This website or its third party tools use cookies, which are necessary to its functioning and required to achieve the purposes illustrated in the cookie policy. If you want to know more or withdraw your consent to all or some of the cookies, please refer to the cookie policy. By closing this banner you agree to the use of cookies.
Loading...

Reactor Design and Selection for Effective Continuous Manufacturing of Pharmaceuticals

Authors
Chuntian Hu

Introduction

Continuous manufacturing, or continuous processing, is defined as “the material(s) and product are continuously charged into and discharged from the system respectively, throughout the duration of the process”. Industries such as food, petrochemicals and automotive, have long since adopted automated and continuous manufacturing, whereas pharmaceutical production remains one of the last industrial processes that mainly use a non-continuous (i.e., “batch”) approach. This is because of the following differences that those other industries did not have to consider: structural complexity, quality and regulatory, and quantity requirements (i.e., the trend towards lower dose drugs). This inefficient batch process can cause drug shortages due to the long lead times (up to 12 months) or quality defects. The current pharmaceutical industry operates at approximately 2–3 sigma quality (~6.7–30.9% defects, i.e., failed / rejected products), thus, much improvement is required to achieve 6 sigma quality (~0.0003% defects). Motivated by the benefits shown in the figure below, the pharmaceutical industry is transitioning to continuous processes, including end-to-end integrated continuous manufacturing (ICM) approaches.

Abstract

Continuous heterogeneous crystallization processes in mixed-suspension mixed-product removal (MSMPR) crystallizers of different configurations (e.g., single-stage cooling, multistage cooling, and multistage evaporative cooling) are developed, in which an active pharmaceutical ingredient (acetaminophen, APAP) is crystallized directly on the surfaces of both porous and nonporous polymer excipient substrates (poly(vinyl alcohol), PVA). The heterogeneous crystallization step is part of an integrated continuous manufacturing (ICM) processing train, which starts from raw materials and includes chemical synthesis, crystallization, filtration, and drying. The product from this ICM process is a stream of dried composite particles (i.e., APAP on PVA substrates) that are directly compressed into tablets, eliminating the need for any further processing steps (e.g., milling, sieving, blending, and granulation). The dried composite particles are characterized with scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction. The use of porous polymer substrates (instead of nonporous substrates) increased the crystallization yield by >4× in one set of experiments. In subsequent experiments, the use of porous polymer substrates reduced the risk of bulk nucleation (due to increased internal free volume and surface area) in an evaporative-cooling MSMPR crystallization system. Yields as high as 71% and drug loadings as high as 61.1 ± 2.8% were observed with this evaporative-cooling MSMPR system. Furthermore, it is shown that by altering the suspension density of the excipient particles, the drug loading of the composite particles can be controlled. Finally, the design of the ICM process is discussed. The use of heterogeneous crystallization as a process intensification technology (e.g., incorporation into an end-to-end ICM pharmaceutical production process) has the potential to reduce overall system complexity, capital investment, and operating costs on the commercial scale by reducing the number of downstream processing steps that are required.

Abstract Image

Discover more papers

Design of an In-Line pH Neutralization System with Coarse and Fine Adjustments for the Continuous Manufacturing of Pharmaceuticals
Design of an In-Line pH Neutralization System with Coarse and Fine Adjustments for the Continuous Manufacturing of Pharmaceuticals
Reactor Design and Selection for Effective Continuous Manufacturing of Pharmaceuticals
Reactor Design and Selection for Effective Continuous Manufacturing of Pharmaceuticals
Heterogeneous Crystallization as  a Process Intensification Technology in an  ICM Process for Pharmaceuticals
Heterogeneous Crystallization as a Process Intensification Technology in an ICM Process for Pharmaceuticals
Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study
Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study
E-factor analysis of a pilot plant for end-to-end integrated continuous manufacturing (ICM) of pharmaceuticals
E-factor analysis of a pilot plant for end-to-end integrated continuous manufacturing (ICM) of pharmaceuticals
Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing (ICM) of Pharmaceuticals
Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing (ICM) of Pharmaceuticals
Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs
Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs
An automated modular assembly line for drugs in a miniaturized plant
An automated modular assembly line for drugs in a miniaturized plant
Why We Need Continuous Pharmaceutical Manufacturing and How to Make It Happen
Why We Need Continuous Pharmaceutical Manufacturing and How to Make It Happen

Request consulting

Phone: (781) 281-0115 Main Office

Email: [email protected]