Future Pharma Partner Models: Pharma 3.0

“Pharma 3.0,” “Next-Gen Pharma,” “Future Pharma” — call it what you will — contract service providers are redefining their mission and reframing their strategic roles with customers. Contract manufacturers, CDMOs and CROs alike are aligning their capabilities and organizations in an ongoing effort to support the next-generation drug innovation owners and the industry need to stay relevant, competitive and critically patient-centric.

Regulation 3.0
A funny thing happened on the way to pharma’s future: it’s no longer on its way. It’s here, it’s arrived thanks (to a significant degree) to the contract services industry. But what is (or was) pharma’s future in the first place? 

At one point the future was more about the drug — finding the compounds and molecules that stopped the pain, killed the infection or immunized humans from history’s great diseases. For most of the 20th Century the industry followed the “Pharma 1.0” business model of massive R&D efforts designed to deliver the exalted “blockbuster” to ready markets of millions of patients, while earning billions in the process. The industry pursued this strategy to great success, but over time, the inertia of Pharma 1.0 slowed, weighed down by (among other things) the methodology’s waning ability to find primary care drugs with a large enough patient base to justify and deliver an adequate return on the nearly $2.6 billion, according to Tufts Center for the Study of Drug Development, it currently takes to create a category-defining drug.¹ 

During the Pharma 1.0 era, regulators were also experiencing change and adaptation. The international cadre of pharmaceutical regulators, FDA chief among them, began to question whether or not their methodologies and directives were actually contributing to “drug safety,” as opposed to drug efficacy, and its Hippocratic ethic of “first, do no harm.” Regulators, instituting cGMP guidance (now 40+ years in the making), began to focus on quality issues associated with drug manufacture as a root-cause source for many drug quality and safety issues post approval; this meant increased scrutiny of drug-making operations.

For the industry, speed-to-market is a critical measure of most compounds’ commercial success, regardless of category. In a recent white paper on “Accelerating the Development of New Pharmaceutical Therapies,” the FDA said it has drastically reduced its review time and worked with the industry to reduce overall drug development time by engaging earlier to discuss flexible approaches to developing data needed for approval.² “Rapid developments in technology and scientific discovery are creating increasingly complex products,” said FDA authors. “To keep pace with these developments, over the past several years the FDA has been striving to further develop regulatory science: the knowledge, methods, standards and tools needed to increase the certainty and consistency of regulatory decisions and improve the translation of basic discoveries to viable medical products.”

According to a 2014 Ernst & Young white paper, “Commercial Excellence in Pharma 3.0,” the traditional Pharma 1.0 model has made way for a more diversified “Pharma 2.0” model, describing it as “the quest to bring broader, more diversified product offerings to a more global market.”³

Ernst & Young’s analysts explain that during the past decade, pharma’s leaders have been following a strategy of diversifying into the Pharma 2.0 model, exploring product lines that are less exposed to R&D and market vagaries, including generics, vaccines, over-the-counter medicines and medical technologies. “While this approach is helpful in the mid-term, long-term sustainability will require shifting to a new business model, one that will address the real needs of the industry’s customers — the patients, payers and physicians — and contribute significantly to the ultimate goal: improving patient health.”

How to get there? Ernst & Young said this requires shifting away from pharma’s traditional arm’s-length approach, one centered on just delivering drugs to the healthcare system. According to the FDA, companies are evolving past Pharma 2.0, and moving forward to the next phase of development, “Pharma 3.0.”

At the center of this model are service components that enable companies to deliver health outcomes — defined as (clinical and economic) health benefits per dollar spent. This shift represents a prime opportunity for the pharmaceutical industry to explore a variety of new business models focused on health outcomes, ranging from improving the performance of their current products on the market to tapping into new revenue streams associated with healthcare delivery. The pace at which this change has occurred presents a pathway for CDMOs looking to explore new venues.

Innovation Generation

In a North Carolina State University case study, “Bringing the Customers Back Into the plant: The Strategic Transformation of Patheon,” school alumni and Patheon affiliated authors noted “Outsourcing has for many years been an essential component of the pharmaceutical industry as companies confront R&D productivity challenges, increased regulatory hurdles, global pricing pressures and the need to compete in rapidly growing, emerging markets.”4 In other words, to attain the innovation and operational excellence required to operate in the Pharma 3.0 universe, drug owners and sponsors will continue to turn to the contract services sector to sustain financial success and patient-centric development strategies. The Patheon case study posits that as pharmaceutical and biotechnology companies seek to invest and focus on their core strengths, these companies are turning to outsourcing manufacturing and other supply chain and R&D collaborators. That key partnerships with CDMOs have become an integral part of manufacturing, research and development is apparent.

