Review of real-time release testing of pharmaceutical tablets: State-of-the art, challenges and future perspective

Abstract

In the last decade significant advances have been made in process analytical technologies and digital manufacturing of pharmaceutical oral solid dosage forms leading to enhanced product knowledge and process understanding. These developments provide an excellent platform for realising real-time release testing (RTRT) to eliminate all, or certain, off-line end product tests assuring that the drug product is of intended quality. This review article presents the state of the art, an RTRT development workflow as well as challenges and opportunities of RTRT in batch and continuous manufacturing of pharmaceutical tablets. Critical quality attributes, regulatory aspects and the scientific basis of enabling technologies and models for RTRT are discussed and a systematic development workflow for the robust design of an RTRT environment is presented. This includes the discussion of key considerations for the identification of the critical quality attributes and points of testing as well as the development of the sampling strategy, a hard and/or soft sensor approach and operational procedures. The final sections present two RTRT use cases in an industrial setting as well as critically discuss challenges and provide a future perspective of RTRT.

Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

“…A recent review paper on RTRT describes the critical quality attributes which might be monitored at different stages with examples in CM processes to produce tablets by direct compression, wet granulation and dry granulation (roller compaction) [ 59 ]. Methods used to make quality-based control decisions during RTRT are referred to as primary methods and are considered as high-(impact) risk methods according to the risk impact matrix as described in ‘ICH Quality Implementation Working Group Points to Consider (R2)’ [ 23 ].…”

“…CQAs for a solid oral dosage form are typically those relating to purity, strength, drug release and stability. Examples of the measurement techniques used for each attribute follow [ 59 ].…”

“…Measurement typically occurs on the blend prior to tabletting. Bhaskar et al [ 57 ] note there is no sensor currently available that can accurately measure tablet potency and/or drug concentration of tablets in real-time, although Markl et al [ 59 ] suggest a sensor incorporated in the feed frame of the tabletting machine.…”

Rapid Prototyping of Miniaturized Powder Mixing Geometries

“…Continuous manufacturing has recently gained more interest as an alternative to conventional batch manufacturing due to, e.g., the ability to perform straightforward scale up, to achieve a more constant quality product and a possibility for reducing the cost of production. [1][2][3][4] In addition, this approach is supported by regulatory initiatives including a risk-based approach with implementation of Quality by Design (QbD) and Process Analytical Technologies (PAT), [5][6][7] as well as an initiative for a guideline from The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH (ICH Q13 Continuous Manufacturing for Drug Substances and Drug Products).…”

“…13,15 For the detection and measurement of powder within a mixing unit, in-line process interfacing would be ideal for continuous manufacturing processes. 4 A well-established in-line process analytical method is near infrared spectroscopy (NIR) that is suitable for continuous manufacturing due to the speed of analysis and size of the analytical equipment. [16][17][18] Moreover, NIR is suitable for in-line measurements as the method is non-destructive and the accessibility of specifically optic fiber probes for diffuse reflectance measurements creates the possibility of cheap implementation in continuous manufacturing lines.…”