An Overview of Drug Substance Manufacturing Processes
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Brief/Technical Note An Overview of Drug Substance Manufacturing Processes Noah J. Wichrowski,1 Adam C. Fisher,1 Nilou S. Arden,1 and Xiaochuan Yang1,2
Received 8 June 2020; accepted 27 August 2020 Abstract. To develop a comprehensive understanding of pharmaceutical drug substance manufacturing (DSM) processes, we conducted a data mining study to examine 50 new drug applications (NDAs) approved in 2010–2016. We analyzed the prevalence of several frequently deployed in-process control (IPC) techniques and postreaction workup procedures, as well as the operational conditions specified for reactions and workups. Our findings show that crystallization and high-performance liquid chromatography (HPLC) were the most commonly used workup steps and in-process controls, respectively, in drug substance manufacturing. On average, each NDA implemented 12.6 in-process controls and 11.3 workups. Operation time for reactions and workup procedures varied from a few minutes to multiple days, though 61% of these were between 1 and 10 h. KEY WORDS: drug substance; manufacturing; in-process control; workup procedure.
INTRODUCTION The two main components that make up the pharmaceutical manufacturing process are those of drug substance and drug product manufacturing. Drug substance is an active ingredient that is intended to furnish pharmacological activity, directly impact the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (1). Drug product is a finished dosage form, e.g., tablet, capsule, or solution that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (1). In drug substance manufacturing (DSM), the process comprises chemical reactions, any workup steps that follow a reaction to prepare the process mixture for a subsequent stage, and the in-process controls (IPCs) that monitor and maintain critical process variables within the limits required for successful drug production. As the regulating body with respect to pharmaceutical processes, the US Food and Drug Administration (FDA) has a strong interest in promoting advances in We conducted a data mining study on drug substance manufacturing processes to examine 50 New Drug applications (NDAs) approved in 2010–2016, and findings on the prevalence and trends of frequently deployed in-process control (IPC) techniques and postreaction workup procedures are presented. 1
Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Massachusetts, USA. 2 To whom correspondence should be addressed. (e–mail: [email protected])
manufacturing technology that will ensure consistent product quality and minimize output-reducing failures (2–4). The control strategy for DSM processes is critical because drug substance properties, such as purity and particle size, may significantly influence the final drug product quality (5–7)
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