This reliance on outsourcing, and thus partner models, is reflected in the 2016 Nice Insight CDMO Outsourcing Survey; 95% of respondents to the survey are either interested, or very interested, in a strategic partnership with a CDMO. These numbers reflect the interest of those seeking a strong collaboration within the next 12-18 month timeframe. The type of partnership these firms are looking for is largely dependent on the drug product pipeline of each company type. Big pharma’s future pipeline is overwhelmingly geared towards New Biological Entities (NBEs) at 67%, compared to just 33% for Over the Counter Medications (OTC). Both mid and small pharma/biotech are still strongly focused on generics (56% each), while mid-size pharma hovers around that rate for biosimilars (54%). Small pharma is only planning for the “new generics” (biosimilars) at 47%, most likely due to lack of capital. Emerging pharma, which is experimental across the board, has a pipeline 71% concentrated on New Chemical Entities (NCEs). This divergent range of molecules for future pipelines will lead to a heightened need for, and an increased role of, contracting organizations.  

The industry’s trajectory and its swift transition to the Pharma 3.0 business model can be attributed to the contract service industry’s business and technological leadership. Every player has a role in this narrative. Pharma is delivering, or rather collaborating, with the healthcare industry in new and effective ways to produce better patient and social outcomes. New supplier/partner models are supporting this effort. Advancements in effective drug delivery, API formulation and manufacture, unique delivery and next-gen therapies are key Pharma 3.0 development themes where contract service companies are having great impact. Nice Insight took an in-depth look at these segments and what follows reveals how contract service providers and drug owners are integrating their operations to achieve the patient-centric goals of the Pharma 3.0 business model.

References 

1. DiMasi, Joseph A., Henry G. Grabowski, and Ronald W. Hansen. “Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs.” Journal of Health Economics 47 (2016): 20-33. Web.
2. Hubbard, William. FDA and Accelerating the Development of the New Pharmaceutical Therapies. Rep. U.S. Food and Drug Administration. 23 Mar. 2015. Web.
3. Commercial Excellence in Pharma 3.0. Rep. Ernst & Young. Web.
4. McGurrin, Daniel P., Rebecca Holland New, and Jennifer Almond. Bringing the Customers Back into the Plant: The Strategic Transformation of Patheon (A). Patheon. 8 Aug. 2014. Web.

Effective Drug Delivery
Drug delivery plays a vital role in bringing a drug’s therapeutic value to patients. Facing intensive competition, drug makers are not only racing for new therapeutic entities, but also for novel drug delivery systems to fully realize the value of a known or new drug. 

The primary function of drug delivery is to facilitate active pharmaceutical ingredients reaching the target site and exerting a desired efficacy and safety profile. Drug makers have been relying heavily on drug delivery systems (including excipients and formulations) to improve solubility of drug compounds and achieve better bioavailability. Poor solubility presents a major challenge for the pharmaceutical industry. Approximately 40% of marketed drugs and 80% of compounds in discovery and development suffer from low solubility and/or low permeability.¹ Based on their water solubility and intestinal permeability, these compounds are categorized as Biopharmaceutical Classification System (BCS) II, III and IV compounds. In general, poor solubility leads to poor bioavailability, an indicator for therapeutic efficacy.

Pharmaceutical companies are actively seeking drug delivery technology to enhance bioavailability. According to the 2016 Nice Insight CDMO Outsourcing Survey, 53% of the buyer respondents acquire/plan to acquire bioavailability enhancing excipients from CDMOs/CMOs for BCS II–IV compounds, including peptides.² A variety of excipients can be used to improve solubility including surfactants, solvents, lipids (i.e., liposome), and polymers. Several technologies have been developed to improve oral bioavailability, such as solid amorphous dispersions, self-emulsification and self-microemulsification and hot-melt extrusion.³ Prodrugs also have shown to be an effective strategy to circumvent poor solubility and improve pharmacokinetics. In addition, novel drug delivery systems utilizing nanotechnologies, such as nanosizing techniques and nanocarriers, have been proven to be effective in enhancing bioavailability.⁴ One successful example is from NanoCrystal technology (Alkermes). Since 2000, NanoCrystal has been used in five FDA-approved products earning annual sales over $2 billion.³ The main technology used to boost bioavailability of biologics is pegylation — attaching polyethylene glycol chains to protein or peptide drugs can significantly improve the efficacy of biologics by increasing their stability in the serum.

