SPECIAL REPORT - Outsourcing Formulation Development and Manufacturing: An Early Approach Saves Time and Money

The global pharma outsourcing market will likely climb from about $85 billion in 2011 to as much as $150 billion by 2015, states JZMed, Inc., a market research company. Key components of the outsourcing market are formulation development and manufacturing. Demand for outsourced manufacturing will increase from drug developers of all sizes. A new report, Pharmaceutical Contract Manufacturing: World Market Outlook 2012-2022, predicts that the world market for pharmaceutical contract manufacturing was worth $47.6 billion in 2012, and the overall market will grow with a compound annual growth rate (CAGR) of over 6% through 2016.

In 2011, active pharmaceutical ingredient (API) manufacturing services formed the largest market sector, accounting for more than two-thirds of revenues. APIs will account for the majority of revenues throughout the coming years. Increased demand for generic drugs will drive revenue growth for emerging-marke contract manufacturing organizations, highly potent API manufacturing will drive growth in the US, increased outsourcing of finished dosage manufacturing will also stimulate developed-market growth. Development of biologics will increase demand for injectable dosage manufacturing services, including fillfinish and lyophilization, the report also notes.

With regard to formulation development, an October 2012 survey (commissioned by Capsugel and conducted by an independent market research company) revealed that 82% of the respondents believe innovative dosage form technologies are required to meet the needs of today’s pharmaceutical research and development challenges. Yet, the development of suitable drug formulations and delivery systems remains a major challenge and there is an increasing need for outsourcing to fill the knowledge gap. More than half (58%) of the companies indicated that they outsource dosage form development. Poorly soluble compounds represent a very high proportion of the industry’s development pipeline. Yet survey respondents cited only moderate expertise on specific technologies related to poorly soluble compounds, specifically lipid drug delivery technologies. Half (50%) reported plans to specifically outsource lipid drug delivery technologies for poorly soluble compounds.

In this annual Drug Development & Delivery report, leading manufacturing and formulation development providers reveal why it is important to partner with a contractor early in the process to avert risk and save time and money in getting a drug through the development pipeline.

AGERE PHARMACEUTICALS, INC.-DEVELOPING BIOAVAILABILITY SOLUTIONS

Outsourcing of development services continues to be in high demand, and formulation and development service addressing bioavailability have experienced strong growth over the last several years Agere Pharmaceuticals, Inc. has experienced that growth first hand. Its CRO/CMO services span formulation design and development through cGMP analytical and clinical final dosage forms. All services are customized on a percompound basis and delivered as fee-forservice. Its global client base includes virtual and small- and mid-sized companies as well as big pharma.

One trend that Casey Jones, VP of Corporate Development at Agere has identified is the realization that a different approach is needed to improve the predictability of outcomes. “Far too many compounds are failing: We estimate that today nearly 30% of NDEs attrite from Phase I clinical trials due to solubility issues. This trend is getting worse, and requires a new way to look at analyzing and formulating drugs for bioavailability,” she says.

To address the issue of greater predictability, Agere is developing and integrating a suite of computation tools that perform more accurate and agnostic polymer selection, predict in vivo performance, and model shelf life. “We have been working on this for years, and in early 2013, we introduced a model-free method of measuring phase diagrams for solid amorphous dispersions.”

Another trend that Jones sees is that solid and liquid dispersions have become more popular for enhanced solubilization, and there is an increase in suppliers of excipients and the types of excipients that target this segment. In response to its clients’ requests, Agere expanded its cGMP operations to include Phase IIb manufacturing. And, it added regulatory guidance services in 2012 to leverage Agere’s expertise in solubilization.

“Most of our customers are seeking a full service pre-clinical formulation development carried through to cGMP into mid-stage clinical trials,” says Ms. Jones. A one-stop-shop makes our clients lives easier by limiting the number of contractors they have to manage.”

In addition, she says pharma expects service providers to have the level of quality and expertise they’d want in an internal group. This includes a strong team of scientists and technologists, robust quality systems, effective project management, streamlined technology transfer and overall transparency.

