* DD&D March 2014 Covers.qxp_DDT Cover/Back April 2006.qx 3/23/14 12:50 PM Page 2
`
`March 2014 Vol 14 No 2
`
`www.drug-dev.com
`
`IN THIS
`ISSUE
`
`INTERVIEW WITH
`GERRESHEIMER’S
`MEMBER,
`MANAGEMENT BOARD
`PLASTICS & DEVICES
`DIVISION
`ANDREAS SCHÜTTE
`
`Pursuing
`Ethics 18
`Derek Hennecke
`Fixed-Dose
`Combinations 32
`Tugrul Kararli, PhD
`Repurposing
`Drugs 36
`Roger Garceau, MD
`
`The science & business of drug development in specialty pharma, biotechnology, and drug delivery
`
`Sam de
`Costa, PhD
`New Drug Delivery
`& Stabilization
`Platforms Gaining
`Global Interest
`
`Marshall
`Crew, PhD
`Analysis of the
`Historical Use of
`Solubilization
`Technologies
`
`Lior Raviv,
`MMedSc
`Challenges &
`Possible Solutions
`for Transferring Cell
`Therapy From the
`Bench to the Industry
`
`Analytical
`Testing 40
`Cindy H. Dubin
`
`Biosimilars
`Market 50
`Lucila Rocca
`
`User-Friendly
`Dosage Forms 68
`Thomas Hein, PhD
`
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`p.22
`
`A
`ri
`“This analysis covers the drugs that have been
`approved, ECMCome| efRc) and
`increasing adoption of various technologies -
`
`especially throughout the past 15 years. What
`
`CeCeOMmeaMMeTecatele(ee
`
`The combination of three key factors.....”
`
`Derek Hennecke says our industry is not supposed to be like
`Big Steel, or Big Auto. We are not motivated by profit. We have
`a higher purpose; saving lives and improving quality of life.
`Don’t we?
`
`Marshall Crew, PhD, President & CEO, Agere Pharmaceuticals,
`Inc., continues his multiple-part series discussing today’s most
`challenging issues in solubility.
`
`\
`
`Tugrul T. Kararli, PhD, MBA; Kurt Sedo; and Josef Bossart, PhD;
`believe the pharmaceutical industry has been paying increasing
`en
`attention to the potential of Fixed-Dose Combination products,
`and in a series of three articles, examine the past, present, and
`future of these products with the intent of understanding their
`whats and whys.
`
`Roger Garceau, MD, FAAP, presents a drug that might have
`slipped into obscurity if the team at NPS Pharmaceuticals had
`accepted defeat, but instead, the medicine has received an
`
`extraordinary second chance to address a different, and
`significant, unmet medical need,
`
`Special Feature: Contributor Cindy H. Dubin talks with some of
`the leading
`experts in the industry about the importance of
`ee
`P
`outsourcing analytical testing in the biologic/biosimilar space,
`the associated challenges, and how to ensure products get to
`market safely and quickly.
`
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`Cell Therapy
`Challenges
`
`“These technologies are evolving from tissue culture
`dishes and flasks to high-end, fully controlled
`bioreactor systems, which will allow production of large
`quantities of cells under cGMP. The challenge becomes
`even bigger when looking at off-the-shelf allogeneic
`therapy. When mature, the industry will face an even
`larger challenge of downstream processing of the cell
`products.”
`
`8
`
`p.58
`
`50
`
`Latin America Next-Generation
`Biosimilars Market: Opportunities &
`Future Growth
`Lucila Rocca, Healthcare Industry Analyst, Frost & Sullivan,
`
`indicates the Latin American Biosimilars market will grow at a
`
`significant rate in the next 5 years, and the importance of
`
`establishing rigorous regulation will stimulate this market growth.
`
`54
`
`58
`
`68
`
`Gerresheimer: Understanding Customer
`Requirements
`Drug Development Executive: Andreas Schütte, Member of the
`
`Management Board, Plastics & Devices Division, discusses his
`
`important role in Gerresheimer’s divisional restructuring process,
`
`and how he is convinced the new structure better reflects
`
`customer requirements.
`
`The Challenges & Possible Solutions for
`Transferring Cell Therapy From the
`Bench to the Industry
`Lior Raviv, MMedSc, and Ohad Karnieli, PhD, discuss the
`
`significant emerging challenges in downstream processing of cell
`
`therapies focused mostly on allogeneic therapies.
`
`Hermes Pharma: User-Friendly Dosage
`Forms, a Win-Win Situation for Patients
`& Pharma
`Drug Development Executive: Dr. Thomas Hein, Director, Sales &
`
`Business Development at Hermes Pharma, discusses how user-
`
`friendly dosage forms help put patients first, their advantages for
`
`patients and pharmaceutical companies, as well as the challenges
`
`associated with their development and production.