Another drug delivery technology in high demand is controlled release formulation. In the Nice Insight 2016 CDMO Outsourcing Survey, 63% of the respondents expressed interest in acquiring or planning to acquire controlled release formulations.² Controlled release delivery system allows therapeutic agents to be released at a constant rate over an extended period. In comparison to traditional immediate release formulations, they are more effective and safer with lower dosing, less plasma variations and reduced side effects.5 Due to their simplified treatment regimen, a high level of patient adherence, can be expected.

The Cost Of Not Taking Your Medicine

In the U.S., medication nonadherence is a growing public health concern. Every year, 125,000 deaths and about 10% of hospitalizations are due to medication nonadherence, which costs healthcare $289 billion.6 In order to address this issue, new drug delivery systems that provide or enhance patient-friendly features are needed. Improving the ease of administration is one way to improve patient adherence. Smart drug delivery systems (SDDSs) or stimuli-sensitive drug delivery systems are likely to play a more prominent role in patient treatment. Instead of releasing drugs on a fixed rate, SDDS releases drugs in response to a physical, chemical or biological signal in a programmable and predictable manner.5 The development of an artificial pancreas, in which insulin is automatically released in response to the blood glucose level has fully incorporated the concept of SDDS. The first artificial pancreas (Medtronic) for type I diabetes patients is expected to hit the market in spring 2017.⁷  

Among the various drug delivery routes, oral dosage forms constitute the largest drug delivery category. With biologics being the fastest-growing segment in the pharmaceutical market, drug delivery technologies supporting biological administrations are gaining ground, including parenteral, transdermal, intranasal and pulmonary delivery. As demonstrated in the 2016 Nice Insight CDMO Outsourcing Survey, oral solid dose, namely in tablet or capsule form, represents two of the most popular dosage forms manufactured at the commercial scale (65%). Meanwhile, 41% of the respondents focus on specialty dosage forms manufacturing — transdermal and inhaler.²

Transdermal and pulmonary delivery are two hot areas in developing novel drug delivery technologies. These delivery systems provide fast onset of action, needle-free administration and versatility in delivering both small-molecule and macromolecule drugs. The transdermal/intradermal delivery is driven by microneedles or energy derived from battery, ultrasound or laser. The underlying technology for pulmonary delivery includes dry power inhalation (DPI) and pressurized metered dose inhalation (pMDI) systems.3 The approval of Zecuity (Teva), a transdermal, battery-powered patch for migraines in 2013 and Afrezza (MannKind), a rapid-acting inhaled insulin for diabetes in 2014, have infused excitement and energy into these fields.^{8, 9} Marketwise, injectable, pulmonary and transdermal delivery are the fastest-growing sectors in the drug delivery market and will grow at estimated double-digit rates from 2015 to 2020. The total market value for drug delivery was $1,048.1 billion in 2015 and is expected to reach $1,504.7 billion by 2020 at a CAGR of 7.5%.¹⁰

The drug delivery market is driven primarily by technology innovations and development of novel therapeutics. It is also driven by drug makers’ desire to extend patent lives and develop differentiated products. Innovative drug delivery has played an increasingly prominent role in helping drug developers gain a competitive edge. Big pharmaceutical companies are at the forefront to embrace novel drug delivery technologies. For example, GlaxoSmithKline is aimed to leverage innovative drug delivery technologies in 80% of its portfolio by 2020.¹¹  

Novel drug delivery technologies can be acquired through in-house development, codevelopment, outsourcing and licensing. More often than not, though, companies are looking externally for drug delivery expertise. As a result, drug delivery has become the most active area within the pharmaceutical industry for partnerships.¹² Drug delivery systems for biologics (e.g., injectable, transdermal, pulmonary delivery) are popular areas for collaborations. There is an increasing demand for targeted drug delivery, especially in oncology and the central nervous system (i.e., cross blood-brain barrier).¹³ The goal of targeted drug delivery is to transport drugs to the targeted site (i.e., intracellular structure) in a controlled manner, a step towards personalized medications.

