Chapter 60: New Product Development Studies and Reports

Drug development is the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials, and of identifying the process boundaries for realization of safe and effective products. Drug discovery is the first stage of drug development. At this stage, new chemical entities (NCEs) that have promising activity against a particular biologic target important in disease are discovered.

After discovery, the safety, toxicity, pharmacokinetics, and metabolism in humans, including dose and schedule, are assessed before human clinical trials. Studies are conducted to determine the major toxicities of the NCE, including an assessment of major organ toxicity (effects on the heart and lungs, brain, kidney, liver, and digestive system), and effects on other parts of the body that might be affected by the drug (for example, the skin if the new drug is to be delivered through the skin). These studies can be made either in vitro or by using experimental animals. The physicochemical properties of the NCE are established (that is, the chemical makeup, stability, and solubility, determination of the starting materials and their reaction paths, and basic specifications). The process to make the chemical is developed for suitability (for example, as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations). With the process of gathering human clinical trials data, long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (that is, fertility, reproduction, immune system).

The process for realization of safe and effective products is identified after the discovery phase, and confirmed with the clinical study. The process may have started as small-scale experiments, and may have been increasingly scaled-up with appropriate quality control (QC) and manufacturing methods identified to ensure consistent product quality. The finalized process is summarized in a comprehensive development report, which should be approved by high-level company management. Technology transfer and other pre-validation activities should be considered part of the overall development report. The process of transfer includes verification of the parameters, controls, and associated supporting systems through formal studies, with implementation of any new required upgrades to ensure consistent quality product before moving into the process validation. The development report should include historical data, dosage form and formulation designs, design of manufacturing methods, specification and test method, and other information:

• Historical data. Information on the pharmaceutical development of new drug substances and drug products at stages from early development phase to final steps before process validation.

• Dosage form and formula designs; design of manufacturing methods. Successes and failures that contributed to learning more about the process, change histories of important processes and control parameters, and quality profiles of batches (including stability data).

• Specifications and test methods. Available for drug substances, intermediates, drug products, raw materials, and components, and their rationale (validity of specification range of critical tests such as assay, impurities, and dissolution; rationale for selection of test methods, reagents, and columns; and traceability of raw data).

• Laboratory method development and validation. Testing methods (for example, chemistry and microbial) are developed and validated before the human clinical trials, including, if applicable, successful transfer to the testing site.

• Process model. Brief description of the process, typically accompanied by a process flow diagram; each major step and equipment in the process are indicated, and, ideally, the batch record with all appropriate procedures and specifications should be finalized when the development report is finalized.

• Active pharmaceutical ingredient (API), raw materials, and components. APIs must be appropriately characterized, validated (manufacturing process), and identified as to source, and must satisfy quality specifications for manufacturing of drug product; critical excipients must be defined and well controlled.

• Critical process parameter (CPP). CPPs are the measured variables that are known to have an effect on one or more product quality attributes; all CPPs must be identified and controls established within a defined acceptable range, and the ranges for these parameters may be typically obtained in later development studies (that is, full-scale engineering studies, technology transfer studies aimed to optimize the process for commercialization, conducted in parallel with the human clinical trials); process optimization efforts must ensure that the enhanced process remains equivalent to that used for the making of the clinical trials product.

• Critical quality attribute (CQA). CQAs are intrinsic quality characteristics that are desired or needed to ensure patient safety and benefit of the drug product; in ICH Q6A, some API attributes should be considered critical, regardless of the drug product end use; identification, physicochemical properties, appearance, assay, and purity are applicable to all drug products; particle size, microbial purity, and polymorphism depend on the drug product; ICH Q6A decision trees can be used to determine the criticality of these quality attributes for solids, solutions, or sterile products; all CQAs must be identified and established acceptance criteria.