`
`DEPARTMENTS
`
`Market News & Trends . . . . . . . . . . . . . . . . . . . . . 12
`
`Advanced Delivery Devices . . . . . . . . . . . . . . . . . 26
`New Drug Delivery & Stabilization Platforms
`Gaining Global Interest
`
`Technology & Services Showcase . . . . . . . . . . . . 64
`
`External Delivery . . . . . . . . . . . . . . . . . . . . . . . . . 74
`The Compensation Paradox
`
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`The Second
`Quadrant
`
`Analysis of the Historical Use of
`Solubilization Technologies
`In 2013, contributors to The Second Quadrant gave insights into how to decide what solubilization technologies
`
`compounds to the marketplace. The Developability Classification System (DCS) further refines the FDA
`
`Biopharmaceutics Classification System (BCS), overlaying dissolution rate onto solubility and permeability and
`
`providing a third dimension to assist in categorizing an API and understanding what type of solubilization strategy is
`
`most likely to succeed.
`
`Drug Development & Delivery March 2014 Vol 14 No 2
`
`22
`
`By: Marshall Crew, PhD, President & CEO, Agere Pharmaceuticals, Inc.
`
`might be most appropriate based on the API’s characteristics and dosage form requirements for the drug product.
`
`Pharmaceutical companies are increasingly focusing on the use of solubilization to advance their most promising
`
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`|, individual, expert.
`URL
`
`As one of the pioneers in the developmentof — Innovative product range
`
`excipients for direct tableting, Meggle has more
`- Leading quality systems
`- Fully implemented GMP/GDP system
`than SO years of experience and offers a broad-
`- Global partner network
`based and detailed porttolio of lactose products
`- Customers in more than 100 countries
`for any application worldwide. The benefits
`speak for themselves. And for MEGGLE:
`
`Lactose from MEGGLE —
`the experts in excipients.
`
`eeecaeanyae
`
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`F I G U R E 1
`
`Approved Drugs: Use of Solubilization Technologies Since the 1980s
`
`Based on the trends throughout the past 4
`
`amorphous APIs, lipids, and nanocrystals.
`
`decades and the changing chemical space in
`
`From our analysis, we confirm that lipid
`
`drug development, we expect the decade will
`
`technologies have the most widespread use in
`
`show additional and significant current growth
`
`terms of drug approvals in the years prior to
`
`in use of solubilization technologies once we
`
`2005. The use of solid dispersion technologies
`
`have visibility into the full 10-year period.
`
`has also seen strong growth but has lagged
`
`The progress being made in the
`
`knowledge base around addressing BCS Type II
`
`compounds has been significant in the past
`
`decade, and appears to be accelerating. In this
`
`month’s column, we take a historical look at the
`
`marketed drugs that have been solubilized, the
`
`technologies used, and the therapeutic areas
`
`these drugs address. The goal of this analysis is
`
`to gain better insight into the commercial use of
`
`solubilization and its impact on the
`
`pharmaceutical industry.
`
`THE GROWING USE
`SOLUBILIZATION
`TECHNOLOGIES SINCE 1975
`
`Since 1975, we have found that
`
`approximately 60 marketed drugs have
`
`leveraged solubilization technologies to enhance
`
`oral bioavailability. In the preceding 36 years,
`
`from the time the FDA required submission of
`
`an NDA in 1938, solubilization technology was
`
`virtually unused on a regular basis. Apparently,
`
`the disease areas focus, drug discovery
`
`methodologies, and the lack of mature
`
`lipids by approximately 5 to 7 years. However, it
`
`appears that throughout the past decade, the
`
`growth rate of solid dispersions has been twice
`
`that of the lipid formulations. While it is not
`
`possible to determine the reasons in the
`
`available data, the more rapid adoption of solid
`
`dispersions may be a result of many factors,
`
`T A B L E 1
`
`FDA Drug Approvals Since 1970 & Percentage
`of Solubilized Drugs by Decade & Showing
`Drugs that Used Oral Solubilization
`Technologies
`*The 30-year period of 1940-1969 is included to show
`the lack of solubilization technology utilization prior
`to the 1970s. 2010-2013 is included to reflect the
`data available to date for the current decade.