References

1. “Special Feature – Excipients: Enhancing the New, Poorly Soluble APIs.” Drug Development & Delivery. 1 June 2015. Web.
2. The 2016 Nice Insight Contract Development and Manufacturing Survey.
3. Brooks, Kristen. “Advances in Drug Delivery.” Contract Pharma. 6 June 2011. Web
4. Beg, Sarwar, Suryakanta Swain, Md. Rizwan, Md. Irfanuddin, and D. Shobha Malini. “Bioavailability Enhancement Strategies: Basics, Formulation Approaches and Regulatory Considerations.” Current Drug Delivery 8.6 (2011): 691-702. Web.
5. Demir Sezer, Ali. “Recent Advances in Novel Drug Carrier Systems.” InTech Open Access Publisher. InTech. 31 Oct. 2012. Web.
6. Fung, Brian. “The $289 Billion Cost of Medication Noncompliance, and What to Do About It.” The Atlantic. Atlantic Media Company. 11 Sept. 2012. Web.
7. Miller, Annetta. “Personalized Medicine: Artificial Pancreas for Diabetics to Hit Market.” CNBC. 30 Mar. 2016. Web.
8. Petrochko, Cole. “NuPathe’s Patch for Migraine Wins FDA Approval.” Public Health & Policy. MedPage Today. 18 Jan. 2013. Web.
9. FDA Approves Afrezza to Treat Diabetes. U.S. Food and Drug Administration. 27 June 2014. Web.
10. Drug Delivery Technology Market by Route of Administration (Oral (Solid), Pulmonary (Nebulizer), Injectable (Device), Ocular (Liquid), Nasal (Drop), Topical (Solid), Implantable (Active), Transmucosal (Oral)), End User (Hospital, ASC, Home Care) – Forecast to 2020. Rep. Markets and Markets. Nov. 2015. Web.
11. Saxena, Varun. “GSK Exec Stresses Need to Move Away from ‘fragmented’ Approach to Drug Delivery.” Fierce Pharma. 21 Oct. 2014. Web.
12. Roumeliotis, Gregory. “Striking the Right Drug Delivery Partnership.” In-PharmaTechnologist. 31 July 2006. Web.
Choudhurie, Ruplekha. “Bioavailability Enhancement Strategies & Opportunities.” Drug Development & Delivery. 13 Mar. 2013. Web.

Outsourcing Trends in API Development & Manufacturing
Considering the healthy growth of the pharmaceutical market and the escalation of outsourcing, the concurrent growth of the active pharmaceutical ingredients (API) market comes as no surprise. In response, contract service providers are ramping up their expertise in this area and acquiring API manufacturers to strengthen their capabilities.

As the population increases and the number of regional markets entering the global landscape continues to mount, drug companies are feeling pressure to bring drugs to market more quickly. CDMO outsourcing remains a key strategy for alleviating the pressures of development. In particular, API manufacturing has maintained a firm position as the most outsourced area for drug manufacturers. This has led to robust growth associated with the sector, which is expected to steadily rise, especially over the short term.¹ The API market is expected to grow at a compound annual growth rate (CAGR) of approximately 6.5% through 2020, when it will have a forecasted value of $185.9 billion.²

Chemistry Matters

The overwhelming majority of drugs currently on the market are small-molecule compounds.¹ In addition, while interest in biopharmaceuticals continues to grow, R&D efforts focused on chemical APIs continue unabated. Highly potent APIs (HPAPIs) in particular — although acutely toxic and challenging to produce — are attracting significant interest, notably those that serve as cytotoxic payloads in antibody-drug conjugates.3 In fact, an estimated 25% of drugs manufactured worldwide contain HPAPIs.⁴  

Interest In Early-Stage Development Leads To Growth And Partnership

Overall, early-phase clinical trial materials are a “booming” segment, according to industry expert Jim Miller.5 Miller cites demand for early development processes as a key component in acquisition activities. Specifically, growing demand for API and early-phase clinical trial materials (CTM) services, including manufacturing, formulation and development, have boosted CDMO expansion into innovative areas and provided opportunities for the introduction of new chemistry platforms.⁵ CDMOs achieving the greatest success growing their development services have reported revenue gains of 20% or greater. Catalent, Patheon and Metrics Contract Services have all achieved such growth.⁵ Another example is illustrated through Lonza; the CDMO has carved out a niche in the development services space by adding capacity in formulation development and drug product analytical development. This added capacity will be viable in the fourth quarter of 2016; drug product manufacturing capabilities for preclinical and clinical use (cGMP) are to follow. This added capacity will put the company on track to function as a “One-Stop-Shop” service solution for customers.⁶

Another option to expand capacity is through acquisition. Major CDMOs are acquiring less active, but attractive firms, with certain players making numerous transactions. This strategy of partnership, in which collaborators are acquired, is employed throughout the CDMO space. For instance, AMRI and Capsugel have adopted this method, with special attention on preliminary drug development. With the acquisition of Xcelience, Capsugel has bolstered its abilities in early-stage manufacturing. The company’s Dosage Form Solutions (DFS) arm includes Xcelience, Powdersize, Bend Research and Encap Drug Delivery. With these acquisitions, the firm’s technical capabilities have extended to include clinical trial manufacturing for solid dosage forms, among a host of other capabilities.⁷

