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Process Analytical Technology (PAT) & Quality by Design (QbD)

A selection of articles from European Pharmaceutical Review covering Process Analytical Technology (PAT), Quality by Design (QbD), Six Sigma, Near Infrared (NIR) and Chemometrics:


Exploring the advantages of PAT for pharmaceutical cleaning in Ireland

Exploring the advantages of PAT for pharmaceutical cleaning in Ireland

4 May 2016  •  Adeyinka Aina, University of Nottingham / Manuel Kuhs, Bernal Powder Engineering Research Group / Shaza Darwish, University of Limerick / Chris Edlin, Pharmaceutical Technology Manufacturing Centre

Process analytical technology (PAT) and its applications have been used in various industrial processes for a long time. It originates from the last century where its first application was in Germany after World War II within the chemical and petrochemical industry. Following this, it was implemented and refined in different industries worldwide – for example in refineries and petrochemical plants – until it became an integral part of process control. However, it is considered a young technology in pharmaceutical manufacturing where the processes have always been restricted to conventional approaches. This forces many limitations on product quality monitoring since the control relies mainly on collected samples being tested off-line in a laboratory...

The application of skip testing to drug substance manufacture

The application of skip testing to drug substance manufacture

29 February 2016  •  Phil Borman, Simon Bate and Keith Freebairn, GlaxoSmithKline

Skip testing is a process employed to reduce the analytical drugs testing burden and lends itself to processes with high frequency batch production. Rather than test all batches within a given interval, pre-selected batches are assessed and the other batches ‘skipped’. This reduction is justified as it is shown that there is a low risk of any batches failing specification. In this article, a process is described (supported by an example) that could be followed to justify the use of skip testing. The process involves identifying attributes that are candidates for skip testing, performing a statistical evaluation to confirm there is a low risk of batch failure if skip testing is instigated and making ongoing assessments to confirm the process remains highly capable and the attribute(s) is predicted to be well within specification...

Dissolution testing in the modern world

Dissolution testing in the modern world

29 February 2016  •  Juliet Symonds and David Elder, GlaxoSmithKline

Historically, dissolution testing has been used primarily as a quality control (QC) test for solid oral drug products . Indeed, it is the only QC test which provides a measure of the quantitative release rate of the drug from the pharmaceutical product. More recently, the test has been proposed in lieu of bioequivalence testing. However, can the same dissolution test have enough robustness (as per 5 ) to be used as a routine QC tool, whilst simultaneously being sensitive enough to be truly bio-predictive? This article will explore this conundrum...

PAT In-depth focus 2015

PAT: In-depth Focus 2015

6 January 2016  •  Caroline Richards

Featuring an overview of process analytical control; Beyond API monitoring: in-line Raman spectroscopy for process control; Monitoring, understanding and assessing pharmaceutical process and product quality; and a PAT roundtable...

David Elder

Use of the ‘purge tool’ in assessing mutagenic impurities

6 January 2016  •  Dave Elder, GlaxoSmithKline and JPAG

The International Conference on Harmonization M7 text provides guidance on establishing acceptable levels of mutagenic impurities (MIs) . It also outlines the safety and quality risk management processes that manufacturers need to undertake to control MIs that may potentially affect the drug substance or drug product. Over the past decade, some of the most significant challenges facing the pharmaceutical industry have been linked to performing genotoxic risk assessments (GRAs) and implementing a control strategy, including the analysis of these MIs and potentially mutagenic impurities (PMIs) at very low levels (ppm) in drug substances and products...

Continuous manufacturing in the pharma industry – an unstoppable trend?

Continuous flow processing in the pharma industry – an unstoppable trend?

22 October 2015  •  Bernhard Gutmann and Christian Oliver Kappe, University of Graz

Continuous flow processes have many distinct advantages over discontinuous batch production and therefore, in the last century, continuous operation has become by far the most dominant form of production for high-volume and low-cost materials such as petrochemical and commodity chemicals. The first applications of continuous processes in the pharmaceutical industry emerged only comparatively recently and the vast majority of production is still undertaken in batch reactors. Herein, we highlight some of the advantages that continuous flow processing offers for the synthesis of pharmaceuticals and fine chemicals...