`
`SOLUBILIZATION
`TECHNOLOGIES: BY
`MARKETED DRUG
`APPROVALS BY DECADE
`
`solubilization platforms restricted the use prior
`
`The popularity, utilization, and success of
`
`to the 1970s. In comparison, the past nearly 4
`
`the diverse technologies throughout the past 6
`
`decades have shown robust growth in the
`
`decades is reflected in changing landscape of
`
`reliance on solubilization platforms, accounting
`
`approved drugs applying solubilization
`
`on average for around 6% of all NMEs
`
`approaches since the 1970s. In order to gain a
`
`approved from 1975 through 2013, and more
`
`quantitative understanding of the historical role
`
`than 10% in the past decade (Table 1).1-7 Some
`
`of solubilization, we have compiled a
`
`years stand out to validate the need and use of
`
`comprehensive database of approved drugs that
`
`solubilization platforms. For example, in 2005,
`
`are formulated using a variety of solubilization
`
`20% of NMEs approved used technologies
`
`technologies and delivered orally. In addition,
`
`including solid dispersion, lipid, and nanocrystal
`
`we further filtered the dataset to only include
`
`platforms. The data for the most recent 4-year
`
`formulations delivered as tablets or capsules
`
`period (2010-2013) seems to represent a slight
`
`(excluding solution and suspension vehicles).
`
`decline in growth, but it is still early in the
`
`The technologies that have been used were
`
`decade, and the data set is relatively small.
`
`divided into four classes: solid dispersions, pure
`
`Drug Development & Delivery March 2014 Vol 14 No 2
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`24
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`Drug Development & Delivery March 2014 Vol 14 No 2
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`25
`
`oncology. One explanation for this may be that the approach to treating
`
`cancer has shifted from cytotoxic agents to targeted therapies, and these
`
`compounds, which are largely still in development, have lower solubility
`
`in general. In addition, many oncology drugs in the past have been dosed
`
`using methods other than oral delivery and as solubilization technologies
`
`have improved significantly, more therapeutic agents are now being
`
`developed for oral use.
`
`CONCLUSIONS
`
`This analysis covers the drugs that have been approved, and the data
`
`suggests a strong and increasing adoption of various technologies -
`
`especially throughout the past 15 years. What lies ahead for the rest of the
`
`current decade? The combination of three key factors – the complexity of
`
`diseases being addressed, that modern drug targets favor compounds with
`
`poor solubility and today’s methods for designing, synthesizing and
`
`optimizing chemical libraries – promise to increase the reliance on
`
`solubilization technologies to realize the potential of promising drugs in
`
`development. It’s a safe prediction that the utilization of bioavailability-
`
`enhancing platforms will rapidly accelerate before the end of the
`
`decade.u
`
`To view this issue and all back issues online, please visit www.drug-dev.com.
`
`REFERENCES/NOTES
`
`1. FDA, Summary of NDA Approvals and Receipts.1938-present.
`2. FDA New Molecular Entity Approvals. 2012-2013.
`3. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, Neveu V, Djoumbou Y, Eisner R, Guo
`AC, Wishart DS. DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res.
`2011;Jan;39(Database issue):D1035-41. PMID: 21059682.
`4. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. DrugBank: a
`knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008;Jan;36(Database issue):D901-6.
`PMID: 18048412.
`5. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. DrugBank: a
`comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006;Jan 1;34(Database
`issue):D668-72. PMID: 16381955.
`6. Agere analysis.
`7. This estimate is thought to be conservative, as drugs thought to have used solubilization technologies but that were
`not yet verified were not included in this calculation.
`
`Marshall Crew
`President & CEO
`Agere
`Pharmaceuticals, Inc.
`crew@agerepharma.com
`LinkedIn:
`https://www.linkedin.com/
`profile/view?id=17815140
`
`T A B L E 2
`
`Therapeutic Areas of Approved Drugs & Solubilization Technologies
`Applied3-7
`
`including the attractiveness of a tablet dosage form (and conventional
`
`processing equipment), generally higher unit dose achievable, the
`
`widespread availability of manufacturing capabilities (HME and spray-
`
`drying), and the exponential growth in scientific knowledge of solid
`
`dispersions in the past decade as reported in last month's column.3-6
`
`TECHNOLOGIES USED & THERAPEUTIC
`AREAS ADDRESSED
`
`The PhrMA 2013 Profile of the Biopharmaceutical Industry points
`
`to a study finding that since 1975, medicines have contributed to a 60%
`
`increase in survival rates of cancer patients, and that research done by the
`
`American Heart Association has found that in the 10-year period of 1999-
`
`2009, death rates due to cardiovascular disease have dropped by 33%.
`
`Even more dramatically, since the approval of antiretroviral treatments in
`
`1995 the HIV/AIDS death-rate has dropped by 85%.
`
`We performed a study to evaluate the role solubilization
`
`technologies play to support drug success in the various therapeutic areas,
`
`and the findings were surprising. Table 2 shows the number of
`
`commercial products that are in the various delivery platforms and in each
`
`therapeutic area. The industry has long been aware that there’s a strong
`
`need for solubilization in the drugs addressing the therapeutic areas of
`
`anti-infectives, cardiovascular, and immune/inflammatory. One surprising
`
`observation that this analysis reveals is the relatively few applications of
`
`solubilization to oncology. This is surprising to us at Agere since a large
`
`proportion of the compounds in our development portfolio are in
`
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