This approach to partnership is also a successfulway to acquire fully developed capabilities without starting from scratch. Thus, AMRI has actively purchased firms with crucial technical expertise, as demonstrated by the acquisition of analytical testing services supplier Whitehouse Laboratories.⁸ Furthermore, in May 2016 AMRI solidified its position as a leading API manufacturer (custom synthesis and generics) with the purchase of Euticals, a European CDMO positioned as an API specialist.⁹

Outsourcing API Production On A Global Scale

The global nature of this strategy is not without recognition. At DCAT Week 2016, fine-chemicals-industry veteran Dr. Enrico Polastro stated that 3rd party API outsourcing is at 55%, from 45% in 1995.  In addition to this, 30 companies account for two-thirds of the industry. 10 For European API manufacturers, 200 suppliers produce approximately $12 billion in product, with the focus on custom synthesis and complex APIs. Custom synthesis remains the primary space internationally, including Japan, where nearly 50 producers generate an estimated $3 billion of APIs. China and India have a market share of 60%, with API production valued at $27 billion. In North America, the demand for APIs has reached approximately $13 billion, with $2.5 billion produced by 40 suppliers (primarily large-volume analgesic and niche-type APIs). Although China and India are the leading manufacturers of APIs, nearly two-thirds ($17 billion) of the generated value is exported.¹¹

Regardless of sponsor company location, API and CTM outsourcing is increasingly preferred due to cost issues. The high cost of in-house production and R&D, coupled with the growth of niche and specialized products and overarching pressures to keep finished drug products affordable, has contributed to the rising incidence of outsourcing. Notably, outsourcing to firms in emerging markets is particularly profitable.11 That API development is at the forefront of outsourcing is reflected in the 2016 Nice Insight CDMO Outsourcing Survey. Most companies (72%) acquire or plan to acquire small-molecule API R&D services (84% of those in Asia, 55% of those in the EU and 70% of those in North America). More than half (56%) of companies outsource small-molecule API clinical-scale manufacturing, and about one-third outsource small-molecule API commercial-scale manufacturing.12 These results mirror the trend of increased spending, which has persisted and is likely to continue. The majority of companies currently have a $51 million to $100 million and above budget for contract manufacturing, at 71%,¹² whereas in 2015 the majority (62%) spent $10 million to $50 million.¹³

While outsourcing is on the rise, sponsor firms are becoming more selective about which service providers they are willing to partner with. Quality performance, reliability and regulatory compliance are all ranked within the “Top 5” selection factors for participants in the 2016 Nice Insight CDMO Outsourcing Survey.¹² On the other hand, with increased regional and supplier options, the numbers of FDA and European Union warning letters have increased.¹¹ CDMOs that consistently meet various global regulatory standards, customer quality and reliability expectations clearly have a competitive advantage.

References

1. Shanley, Agnes. “Specialty Markets and Services Drive API Growth.” Pharmaceutical Technology. 2 Mar. 2016. Web.
2. Active Pharmaceutical Ingredients (API) Market to Soar at 6.5% CAGR till 2020 Thanks to Rise in Abbreviated New Drug Applications (ANDAs). Rep. Transparency Market Research. 21 Oct. 2015. Web.
3. “Minimizing Risk during HPAPI Manufacture.” Pharmaceutical Technology. 2 Mar. 2015. Web.
4. “Increase In HPAPI Manufacturing Highlights Need For Containment And Isolation Systems.” Pharmaceutical Online. 21 July 2015. Web.
5. Miller, Jim. “CMC Development Is Hot.” BioPharm International. 1 Apr. 2016. Web.
6. Lonza to Build Capabilities for Drug Product Development Services, Enabling One-Stop-Shop Solutions for Customers. Lonza. 2 Feb. 2016. Web.
7. Capsugel Completes Acquisitions of Xcelience and Powdersize. Capsugel. 5 Jan. 2016. Web.
8. ”AMRI Acquires Whitehouse Laboratories.” PR Newswire. 15 Dec. 2015. Web.
9. ”AMRI To Acquire EUTICALS In A Strategic Transaction That Expands Its API Development And Manufacturing Business.” PRNewswire. 5 May 2016. Web.
10. Brooks, Kristin. “DCAT Week ’16 Session Highlights.” Contract Pharma. 24 Mar. 2016. Web.
11. Peters, Rita C. “More Outsourcing? More Monitoring.” Pharmaceutical Technology. 2 Apr. 2016. Web.
12. The 2016 Nice Insight Contract Development & Manufacturing Survey.
Nice Insight’s Annual Pharmaceutical and Biotechnology Outsourcing Survey 2015

Unique Delivery and Design
Uniquely delivered drugs have great potential, including playing a role in curing cancer. However, development of these technologies is challenging — fortunately, contract service providers are delivering these capabilities, as well as the emerging delivery technologies and breakthrough therapies needed to be effective.

