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Drug development is a complex process that involves many scientists, a lot of money and at least 10 years. The process starts with target identification where chemicals are manufactured to ‘fit’ the receptor of interest and they are typically ranked by potency for that receptor. At this stage, there is little biopharmaceutics input. The next step is to evaluate the lead chemicals using preclinical models; this can be cell lines or animal models to determine whether the chemical is as potent in vivo. At this stage, some biopharmaceutics input is crucial as the drug may need to be formulated for administration to the animal model and may even be administered orally so the fraction absorbed can be measured. This often relates to the ‘drugability’ of the lead candidates; defined as the technical evaluation of whether a compound will be a commercially successful drug. Drugability here relates to the likelihood for sufficient and non‐variable pharmacokinetic exposure.

Success in preclinical models will trigger clinical evaluation in humans. There are three phases of clinical trial prior to launch of a product: phase 1 will measure safety and efficacy of a compound in healthy volunteers where possible; at this stage the bioavailable dose will be assessed. Phase 2 studies explore the safety and efficacy of the drug in patients with the disease of interest. The product used for phases 1 and 2 is often different to the final commercial product as the dose is still to be defined. Thus there may be differences in the bioavailable fraction of each formulation administered that needs to be accounted for when interpreting the data and determining the dose. The term bridging is used to describe how any differences between formulations used in preclinical and clinical testing are managed during the clinical testing. Phase 3 studies evaluate the efficacy and safety in a large patient population. Where possible the final commercial formulation will be used in phase 3 studies as these are pivotal to underpinning the evidence to justify the introduction of a new product. Biopharmaceutics is integral to the phases of clinical testing as predictive models to understand absorption and consequences of bridging are critical to the success of the interpretation of clinical data.

In parallel to the clinical evaluation (phase 1, 2 and 3 studies) work will be ongoing to ensure that the chemistry manufacturing and controls (CMC) activities are on track. These CMC activities ensure that the product and manufacturing process meet the stringent regulatory requirements ensuring that a safe and high‐quality product is available to the patient population. Any changes to the product or manufacturing process need to be understood, particularly if there are likely to be consequences to the patient; thus biorelevant predictive tests are of value in de‐risking the development process. In addition to biorelevant tests, often discriminatory dissolution testing is required; this is a method that links to clinical data and shows where changes in the product (as a result of composition or manufacturing changes) are likely to have an effect on the clinical performance. These discriminatory dissolution tests are generated by links to in vivo clinical data; either using an in vitro in vivo relationship (IVIVR) or using the principles of quality by design (QbD).

Regulatory approval of new products is essential. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH guidelines include information on biopharmaceutics that are essential for the approval of medicines. Two guidelines are focussed on biopharmaceutics specifically: ICH M9 Biopharmaceutics classification system based biowaivers and M13 Bioequivalence for Immediate release solid oral dosage forms. Within the US the major regulatory agency is the FDA (Food and Drug Administration); the FDA have a Biopharmaceutics council within the centre for drug evaluation and research. This office is responsible for the generation, implementation and review of biopharmaceutics‐related guidance, policies and practices. There are several biopharmaceutics specific FDA regulatory guidance papers issues that are critical to the approval of new drugs. Similar to the USA there are many global regulatory bodies where biopharmaceutics guidance has been issued including the EMA (European Medicines Agency) and the Japanese Food and Drug Administration. Recently the ICH M9 guidance has sought to align these where possible for the BCS classification.

Biopharmaceutics interfaces with several other scientific disciplines, this book aims to provide a background to biopharmaceutics and to showcase how knowledge can be applied to the efficient development of drug products. The level of detail in terms of biopharmaceutics knowledge of a drug and a drug product will increase during the drug development process. This is shown schematically in Figure 1.4.

Biopharmaceutics is an important scientific discipline, particularly for those developing new drugs. An understanding of biopharmaceutics aids in the design of appropriate drug candidates (Chapter 7) as well as optimised drug products (Chapter 8) to ensure that the drug is well absorbed from the site of administration. Clinical testing of drugs, from phase 1 to phase 4 clinical trials is expensive and time‐consuming. Biopharmaceutics tests and knowledge are critical to de‐risk changes in the clinical performance as a result of minor changes in the product and process used to manufacture the drug product used within these clinical trials. There is a strong relationship between biopharmaceutics and regulatory science during the development of drug products.

Figure 1.4 Overview of biopharmaceutics input in the drug development pathway.