep the process within a design space.
This control strategy may involve closed loop control (of the
entire process) if a particular anticipated variation has a
significant impact on a critical product quality attribute.
5. After production starts, continue to map process parame-
ters to product properties. When those relationships
change, assess the quality of the product, and investigate
the possible causes of change, including material varia-
tion (that is, strive to develop a more nuanced under-
standing of the process).
6. If necessary, integrate new knowledge into the control
strategy going forward.
The big benefits
Money is always an issue in pharmaceutical manufacturing,
and continuous manufacturing can save lots of it. On one cur-
rent project, continuous manufacturing reportedly saved tens of
millions as the company did not have to run multiple manufac-
turing-scale development batches during process develop-
ment, thereby reducing material costs.
But perhaps more important than cost savings, continuous
manufacturing can gather knowledge at every stage of a prod-
uct’s lifecycle (from development through production) and loop
it back into a single, risk-based control strategy. That leads to a
general improvement in quality, and, consequently, fewer rejec-
tions. The latter is particularly important because the majority
of failed batch investigations end up with no root cause analy-
sis, according to the FDA’s Center for Drug Evaluation and Re-
search. Often, when manufacturing conditions change enough
to throw a product out of spec, the manufacturer never finds out
what specific conditions have changed. That is hardly a recipe
for improvement, and it is a leading cause of batch failures.
23

By continuously improving the process, a manufacturer can re-
duce end-product testing — or even eliminate it over time — as the
process becomes increasingly well understood, and controlled.
Well, if it’s all so easy…
Actually, it’s not so easy, and the barriers to adopting and imple-
menting continuous manufacturing are varied.
Inertia leads the list of challenges. Pharmaceutical manufactur-
ing processes and techniques have changed little over the last
50 years. Part of the reason for that is that the industry is highly
(and appropriately) regulated, and regulatory agencies
traditionally approved process applications based on previously
approved approaches. Today, however, the FDA has begun
championing emerging technologies for pharmaceutical manu-
facturing, and right now there are two FDA-approved continuous
lines in operation: Vertex, which received approval for the cystic
fibrosis drug Orkambi in 2015, and Janssen, which in April 2016
received FDA approval to move its drug for HIV-1 drug infection
from batch to continuous manufacturing. The European Medi-
cines Agency (EMEA) has been similarly supportive and has ap-
proved the same Vertex process for Orkambi.
Inertia also stems from long-held cultural beliefs and norms.
The pharmaceutical industry has been accustomed to look to
its vendors for equipment expertise, even as it expects its de-
velopment scientists to optimize each unit’s operation. Continu-
ous manufacturing, however, is an integrated process and must
be designed and run holistically. In fact, just like nearly all other
manufacturing industries (oil, chemical, food, agriculture, and
so on), continuous manufacturing ultimately demands a leading
role for Process Engineering.
Accordingly, to reap the benefits of continuous manufacturing,
the pharmaceutical industry will have to assume responsibility
for the entire manufacturing process, including process design.
Finally, another, less imposing hurdle is the fact that the equip-
ment used in continuous manufacturing is both smaller and
24 www.patheon.com ● doingbusiness@patheon.com
more intricate than that employed in the traditional batch model,
so cleaning is both more difficult and more time-consuming.
However, the time gains that come with continuous manufactur-
ing more than make up for that.
Patheon’s commitment to the future
Patheon is designing and building continuous manufacturing lines
today, incorporating several features to overcome those barriers.
We are designing the lines in a modular fashion, allowing equip-
ment (such as feeders and blenders) to be switched out as de-
sired. This makes changeovers faster as clean units can be put
on the line while the ones they are replacing are being cleaned.
A modular design is also more flexible, allowing the process
flow chart to be customized for each product. If a product works
well with a particular make and model unit — or if the product
was validated on that unit — then it can be installed easily in
any line making that product.
Patheon is also taking responsibility for the design and devel-
opment of the supervisory control system responsible for
coordinating unit operations. Again, because the process is an
integrated one, these responsibilities can no longer be left to
individual equipment vendors, and Patheon has worked to build
this capability internally.
Also, we are building up our ability to do risk-based process and
product development for OSDs. Because Patheon possesses
this knowledge internally, companies will be able to continue to
update and improve processes to ensure the highest level of
quality, even after filing, secure in the knowledge that the
changes they make will not adversely affect production or prod-
uct quality. Indeed, Patheon is aiming to implement dynamic
processes that can adjust to keep products in-spec in the face
of any variation, including natural ones.
In the scientific community, we tend to establish ideal standards
and assume that, with enough attention to detail, we can always
produce to them. However, perfection is not attainable. In phar-
maceutical manufacturing, there will always be variations in in-
gredients, or changes in temperature and humidity, that can
work to frustrate the best-laid plans, not to mention scientific
ideals. With continuous manufacturing, we can monitor product
quality continuously, and make adjustments in real time to keep
the product in spec. And when it isn’t, as will sometimes (albeit
rarely) happen, we can step in more quickly than ever before to
limit the volume of OOS product — saving time, money, and
staying ever closer to the ideal quality standard. ■