“As big pharma continues cut overhead by sending formulation development and dosage form manufacturing to CMO’s, it’s more critical now than ever before for service providers to obtain preferred provider status.” This status isn’t easy to come by, as clients are becoming more demanding about some of the characteristics vendors must have.

“As the outsourcing market is growing, no doubt it will attract even more CROs, increasing the competitive nature of the business,” says Ms. Jones. “Differentiating the quality of services provided — including better predictability to reduce downstream risk — will become even more essential. Innovative use of technology, science and expertise to efficiently deliver customized and optimized services will become a must-have.”

ALKERMES-CONTRACT PHARMA SERVICES DEVELOPMENT AND COMMERCIAL CAPABILITIES

There is an increase in the number of highly potent compounds coming through development – approximately 25% of drugs currently in development are classified as highly potent. This number is expected to grow by a CAGR of 8.4% to 2015.

To address this growing area, Alkermes Contract Pharma Services has increased its expertise in the manufacture of highly potent compounds. “We are currently tech-transferring a highly potent compound into commercial manufacture for a large pharmaceutical company,” says Fidelma Callanan, Senior Director, Marketing & Commercial Development at Alkermes Contract Pharma Services.

She says there has also been increasing interest in compounds that are poorly water soluble and require bioavailability enhancement and in the commercial manufacture of poorly water-soluble compounds using its NanoCrystal® technology. “It is one of the very few solubility enhancement technologies that has been successfully scaled to commercial level and is the technology behind five commercially available poorly water-soluble compounds on the market-Emend® Merck; Invega® Sustenna® Janssen; Rapamune® Pfizer; Megace ES® Par Pharmaceuticals; and TriCor® Abbott,” she says.

Alkermes plc was formed following the merger of Alkermes Inc and Elan Drug Technologies in September 2011. The contract pharma services part of the business provides late-stage development, tech transfer, and manufacturing services to third parties, with a focus on solid oral dosage forms – particularly in controlled release formulations, poorly water-soluble compounds, and high-potency manufacturing. In the US, Alkermes has a dedicated sterile fill/finish facility as well as a controlled substance manufacturing facility.

Whether it’s to address highly potent drugs or issues of solubility, Ms. Callanan says it is strategically sound to pursue outsourcing services to fulfill specific tasks, solve problems, and improve efficiency and productivity. One of the growing trends is the outsourcing of late-stage scale-up and commercial manufacturing activities, evidenced by the fact that in the last three years, more than 100 manufacturing facilities owned by pharmaceutical companies closed their doors for business in the US alone. “The value of partnering with a contract partner can very positively impact a pharma company’s bottom line by alleviating capacity constraints, reducing capital spending and improving supply chain predictability,” she says. “Building a solid relationship based on experience and expertise, with an enthusiasm to successfully execute on a project, backed up with a positive quality record with key regulatory agencies, has the power to turn a third-party arrangement into a long-term, strategic, winwin partnership for all parties concerned.”

ALMAC PHARMA SERVICES- DEVELOPMENT TO COMMERCIALIZATION

With its clients facing increased pressure to bring clinical candidates through their pipeline, faster, more efficiently and at a lower cost, Almac Pharma Services opened a non-GMP development facility to offer flexibility and speed when assessing the feasibility of technical concepts and formulations, creating a streamlined progression from development to clinic to scale-up to commercialization.

“The formulation development facility is supported by additional GMP analytical laboratories,” explains John McQuaid, Vice President, Technical Operations. “Having established ourselves as a development partner of choice, this expansion was quite simply due to increased client demand. With regard to formulation development, I expect a continuation of the trends of more potent drugs requiring high containment and also development of drugs that have bioavailabilty challenges.”

Formulation development and manufacturing activities are supported by analytical development and testing activities, so the technical strength and scale of the analytical discipline is an important consideration. Almac has more than 200 analytical personnel dedicated to formulation development and manufacturing services. There are also chemical development and clinical packaging and distribution operations. “This offers tangible savings in cost and time in the supply chain for clinical materials, and also reduces risks associated with unnecessarily transporting in-process materials,” says Mr. McQuaid.

Over the last few years, he says that within solid oral dose development in earlystage development, there has been an increasing trend towards API in capsule “If the attributes of the API are suitable, API in capsule can be good choice as it uses less material.”

