Outsourcing Perspectives from Catalent Pharma Solutions

Participants:
Richard J. Holl, Ph.D., Director, Pharmaceutical Science
Todd Stutzman, RPh, Director, Pharmaceutics
Aileen Ruff, Strategic Director, Advanced Delivery Technologie
Min Park, Group Product Manager, Advanced Delivery Technologies

Technical/Scientific Trends

Analytical services
Biologics drug development and manufacturing
Solid/semi-solid dosage development and manufacturing

PharmTech: What emerging technologies or practices do drug sponsors expect your organization to provide?

Richard J. Holl: In addition to developing clinical candidates that do not have special regulatory designations, drug sponsors expect us to be able to execute accelerated development programs to support their clinical development candidates that have expedited, breakthrough or orphan designations while maintaining the highest quality standards.  In terms of emerging technologies or practices, drug sponsors expect some degree of familiarity with the use of bioavailability and solubility enhancement approaches and an expertise in dry granulation processes.

Aileen Ruff: Companies with fast-track development programs look to Catalent for faster integrated solutions from development to manufacturing. We have seen increasing demand for Biologics and biosimilars development, where we have proven cell line technology and have recently launched new manufacturing facilities in Madison, Wisconsin. Antibody Drug Conjugates (ADCs) are also attracting much interest, and Catalent's SMARTag next-generation ADC technology, exclusively licensed from Redwood Bioscience, continues to demonstrate its huge potential in in vivo studies. Catalent is developing the oral delivery of vaccines to treat the Flu, Pneumonia and HPV through our Zydis Bio technology platform. This development will help reduce the high administration cost and potential poor adherence of parenteral vaccine delivery, and will expedite the distribution in potential developing markets, pandemic and emergency situations. In addition the Zydis Bio technology platform has proven capability to deliver antigens and peptides. Further innovations for oral macromolecule delivery include our OptiGel Bio technology that may overcome the traditional hurdles by enhancing permeability combined with targeted delivery. Catalent's development expertise can rapidly identify an optimal oral formulation, enabling the traditional benefit of an oral softgel formulation with proven commercialization capabilities.

Min Park: Our customers expect deep expertise and innovative solutions to help them get more molecules to market faster while creating better treatments for patients, in an increasingly competitive environment, that is subject to strong payer pressures. For example, emerging trends include more combination therapies, molecules that require absorption beyond the gastric tracts, non-invasive methods of delivering biologics and delivery methods resistant to abuse. Catalent invests extensively in global capabilities and technologies to meet these needs.

PharmTech: What scientific or technical advances have positively or negatively impacted drug development processes in this market segment?

Richard J. Holl: On a negative note, in efforts to accelerate timelines, clients are electing to not fully assess their design space and optimize their drug product manufacturing processes which can result in later stage development challenges and delays in market approvals.

Todd Stutzman: On a positive note, a renewed interest in the use of bioavailability and solubility enhancement in formulation development has allowed drug substance candidates that previously would not have been considered for clinical development to achieve sufficient bioavailability to be advanced into further development.

Aileen Ruff: The wider use of ADCs and the introduction of improved, potentially safer ADCs in particular, will undoubtedly have a positive impact on this market- there are currently only two with FDA approval- Brentuximab vedotin for the treatment of Hodgkin's and anaplastic large cell lymphoma and trastuzumab emtansine gained FDA approval for the treatment of HER2+ breast cancer. The current ADC pipeline is large, with more than 100 ADCs currently in clinical trials; this effort underscores the industry's belief that ADCs will help create safer, effective biotherapeutics.

Min Park: Innovation in oral solid dosage modified release technologies and applications has experienced a surge in in recent years. This can be largely attributed to the need for further differentiation of innovator drugs, to optimize therapeutic product profiles to effectively compete in a more competitive and global marketplace. Positive advances include the adoption of newer delivery technologies such as oral absorption of biologics, and Hot Melt Extrusion (HME) among others.

PharmTech: Are you seeing shifts in demand for particular types of services? Please describe.

