As drug candidates have become increasingly complex, the risk of failure down the line appears to be greater than ever. Robert Harris, director – Early Development, Molecular Profiles, looks at the challenges with early phase development and the benefits offered by CROs.
According to data from IMS Health, the world pharmaceutical market was worth an estimated €579,510m at ex-factory prices in 2009 and Europe accounted for 30.6% of the world pharmaceutical sales. As the European Federation of Pharmaceutical Industries and Associations (EFPIA) reports, the research-based pharmaceutical industry is a key asset of the European economy, representing 17% of the total EU business r&d investment and 3.5% of the total EU manufacturing value added.1
Pharmaceutical r&d is a particularly lengthy, expensive and risky process, requiring increasing investment efforts. The chances of new compounds becoming marketable and profitable medicines are relatively small. It is not uncommon for seemingly promising new compounds to reach an advanced stage within clinical research before trial results reveal that these substances offer no potential. This incurs extremely high costs. And while the cost of producing new drugs continues to escalate, drug sales are declining due to patent expirations. In this era of shrinking pipelines and revenues, the industry is looking for ways to bring new drugs to market more efficiently.
In this era of shrinking pipelines and revenues, the industry is looking for ways to bring new drugs to market more efficiently
Outsourcing early phase development to an expert CRO has emerged as a reliable, time-efficient and cost-effective alternative to operating an in-house r&d department. According to market research performed by Frost and Sullivan,2 the European CRO sector will be worth US$13.52bn (€10.27bn) by 2015, up from $7.10bn (€5.4bn) in 2008. Growth is expected to be triggered by the need of pharmaceutical and biotechnology companies to control costs and accelerate product development. The stringent regulatory environment and increase of product life cycle management programmes will also provide major impetus for the growth of CROs.
The Frost and Sullivan research also revealed that, when selecting a CRO, pharmaceutical and biotechnology companies place increased emphasis on expertise and capabilities, with the focus being on quality management. Large companies, in particular, perceive CROs as possessing better expertise in the early stages of drug development. At the same time, there is an evident preference towards CROs that adopt a full-service model.
development challenges
Early phase development of new drug compounds is challenged by increasingly poor bioavailability, most often because the compound exhibits poor water solubility. At the same time, scientists have to formulate an increasing number of complex drug candidates to support pre-clinical programmes and human clinical studies. Conventional pharmaceutical formulations have been relatively simple, developed mainly through trial and error techniques.
The degree of bioavailability for a given compound is influenced by its physicochemical properties. In addition, selection of a suitable formulation is easier when the physicochemical properties are fully understood. As a result, pre-formulation and solid state characterisation strategies are a necessary step to aid identification of critical quality attributes and optimise the physicochemical properties of molecules to produce viable candidates for drug development.
These assessments must take place at a very early stage during development to identify potential quality problems and address them prior to reaching a later phase. For example, improving bioavailability prior to formulation (e.g. by suitable salt selection) helps to ensure that toxicology and first time in human studies will produce meaningful data. Overall, ensuring early control over formulation development can strengthen end value.
Proficient smaller CROs are creating a new market for services all ‘under one roof’, adopting a full-service model that can provide the entire range of early phase pharmaceutical development services
Whereas large CROs are ideal for offering late phase II to commercial services, specialist CROs are preferable for often complex early phase development services. Proficient smaller CROs are creating a new market for services all ‘under one roof’, adopting a full-service model that can provide the entire range of early phase pharmaceutical development services, including formulation and analytical development, clinical trial manufacturing and advanced analytical support. As large pharmaceutical companies expand their portfolios, while being short of cash flow they will increasingly turn to the solution of outsourcing early phase development services to expert CROs to help sustain their current place in the market. Additionally, for smaller pharmaceutical companies, a lack of internal funding often makes it a cheaper solution to outsource.