There is also an increase in developing both highly potent compounds and compounds with challenging oral bioavailability attributes. The increased demand for potent handling capabilities resulted in Almac investing in bespoke, containment solutions within its development facilities.

Almac Pharma Services is an FDAand EU-approved outsourcing partner to the global pharmaceutical and biotechnology industries with more than 30 years’ experience in the development and manufacture of solid oral dosage products. Scientists develop clinical candidates into optimum formulations, and manufacture drug products for all phases of clinical trial supply and through to commercialization- all at a single location. Its customer base is global and includes academic institutions, small virtual companies, biotech companies, mid pharma, and big pharma.

APTUIT-AN EARLY START TO FORMULATION IS LESS RISKY

Aptuit LLC provides early- to midphase development services for small, mid to big pharma as well as fully virtual drug development companies. In the past year, Aptuit has invested substantial resources in expanding some key manufacturing technologies. For poorly soluble compounds, the company has optimized a wet bead milling (WBM) technology to support toxicology studies with “simple” solid and liquid formulations containing nanosized API, which can guarantee an increased API exposure in animals without using organic vehicles, explains Roberto Bartolini, Formulation Development Group Leader, Chemistry, Manufacturing & Control, The Aptuit Center for Drug Discovery & Development – Verona, Italy. “We have already extensively studied and developed our WBM platform technology for the development of tablet or capsules to support clinical studies in humans.”

Using its foundation competencies in characterization of DPI (dry powder inhaler) and blending mechanisms, Aptuit offers formulation development and GMP manufacturing of DPI from early clinical phase to late phase. “We are able to offer our early-phase approach to DPI formulation development using both low and high shear blending capabilities and semi-industrial microdose capsule filling technology,” says Mr. Bartolini.

He continues: “With regard to solid dosage development, there is an increasing demand to shorten the time to the start of the clinical study, saving money and reducing the API demand. Instead of producing a fully formulated drug product, simple formulations (API in capsule, simple blend or granule in capsule) can be prepared and assessed for stability and in vitro performance.” Mr. Bartolini says that preparation of this simple “fit for purpose” formulation requires a clear understanding of the biopharmaceutical profile of the API with its complete physico-chemical characterization and the evaluation of the risk associated with the possible inadequate performance. “A contractor with specialized expertise, capabilities and proprietary technology in the early development phases can make such outsourcing quicker, cost effective and less risky.”

And with the growth of the biologics market, Aptuit has expanded its Glasgow, UK, sterile fill/finish capability to enable automatic filling of vials within a restricted access barrier system. “This has substantially increased our batch sizes for GMP sterile filling and lyophilization of both small molecules and biologics,” he explains.

Outsourcing early formulation development and manufacturing should be considered the cornerstone of a successful project strategy, says Mr. Bartolini. “It is not only a matter of accelerating the development or reducing the costs, but being able to access expertise to design the most efficient drug delivery platform. This reduces risks and provides all the required scientific knowledge to safely move into the next project phase.”

BEND RESEARCH-SOLVING SOLUBILITY ISSUES

A current trend in the pharmaceutical industry is the advancement of increasing numbers of compounds 44 that have low solubility. It is estimated that more than half of all new chemical entities have poor bioavailability. To overcome this growing challenge, Bend Research offers solutions such as spray-dried and hot-melt-extruded amorphous dispersions.

Bend Research has capabilities to support the advancement of drug candidates from discovery through commercialization. These include formulation and dosage-form support, process development and optimization, and cGMP manufacturing. With a client base ranging from big pharma to virtual biotechnology companies, Bend Research also serves the non-profit, academic and generic sectors, as well as non-pharma companies with projects that use its expertise in materials science, process development, and applied mathematics.

In the past year, the company has significantly expanded its facility footprint to enhance its Phase 1 to Phase 3 development and clinical spray-drying, and hot-melt extrusion, as well as adding commercial manufacturing offerings. In the spring of 2012, a new facility was validated that expanded GMP capabilities to include the spray-drying of high-potency compounds and biotherapeutics. Further expansion is expected to continue throughout this year.