Single-Vendor
CDMOs Bring
Speed and
Cost Savings
to the Table
Anil Kane, Ph.D., MBA
Global Head of Robert Fry, Ph.D.
Technical & Scientific Chief Economist,
Affairs, Formulation, Robert Fry
Patheon Economics, LLC
As drug developers face the ever-pressing need to get mol-
ecules to market as efficiently as possible, firms large and
small are increasingly turning to CDMOs for help. The
CDMO industry is evolving to meet this need, spurring some
larger providers to offer forward-thinking services in the
form of end-to-end supply chain models for pharmaceutical
and biopharmaceutical clients.
At a panel discussion held at CPhI North America 2017 in
Philadelphia, four industry experts discussed how working
with a single-source CDMO partner can accelerate time to
market, add cost savings, and improve a formulation’s
chances of achieving regulatory success.
Speed and the single-source model
According to Anil Kane, Ph.D., MBA, Global Head of Technical
and Scientifiec Affairs of Formulation at Patheon, speed is es-
sential in drug development. Patients need their medications,
and competitors are vying to get their products to market first.
Working with even more compressed timelines are firms racing
toward commercialization with life-saving therapies that have
fast-track status. Likewise, small biopharmas deal with incredible
time pressure as they function in a market-driven environment.
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Patheon
OneSourceTM
Paul Nelson, MBA
VP of Supply Doug Johnson
Chain and R&D, President,
Amring OCAM
Pharmaceuticals Solutions, Inc.
Unfortunately, a multi-vendor approach often adds more
time and effort than many firms would like. Drug developers
need to negotiate numerous vendor contracts, complete
technology transfers, conduct revalidation, and complete
other time-consuming tasks.
Compare this approach to a single-source vendor option,
which has the unique ability for both drug substance and
drug product teams to collaborate from development through
commercialization, representing a major shift in the drug de-
velopment world. Aligned services in end-to-end supply
chains include the development and optimization of drug
substances and products; the manufacture of supplies in
batch through commercial sizes; clinical and commercial
packaging; supply chain management; and more.
Because cross-team collaboration allows for real-time feedback
about both the drug substance and drug product, one can move
efficiently from an API to a drug product with fewer errors. Potential
problem areas (like poor solubility, bioavailability, or process-abili-
ty) can be worked out before the process is scaled up. If formula-
tion problems are caught in early development phases and work is
completed to understand the molecule and its characteristics, de-
velopers will benefit from more robust process development that
avoids costly and time-consuming “re-dos” during scale-up.
25
Other time-savings that surface when all aspects of a proj-
ect lie with the same vendor are those associated with
external technology transfers, vendor qualification, negotia-
tions, and follow-up. All these activities are eliminated on
the client end. According to one CDMO, its trademarked
single-vendor network “eliminates 8-12 weeks of develop-
ment time for small molecules and 14-20 weeks for large.”1
While the single-source CDMO option may well be a for-
ward-thinking approach in the world of pharmaceuticals and
biopharmaceuticals, there is a strong precedent for it in oth-
er manufacturing sectors. For instance, Robert Fry, Ph.D.,
Chief Economist at Robert Fry Economics, LLC, explained
that Toyota’s lean manufacturing model limited the number
of suppliers it worked with so that the car maker could pro-
duce new models much faster than its competitors.
Breaking down barriers: Communication in
a single-source model
A single vendor offers access to a network of experts across
several disciplines who can share knowledge about a proj-
ect as a molecule moves from phase to phase, thus helping
to ensure it stays on a path toward commercial success.
Paul Nelson, MBA, Vice President of Supply Chain and R&D
at Amring Pharmaceuticals, offered an example of how hav-
ing such knowledge through a single vendor could have
benefited a recent R&D project he worked on. Several mol-
ecules in his pipeline had development work completed in
India while the manufacturing activities were conducted in
France. The project came to a halt after the first pilot batch-
es were made poorly. An investigation was launched to de-
termine the source of the problem, probing the possibility of
a development issue, tech transfer problem, manufacturing
issue, or something else. The time-consuming process
caused a significant delay.
If the development and initial manufacturing work had both
been done by a single vendor, the problem may not have
occurred. But if it had, the open channels of communica-
tions that a single provider offers would have made identify-
ing the root cause of the issue much easier.
Doug Johnson, President of OCAM Solutions, Inc., adds
that communication in a single-vendor network helped fix a
major problem his client had with an API. Had the client
used multiple vendors, resolving the issue would have re-
quired breaking a commitment with one manufacturer and
1 Patheon OneSource™, www.patheon.com/onesource/index.html, accessed
June 1, 2017.
26 www.patheon.com ● doingbusiness@patheon.com
starting a new contract with another vendor. Rather, the sin-
gle-source vendor was responsible for figuring out how to
remedy the problem with the API because it was their work
to begin with.
A single vendor with involvement in a project from soup to
nuts has a unique opportunity to help their client by integrat-
ing information that is generated from all points along the
project continuum. “A single vendor can leverage expertise
typically stashed in silos across different stages of the pro-
cess, from API development to formulation and the supply
chain,” noted Kane.
For example, in the Patheon OneSource™ model, a single
program manager oversees all activities, and bridges vari-
ous teams and sites performing the work. Having a program
manager so close to the client and the operations brings
efficiency and speed to the process.
Nelson agreed that this type of program management strat-
egy can be key to a project’s success. Decisions on sourc-
ing of API development and subsequent manufacturing are
usually made before an application for regulatory approval
is filed. Many companies do not have the coordination need-
ed to determine where final commercialization will be done
at the time they are getting ready to file. A program manager
can facilitate good coordination and look at the value stream
that cuts across all business units and functions.
Due diligence: Selecting the right partner
When helping pharma clients evaluate single-source ven-
dors, Johnson said he looks for four must-have characteris-
tics: capability, flexibility, stability, and caring.
●● A variety of capabilities are essential for helping to im-
prove a process and elevate a compound from ear-
ly-stage work through commercialization. When trying
to make a good match between what a client is looking
for in an outsourcing partner and the CDMO’s capabil-
ities, Nelson added that the process is as much an art
as it is a science. Several CDMOs may all have similar
equipment, but what really differentiates them are the
dedication and knowledge of the individuals working
on the projects. Is that know-how and capability em-
bedded in the organization? In some cases, clients
have been burned by the claim that an outsourcing
partner had competencies in areas it did not.
●● Without fail, unexpected twists and turns will surface
during drug development. A CDMO’s flexibility is criti-
cal, especially in early phases. Firms should have the
 dexterity to address unanticipated problems quickly
and adjust.
●● The vendor cannot simply provide a service; they must
have a track record of providing services well. CDMOs
tend to acquire other companies with expertise in a
specific area. A single-source vendor must also be re-
liable and stable — fiscally and in terms of longevity,
all while putting out high-quality work.
●● Larger CDMOs may be working on hundreds of proj-
ects simultaneously, but a good partner also ensures
every client receives the attention it deserves.
If a client pays more to have these four elements in a single
provider, Johnson said it is money well spent in exchange
for time saved and a better end-product.
Streamlining from the start:
One vendor, one contract
A key advantage of the single-vendor network is that clients
will only have one contract. Having to negotiate contracts
and legal agreements with multiple vendors requires a lot of
time and energy — even if just two suppliers are involved.
Nelson said he has seen contract negotiations between two
vendors working on the same project take as long as
18 months to finalize. This, of course, takes time away from
doing more valuable tasks, thus the single-source provider
is far more efficient in this respect.
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When negotiating a contract with a single supplier, it is criti-
cal to get the language right. From the stance of an econo-
mist, Fry said incentives must be balanced such that both
parties benefit from doing the right thing. It is crucial to con-
sider all contingencies and to cover all the bases. For
example, is the client protected if the price of raw material
sharply increased?
Nelson noted that risk management is also important when
looking at an end-to-end supply chain. There is economic
risk, the change of a supply interruption, and even location
risk, for instance, if the vendor is in a hurricane zone. All
types of risk must be examined to build the best risk-man-
agement strategy.
Summary
Like any new technology, some pharmaceutical companies
are still hesitant to adopt the single-vendor sourcing model,
especially small, emerging firms. While some companies are
taking a watch-and-wait approach to see how the single-ven-
dor concept pans out, those that are already embracing it are
reaping the benefits of efficiency and expertise. ■
27
 Patheon
OneSource™
4 Perspectives
on Single-
Vendor Drug
Development
Models

Bringing the Single-Vendor Approach

to the Pharma Industry

Robert Fry, Ph.D.

Chief Economist,
Robert Fry Economics LLC

From the perspective of an economist, time is money. And, partic-
ularly in the pharmaceutical industry, speed is of the essence. As
drug developers face increasing pressure to get their products to
market as quickly as possible, the CDMO industry is evolving to
meet this need by offering end-to-end services. In a recent inter-
view, Robert Fry, Ph.D., who, as a macroeconomist and Chief
Economist at Robert Fry Economics LLC, offered his observations
on these important trends.
single-supplier production process, which was an innovative part
of its lean production system. The single-source network was
mainly implemented for the purposes of better inventory man-
agement, but it also enabled Toyota to create faster turnaround
times than its competitors. Toyota could launch a new model on
the market every four years while other companies were doing it
every 5 to 10. Toyota was faster because it was working with
fewer vendors; therefore, the car maker spent much less time
negotiating contracts and eliminated many logistical problems.

Q: What are the benefits to a
pharmaceutical company (large or small)
adopting a single-vendor approach?
Fry: For the pharmaceutical industry, speed is an attractive
benefit. To my knowledge, Toyota was the first company to use a
Speed is also an important factor for the pharmaceutical indus-
try. In the context of drug development, where competitors may
be coming out with similar products or patents are expiring, com-
panies want to get their products on the market as soon as
possible. Speed is of the essence, which is perhaps the best ar-
gument for using a single supplier in the pharmaceutical industry.