For optimal pharmacokinetics, sometimes it’s about getting the right amount of a drug to the right place at the right time. Whether a drug is delivered orally, parenterally or through some other method like inhalation, bioavailability might be greatly enhanced when a drug is combined with certain types of nanoparticles in development today. These nanoparticles, when attached to small-molecule drugs, often act as vehicles to get the drug where it needs to go, sometimes by getting it to where it might not ordinarily be allowed to go. Thus, medications that could help alleviate central nervous system (CNS) disorders such as Alzheimer’s disease and Parkinson’s disease are given the opportunity to work more efficiently.¹  

Nanotechnology’s Pharmaceutical Potential

In a recent article appearing on Phys.org, Sam Gambhir, MD, Ph.D., professor and chair of radiology at Stanford School of Medicine said, “Nanotechnology offers an exquisite sensitivity and precision that is difficult to match with any other technology.”² The U.S. government has recognized these medical advantages and deemed it necessary to help fund research in nanotechnology. The president’s budget for the National Nanotechnology Initiative was $1.5 billion. That money inevitably trickles into greater opportunities and resources for research and development for medical companies such as drug owners and CDMOs, nationally as well as internationally.²

Cancer’s Role In Design Of Unique Delivery

It is in the area of cancer research where the most interesting unique drug delivery breakthroughs seem to be happening. Many patients already receive treatments with liposomes that carry drugs in lipid-nanoparticles. Other forms of treatment await their fate in the clinical trials pipeline. There are many different ways that particles are being tested to specifically target and treat the cancer, from binding gold onto certain drug molecules to using specifically sized nanoparticles and reading their sound frequency, or “tune,” in order to locate cancer cells.² The marriage between biologics and small molecules in the form of antibody drug conjugates (ADCs) has also been a growing source of unique deliveries within the cancer realm. According to the 2016 Nice Insight CDMO Outsourcing Survey, 57% of North American CDMOs currently list an ADC in their pipelines.³

The FDA And Nanotechnology

However, more efficient drugs, uniquely delivered and microscopically refined, mean nothing if they cannot reach the right people and places on a macro level. It is often through assistance or by coordinated effort and/or partnership with the public sector that private companies have the ability to get drugs into the hands of the right patients. Regulatory agencies like the FDA are facilitators in the process. But they are also the main barriers for a drug’s entry into the marketplace, and thus to doctors, hospitals and patients. Yet, despite its enforcement mission, FDA continues to evolve in a way that advances along with technology in order to take advantage of it. For instance, Dr. Leonard Sacks, the former acting-director for the FDA’s office of Critical Path Programs, noted that the use of “novel scientific tools in the service of medical product development has been a central priority for FDA.”⁴

In the U.S., several broad measures have recently been adopted that may add extra regulation but are designed to facilitate the development of uniquely designed drugs. In 2012, congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). As most know, the act gives the FDA authority to enforce certain measures to ensure safety of the market on a global level (for example, policing of counterfeit drugs). According to the FDA’s website, this act also “accelerates patient access to new medical treatments and breakthrough therapies.”⁵

CLO’S To Smooth The Supply Chain

When the public and private sectors are working in tandem to deliver drugs safely and efficaciously to market, the supply chain is most effective. But the drug supply chain can sometimes be a chaotic and arduous road for a company to navigate alone. Clinical logistics organizations (CLOs) are equipped to partner with drug owners in order to facilitate trials and help lessen the obstacles of getting a drug from discovery to market. CLOs, such as Marken, use interactive response technology (IRT) to deliver drugs to depots in the EU, and often navigate import regulations to get some of those drugs into certain countries such as Russia and Ukraine.⁶

The Future of Uniquely Delivered Drugs

It’s likely that due to the nature of these drugs, given their complicated design, there will be more hurdles for companies to bring them to market in the future. FDA’s 2013 Nanotechnology Regulatory Science Research Plan promises more oversight into the use of nanoparticles, with the agency overseeing how safe drugs of unique delivery will be.⁷ Yet, measures like the National Cancer Moonshot Initiative may pump some needed speed and efficiency into FDA’s pipeline. The Cancer Moonshot Task Force looks to break barriers and silos (silo mentality being the lack of sharing and transferring of information from one agency to another) and to facilitate partnerships, in order to hasten the cure for cancer.⁷ Were it to happen, that cure may very well come about with the help of drugs in their own kind of partnership with nanoparticles.

