Process analytical technologies in the pharmaceutical industry: the FDA’s PAT initiative

Application of Quality by Design Paradigm to the Manufacture of Protein Therapeutics

“…In QbT, product quality attributes (the ranges for drug substance properties that yield acceptable safety and efficacy) are linked with a specific manufacturing process and its corresponding set of inputs (raw materials and process parameters) during clinical phases of development. The process inputs that empirically show to yield acceptable product quality are defined and are often maintained unchanged after phase II clinical trials so that manufacturers avoid costs associated with additional testing for regulatory compliance [69]. During manufacturing, the process inputs are controlled to remain at their pre-defined set points, and at the end of each batch, the product is tested for compliance with the desired quality [68][69][70][71].…”

“…The process inputs that empirically show to yield acceptable product quality are defined and are often maintained unchanged after phase II clinical trials so that manufacturers avoid costs associated with additional testing for regulatory compliance [69]. During manufacturing, the process inputs are controlled to remain at their pre-defined set points, and at the end of each batch, the product is tested for compliance with the desired quality [68][69][70][71]. This black box approach does not require mechanistic knowledge that relates process inputs with product quality, and because of this, the QbT approach uncouples product end quality from the manufacturing process.…”

“…This black box approach does not require mechanistic knowledge that relates process inputs with product quality, and because of this, the QbT approach uncouples product end quality from the manufacturing process. The main drawbacks of QbT are [10,69,72]:  Development and approval of pharmaceutical processes under QbT has proven to be extremely time-consuming (between 7 and 10 years [73,74]) and very expensive (US$1.2 to 1.8 billion per approved drug when the risk of failure is included [67,75]). This could be attributed, in part, to limited understanding of the relationship between product quality characteristics, therapeutic mechanisms and the effect process inputs have on quality.…”

“…The inefficiencies associated with the QbT approach along with more stringent regulatory requirements have led to manufacturers investing more in drug discovery than process understanding and optimization, which in turn, has translated into a decrease in the costeffectiveness, number and quality of innovative drugs and pharmaceutical manufacturing processes [67,69]. In order to overcome these limitations, regulators and industry specialists have proposed the implementation of Quality by Design (QbD) concepts to the manufacture of all new drugs, including therapeutic proteins, in the development pipeline [68,72,76].…”

Development and validation of an at-line fast and non-destructive Raman spectroscopic method for the quantification of multiple components in liquid detergent compositions

“…Since the publication of the process analytical technology (PAT) guidance by the American Food and Drug Administration (FDA) in 2004, it is generally accepted that quality should be built into products rather than be tested afterwards, preventing the process from being an un-comprehended black box system [1], [2]. Thus, advanced manufacturing practices are being implemented in the pharmaceutical, chemical, biotechnological and food industry, enhancing process efficiency and guaranteeing product quality [3][4][5][6][7][8][9].…”