28 www.patheon.com ● doingbusiness@patheon.com
Q: During the panel discussion at CPhI
North America 2017, you described the
single-supplier approach as a middle
ground between two ends of a spectrum.
Why do you feel that’s the case?
Fry: The single-supplier model is a middle ground between one
extreme, where there are many suppliers in a competitive indus-
try. At this end of the spectrum, it’s an options market, where
products are bought from the cheapest vendor. In this scenario,
the item is a commodity, multiple suppliers are producing it, and
many consumers are buying it. The other extreme is an integrat-
ed company that both produces and sells the product.
In some industries, a single supplier is desirable whereas in
others, an options model is sufficient. In the pharmaceutical
industry, having a single supplier (i.e., the middle ground) may
work better than having multiple suppliers (the options model)
or doing everything in-house (i.e., the integrated approach).
Drug development, which is research and labor intensive and
involves products that are very specific to the buyer, lends itself
to the single-supplier model.
Q: From the perspective of an economist,
what is the monetary value of using a
single supplier?
Fry: Time is money. Economists talk about a discount rate, or
the capital that is tied up in the rate of return paid on capital.
New Resource Saves Drug
Developers Time and Money
Anil Kane, Ph.D., MBA
Global Head of Technical and Scientific Affairs,
Formulation
In the pharmaceutical industry, speed is of the essence. As
drug developers face increasing pressure to get formulations to
market as efficiently as possible, the CDMO industry is evolving
to meet this need. The Patheon OneSource™ model exempli-
fies the benefits of an end-to-end supply chain model for phar-
www.patheon.com ● doingbusiness@patheon.com
The longer the wait between when the money is expended and
when a return on it is realized, the more it costs. In the context
of drug development, more money is probably spent on good,
solid research than on actual materials. In this scenario, what is
really being paid for is human capital. In other words, the value
of the materials is secondary to the brain power that knows
what to do with them.
Q: When a drug maker is evaluating these
types of contracts, what are the most
critical ingredients?
Fry: When building a contract, expertise is needed from many
different areas. It is important to involve an economist or busi-
ness person. The incentives must be structured such that both
parties in a contract are acting in their combined best interest.
Good lawyers are required to cover contingencies. It is also
important to involve personnel from the technology side. In the
context of drug development, it is not a case of simply minimiz-
ing the price of materials; the contract should be approached
much more holistically.
From an economist’s point of view, there should always be a
clause in case the cost of a material increases dramatically. For
example, if the price of a material doubles, the pharmaceutical
client must agree to pay more for it. Otherwise, no one will sup-
ply it because it’s too risky. Including ways to cover contingen-
cies, such as price index clauses, are important to ensure that
risks are shared by both parties. ■
maceutical and biopharmaceutical clients by accelerating time
to market, adding cost savings, and putting formulations on the
path toward regulatory success. Here, Anil Kane, Ph.D., MBA,
Global Head of Technical and Scientific Affairs of Formulation
at Patheon, elaborates on his views on the subject.
29
By accelerating the development
process, a single vendor can
deliver better healthcare to
patients faster and bring
business benefits to the sponsor.
Q: What are some top benefits of working
with a single-source CDMO?
Kane: We believe there are several key advantages when a
CDMO aligns its drug substance and drug product units. Be-
cause a single-source network encompasses the entire process
from end-to-end, a single program manager oversees a client’s
project from its early preclinical stages, through to commercial
supply. A single-vendor CDMO ensures continuity, accelerates
scale-up, and helps set the stage for regulatory success.
During development, strategies often change as the result of
clinical outcomes or regulatory requirements. With a sin-
gle-source network like Patheon OneSourceTM, the pathway is
nimbler than what a multi-source network offers, and can quick-
ly address issues that surface at any point from the preclinical
stage through clinical development and commercialization.
In addition, working with a single vendor throughout a product’s
lifecycle eliminates the need for expensive and time-consuming
technology transfers. It also ensures no knowledge is lost
during a transfer to a third party.
Any delays in bringing a product to market mean lost opportuni-
ty from a business perspective and lost benefits to patients. By
accelerating the development process, a single vendor can de-
liver better healthcare to patients faster and bring business
benefits to the sponsor.
Q: Do you have a case study that illustrates
the benefits realized by a small startup
company working with a single CDMO?
Kane: Patheon developed low-kilogram quantities of a cli-
ent’s drug substance for preclinical toxicity studies. The client
then took the compound to another vendor for early-stage for-
mulation. They tried several strategies that failed. The
compound was poorly soluble and did not attain the needed
exposure in animal models or Phase I clinical trials.
Two years later, the client asked us to revisit the compound.
They needed a strategy to improve its solubility and bioavail-
30 www.patheon.com ● doingbusiness@patheon.com
ability, and, thus, its probability of success. Patheon was able to
significantly improve the solubility of the compound by making
a solid dispersion, which resulted in better exposure.
If the drug substance had been kept in-house, Patheon could
have applied its solubility-enhancement programs at an earlier
stage, thus saving the client time and money.
Q: What concerns do prospective clients
have about the single-vendor approach?
Kane: The industry is still learning about the single-vendor
approach. However, many companies have experienced chal-
lenges with managing multiple vendors. A lot of time and
resources are required to oversee projects that are done at var-
ious sites, which has spurred many large pharma companies to
reduce the number of vendors they work with.
There are also benefits to having a single legal contract and
quality agreement. A lot of time is spent negotiating terms and
conditions with multiple vendors. Having to negotiate only one
contract with a single vendor has benefits for companies that
do not have the time and resources to audit multiple vendors.
Q: Does the single-vendor approach have
benefits regardless of a company’s size?
Kane: The pharmaceutical industry has traditionally worked
in silos with separate drug substance and drug product
groups. Companies with a much smaller team may not have
the necessary background to support the entire process from
drug substance to drug product, making the single-source
vendor quite advantageous.
In addition, resources have been shrinking at medium and large
pharma companies, which are consolidating to focus on higher
priority products and portfolios. They are also reducing the num-
ber of staff members that manage outsourced products and ser-
vices. Thus, the single-vendor concept is becoming increasingly
beneficial to medium and large pharma companies, too. ■
 A Single-Vendor CDMO Eases
Communication Flow
Paul Nelson, MBA
Vice President of Supply Chain and R&D,
Amring Pharmaceuticals
A single vendor offers access to a network of experts across sev-
eral disciplines who can share knowledge about a project as it
moves from phase to phase, thus helping to navigate its path to-
ward commercial success. In this article, Paul Nelson, MBA, Vice
President of Supply Chain and R&D at Amring Pharmaceuticals,
discusses his experience with single-source CDMOs.
Q: What does it take for a single-source
CDMO to be successful and to overcome
the silo mentality that is often found in
pharma companies?
Nelson: I had an experience where the silos did, in fact,
show up in a single-vendor model. In that case, having one
CDMO didn’t overcome the silo mentality, and the partnership
didn’t work very well.
For the single-vendor model to work, the CDMO must have a
single project management strategy throughout the relationship
from beginning to end. That way, the client doesn’t have to work
with one part of the CDMO for raw materials and API develop-
ment, another group for conversion to finished product, and yet
another unit for packaging. It’s a more streamlined and suc-
cessful approach to drug development.
Q: What risk management issues must be
resolved for a pharma company to fully
embrace the single-vendor model?
Nelson: It depends. Risk management is improved if the
CDMO has been in business for a long time, is financially sta-
ble, has a well-established management team, and possesses
the know-how to do the work from the beginning to the end of
product development and supply.
www.patheon.com ● doingbusiness@patheon.com
Several risks must be managed to ensure that medicine gets to
patients consistently. I look at all the risks along a supply chain
such as staff turnover at the vendor, financial issues, or location if
the firm is in a hurricane area, for example. If a single vendor can
show that this model works by reducing the risks associated with
clinical and commercial supply, I think the market will embrace it.
Q: What is the most important thing to know
about a vendor before signing a contract?
Nelson: The vendor must have the expertise to deliver on its
promises. Contracts are developed on the basis of assumptions
about how well the CDMO will perform. The decision to sign on
the line involves more than just a good PowerPoint presentation.
There must also be tangible experience that gives the sponsor
confidence that the CDMO will meet the outlined expectations.
For example, it is important to know who works for the vendor
(that is, who are the subject-matter experts), and there must be
some level of confidence that they are going to stay. It would not
be ideal to sign a contract with a vendor on the basis of exper-
tise that is in place at the time, only to have those key personnel
leave the company soon thereafter. In that case, the client is left
hoping that the vendor’s know-how has not left with the people.
For the single-vendor model
to work, the CDMO must
have a single project
management strategy
throughout the relationship
from beginning to end.
31
Q: Are there other benefits to working with
a single vendor from preclinical product
development to supply?
Nelson: In addition to silos, there are barriers to
communication between organizations. I’m working on
several products that are being developed in one country,
and scaled up and packaged in others. Getting the different
languages, cultures, and priorities of multiple companies in
sync and maintaining it from preclinical development through
finished product is very time consuming. A lot of resources
are required to manage cooperation among different
organizations. In this respect, working with a single vendor
would have numerous advantages.
Smaller Biotech Companies
and the Single-Source CDMO
Doug Johnson, Ph.D.
Founder,
OCAM Solutions
A single-source CDMO that manages the end-to-end relation-
ship with pharmaceutical or biopharmaceutical clients can bring
many benefits and efficiencies to the development process.
However, smaller companies, in particular, may still be reluctant
to work with a much larger, single-source vendor. Expanding
upon the discussion, Doug Johnson, Ph.D., Founder of OCAM
Solutions, points out these important issues.
Q: During the panel discussion at CPhI North
America, you stated that the value of the
single-vendor model is increasing. How so?
Johnson: How vendors have developed competencies has
changed over time. More recently, single-source contractors
have been expanding by acquiring very competent companies
rather than by trying to cultivate a particular competency in-
house (i.e., without the starting point of capability). The merging
32 www.patheon.com ● doingbusiness@patheon.com
Q: If a larger pharma company has a lot of
in-house capabilities, including a good
preclinical/early development team, is there a
benefit to outsourcing early in the process?
Nelson: In the case of larger companies, the most benefit
from having an outsourcing partner comes in Phase III and
beyond. However, mainly from a knowledge-transfer stand-
point, there could be some benefit to having the same
CDMO that is going to provide the final medicine be involved
early on. For example, it could be useful for the CDMO to
have in-house, first-hand knowledge of how the compound
behaves in the laboratory before the transition to scale up. ■
of two strong, capable companies brings advantages in time-
line synergies, information flow, and general project integration
without having to sacrifice competency.
Q: What might be a pharmaceutical or
biotech company’s biggest concerns
with using a single-source vendor?
Johnson: I work mostly with small companies, which are
sometimes concerned that they won’t get the equivalent amount of
attention from the contractor as a large pharma company. This is
less of an issue when a small pharma/biotech company is working
with a small contractor, because in that scenario, the client gets to
know the executives at the contract organization. When larger
CDMOs are created through acquisitions, it is not always possible
for clients to get that personal touch from the top.
I work mostly with small
companies, which are
sometimes concerned that
they won’t get the equivalent
amount of attention from
the contractor as a large
pharma company.
Also, large companies sometimes have the reputation of being
more policy-driven than science-driven, or of being more bureau-
cratic and less flexible. Small companies have an affinity toward
working with contractors that they perceive to have modus operan-
di similar to their own (e.g., being highly flexible and entrepreneur-
ial). This concern is allayed if a company has a good experience
with a large, soup-to-nuts contractor. If the contractor has to make
changes on the fly and proves to be responsive and flexible, then
the small company will be more willing to sign a contract with them
for their next project.
Q: Do you have any specific examples of
how a single-source CDMO may benefit a
small start-up company?
Johnson: In one case, a client selected a drug substance
manufacturer because of its unique fit between what the vendor
had to offer and what the client needed. This was for a Phase I/II
clinical supply run. The manufacturer was also able to produce the
active pharmaceutical ingredient (API) in capsules, which was ex-
actly what the client needed. A lot of hassle that would have been
associated with method transfer was avoided, because the meth-
ods were very similar. In addition, the timing was more coordinated
between production of the API and production of the drug product.
www.patheon.com ● doingbusiness@patheon.com
In another case, our client did not initially choose to work with a
large contractor. The vendor they contracted to manufacture their
drug substance was subsequently acquired by a larger company.
The transition was managed well and didn’t create any glitches for
the client. They were so pleased with the work done by the drug
substance group that they opted to stay with the company for their
drug product work. Even though the client didn’t initially plan to use
a single vendor, it worked out well.
Q: Are there advantages in terms of
when clients begin working with a
single-source CDMO (e.g., in Phase III
versus early formulation)?
Johnson: There has been a shift on the part of larger contrac-
tors to being more interested in working with clients from the begin-
ning. I have two clients for whom this has been particularly beneficial.
In one case, the project progressed as far as it could and was put on
hold. However, because the same company worked on both sec-
tions of their project, it means there will only be one source of data
when they have to perform due diligence, which will be cleaner and
easier. The other case involved steps in which there were delays.
Managing delays in the process is much easier when both the drug
substance and the drug product are worked on within the same
company because a delay in one company doesn’t have to be ex-
plained to another. If one company is involved from start to finish,
the client’s project has the advantage of being less fragmented. ■
For more perspectives on
single-vendor vs. multi-vendor
manufacturing approaches,
visit patheon.com/onesource.
33
 Clinical
Services