References

1. Kreuter, Jörg. “Drug Delivery to the Central Nervous System by Polymeric Nanoparticles: What Do We Know?” Advanced Drug Delivery Reviews 71 (2014): 2-14. Web.
2. Conger, Krista. “Small Wonder: How Nanotechnology Could Detect and Treat Cancer.” Stanford Medicine. 17 May 2016. Web.
3. The 2016 Nice Insight Contract Development & Manufacturing Survey.
4. “Food and Drug Administration Safety and Innovation Act (FDASIA).” U.S. Food and Drug Administration. Web.
5. “2013 Nanotechnology Regulatory Science Research Plan.” U.S. Food and Drug Administration. Web.
6. Wheeler, Wes, and Ariette Van Strien. “Clinical Logistics – Meeting The 21st Century Cures Challenge.” Pharma’s Almanac. Jan. 2016. Web.
FACT SHEET: Investing in the National Cancer Moonshot. The White House: Office of the Press Secretary. 1 Feb. 2016. Web.

Next-Generation Therapies
Next-generation treatments have shown immense success in early clinical studies. The challenge today is getting these novel medicines into the hands of patients in need. In many cases, the development of new manufacturing, delivery and logistics technologies must occur first. Partnerships between all members of the pharmaceutical value chain are therefore crucial to realizing the true potential of these promising next-gen therapies.

Many of the most promising next-generation drug products are based on biologic active pharmaceutical ingredients that require new technologies that enable their manufacture, characterization (identity, viability, purity, potency, viral safety) and other testing (sterility, release, etc.) and distribution at the large scales required for commercial drugs. To date, these new treatments have only been produced for the most part on very small scales for early (phase I and II) clinical trials, either in in-house bio/pharma company process development labs or academic laboratories that provide small-scale contract manufacturing services. The methods used to produce, analyze and handle such small quantities are generally not economically viable or practical at the commercial scale. 

For cell therapies, for instance, live cells are harvested as the active agent, rather than being separated from the desired protein or antibody. Technologies related to tissue processing, cell selection, expansion, activation and genetic modification and cryopreservation are all needed. While allogeneic cell therapies, which are based on cells from healthy donors and are intended to be produced in large quantities as “off-the-shelf” treatments, can theoretically be produced in large quantities using conventional bioreactors,¹ autologous — or patient-specific — cell therapies cannot.

In the latter case, high-throughput systems run in parallel and processing multiple separate products at one time will be necessary.² Highly automated, functionally closed systems are of particular interest for autologous therapies in order to minimize operator intervention and prevent contamination.² Many also believe that cell therapy manufacturing will not be economically sustainable without the extensive use of automation to reduce costs, but the development of needed technologies will require cooperation among equipment vendors and with cell therapy manufacturers.³ Such systems will need to be designed to enable multiple manufacturing functions in an integrated manner. 

Given that many next-generation therapies will require new manufacturing capabilities, significant investment in infrastructure will be required to support current Good Manufacturing Practice (cGMP)-compliant manufacturing processes and testing capabilities. The largest bio/pharma companies involved in the development of novel treatments are electing to keep those investments in-house (through construction of new facilities or acquisition of existing capabilities). However, many next-generation therapies are being developed by smaller, emerging companies backed by venture capital. Most of these firms lack the capabilities required to manufacture cell and gene therapy products on a large scale and do not have the resources to establish their own in-house facilities. As a result, there will be significant need for the support of specialized contract development and manufacturing organizations (CDMOs) focused on the production of novel medicines.⁴

Regulatory Questions

Uncertainties regarding the regulatory requirements for novel medicines such as cell and gene therapies and the lack of standardization of regulations from agencies in different geographic regions represent additional challenges to the commercialization of next-generation therapies. Most notably, both in the U.S. and Europe, existing regulations require that pharmaceutical manufacturers establish and maintain comparability of drug products produced at multiple sites, which would make the production of patient-specific treatments at more than a couple of locations very difficult.⁵ The picture is further complicated for autologous cell therapies where appropriate manufacturing and distribution approaches may be dictated by the characteristics of the disease that is being treated and other factors, such as the capabilities of the clinics that will be administering the treatments.⁵ In addition, regulatory requirements for cell-based therapies differ in the EU and the U.S., adding additional costs for compliance; it is widely considered that existing regulations do not take into account the unique properties of personalized medicines and thus place impractical requirements on pharmaceutical companies, many of whom are small and lack the resources to meet them, particularly given the lack of harmonization between regulatory bodies.5 Managing the outsourcing of manufacturing to CDMOs adds yet another layer of complexity.