Bend Research finds that its clients’ discovery organizations are producing an increasing quantity of poorly bioavailable compounds. Thus, Bend Research is aiming in two directions-supporting existing bioavailability-enhancing technology platforms and developing nextgeneration technologies-according to David Lyon, PhD, Senior Vice President, Research, at Bend Research.

“With fewer molecules in the pipeline, it is crucial for us to provide innovative formulation development and dosage form solutions to our clients. This will ensure a higher chance of success for their drugs,” Dr. Lyon said.

Additionally, Bend Research has been granted certification of compliance with European Union GMP regulations. This certification was granted in January 2013, after an extensive audit of operations that was requested by Bend Research. “This means that investigational drug products we make for our clients can be used in clinical studies in the EU and all of the many countries that recognize the EU authority,” says Dr. Lyon.

CMIC CMO USA CORP.- MINDFUL OF MULTIPARTICULATE AND MODIFIED-RELEASE DELIVERY

CMIC CMO USA Corporation is a member of the CMIC Group, a pharmaceutical focused company with facilities in 6 countries and more than 4,500 employees worldwide. Its FDAregistered facility is located in Central New Jersey. With a focus on formulation and process development, GMP commercial manufacturing, analytical and quality assurance of NDA and ANDA soliddosage products, the company’s clients include big pharma, generic pharma, specialty pharma and excipient suppliers.

Currently, Jeffrey Dopf, Director of Business Development for CMIC, says the company is seeing high interest in multiparticulate and modified-release delivery to support life cycle management projects and to improve patient compliance. To that end, CMIC has completed the construction and validation of 3 new development and GMP clinical supply suites. “These suites are designed for flexibility and quick initiation of development and feasibility batches,” he says.

CMIC’s Freund-Vector Granurex® GXR technology in New Jersey is a onepot system for granulation, spheronization, drug layering, and spray coating. “This equipment allows us to produce eloquent beads for multiparticulate systems and a robust layering process for tight assay and dissolution specifications,” he says.

The company is also vigilant in its understanding of the current FDA requirements. According to Mr. Dopf, the agency continues to be concerned with dose dumping of controlled release products. “Our extensive experience with the development of controlled release products and with coating systems helps us meet the challenges of dose dumping.”

The FDA is also looking for a greater understanding of the design space for a formulation and process. CMIC scientists’ experience and expertise with a focus on oral solid dosage contributes to a greater understanding of the most common formulation and process failures and typical root causes, explains Mr. Dopf. “We have the ability to improve productivity with our initial Quality by Design (QbD) programs and through formulation and process optimization.”

DR. REDDY’S- PREFORMULATION AND FORMULATION DEVELOPMENT

The pharmaceutical development process is a complex and dynamic area requiring detailed knowledge of API characterization, formulation, process, analytical development, sound experimental design, and regulatory requirements. Given the breadth and depth of expertis necessary to successfully develop a pharmaceutical product, many companies opt to outsource formulation activities. Some may not have development capabilities in-house, may have expertise limited to a specific area, or may have certain knowledge or capability gaps that influence the need for outsourcing. Others may be seeking novel technology, intellectual property, or unique capabilities offered by an outsource provider. Cost constraints, tight timelines, lack of staffing, competing priorities, or the need to allocate resources for other strategic purposes may also drive a decision to outsource. And, as the landscape of the pharmaceutical market evolves with mergers and acquisitions, the need to outsource may be critical as organizations are disrupted and integration activities are implemented.

Dr. Reddy’s Custom Pharmaceutical Services division (CPS) is serving the pharmaceutical, generic, and biotech space with two R&D centers for preformulation and formulation development studies of NCEs and generic drug products, as well as 8 formulation manufacturing units. Preformulation services are designed to evaluate the basic properties of drug substances for developing drug products in both the solution phase and solid state.

The current trends in the formulation and manufacturing market include th development of various dosage forms over the entire spectrum of development such as preclinical studies and clinical studies up to registration batch for one compound. Design of Experiments (DoE) and Quality by Design (QbD) during scale-up stages have now become mandatory by a few regulatory agencies and customers are further emphasizing the need for a vendor to have this expertise.