Cold-Chain Fully
Automated
Assembly and
Labeling of
Pre-Filled Syringes
for Clinical Trials

Cold is undeniably the new normal for the biopharmaceutical
industry. By 2020, greater than half of bestselling drugs will be
cold-chain products, most of which are injectable.1
With sponsors devoting much of their resources to developing
these large molecule products, the demand for pre-filled syringes
is escalating rapidly. Many large biopharma companies have their
own dedicated automated facilities for assembling and labeling
pre-filled syringes for commercial products. However, some lack
sufficient capacity to meet both commercial requirements and the
growing demands of global clinical trials. Efforts to address both
needs can lead to time-consuming bottlenecks as commercial
and clinical operations compete for finite internal resources.
In an effort to forestall bottlenecks and conflicts, sponsors are
turning to outsourcing partners for help. The process of assem-
bling and labeling prefilled syringes is considerably more chal-
lenging than that of inserting tablets into blister packs, due to
the special handling requirements of biologics.
To protect the shelf life of costly biologics, these products re-
quire refrigeration, with time out of the cold chain — also known
as time out of environment or TOE — sharply limited. In fact, as
many as 40% of biological products in development today are
permitted zero time out of environment, meaning that the entire
process of assembly, labeling, and packaging of pre-filled sy-
ringes must take place in cold rooms. The proportion of these
biologics requiring 24/7 refrigeration is projected to rise.
automated assembly and labeling of pre-filled syringes under
cold (2° C to 25° C) or ambient conditions available. Introduced
in 2017, this service is exclusively available at the Basel, Swit-
zerland facility, where a dedicated cold facility maintains cold
room conditions from truck to dock, through assembly, storage,
and distribution.
Accessing automated solutions
Placing tablets into blister packaging is simple compared with
assembling and labeling pre-filled syringes.
As recently as five years ago, help from a clinical supply chain
partner in assembling and labeling pre-filled syringes for a clin-
ical trial meant a painstakingly time-consuming manual pro-
cess. This limited the use of pre-filled syringes to relatively
small trials or production runs. Thankfully, times have changed,
and so have the options.
To illustrate the difference between then and now, imagine a
production suite containing 10 trained operators who spend a
day manually assembling and labeling pre-filled syringes. At
the end of the shift day, the yield would be about 400 syringes.
Today, using precision automated equipment in that same pro-
duction suite, the yield at the end of the shift day is about

To address this growing need, Fisher Clinical Services has be- 1 “2015 Biopharma cold-chain forecast.” Pharmaceuticalcommerce.com.
Pharmaceutical Commerce. 19 December 2016. http:// pharmaceuticalcom-
come the first supply chain partner in the industry to make fully merce.com/special-report/the-2015- biopharma-cold-chain-landscape/

34 www.patheon.com ● doingbusiness@patheon.com
13,000 syringes. This tremendous productivity increase makes
it practical and cost-effective to use pre-filled syringes instead
of higher-priced vials and needles for studies involving thou-
sands of subjects.
Quality assurance: Consistency and control
Precision automation also offers quality assurance that is supe-
rior to that of manual assembly when conducting large runs,
making the use of pre-filled syringes as risk-free an experience
as possible for healthcare professionals and patients.
Variations in the manual assembly of pre-filled syringes are in-
evitable and can affect performance. For example, an under- or
over-turned plunger rod can lead to leakage that compromises
syringe integrity, ruining the unit, and wasting costly IMP.
Similarly, an imprecisely applied needle safety device (NSD)
could result in a needle stick injury, an unnerving experience
even for a healthcare professional who knows the syringe was
not previously used.
Automated assembly and labeling de-risk the process through
consistency and control. Automated systems vary, but the best
ones are highly precise and efficient, assembling and labeling
pre-filled syringes in one fully automatic process. The systems
employ a combination of customized equipment, sensors,
torque control, and camera systems that permit operators to
maintain full control over the entire process from start to finish.
For instance, a fully-automated compliance check uses a cam-
era system to detect the position of the syringe at all times.
Sensors monitor every step of the assembly and labeling pro-
cess, reading exactly how much force is being applied to a
backstop or plunger, for instance, and thus eliminating the risk
of under- or over-turning. Using camera checks, a labeling plat-
form ensures that the correct patient label is affixed to the cor-
responding syringe.
Automated assembly and labeling of pre-filled syringes are in-
creasingly preferred by most sponsors, but manual assembly
may be the most flexible and cost-effective option for small tri-
als or production runs. New options are now available that
couple some elements of automation with manual assembly to
deliver greater precision to smaller runs.
Sponsors can benefit from these options by building flexibility
into their planning and by exploring the assembly and labeling
services that are most suited to their needs. It’s important to
engage a supplier that is capable of meeting both automated
and manual needs.
www.patheon.com ● doingbusiness@patheon.com
Innovative automated solutions
positioned globally
As the use of pre-filled syringes continues to grow, flexibility
and careful planning in clinical settings will benefit sponsors
during development and beyond by establishing a strong foun-
dation for a commercial plan. Meanwhile, suppliers must adapt
to the changing needs of sponsors by continuously innovating
new solutions.
So rapidly has demand grown that Fisher Clinical Services now
offers precision pre-filled syringe assembly and labeling at
three of its facilities — in Allentown, PA, U.S.; in Basel, Switzer-
land; and in Horsham, U.K. All three facilities employ a consis-
tent global process. This global expansion of services include
eliminating glass-to-glass and glass-to-steel contact in equip-
ment. Glass-to-glass contact can cause syringes to crack,
causing safety issues, compromising product sterility, and re-
sulting in waste. Glass-to-steel contact can scratch syringes, a
cosmetic effect that can nonetheless cause units to be rejected.
The latest innovation includes the labeling and secondary packag-
ing of pre-filled syringes by fully automated, quality-driven, pro-
cesses and technology under both cold and ambient conditions.
Introduced in 2017, the fully automated, cold chain services are
currently available at the Basel facility, while both the Allentown
and Basel facilities support fully-automated operations. Semi-au-
tomated services continue to be performed at Horsham.
Like all Fisher Clinical Services’ options for assembling and la-
beling pre-filled syringes, the patent-pending, cold-chain
system in Basel is designed to meet the specific, unique re-
quirements of clinical trials. Here are the key benefits:
●● Reduces IMP wastage
●● Mitigates TOE via cold room assembly
●● Maximizes flexibility to meet the needs of every trial and
every syringe
●● Ensures accuracy and legibility of fixed and variable text
●● Safeguards patients and medical staff
●● Mitigates risk through global processes and quality
●● Delivers efficiencies and eliminates costly bottlenecks. ■
35