Richard J. Holl: Yes, we are seeing an increase in demand for dry granulation services, especially in roller compaction, large molecular characterization, and an increased interest in the development of dosage forms specially designed for pediatric administration.

Aileen Ruff: As a high proportion of drugs in development suffer from poor solubility and/or permeability, customers are increasingly looking for partners to help improve the bioavailability of their development products or to optimize the treatment to patients. Formulations vary significantly so it is helpful that Catalent is able to offer a variety of technologies that improve the effectiveness of pharmaceutical products for certain patient groups. Catalent has recently built a completely single-use site in Madison, Wisconsin, which includes single-use cGMP bioreactors up to 1000 liters, producing material for Phase I and Phase II clinical trials, with potential to expand to Phasic and commercial manufacturing. By switching to single-use systems we provide greater flexibility to our customers and significantly decrease the potential for cross contamination issues. Additionally, the enhanced flexibility of scale allow us to provide options for the smaller (orphan) products that are in high demand within the industry.

Min Park: We have seen an increase in demand for technologies that are effective for the delivery of poorly bioavailable products. Our recent investments in HME, to broaden our OptiMelt technology platform, are in response to increased customer demand, particularly in the post proof-of-concept stages of process development and scale-up. Additionally, our customers are becoming increasingly global and need global supply capabilities, as well as global R&D capabilities, and an understanding of regional needs.

PharmTech: What pressing technical challenges have you seen in this market segment? What actions has your company taken to resolve the challenge? What actions does your company suggest?

Richard J. Holl: Because of the aggressive development timelines associated with today’s drug product market and a renewed interest in drug product candidates with expedited, breakthrough and/or orphan designations, we have seen a decrease in the amount of time and effort available to fully assess their product and process design space to support process performance qualification (PPQ).  To address this growing trend, we incorporate QbD into our development strategy and have established what we term “QbDLite” which is an abbreviated yet thorough assessment of our clients design space to support PPQ.

Aileen Ruff: Technical challenges include 'big picture' ones, such as finding more efficient ways to purify protein and better ways to grow cells to obtain higher titers, cleaner starting material etc., but also smaller, less exciting ones, such as standardization of single use connectors and films that will also fundamentally effect the industry.

Min Park: According to surveys that Catalent conducted at its recent Applied Drug Delivery Institute events, Drug Release Profile, Stability and Solubility of the API, and Abuse Deterrence were the most significant challenges. Customers are increasingly looking for partners to provide solutions to improve the bioavailability of their development products or to optimize the treatment to patients. Formulations vary significantly so it is helpful that Catalent is able to offer a wide range of solutions.

PharmTech: What advances do you see in science or technology in this market segment in the next five years?

Todd Stutzman: We see increased interest in anti-counterfeiting measures to address the growing global pharmaceutical manufacturing activities that can result in compromised global supply chain. In addition, we see the growing importance of assuring patient compliance through the use of advanced technology approaches, including those that can sense and signal the administration of dosage units to patients. There are also new advances in tablet presses that allow for unique dosage unit configurations that were not possible even a few years ago. These advances can result in the design of bisected compressed powder tablets that maintain sustained release delivery even after bisection or the ability to form dry coated dosage units containing multi-particulates.

Aileen Ruff: Look for breakthroughs in efficiency in manufacturing and for new technologies, such as ADCs with advanced linker technologies, to drive safer, better treatments. Many of these products will be more complex than current biologics, leading to more extensive characterization and testing.
We also expect to see more countries looking within their own borders for biologics manufacturing as they want to control manufacturing of these products due to concerns about supply chain of these products.

Min Park: Innovation in solid and semi-solid dosage forms will continue. Examples of recent advances in oral dose form development and supply include Catalent's OptiMelt HME Technology and Zydis Fast Dissolve Delivery Technology. OSDrC OptiDose is an innovative flexible core tableting technology that enables the formulation and manufacturing of single or multi-cored tablets with differentiated controlled release functionality and unique dose forms including fixed dose combination tablets.

