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www.biopharminternational.com Quality and Regulatory Sourcebook March eBook 2023 BioPharm International ® 5 AnAly tics impurity profile, etc. Successful outcomes of (pre) clinical studies only allow the drug to move further into development if the quality of the material re- mains consistent. Hence, drug synthesis of small molecules or biologics for (preclinical) animal stud- ies set the initial standard that will be built upon for future clinical development. Capturing the quality of a batch of drug substance Drug substance synthesis must be accompanied by product-specific analytical processes. Analytical meth- ods used for release testing of batches used in early de- velopment will provide a benchmark for the drug sub- stance profile that can be followed from the clinical to commercial phases. When embarking on an investigational new drug application (IND), it is important that the evolving process of drug development is built upon sound sci- entific processes and data, but may differ from study to study, before it reaches its final form. This is de- scribed by FDA in 21 Code of Federal Regulations (CFR) 312.23 Investigational new drug application (IND) (5), which states, "FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form it- self are likely as the investigation progresses. There- fore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug sub- stance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process." For classifying the drug substance, 21 CFR 312.23 states that an effective description of the drug sub- stance will include physical, chemical, or biological characteristics. Acceptable limits and analytical meth- ods used to determine the identity, strength, quality, and purity of the drug substance will also be required, as well as evidence of drug substance stability during the toxicological and clinical studies. On the laboratory level, this means that the critical attributes for a drug substance, as well as the methods to measure them, are summarized in the specifications. Due to the decades of experience with small molecule APIs, the attributes, as well as the preferred analytical methodology to measure them, are well known. The development dilemma and phase-appropriate development Notwithstanding that development starts with syn- thesis development, the synthesis processes will in- evitably change to some extent between key phases in its development with optimization and improvement. Analytical methods will need to convergently adapt to drug synthesis optimization to remain able to com- pare the quality profiles of the batches. Now, the analytical development dilemma presents itself. On the one hand, the developed analytical meth- ods need to be reliable and robust to ensure proper as- sessment of the drug substance attributes and allow good comparison between development batches. On the other hand, the aforementioned changes in synthetic processes, as well as high attrition of develop- ment candidates, urge developers to spend as little time and money as possible on analytical methods. Only when effective and structured analytical devel- opment processes are in place can the correct balance be found in this dilemma. Methodology must be devel- oped to a level that ensures it can be validated when the drug moves to the good manufacturing practice (GMP) drug substance and drug manufacturing stages. As the process develops along the pipeline, analytical pa- rameters should be evaluated and altered, dependent on guidelines and the determined limits for individual targets. The process parameters for detection and quan- tification often become more stringent as the drug pro- gresses closer to the final dosage format. This progres- sion of analytical methods is called phase-appropriate analytical development. Pre-clinical and IND phases require analytical pro- cesses to demonstrate suitability for the intended pur- pose (6). This necessitates the adoption of analytical methods to detect and quantify the production of the targeted drug product and any unpredictable impuri- ties. Full analytical method development and validation according to International Council for Harmonisation (ICH) guidelines need only be provided with the final drug product when entering Phase III clinical trials. Trends in pharmaceutical development towards more complex modalities In an ongoing effort to improve on drug candidates to address unmet medical needs, the focus of pharma- ceutical research has shifted from traditional small molecules to biologics and new modalities, including drug delivery technologies capable of carrying the drug intact to specific sites in the body, and across cellular membranes, to reach their targets (7). One such new modalit y comprises nanomateri- als, with a broad range of chemistries (e.g., based on lipids, peptides, polymers, or metal oxides), archi- tectures (micelles, vesicles such as liposomes, lipid nanoparticles, solid nanoparticles, and core-shell like structures), and surface properties. Their unique properties are based on their physicochemical prop- erties, especially their average size and size polydis- persity. These properties can be optimized to enable the entrapped or conjugated drug to be delivered to a specific target or to improve physicochemical sta- bility in the biologic f luids. In addition to the attributes mentioned for APIs, a range of specific attributes for nanomaterials is de-