Considerations
in Selecting an
Outsourced
Solution
Gavin Murdoch
Senior Director, Strategic Partnerships
Business Development
The traditional business model for in-house pharmaceutical
manufacturing is nearly a thing of the past. More companies are
turning to outsourcing to achieve flexibility and efficiency in a
highly competitive market. According to a recent report by busi-
ness intelligence provider Visiongain, the global contract bio-
pharmaceutical manufacturing market is predicted to reach
$79.24 billion in 2019. This is a substantial increase from
$54.54 billion in 2013.1 Nevertheless, this does not mean an out-
sourcing strategy is necessary for every project. A thorough
evaluation of a manufacturer’s capabilities and true cost struc-
ture must be completed early to determine if its goals can be
achieved in-house. More importantly, this decision must be made
early to allow enough time to initiate an outsourcing partnership.
Expertise and capacity:
Do you have what it takes?
The drug development process begins with discovery, where
most companies rely on in-house scientists to create the
1 Visiongain, Pharmaceutical Contract Manufacturing World Market to Reach
$79.24BN in 2019 — https://www.visiongain.com/Press_Release/761/%E2%
80%9CPharmaceutical-Contract-Manufacturing-World-Market- To-Reach-
79-24bn-In-2019%E2%80%9D-New-Visiongain-Study-Predicts
36 www.patheon.com ● doingbusiness@patheon.com
Commercial
Manufacturing
and Technology
Transfer
chemical or biologic process. However, a small company may
choose to outsource this stage virtually. Either way, most of
the focus at this point is getting the molecule to the clinic with
little consideration for future scalability or its commercial sup-
ply. It is in Phase II clinical development when manufacturers
often consider more advanced formulation development.
For those companies that have been working virtually to de-
velop a product and formulation, Phase II can be the ceiling
for scalability with existing partners. Typically, smaller-scale
virtual providers are not capable of scaling up or may not
have commercial good manufacturing practice (GMP) com-
pliance. It is at this stage when small companies must start
to consider outsourcing for registration and commercial
supply for their project. For larger pharma companies, the
traditional perception is that, because they have the neces-
sary capabilities in-house, it is best to keep manufacturing
there. Yet, given the complexity of new products, past man-
ufacturing capabilities and technical know-how may not be
adequate, and outside options should be considered. CD-
MOs may have a strategic advantage based on their expo-
sure to a variety of projects with multiple types of processes,
and that type of experience can translate to a higher level of
knowledge in both operations and development.
Capacity is also a factor at this stage, as a company must
ensure it has the space to manufacture its product. Demand
forecasting for the future commercial product and, in partic-
ular, launch forecast accuracy are often significantly wrong.
In fact, over 60% of drug forecasts over- or underestimate
peak revenues by more than 40%. 2 These inaccurate fore-
casts have damaging and costly impacts. When demand is
overestimated, a decision to manufacture in-house results
in expensive, unused facility capacity for both drug sub-
stance and drug product. When demand is underestimated,
the manufacturer faces a race against the clock to quickly
produce lifesaving medications that must still be of the high-
est quality. This takes place while facing lost sales.
In addition to standard capacity needs, it is important to
consider any specific or unique technologies needed for the
product. New and emerging technologies, including sterile
single-use processes, biologics perfusion, HME or continu-
ous manufacturing, create exciting possibilities for improved
development and commercial efficiency and flexibility. As
these technologies are not as widespread, they can be diffi-
cult to apply internally for just a single project or product.
When it comes to expertise and capacity, a manufacturer
must consider if it wants to invest in the equipment and ex-
pertise needed for these technological approaches; or if it
wants to defer to a CDMO with greater experience and a
variety of projects to stabilize the expertise.
Timeline considerations
after partner selection
Companies that ultimately decide to outsource often under-
estimate the time required once the decision has been
made. The supplier selection process, including requests
for proposals (RFPs), evaluation of capable suppliers, and
final selection, takes considerable time and is often man-
aged by groups far removed from the technology experts.
This step can take up to six months to complete, time which
becomes critical at start up. A quality audit should be part of
a CDMO evaluation, which, depending on availability of in-
ternal and/or external quality experts, could require a wait-
ing period of up to three months.
ing participated in the initial selection of the partner. They
often bring new questions and new needs that can compli-
cate the deal and delay the project. A company can prevent
this kind of delay by ensuring all appropriate parties are in-
volved from the beginning rather than handing off to
Procurement or Supply Chain to manage exclusively. Final-
ly, the deal terms and conditions and scope for the project
will be formalized in a master service agreement (MSA).
Even in a scenario where there is an attempt to expedite this
process, it is best to anticipate a three- to six-month waiting
period to complete this part of the process. New stakehold-
ers from legal, finance and supply chain are often involved
here for the first time, and the process of each trying to pro-
tect the interests of their company can affect the original
need and timeline. It is common for companies to not fully
understand their own negotiation and approval processes,
leading to rework and delays, depending on the size of the
companies and number of people involved.
Making a decision between keeping a project in-house ver-
sus outsourcing is not an easy one, especially with so much
at stake. If a company has the expertise, technology, and
experience necessary to work with today’s most innovative
drugs, it may have a case to stay in-house. However, if it
does not have those capabilities, evaluation of an outsourc-
ing solution will provide the optimum long-term solution. By
working back from your desired launch date and including
the steps above in your development and manufacturing
timeline, you will be able to better manage the process in
order to meet your goals. ■

After selection, a kickoff and onboarding process with the

selected partner is necessary, including the commitment of
stakeholders. It is not uncommon at this point for research
and operations personnel to become engaged after not hav-

2 Patheon, Implications of Inaccurate Forecasting on Biologics Drug

Substance Manufacturing – White Paper — https://www.patheon.com/en-us/
Ideas-in-Action/Material-Details/59/Implications-of-Inaccurate-
Forecasting-on-Biologics-Drug-Substance-Manufacturing---White-Paper