“We have offered the following services within the past year: Our own inhouse resource for DoE, data analysis and QbD, technical expertise in developing conventional solid oral dosage forms, delivery of drugs with modified release profile, combination product with multiple incompatible actives, combination product with sequential release, gastro retentive dosage forms, taste masking, and stabilization,” says Praveen Raheja, Formulation Technology Manager.

Over the next 5 to 10 years, the pharmaceutical industry will see generic competition as more blockbusters come off patent, and the emergence of biosimilars. “More and more, clients are looking for true one-stop-shop service providers who have experience and expertise starting from preformulation development through to technology transfer for commercial manufacturing. It has been observed that as more providers, including companies from emerging markets, begin to offer formulation outsourcing services, the emphasis on quality and regulatory compliance, scientific expertise, specialized service, and program management takes higher priority,” says Mr. Raheja.

Additionally, the other areas that will emerge over the next decade include development of biologics at higher concentration, special drug delivery systems like pre-filled syringes, and lyophilized formulations. “A larger piece of formulation outsourcing will go to the large and financially strong CDMOs with integrated services as well as to a few smaller companies that offer specialized technologies.

“There is an increasing trend to reduce complexity in pharmaceutical supply chains. For big pharmaceutical companies, it is becoming more important to concentrate their sourcing at fewer CDMOs with the right capabilities and reduce supply chain and project management challenges. Both trends make it more difficult to select the right CDMO partner,” says Mr. Raheja.

EI INC.-AN EMPHASIS ON QBD

According to John F. Lang, PhD, PE, Associate Director of R&D Technical Services at Ei Inc., pharma clients are becoming increasingly aware of the relationship between the desired attributes of a product and process conditions. “To simply achieve the desired attributes of a product with little or no awareness of the underlying scientific basis for those attributes can lead to a lack of process robustness as well as scale-up and product stability problems,” he says. “Once the relationship between the product attributes and process conditions is understood, the process can be adjusted to improve the product. If you add to this the increasing regulatory expectations (especially Quality by Design), the trend for greater scientific understanding of products seems inevitable.”

The areas that are receiving the most attention are identification of process parameters that affect the critical quality attributes of the product, chemical interactions between the components of a formulation that affect stability, API characterization (especially particle size and polymorphic state), efficient HPLC methods for assaying multiple active ingredients, and scale-up methodology.

Ei, a Pharmaceutical SolutionWorksTM, develops and manufactures topical Rx, OTC, and cosmetic skin care and animal health products for customers ranging from big pharma to virtual start-ups. Ei recently constructed a 165,000-square-foot development and manufacturing facility outside of Charlotte, NC. Ei’s facilities are cGMP compliant and have been audited by FDA and EMA. Services include API characterization, formula development, technology transfer, method development, packaging development, ICH stability, process scale-up, clinical and commercial manufacturing, filling, and regulatory filing assistance.

Dr. Lang says that big pharma has been slow to adopt QbD approaches to product development, which he says lead to a clear understanding of the design space of a product. “The design space, which is obtained by experimentation, describes the process ranges within which a product can be reliably manufactured with achievement of all of the desired product attributes,” he explains. “Our clients report a warm reception at FDA for product development conducted with a QbD approach. When one considers the importance of speed to market, faster regulatory approval easily pays for the added cost of QbD development.”

In addition to rapid formulation and process development and cost-effective manufacturing services, efficient analytical method development services are becoming increasingly important. This is especially true when there are multiple active ingredients, each with several known impurities. The active ingredients in a liquid formulation are more prone to degradation than those in solid dosage forms. In addition, FDA is placing increasing emphasis on tracking impurities not listed in compendial sources. In the drug product, each active must be assayed and each degradant impurity tracked. “Because not all impurities are degradants, an understanding of the chemical degradation pathways is important to limit the number of impurities whose quantitation must be validated in the analytical method. Given this complexity, analytical development can easily delay projects unless a well-organized team is in place,” says Dr. Lang.