Industry Trends

PharmTech: What regulatory changes have positively or negatively impacted drug development/manufacturing processes in this market segment?

Richard J. Holl: With the enactment of FDASIA, pediatric study plans are now expected for any new market application reviewed by FDA. This has resulted in the need to develop pediatric dosage forms specifically designed and tested for the pediatric population. Because of the special needs of children with regard to administration, dosage unit design needs to address taste, ease of swallowing, and ease of administration.

Todd Stutzman: Foreign regulatory agencies have also increased their inspection of drug manufacturing facilities. These organizations sometime have unique interpretations of cGMPrequirements and differing opinions as to how to achieve compliance.

Aileen Ruff: Regulations are changing daily, affecting our industry in multiple ways, in multiple markets. Recent GDUFA and related regulations in the US have made an impact, as have recent initiatives regarding Quality Agreements. Catalent has a dedicated Regulatory Services group, offering both regulatory strategy and operational excellence, working closely with over 30 global agencies for our clients. This is essential as we write and publish over 120 regulatory submissions on our customers' behalf globally every year.

Min Park: Recent FDA changes such as 2013 new guidelines for dividable tablets and 2014 proposed NCE exclusivity for certain fixed-combination drug products had some impact in this market segment. OptiDose Technology provides new technological innovations enabling the highest levels of flexibility in designing modified release, advanced fixed dose combination, pulsatile delivery, and dividable dosage forms that enable the customization of medication to exactly meet patient needs while meeting the higher regulatory guidance for oral solid dosage forms.

PharmTech: What business trends have positively or negatively impacted drug development/ manufacturing processes in this market segment?

Richard J. Holl: The reductions of in-house capabilities of certain major pharmaceutical companies have resulted in an increase in business with outsourcing vendors.  Accompanying this reduction, numerous venture-funded and small start-ups have been established that frequently do not have the infrastructure to support the development of their drug products, and rely more on outsourced vendors to provide these capabilities.

Aileen Ruff: The current Biologics market is successful based on the criteria of revenue growth, and improvements made by biologics to people's quality of life. This is balanced by project failures and reimbursement challenges. To be more successful, the basics need to be addressed. The industry needs to get better at discovery and at determining which products will succeed and applying technologies, clever development strategies, and quality by design to get product to market.

Min Park: Pharmaceutical sector developments, such as the demand for increasing R&D productivity, are a strong influencer on our business. Pharma is also concentrating on more specialised therapies, and companies such as Catalent need to complement this. The emergence of BRIC countries is highly significant and it has become increasingly important to serve these regions with development, delivery and supply solutions, which is why it's imperative to continually invest in new facilities and capabilities.

PharmTech: What changes are you observing in the organization and operations of drug sponsors in this market segment?

Todd Stutzman: With major pharmaceutical companies, we are observing an increase in strategic partnering and outsourcing of development activities that were previously kept more in-house. In addition, we have seen the establishment of operating units within major pharmaceutical companies that have more of an entrepreneurial approach to drug development than we have seen in the past.

PharmTech: How has Quality by Design influenced a drug sponsor’s expectations of suppliers?

Richard J. Holl: Because of the recent process validation guidance issued by FDA that establishes the agency’s expectation that QbD be incorporated into drug product and process development throughout the development cycle, we have increased interest by our clients on how to incorporate these practices into their programs. However, the practical application of QbD practices to specific drug product and process development is left to individual sponsors and their providers. The degree of effort required in assessing a particular drug product and/or process is somewhat dependent on the compositional and manufacturing complexity associated with the product.

PharmTech: Describe the role that quality agreements play in contract services relationships. How will FDA’s draft guidance on quality agreements affect the relationships between contract service providers and drug sponsors?

Richard J. Holl: In our organization, we require quality technical agreements (QTAs) for our development programs in which cGMP activities are anticipated, especially if investigational materials are planned to be included into clinical study sites located in the EU. We believe that QTAs are an important component of our development programs because they further define and establish the working relationship and expectations between ourselves and our clients, especially as they relate to quality and regulatory issues.