www.patheon.com ● doingbusiness@patheon.com 37

Technology
Transfers:
Reaping
Rewards,
Reducing
Risks
Thomas Dax Mirko Gabriele
Director, External Global DPS Technology Transfer,
Manufacturing, API Senior Manager
There are a number of strategic advantages companies can
achieve in pharmaceutical production by transferring production
between sites. They can safeguard supply by producing at more
than one site, and improve distribution by moving production clos-
er to critical markets. They can also reduce program costs and
risks by moving production to sites that are better qualified, can
produce more economically, or are better positioned to meet the
needs of regulators.
For several reasons, transferring production — and the technol-
ogies that undergird it — can be risky. The same product can
behave differently in different equipment, resulting in low yields
or even batch rejections; staff at a receiving facility may not have
the proper technical skills to execute a specific process; or there
may simply not be enough trained staff on site to assure that the
job will be done correctly. Also, even as companies may not take
the time (or expend the effort) to create and provide good docu-
mentation of their product or process, their partners may not in-
vest the necessary resources to ensure efficiency and quality.
If any of the above occurs, time and money will be lost in reme-
diation and patients may not receive their medication.
The net of these risks is that companies do not transfer produc-
tion as often as they probably should.
38 www.patheon.com ● doingbusiness@patheon.com
Commercial
Drug
Manufacturing
Product
and Technology
Services
Transfer
Paul Jorjorian
Director,
Global Technology Transfer
However, Patheon has a great deal of experience in technology
transfers and has developed processes and techniques for
reaping its rewards while reducing its risks.
When it works: Three successful transfers
1. Product X
The product was a registered intermediate of a novel first-in-class
API Patheon was producing for a client in a 10-step process. One
high-temperature step was especially complex, requiring good
control to balance quality and yield. We were spending a dispropor-
tionate amount of time and effort getting this step right, and we
knew that other manufacturers — with more experience in this spe-
cific technology — could likely do it better. Accordingly, we set out
to find a manufacturer who could take over this production step for
us, and we found one in China that could supply our plant in Austria.
To get the process up and running on the supplier site in China,
we sent two of our people to the Chinese plant to work with
them for a week; from the first batch, the product was in spec.
Including four weeks to evaluate suppliers, four weeks of tech
transfer activities, and five-to-eight weeks for raw materials and
lead times, the total time from project start to the first batch
produced in China was about four months.
2. Product Y
This product was a recombinant-fusion protein entering Phase III
clinical trials. Patheon’s client had a partially-developed perfu-
sion process and wanted production to commence simultane-
ously in Europe and Asia-Pacific. Their timeline was tight.
We transferred the process from our client to our plant in
Groningen, the Netherlands, and our plant in Brisbane,
Australia, scaling up production in both at the same time and
writing half the batch records in each location.
The total time from receiving the process information and or-
dering the raw materials to full production at both sites was four
months — about 30% to 40% faster than the industry average.
3. Product Z
Product Z was a small-molecule, lyophilized product. Our client
wanted to transfer commercial production to Patheon. Unfortu-
nately, the technical data we received about the product and
the lyophilization cycle (the freeze-drying process), was not
sufficiently robust to guarantee a consistently high-quality prod-
uct. In particular, we could see from the historical data that the
lyophilizing cycle was not challenged at the edge of the critical
process parameters (CPP), and there were several cake ap-
pearance issues even under optimum conditions.
Instead of replicating the process as it was, we worked with the
client to improve it, thereby getting the product right the first time,
and improving both yield and quality over the prior process.
Why it works: A framework for
successful tech transfers
Through the examples of products X, Y, and Z, we can see four
important elements of our approach in operation.
1. Assessing risks and developing
mitigation plans prior to transfer
To do that, we deploy a seven-step process we call the 7Ms. They are:
I. Machines, meaning their capacity, and the forecast analysis
II. Materials, taking into account such supply issues as lead time,
availability, quality, and whatever supplier issues we foresee
III. Manpower, including staffing requirements as they are af-
fected by demand fluctuations
www.patheon.com ● doingbusiness@patheon.com
IV. Manufacturability, which means looking at product issues
and process robustness
V. Market, assessing the impact on volumes of competing
products, as well as levels of market acceptance, among
other factors
VI. Measurement, which models the boundary limits of the
preceding five Ms
VII. Mitigation, in which we develop a thorough plan to man-
age the identified risks
A comprehensive risk assessment will yield a predictable set of
activities on which a plan can be constructed. Such a plan al-
lows all stakeholders to begin on the same page, ensuring the
alignment of both the sending and receiving teams before the
actual transfer. Furthermore, these steps generate thorough
documentation of both process and product, making knowl-
edge transfer easier and less vulnerable to informational gaps.
Once identified, those can be filled, and steps that need to be
improved can be identified (as was the case with Product Z’s
lyophilization cycle) and resolved before the transfer.
2. Fixing problems prior to transfer
As noted, our assessment of product Z revealed a weakness in
the lyophilization (lyo) cycle, notably cake appearance issues.
Accordingly, and together with the client, we performed a sys-
tematic characterization of the product and its formulation to un-
derstand better its behavior during lyophilization. We mimicked
the lyo process in the lab, identifying the critical process param-
eters that were likely to vary in production, such as equipment
performance, temperature, humidity, and time and velocity rang-
es. Then, in the lab, we measured the impact of those factors on
yield, quality, cosmetic appearance, and varied them to see what
changes produced the highest quality across all measures. In
this way, we developed a more complete understanding of the
factors that affected production and defined the envelope in
which quality and yield would be optimal. During this process, we
also were able to understand better the physical characteristics
of the API, ensuring more reliable behavior in production, and
limiting the impact of these variables on the drug product.
Fixing the lyo problem before the transfer enabled us to im-
prove the process, strengthen the product’s regulatory submis-
sion with the additional information we obtained, and created a
strong relationship with our client that served us both well in this
transfer and in subsequent ones.
3. Standardizing processes and equipment
For the recombinant fusion protein, Product Y, Patheon’s plants
in Groningen and Brisbane essentially had the same upstream
and downstream equipment (such as chromatography columns
39
and skids), so we could be confident that what worked in one
would work in the other. And not only was the equipment the
same, but the two plants also have very similar operating pro-
cedures. For example, each plant operates the 500-liter perfu-
sion bioreactor (a finicky process) in the same way and have
almost identical standard operating procedures for common
downstream processes. Consequently, batch records written
for one plant could be transferred easily to the other.
We also made sure that the materials and supplies were al-
ready in both facilities’ systems, so neither they nor their suppli-
ers needed to be requalified, saving time and ensuring consis-
tency and quality.
4. Paying as much attention
to people as to process
Typically, the staff at the sending plant have expertise in a partic-
ular product and process. That, of course, should be captured in
the documentation. However, even if it is, a specific answer to a
niggling problem may not be easy to find, and even with the best
documentation, a nuance may go missing. The staff at the re-
ceiving plant may have deeper expertise in the type of product,
or process, that can be applied to improve the existing process
and streamline the transfer. However, sender and receiver can
only help each other, and optimize the transfer, if their working
relationship is close, collegial, and congenial. The single most
important ingredient that makes that relationship work is trust.
And trust emerges most reliably from successful collaboration.
For the Fc-fusion protein, Product Y, the teams at each of the two
plants communicated in real time about progress, challenges,
solutions, and so on. Joint project team meetings were held regu-
larly, and communication between the plant managers was
excellent. Given that all the communication was done remotely, it
certainly helped that many of the people in the Groningen and
Brisbane plants knew and had worked with each other previously.
If teams have not worked together before, partners need to take
the time and trouble to allow trust to develop naturally through
proximity. For example, for the API production step on
Product X that we transferred to China, we assumed the not in-
considerable cost of sending knowledgeable people thousands
of miles to the site. That was money well spent. It served to ac-
celerate the knowledge transfer and when problems did surface
(as they inevitably do), the receiving plant was not left to its own
devices to try to solve or fix them without adequate support.
In the case of Product Z, we assembled a joint team with the cli-
ent to work on improving the process, giving both parties time to
get to know each other before the transfer. This paid off down the
road as the team was able to work together productively through-
out the lifetime of the product, supporting each other in matters
concerning strategy, supply, distribution, and regulatory affairs.
40 www.patheon.com ● doingbusiness@patheon.com
Why companies are leery of
technology transfers
As noted, technology transfers don’t happen as often as they
might, or as often as perhaps they should. Companies have
legitimate concerns about supply interruptions and the costs
they may incur as a result.
Then there is the expense. To plan one thoroughly and execute
it carefully requires a significant investment. To minimize the
cost, companies are sometimes tempted to shortcut the plan-
ning and rely on what’s worked before for similar products. This
is a false economy. Looking at our history of transfers, we have
found that the chance of getting them right by mimicking the
transfer of a similar product are no better than 50% — a coin
toss. Conversely, beginning fresh, with a blank sheet, and ana-
lyzing the process as if you have never done it before, the
chance of right-the-first-time success is better than 90%.
Yes, technology transfers require investment. However, the
cost is less than that of fixing one that went wrong.
In addition, a technology transfer provides the opportunity to
make product and process improvements that might otherwise
be missed. In practice, production processes often run for years
without being improved meaningfully. Companies always have
other priorities, including new projects, which steal attention from
ongoing products. But in making a transfer, a company is forced
to make changes; there will always be differences at the receiv-
ing site that need to be accommodated. Those changes — prop-
erly planned for and executed — can realize enduring strategic
advantages by lowering production or distribution costs, or by
improving a company’s competitive position in a given market.
A challenge worth accepting
Transferring the production of sophisticated products from one
site to another, or to several others, will always be challenging,
and will always involve risk. But not only are there more opportu-
nities today for companies to improve how they have their
products made, there are also more options for securing supply,
producing closer to critical markets, being more agile in respond-
ing to changes in demand, and securing sophisticated help with
technically challenging production steps. Specialist expertise,
solid processes, and standardized operating procedures and
equipment all work together to minimize risk and costs.
A consistent risk-based approach, continually updated with new
data from quality by design and design of experiments initiatives,
will improve both Patheon’s and the industry’s ability to efficient-
ly, effectively, and seamlessly transfer production going forward.
The rewards can be substantial, and transferring technology
should be an option every company places top of mind. ■
 Client
Success
Stories

How Pacira
Pharma is
Working to
Help Curb the
Opioid
Epidemic

Poorly managed postoperative pain can have a significant impact
on a patient’s recovery. For example, it can put them at risk for
medical complications, including deep vein thrombosis, pulmonary
embolus, and pneumonia.1 In addition, today’s methods for drug
delivery often introduce a drug into the body in large quantities
where it must then systematically travel until it reaches the intended
area. This wide-scale distribution increases the potential for harm-
ful side effects and requires a higher cost for care due to the amount
of drug needed.
this epidemic, the FDA assembled a task force in 2013, which,
among other efforts, encouraged the development of abuse-deter-
rent formulations of opioids. However, the most effective way to
stop opioid dependence is to eliminate the use of these highly ad-
dictive drugs after surgery altogether. This was the goal of Pacira
Pharmaceuticals, a specialty pharmaceutical company focused on
the development of non-opioid products for postsurgical pain con-
trol, when it developed its injectable suspension, EXPAREL®.

Another concern about the impact of poorly managed postopera- Changing the standard of care
tive pain is related to the use of opioids for pain relief and a rise in
EXPAREL is a local analgesic utilizing bupivacaine in combination
the misuse and abuse of these drugs by patients. In a recent study
with the product delivery platform DepoFoam®. DepoFoam is made
from Stanford University, researchers found that patients undergo-
of microscopic polyhedral particles composed of numerous non-
ing 11 of the most common types of surgery were at increased risk
concentric internal chambers that encapsulate a drug. These dis-
for chronic opioid use.2 The increased use of opioids after surgery
crete chambers are separated by lipid membranes and filled with an
has caused a cascade into the abuse of prescription painkillers,
aqueous solution of a drug. Once the drug is inside the DepoFoam
and opioid dependence rose more than 3,000% from 2007 to
technology and injected into the patient, their body begins to break
2014.3 According to AddictionCenter.com, there are an estimated
down the lipid membranes. This is a naturally occurring process
4.7 million people in the U.S. dependent on painkillers.4 To address
that releases the drug without altering its molecular structure.

