| By Dr. Jürgen Epple

Are you prepared to develop biopharmaceuticals?

Biopharmaceuticals are unique and challenging and require a broad range of expertise to accelerate development and time to market and to mitigate associated risks.

Biopharmaceuticals are large macromolecules derived from biological sources including living cells or tissues, or are obtained by means of recombinant DNA technology. They differ considerably from conventional drug products in terms of discovery, structure, formulation and processing. As these products are heterogeneous in nature and undergo complex biotechnological processes, a wide range of state-of-the art techniques and methodologies is required to ensure adequate quality, safety and efficacy of these biologics. Furthermore, these products are highly regulated.

Consequently, the development process for biopharmaceuticals is lengthy and challenging and proceeds through several stages. GMP and regulatory requirements increase in the course of development. This means that more CMC data will be needed as development progresses to enable preclinical and clinical studies. Careful development planning and an accompanying regulatory strategy already at an early stage are therefore crucial to successfully get your biotech product through to commercialization. From research and discovery to preclinical and clinical development, various technical, quality and regulatory requirements have to be met. This poses particular challenges for small and medium-sized companies (SME) which do not have this experience and broad in-house expertise. However, larger companies also have to close temporary gaps in resources in order to be able to complete their projects as planned. In this case external partners play an important role to fill these gaps.

The development process is often described in a linear way, consisting of several stages. Although in practice there are overlapping activities and processes that run in parallel over a period of time, typical tasks can be identified in an early, middle and late development phase, as outlined below:

1. Early stage of development

At this stage of R&D, target molecules are identified and potential drug candidates are discovered. A project plan with development milestones is drawn up and a corresponding regulatory strategy should be established early in development. Once a preliminary target product profile (TPP) has been defined, the physicochemical properties of the drug substance are determined. Analytical methods for characterization, structure elucidation and quality control are developed in line with ICH Q6B. This includes methods for identity, purity, quantity and biological activity testing as well as microbial testing to provide a potent, sterile and endotoxin-free product and to control potential impurities and particulates. Formulation development studies are carried out to define the optimal composition and dosage form and to ensure the manufacturability and stability of the biotech product.

2. Mid-stage of development

After defining the critical quality attributes (CQAs) and process parameters (CPPs), the upstream and downstream manufacturing process is optimized through to formulation and filling. Analytical and bioanalytical method validation as well as technology transfers are performed. Cell-based bioassays to determine the biological activity of the molecule can be challenging and need to be planned early in the development process. For further characterization, stability studies and forced degradation studies are to be conducted. It may also be necessary to perform leachables & extractables studies on the container closure and packaging system as the quality of protein-based formulations strongly depends on the compatibility with the primary packaging. When changes are made to the manufacturing process, a comparability exercise is performed. Preclinical studies are initiated in accordance with ICH guidelines to evaluate the safety and bioactivity of the formulated drug in-vitro and in animals to gain insight into the mode of action, pharmacokinetics and drug disposition. In this phase, clinical trials are designed and the corresponding applications for clinical investigations (IMPD, IND) for phase I and II studies are prepared. Scientific advice meetings with the regulatory authorities should be planned at an early stage to clarify questions regarding critical quality aspects and the preclinical and clinical development program.

3. Late-stage of development and commercialization

Following the scale-up of production to increase production capacity, phase III studies will be conducted to confirm the safety and efficacy of the product. During these studies, the CMC package will be further consolidated. Thereafter, the marketing authorization application will be prepared and submitted to the agency. Once approved, the commercialization phase consists of manufacturing and marketing the product. Life cycle management and pharmacovigilance activities are performed in order to further develop and maintain the biopharmaceutical product on the market.

How can we help you to be successful in development of biopharmaceuticals?

See our flyer for more details regarding our integrated biopharmaceutical services.

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Dr. Andrea Klüting
Vigilance & Regulatory Affairs
Business Development HWI group

Phone: +49 89 2000203-60
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