In light of this, during the analytical development phase of a project, Ei places early emphasis on the application of chemical reasoning and limited experimentation to distinguish between process and degradant impurities of the APIs present in a drug product. While this is occurring, literature and manufacturers’ methods are evaluated as a starting basis for testing the drug product. Careful attention is given to strategy, especially whether multiple methods for each API or a single method for all APIs should be attempted. If the right calls are made, the development time can be significantly shortened.

Looking ahead, Dr. Lang sees three areas where outsourced formulation development and manufacturing relationships can be improved. First, he sees a greater need for the integration of other disciplines, especially chemistry and chemical engineering, into the formulation and process development of topicals. An understanding of the chemical interactions in a product leads to more effective products and more stable ones, he says. It also greatly simplifies the analytical development process. “Chemical engineering plays a role in understanding API characteristics, the internal structure of the product (such as droplet size), and the development of scale-up methodology, and is essential for QbD development.”

Second, there is increasing demand for more detailed pharmaceutical development reports and carefully designed manufacturing documents for both bulk and filling operations. “Given th complexity of many manufacturing processes, the associated documents must be sufficiently detailed to avoid errors during manufacturing, which can be very costly to a drug development program,” says Dr. Lang.

Finally, agility is very important in the contract process development and manufacturing space. “Several of our clients have other business partners and some have divided the development process among multiple suppliers. This leads to a situation where plans can readily change and communication is vital. It has become somewhat clichéd to say that forming partnerships with clients is important, but the fact remains that effective partnerships are essential to a smooth development process when multiple parties are involved. This requires regular communication among all parties to ensure plans are unfolding in the same direction.”

MPI RESEARCH-A PRECLINICAL CRO

MPI Research is a preclinical and early clinical CRO that provides discovery, surgery, safety evaluation, bioanalytical, and analytical services. As a CRO in the preclinical market place, its expertise lies in the production of many different types of formulations for various types of dose administration routes. Compound types range from traditional small molecules, oligonucleotides through to protein therapeutics while dosing vehicles range from simple solutions to complex feeds, gels, and creams. Preparation of preclinical dosing formulations is typically completed based on instructions provided by the sponsors, however, modifications to the instructions may be required to accommodate batch size, available equipment, chemical and physical instability, and homogeneity considerations.

In the CRO preclinical arena, where a large number of compounds are being formulated every day for many different studies for many different sponsors, eliminating the potential for cross contamination is paramount. “Our approach has been to use a state-of-the-art laboratory space incorporating designated clean (‘in’) and dirty (‘out’) anterooms, containment hoods, and extensive cleaning validation studies along with secondary containment of bulk test article and formulated material,” explains Amy Smith, Director of Laboratory Sciences. Laboratory space has been designated for vehicle preparations to eliminate the possibility that a test article is ever introduced into the control material. “Specific cleaning and verification procedures are in place to ensure containment of the test article and to minimize the introduction of any contamination.”

MPI formulation experts work with analytical scientists to ensure timely response to any observed anomalies in the formulation. Some examples of anomalies include, but are not limited to, observation of out-of-specification results, chemical and physical instability, adsorption of the dosing material in the dosing delivery system, and incompatibility of the test article with the vehicle for the specified dosing route.

In the preclinical CRO market, flexibility, rapid response time, and a broad range of scientific experience and quality are essential to ensuring a successful study. Electronic chain-of-custody is maintained from preparation of the formulated material through dosing and subsequent disposal. Flexibility is required in order to accommodate both the large volume and different complexity of test materials and vehicles. This includes preparation equipment, storage conditions, and preparation techniques.

“A CRO that understands the principles and practice of formulation development-that can deliver the experimental results in a timely manner to both the consultant and the client-will be well positioned for success in the market place,” says Ms. Smith.

PFIZER CENTRESOURCE-SOLID ORAL DOSE COLLABORATION

Cancer is a leading cause of death worldwide, and the development of more effective, efficient and targeted cancer treatments is critical and urgent. High potency active pharmaceutical ingredients (APIs) have characteristics that allow the selective targeting of cancer cells, blocking their growth while causing less harm to normal cells. With new classes of high potency APIs being developed, often better tolerated by patients and available in oral dosage forms, this area has become one of the fastest growing segments in the global pharmaceutical industry.

The very thing that makes these APIs so effective – their potency – adds layers of complex