1. Agency for Healthcare Research and Quality, Improving the Quality of Care
Through Pain Assessment and Management — http://archive.ahrq.gov/
professionals/clinicians-providers/resources/nursing/resources/nurseshdbk/
WellsN_SMTEP.pdf
2. National Public Radio, Many More People Seek Medical Help For Opioid
Abuse — http://www.npr.org/sections/health-shots/2016/08/01/487940139/
many-more-people-are-seeking-medical-help-for-opioid-abuse
3. Surgical Products, Stanford Study Confirms Post-Surgical Patients Are
Especially Susceptible
4.To Opioid Abuse — http://www.surgicalproductsmag.com/news/2016/07/
stanford-study-confirms-post-surgical-patients-are-especially-suscepti-
ble-opioid-abuse Addiction Center, Painkiller Addiction Statistics — https://
www.addictioncenter.com/painkillers/
DepoFoam permits both systemic and local delivery, which means
the platform can release drugs into the bloodstream via the intersti-
tial space or into a body compartment, such as a joint. This target-
ed delivery system allows the injection of drugs into the areas of the
body where pain receptors exist, focusing the administration of
EXPAREL to only the areas where it is needed.
The delivery of the non-opioid drug, EXPAREL, through the
DepoFoam technology provides physicians and patients with the
tools necessary to overcome the challenges associated with man-

www.patheon.com ● doingbusiness@patheon.com 41
aging postoperative pain. “EXPAREL limits the amount of drug
needed after surgery, and, as a result, the potential for adverse ef-
fects is reduced dramatically,” says Ray Kaczmarek, Vice President
of Commercial Manufacturing and Supply Operations at Pacira.
“Most importantly, it empowers physicians to change the standard
of care for postsurgical pain and ultimately gets the patient back up
on their feet without the severe adverse events or the side effects of
an opioid.” After it is infiltrated into the surgical wound prior to clo-
sure, EXPAREL can deliver 72 hours of postsurgical anesthesia,
Kaczmarek says. This significantly reduces pain during the first 24
to 48 hours after surgery, when it is experienced the most.
Addressing the challenges of
EXPAREL manufacturing
Beyond the composition of lipid components and the need for
aqueous excipients, the effectiveness of DepoFoam’s delivery plat-
form is dependent on the manufacturing process used to develop
it. Kaczmarek says one challenge is the critical need to properly
handle EXPAREL in its sterile state. “Once we start the process of
creating the liposome, we have to maintain sterility assurance all
the way through to the patient,” he explains. “That means the bulk-
ing process, the filling process, and everything done until the point
where the physician begins to utilize the drug.” Other important
factors for the successful manufacturing of EXPAREL include tem-
perature, agitation, and the design of the sterility assurance pack-
age around the drug.
What also makes the manufacturing process for EXPAREL chal-
lenging is the need for a manufacturer to understand the complexity
of the drug’s critical process parameters and how they interrelate to
each one of its attributes. If any one of the parameters is changed,
the drug product will either fall apart or will not work in an appropri-
ate way. Additionally, the limitations of today’s downstream technol-
ogies create a manufacturing bottleneck that makes the scale-up of
EXPAREL difficult. “The sooner the industry starts improving down-
stream technologies, the sooner we will be able to maximize the
technologies, such as TFF [tangential flow filtration], to improve our
manufacturing scale,” explains Kaczmarek. “Until then, we’re creat-
ing newer platforms and utilizing different technologies to allow the
maximization of scaling by limiting exposure in the downstream pro-
cess and implementing continuous batch processing.”
It was these challenges, as well as the need for global exposure
and regulatory compliance, that caused Pacira to seek a partner
who could provide them with the resources and experience neces-
sary to build upon their existing manufacturing capacity to success-
fully manufacture and globally commercialize EXPAREL. After
vetting other prospects, Pacira decided on Patheon. Kaczmarek
says what was particularly appealing about Patheon is that the re-
lationship between the two companies is not a typical CDMO/spon-
sor relationship. “I’m not just handing the drug product over and
then hoping they manufacture and provide the supply to me,” he
explains. “We’re working together to transfer a complex manufac-
42 www.patheon.com ● doingbusiness@patheon.com
turing process into one of their suites, and then, within that work,
expanding the process out and training their personnel on how to
run it. We will monitor the process as a partner as they manufacture
the drug product.” This is accomplished through the use of
Patheon’s condominium manufacturing model. The “condo” model
is one of six adaptable manufacturing arrangements the CDMO
offers its clients. Through multiple options, Patheon provides spon-
sors with a variety of flexible and scalable manufacturing approach-
es to create the optimal solution to fit a client’s needs.
A stronger partnership through
collaboration and communication
Patheon’s condo model is designed for companies either expand-
ing their current manufacturing capacity or introducing new prod-
uct with unique characteristics that cannot be manufactured on a
conventional manufacturing line, such as EXPAREL. In addition to
providing manufacturing design services, Patheon works with
equipment suppliers, validates the processes, builds the line, and
manages operations on behalf of the client. Overhead is shared,
and the line can operate as needed to meet demand.
Kaczmarek says Pacira personnel support the manufacturing and
quality assurance processes in Patheon’s U.K. facility. “This gives us
the ability to utilize the facility, the staffing, and the support structure
Patheon brings to the table,” he says. “They also have multiple areas
outside of the U.K. facility where we can continue to grow strategical-
ly.” Kaczmarek adds that Pacira wanted a manufacturing agreement
and strategic partner, not just a one-time partner for one product.
The condo model design coupled with the manufacturing agree-
ment gave Pacira a high level of confidence that they not only
picked the right partner, but they would also be able to control the
intellectual property of their drug product design and formulation.
“Other potential manufacturing groups we were looking at did not
have the same type of model, nor did they have the same ability to
provide that type of an operational environment where we could
transfer a very complex process to them with the understanding of
how they would actually be able to manufacture moving forward,”
says Kaczmarek.
The next step toward creating an even stronger relationship,
Pacira and Patheon are establishing a governance relationship,
where both companies speak on a regular basis and provide up-
dates. “Patheon’s openness to the integration of these types of
technologies into their network maximizes Pacira’s ability to sup-
ply EXPAREL to patients, as well as our future pipeline,” says
Kaczmarek. “By having these strategic discussions and agree-
ments, it minimizes the cost of manufacturing for both companies
and it maximizes the ability to provide patients the quality drug
products in a very timely manner. Ultimately, that’s what we want to
be able to do, and both companies are coming together to make
that possible.” ■