Considering Commercial-Scale Needs From The Start

One of the crucial factors creating challenges for movement from process development to commercial-scale production of next-generation therapies is the intense focus that most companies and academic laboratories take regarding the immediate process involved. Lack of consideration of the needs for large-scale production at the earliest stages of product development can hamper the translation and commercialization of such processes.⁵ Recognition of this need to consider commercial-scale engineering and manufacturing issues is increasing somewhat, however, as greater numbers of novel biologics proceed from early-phase trials to late-stage evaluation and require the production of larger quantities of drug product.⁶

There is a careful balance that must be maintained, however; addressing manufacturing issues at early development phases adds additional cost to a project (i.e., for equipment, controls and cGMP facilities) that many pharmaceutical companies cannot afford. On the other hand, significant regulatory and other hurdles must be overcome if a process must be changed at later development stages.⁶ At a minimum, though, raw materials should be selected that will be appropriate for cGMP manufacture. The development effort should focus on identification of a robust, reliable manufacturing process that is suitable for large-scale production, and characterization data should be developed that supports release testing.⁷ 

Many Collaboration Partners

With all of these challenges, it should not be surprising that most bio/pharma companies involved in the development of next-generation technologies also participate extensively in a wide range of partnerships designed to facilitate bringing these novel medicines to the market. Collaborations with academic research groups, research institutes, technology developers (such as for gene editing methods, nanobodies, optides, etc.), other pharmaceutical companies, government funding agencies and regulatory bodies and contract service providers are all commonplace and necessary for the successful translation of developments in fundamental science to commercial therapies produced at large scale.

New types of partnerships are generally necessary to bring the latest generation of novel medicines from initial discovery to commercialization. 8 In particular, the complexity of these advanced technologies is driving the need to bring together many different groups and technical experts with wide-ranging skills and expertise. Many large pharmaceutical companies are, for instance, establishing centers of excellence or innovation focused on the development of next-generation technologies. Patients and clinicians must also be part of the development process for many of the latest cell and gene-based therapies.8

Importance Of Contract Service Providers

To ensure that the initial successful research results obtained for many next-generation therapies are translated into affordable medicines that can be produced reliably at commercial scale, many bio/pharma companies are turning to equipment suppliers, contract research organizations and CDMOs to help them develop optimized processes and analytical methods.9 The challenge is to find service providers with the knowledge and capabilities needed to take such advanced therapies from the lab to the commercial scale. CDMOs must not only have lab and production capabilities, but also scientists with specialized development, manufacturing, and analytical expertise and robust quality systems to ensure compliance and product safety.¹ To have an impact, however, CDMOs must be able to apply existing process knowledge and large-scale manufacturing expertise to the emerging technology platforms underlying next-generation therapies and work closely with scientists that have the experience in developing novel therapies at the process development and early clinical trial scales.²   

References

1. Challener, Cynthia A. “Upstream and Downstream Operations Can Impact Biologic API Uniformity.” Pharmaceutical Technology. 2 May 2016. Web.
2. Burger, Scott R. Commercial Manufacturing of Cell Therapy Products – Considering the Options. Rep. World Stem Cell Report 2009. 5 Apr. 2009. Web.
3. Stanton, Dan. “Vendors Must Collaborate to Develop Cell Therapy Production Automation, Experts.” BioPharma-Reporter. 2 Feb. 2016. Web.
4. Bamforth, Mark, Steve Kasok and Richard Snyder. “Achieving Large-Scale Cell and Gene Therapy Manufacturing.” Pharma’s Almanac. 30 Apr. 2016. Web.
5. Hourd, Paul, Amit Chandra, Nick Medcalf and David J. Williams. “Regulatory Challenges for the Manufacture and Scale-out of Autologous Cell Therapies.” StemBook. 31 Mar. 2014. Web.
6. Dodson, Brittany P., and Aaron D. Levine. “Challenges in the Translation and Commercialization of Cell Therapies.” BMC Biotechnology 15.1 (2015). Web.
7. Brandenberger, Ralph, Scott Burger, Andrew Campbell, Tim Fong, Erika Lapinskas, et al. “Integrating Process and Product Development for the Next Generation of Biotherapeutics.” Cell Therapies Technology (2011): 30-37. Web.
8. “Gene, Stem Cell Therapies Bring New Players to Partnering.”Partnering360. 13 Aug. 2013. Web.
9. Forte, Miguel. “A Call for Cell Support: Engineered Cell Therapies Hold Exciting Potential for the Pharmaceutical Industry – but Only if Contract Manufacturing Organizations and Vendors Play their Part in the Revolution.” The Medicine Maker. Web.