PAT Series: Predictive monitoring and control approaches in biopharmaceutical manufacturing

PAT Series: Predictive monitoring and control approaches in biopharmaceutical manufacturing

3 September 2015  •  Cenk Undey, Tony Wang, Bryan Looze, Yingying Zheng and Myra Coufal - Amgen

Predictive monitoring is a key feature of biopharmaceutical manufacturing; making predictions about the key process end points such as process performance indicators or quality attributes using a process model offers the unique advantages of process improvement and optimisation, and helps give insights into variability. However, whilst model-predictive monitoring is advantageous, it is also desirable to apply model predictions for closed loop control of biologics manufacturing using various process analytical technology (PAT) tools. We summarise some of our experiences with predictive monitoring, closed loop control usingin situRaman spectroscopy and state-space methods for model predictive control of cell culture bioreactors...

PAT Series: Applicability of process analytical tools to bioprocessing trends

PAT Series: Applicability of process analytical tools to bioprocessing trends

3 July 2015  •  Payal Roychoudhury, PhD, formerly AstraZeneca

The past decade has been a period of unparalleled change and development in the fermentation industry. As the nature of this industry evolves, and in particular, with the increasing prominence of the new biopharmaceuticals (therapeutic proteins, diagnostic enzymes and monoclonal antibodies) the need for effective bioprocess monitoring grows in importance. In order to deliver the ‘revolution in clinical medicine’ promised by this new range of therapeutic agents, there is a pressing need to develop effective bioprocess monitoring techniques and technologies which can deliver robust, reproducible, stable manufacturing processes, as well as high quality data, not just on product levels but also relating to product authenticity and purity. So what is wrong with the current manufacturing practice in the biomanufacturing industry? Today, most fermentation processes suffer from poorly understood process interactions, empirical risk assessment and process locked in by validation; therefore, the existing procedural approach has helped foster ‘a climate of fear’ of innovation itself.

The scope of PAT in real-time advanced control of tablet quality

The scope of PAT in real-time advanced control of tablet quality

20 April 2015  •  Ravendra Singh, Marianthi Ierapetritou and Rohit Ramachandran: Rutgers University

Continuous pharmaceutical manufacturing together with process analytical technology (PAT) provides a suitable platform for automatic feed-forward/feed-back (FF/FB) control of the end product quality as desired by quality by design (QbD)-based efficient manufacturing. The precise control of the quality of the pharmaceutical product requires proactive, corrective actions on the process/raw material variability. Therefore, PAT tools are necessary to monitor the FF as well as FB process variables that need to be sent to the automatic real-time control system. This article highlights the scope of PAT in a combined FF/FB control system of a continuous tablet manufacturing process...

PAT Supplement

PAT: In-depth focus 2014

5 January 2015  •  Prabir Basu, João A. Lopes

This PAT In-Depth focus explores current challenges posed by the slow uptake of Process Analytical Technology within the pharmaceutical and biopharmaceutical industries. The advantages of incorporating PAT into the pharmaceutical process are highlighted in two informative articles, and possible solutions to its lack of popularity surmised...

NIR Supplement - 100

NIR: In-depth focus 2014

5 September 2014  •  José Manuel Amigo, Milad Rouhi Khorasani, Jukka Rantanen, Poul Bertelsen, Lizbeth Martinez

In this free-to-view NIR in-depth focus: Moving towards continuous manufacturing with NIRS and NIR-CI systems, Monitoring of pharmaceutical powder mixing by NIR spectroscopy

Multivariate Calibration Maintenance

The flexibility of regularisation processes for multivariate calibration maintenance

5 September 2014  •  Dr. John H. Kalivas, Editor for the Journal of Chemometrics and Applied Spectroscopy.

In the pharmaceutical industry, it is necessary to control, in a tight range, the active pharmaceutical ingredient (API) content of products, e.g., tablets or other powder blends. Thus, the API content needs to be continuously monitored. Preferably, analysis for the API content should be in-line (on site) allowing rapid and efficient quality control. It is well documented that spectroscopic methods, such as near-infrared (NIR) and Raman, in conjunction with multivariate calibration processes, can meet these goals under controlled conditions...


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