Fighting the
Opioid Epidemic:
How Grünenthal’s
Abuse-Deterrent
Technology
Contributes
Title Goes Here
Prescription opioid products are an important component in the
armamentarium of modern pain treatment. While the wider use of
opioids has led to many benefits for patients in pain, it also has led
to higher incidences of misuse, abuse, and development of opioid
addiction. Extended release formulations of opioids, in particular,
have become a major factor in prescription drug overdose deaths
in the U.S. over the last 20 years. According to the Centers for Dis-
ease Control and Prevention, more than 183,000 people died in the
U.S. between 1999 and 2015 from overdoses related to prescrip-
tion opioids.1 It is estimated that U.S. hospital emergency rooms
see more than 1,000 people each day as a result of prescription
opioid abuse, and 91 Americans die daily from an overdose related
to prescription opioids and/or heroin.2
As part of the FDA’s efforts to address this growing issue, the agency
put an Opioid Action Plan into effect in 2011 to “reduce opioid abuse,
dependence, and overdose in the United States.”3 Part of this plan in-
cluded a call to pharmaceutical manufacturers to develop and expand
access to abuse-deterrent formulations (ADFs) in order to discourage
abuse among patients and promote innovation in the industry.
Among other benefits of ADFs, these formulations can create a
hurdle to abuse progression for recreational abusers. This is be-
cause patients often start abusing prescription drugs orally, either
by chewing or swallowing them whole, but during the course of
their dependency, eventually switch to non-oral routes. This typical-
ly begins with intranasal insufflation due to the nasal cavity being a
thin, well-vascularized tissue, which allows faster delivery through
a direct route to the bloodstream. Once a user develops a certain
tolerance to the intranasal route he or she then switches to intrave-
nous injection, which can lead to the sharing of needles. ADFs
www.patheon.com ● doingbusiness@patheon.com
Client
Success
Stories
have the ability to inhibit this progression, thereby preventing many
users from moving to the next phase of addiction, which is com-
monly heroin. The issue of heroin addiction is also a growing issue,
as the number of overdose deaths from this cheaper, more acces-
sible drug has quadrupled since 2010.4
Finally, the growth of prescription abuse and the progression of the
addiction have impacted the medical community as well, creating
negative reputations for both pharmaceutical companies and the
physicians prescribing opioids. This black cloud over the com-
pound class of opioids may become so damaging that, in the future,
eligible patients might not have access to this valuable treatment
option for pain. In fact, issues with availability have already begun
to negatively impact many patients’ access to pain relief medica-
tions due to some state-level restrictions5 and rescheduling for the
hydrocodone combination products.6
In the 2000s, Grünenthal, an international pharmaceutical compa-
ny with a fully integrated R&D, took notice of the growing rate of
opioid abuse. The issue concerned the Grünenthal team not just
1. Centers for Disease Control and Prevention, Prescription Opioid Overdose Data
— https://www.cdc.gov/drugoverdose/data/overdose.Html
2. Centers for Disease Control and Prevention, Understanding the Epidemic —
https://www.cdc.gov/drugoverdose/epidemic/
3. FDA, Fact Sheet — FDA Opioids Action Plan — https://www.fda.gov/
newsevents/newsroom/factsheets/ucm484714.htm
4. Centers for Disease Control and Prevention, Heroin Overdose Data — https://
www.cdc.gov/drugoverdose/data/heroin.html
5. ACP Internist, States aim to limit opioid prescriptions — https://acpinternist.org/
archives/2016/10/laws.htm
6. FDA Blog, Rescheduling prescription hydrocodone combination drug products:
An important step toward controlling misuse and abuse — https://blogs.fda.gov/
fdavoice/index.php/2014/10/re-scheduling-prescriptionhydrocodone-combination-
drug-products-an-importantstep-toward-controllingmisuse-and-abuse/
43
from a perspective of patient safety, but they also did not want to
see legitimate patients prevented from receiving necessary medi-
cation. The company set out to create an ADF with a technology
that creates a physico-chemical barrier to abuse and, as a result,
safeguards patients from the battle of addiction.
A formulation against manipulation
Grünenthal’s abuse-deterrent formulation, INTAC®, guards against
manipulation techniques often utilized by prescription abusers.
These usually involve pulverization and, sometimes, subsequent
dissolution, of the tablets. Grünenthal developed a proprietary pro-
cess using hot melt extrusion to apply heat and pressure to create
a crush-resistant matrix. The resulting extrudate has the resistance
and gelling properties needed to make INTAC’s barrier successful.
The process guards against manipulation while still maintaining the
clinical benefit of the standard form for the patient. The result is a
formulation that deters abusers but does not require the patient to
take additional ingredients that do not add to their therapy or may
precipitate withdrawal.
By making the formulation resistant against crushing, Grünenthal
impedes intranasal abuse, because the tablet cannot be turned
into a fine powder. This also prevents intravenous abuse, as abus-
ers usually first disintegrate the tablet and then dissolve the powder
in small amounts of liquid, which they subsequently inject. With
INTAC, such attempts lead to the creation of a viscous mass that is
difficult to draw into a syringe. While it is impossible to completely
prevent abuse, research by the CDC indicates barriers like these
can reduce the progression of abuse from oral to non-oral routes.7
The INTAC platform addresses various release profiles, from ex-
tended release (ER) to immediate release (IR) and a wide variety of
mixed ER/IR profile (also known as modified release, or MR). Be-
sides the release profiles, the technology also allows formulating
various substance classes. Specifically, there has been a positive
experience when creating INTAC-based formulations of prescrip-
tion stimulants. These drugs are also being abused for recreational
purposes via snorting and injection.
From extrusion to the tablet
While Grünenthal’s core manufacturing process for extrusion is
rather straightforward, it is the combination of certain excipients like
polyethylene oxide (PEO) that, under hot melt extrusion, lead to the
unique properties of INTAC formulation. The proprietary down-
stream process uses extrusion, cutting, and cooling for the formu-
lation of an abuse-deterrent final dosage form that can be further
processed into tablets. The gelling properties of the excipients
used in the formulation are maintained, thereby sustaining the bar-
rier to injection.
During development, manufacturing of INTAC presented several
challenges. First, although the extrusion technology used is well
known in the industry, it requires specific expertise to utilize the pro-
cess optimally. Second, specialized equipment is required to estab-
lish a manufacturing process that can run almost continuously from
extrusion to the solid-dose form. Third, the nonstandard down-
44 www.patheon.com ● doingbusiness@patheon.com
stream operations require a well-trained and educated manufactur-
ing staff to run the process reliably. Finally, Grünenthal’s ADF cus-
tomers are currently all U.S.-based companies, which called for a
development and manufacturing site in the U.S., to simplify the han-
dling of scheduled drugs. To achieve these goals, Grünenthal sought
out a partner with the expertise, capacity, and location that could
accommodate its needs and drive the success of INTAC in the U.S.
Making the cut
In addition to the practical needs mentioned above, Grünenthal
sought a CDMO with a solid reputation in the pharmaceutical in-
dustry for its expertise, reliability, and cost, as well as a willingness
to embrace the challenge of implementing a specialized technolo-
gy. Grünenthal ultimately selected Patheon, which was an
especially appealing option due to the company’s condominium
manufacturing model. The condo model is one of six adaptable
manufacturing arrangements Patheon offers its clients. This highly
customizable manufacturing solution provides sponsors with a va-
riety of flexible and scalable approaches to create the optimal solu-
tion to fit their program’s unique needs.
For Grünenthal, Patheon and its condo model addressed each of
INTAC’s biggest manufacturing challenges. Both companies
worked together to plan a layout for the manufacturing suite dedi-
cated to the needs of INTAC. “Because of the flexibility offered by
Patheon, we were able to optimally set up the equipment in the
INTAC suite without any restrictions,” explains Siegfried Ebner,
Head of the Innovation Unit Devices and Technologies at
Grünenthal. “In addition, operators and engineers traveled to our
Aachen headquarters for training on the INTAC equipment long
before it was installed in the Patheon suite. Patheon’s Cincinnati
location addressed another major need for us, as it brings the IN-
TAC technology infinitely closer to U.S. customers, eliminating the
need for further transfers. As a result of working intensively togeth-
er from the beginning, Patheon’s staff was ultimately able to run our
equipment and processes with complete success.” While distance
can be a hurdle in any global relationship, the companies were able
to overcome the 6-hour time difference between Aachen and Cin-
cinnati with regular teleconferences as well as for any issues that
required special attention. Meeting face-to-face on a regular basis
also proved beneficial as each team believes this strengthens the
relationship of all involved.
Grünenthal further continues its development of the INTAC tech-
nology as a way to help fight against the growth of opioid abuse and
protect patients from this deadly epidemic. Looking forward, the
company believes its technology is suitable to raise the hurdle to
abuse of other compounds, that are prone to misuse and abuse.
Projects with these compound classes are under development,
and research is also being done to investigate the suitability of
Grünenthal’s technology to impede conversion from pseudoephed-
rine to crystal meth. With a strong contender for widespread abuse
prevention and a trusted partner on its side, Grünenthal stands
strong as an innovator in pharma as well as an advocate for the
health and safety of today’s patients. ■
7. J. Ziebell, presentation at Nat Rx Abuse & Heroin Summit 2016 - https://www.fda.
gov/downloads/Drugs/NewsEvents/UCM527899.pdf
Brilliant
discoveries.
Delivered.

We are Patheon, and we bring to

bear 40 years of experience and
expertise, from development to
manufacturing. We also bring global
reach. An industry reputation for
being right on time, the first time.
Supply chain solutions designed
to simplify complexity and speed
up the process. And a passionate
belief that together we can make
the world a healthier place.
 BIOLOGIC DRUG SUBSTANCE API DRUG SUBSTANCE

Ahmedabad, India
Allentown, PA, USA
Basel, Switzerland
Beijing, China
Bend, OR, USA
Bourgoin, France
Brisbane, Australia ●
Buenos Aires, Argentina
Cincinnati, OH, USA
Ferentino, Italy
Florence, SC (West), USA ●
Florence, SC (East), USA ●
Greenville, SC, USA ●
Greenville, NC, USA
Groningen, Netherlands ●
High Point, NC, USA
Horsham, United Kingdom
Indianapolis, IN, USA
Linz, Austria ●
Manatí, Puerto Rico
Mexico City, Mexico
Milton Park, United Kingdom
Monza, Italy
Moscow, Russia
Mt. Prospect, IL, USA
Pretoria, South Africa
Princeton, NJ, USA ●
Regensburg, Germany ●
São Paulo, Brazil
Seoul, Korea
Singapore
St. Louis, MO, USA ●
Suzhou, China
Swindon, United Kingdom
Tilburg, Netherlands
Tokyo, Japan
Toronto, Canada
Weil am Rhein, Germany
Whitby, Canada
 OUR INTEGRATED GLOBAL NETWORK
PHARMACEUTICAL CLINICAL TRIALS SUPPLY
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 Patheon
4815 Emperor Blvd, Suite 300
Durham NC 27703-8470 USA
P: +1 919 226 3200
F: +1 919 474 2269
www.patheon.com

Patheon
Kingfisher Drive
Covingham, Swindon
Wiltshire SN3 5BZ UK
P: +44 1793 524411
F: +44 1793 487053
www.patheon.com

Patheon
7F Wakamatsu Building, 3-3-6
Nihonbashi Hon-cho, Chuo-ku,
Tokyo 103-0023
Japan
P: +81 3 6202 7666
F: +81 3 6202 7676
www.patheon.jp