CROs with specialisms in early phase development services can provide the benefit of teams of in-house specialists who have the expertise to identify and overcome specific problems, benefiting customers by resolving some of the toughest pharmaceutical and biopharmaceutical substance and formulation optimisation issues. Specialist CROs focusing on early pharmaceutical development will work with pharmaceutical companies to understand and refine the quality target product profile, bring elements of quality by design to streamline the identification of critical quality attributes and move forward with a risk-based approach to develop appropriate initial formulations.
formulation development
The fundamental properties of the drug and its stability must be understood before a pharmaceutical product can be developed. During pre-formulation, CROs evaluate and detail the drug candidate’s physical and chemical profiles. These properties will ultimately define the parameters for producing a developable, stable and reproducible product. The chances of success for challenging drug molecules are also improved by assessing developability and providing formulation strategies.
Using a specialist CRO enables a deeper understanding and optimisation of the solid state form of new drug molecules, which is a critical and often complex part of the early phase development process. This ultimately leads to the regulatory requirement for selection of the final drug form. Selection should be completed as early as possible during development to minimise costly and time-consuming delays. An unanticipated change in solid state properties can affect bioavailability, stability and processing parameters. Expert CROs can resolve this challenge by tailoring support, development milestones and timescales.
Following pre-formulation and solid state form development, formulations can be developed that fit the properties of the molecules and the intended use. By ensuring an understanding of the three key formulation parameters, namely the physicochemical properties of the drug, the disease and the destination of delivery, formulations can be developed for a wide range of dosage forms, including immediate and controlled release products, powder-in-bottles/capsules and liquids (oral and parenteral). It is essential that a CRO has the skills to develop challenging compounds and adopt the most appropriate formulation strategy for each one of them, such as particle size reduction down to nanoscale, solid solutions/dispersions, self emulsifying systems or spray-dried drug-polymer matrices.
It is vital that a CRO offers early phase development services in compliance with the Commission Directive 2003/94/EC of 8 October 2003, which lays down the principles and guidelines of good manufacturing practice in respect of medicinal products and investigational medicinal products for human use.3 According to the regulation, the critical process steps, and if necessary the manufacturing process in its entirety, must be validated and also regularly revalidated. The same applies to premises and equipment used for manufacturing operations that are critical for the quality of the products.
In addition to complying with the Commission Directive 2003/94/EC, CROs operating within the European Union must also comply with local state regulations. In the UK, for example, it is vital to choose a CRO that holds an MIA (IMP) licence (manufacturer’s/importer’s licence for investigational medicinal products) for the manufacture, testing and certification of products for use in human clinical trials.4
CROs also underpin formulation development and clinical manufacture by providing comprehensive analytical support and validation
Compliant CROs also underpin formulation development and clinical manufacture by providing comprehensive analytical support and validation, based around current ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines.
The objective of the ICH guidelines is to increase international harmonisation of technical requirements to ensure that safe, effective and high quality medicines are developed and registered in the most efficient and cost-effective manner. The guidelines promote public health, prevent unnecessary duplication of clinical trials in humans and minimise the use of animal testing without compromising safety and effectiveness.5
During early phase development, the pharmaceutical industry faces increasing issues of poor bioavailability of new drug formulations as well as a growing pressure to develop ever more complex molecules. Outsourcing the entire early phase development process to an expert CRO enables companies to address these challenges effectively, while also saving time, money and effort and ensuring regulatory compliance.
references
1. EFPIA, Industry in figures, http://www.efpia.eu/content/Default.asp?PageID=358
2. Frost and Sullivan Research Service, European CRO Markets – A Strategic Analysis, http://www.frost.com/prod/servlet/report-brochure.pag?id=M377-01-00-00-00
3. Europa, Summaries of EU legislation, Good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use, http://europa.eu/legislation_summaries/internal_market/single_market_for_goods/pharmaceutical_and_cosmetic_products/l23111_en.htm
4. MHRA, Manufacturer's and wholesale dealer's licences, Types of Licence, http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Manufacturersandwholesaledealerslicences/index.htm
5. ICH FAQs, http://www.ich.org/about/faqs.html
