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PharmTech.com Quality and Regulatory Sourcebook March eBook 2023 Pharmaceutical Technology ® 5 AnAly tics chemical steps that have too low yield/too high cost or is not safely scalable to large amounts. • T he m ater ia l u sed t h roug hout t he develop- ment of a pharmaceutical compound needs to be of consistent quality in terms of structure/ composition, impurity profile, etc. Successful outcomes of (pre)clinical studies only allow the drug to move further into development if the qua l it y of t he m ater ia l rem a i n s con sistent. Hence, drug synthesis of small molecules or bi- ologics for (preclinical) animal studies 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 pro- cess of drug development is built upon sound scientific processes and data, but may differ from study to study, before it reaches its final form. This is described by FDA in 21 Code of Federal Regulations (CFR) 312.23 Investiga- tional 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 itself are likely as the investigation progresses. Therefore, 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 substance. 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 Not w it h s t a nd i ng t h at de velopment s t a r t s w it h s y nt hesis development, t he s y nt hesis processes w i l l i ne v it ably c h a nge to some e x tent bet ween k e y ph a s e s i n it s d e v e lo pme n t w it h o p t i m i z a- t ion a nd i mprovement. A na ly t ica l met hods w i l l need to convergent ly adapt to dr ug sy nt hesis op- timization to remain able to compare the qua lit y profiles of the batches. Now, the analy tical development dilemma pres- ent s it sel f. On t he one ha nd, t he developed a na- ly tica l met hods need to be reliable and robust to ensure proper assessment of t he d r ug substa nce at t r ibutes a nd a l low good compa r i son bet ween development batches. On the other hand, the aforementioned changes in synthetic processes, as well as high attrition of devel- opment candidates, urge developers to spend as little time and money as possible on analytical methods. On ly when ef fective and str uct ured ana ly tica l development processes are in place can the correct ba la nce be found in t h is di lem ma. Met hodolog y must be developed to a level that ensures it can be validated when the drug moves to the good manu- facturing practice (GMP) drug substance and drug m a nu fac t u r i ng st ages. A s t he process develops along the pipeline, analytical parameters should be evaluated and altered, dependent on guidelines and the determined limits for individual targets. The process parameters for detection and quantification often become more stringent as the drug progresses closer to the final dosage format. This progression of analytical methods is called phase-appropriate analytical development. Pre-clinica l and IND phases require ana ly tica l processes to demonstrate suitability for the intended purpose (6). This necessitates the adoption of analyt- ical methods to detect and quantify the production of the targeted drug product and any unpredictable impur it ies. Ful l a na ly t ica l met hod 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 I n a n ongoi ng ef for t to i mprove on d r ug ca nd i- dates to address un met medica l needs, t he focus of pha r maceut ica l resea rch has sh if ted f rom t ra- d it ion a l s m a l l mole c u le s t o biolog ic s a nd ne w modalities, including dr ug deliver y technologies capable of carr ying the drug intact to specific sites i n t he body, a nd ac ross cel lu l a r membra nes, to reach their targets (7). One such new moda lit y comprises nanomateri- als, with a broad range of chemistries (e.g., based on lipids, peptides, polymers, or metal oxides), ar- chitect ures (m icel les, vesicles such as liposomes,