*2.1.2.1 Contamination quality control during manufacturing*

*Mass Production Processes*

Pharmaceutical production is now progressing more into mass personalization, down to lot size *N* = 1. Each product is not only produced as part of a batch during mass production but it is also designed uniquely for the benefit of a specific patient. Based on demand certain drugs are custom designed and manufactured for large hospital or community pharmacies. An ongoing trend is an increased usage of contract manufacturing/filling by most pharmaceutical companies. Highly flexible aseptic production and filling lines have now become trendy until recently was not feasible through filling line concepts available in the present day but only through highly flexible automated systems driven by robotics [12]. The popular technology of individualised/customised mass production of cars in terms of colour, engine specification and performance, wheels, lighting and extras is still remote in current pharmaceutical production technologies. If successfully implemented, this would be a revolution in pharmaceutical manufacturing and also for the Food and Drug Administration (FDA). Bhaskar [13] designed an advanced model predictive control (MPC) architecture integrated with a novel real-time tablet weight measurement method aimed to develop and implement continuous direct compacting tablet manufacturing pilot-plant which has the potential to control tablet weight and tablet breaking force simultaneously by systematically decoupling and cascading the control loops. The predictive control algorithm (PCA) was superior to the proportional, integral and derivative (PID) controller and consequently could be utilised for a wide range of applications to improve the quality of pharmaceutical products during continuous manufacturing. The MPC enabled control of the main compression force and pre compression force using main compression height and fill depth respectively as the actuators. The researchers claimed that developing this technology made it possible to measure tablet weight and other variables that

Lakerveld et al. [14] in a separate study designed a plant-wide control structure for a continuous pharmaceutical pilot plant used to classify control objectives. By means of simulation software they demonstrated that for selected parameters the critical quality attributes (CQAs) of the final product can be kept close to specification in the presence of significant and persistent disturbances. This shows flexibility

Mesbah et al. [15] developed a control strategy based on a non-linear moment model whose optimal operation was based on manipulation of heat input to a crystallizer such that a maximal allowable crystal growth rate was maintained during a production process. The feedback structure of the control framework enabled the optimizer to reject process uncertainties and accurately account for plant-model

Advanced feedback control concepts which are capable of improving performance of batch processes, as well as enable technologies from batch to continuous manufacturing were developed by Nagy et al. [16]. These were used in the improvement of pharmaceutical particulates, especially in the application to continuous drug substance/product manufacturing. Mathematical modelling of the optimal design, start-up and control of anti-fouling and continuous crystallisation processes to achieve and maintain the desired controlled stage of operation was demonstrated. Su et al. [17] demonstrated the use of a rotary tablet press, integrated into a pilot scale continuous direct compaction process. The outcome was that active process control which was based on product and process knowledge and advanced model-based techniques, data reconciliation, model predictive control and risk analysis, appeared to be indispensable when implementing a comprehensive Quality by Control. It also appeared to guarantee robustness and production efficiency. Recently, Singh [18] developed an automated version of the continuous pharmaceutical manufacturing pilot plant. The feeder, comill, blender and tablet

enhanced manufacturability of pharmaceutical tablets.

mismatch while fulfilling product quality requirements.

to control CQAs independently of each other.

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Contamination quality control is a huge challenge during manufacturing especially for products with ultra-low tolerance for impurities and contaminants. For instance during the manufacture of premium chemicals, highly sterile pharmaceuticals and hygienic products and other products with high purity requirements and specifications, it is essential to provide an environment that will obviate any form of contamination. A common source of contamination is from manufacturing machines and equipment that can conceal microscopic particles and microbes. Decontamination can be achieved through effective cleaning and disinfecting manufacturing equipment at regular intervals and ensuring that all surfaces exposed to raw materials and products can be reached by the cleaning and disinfection processes. Hydrogen peroxide is widely recommended for the cleaning and fumigation process and therefore all machine housing and operating components and interfaces need to be robustly designed to minimise any form of contamination from these. Manufacturing equipment therefore should be designed to be resistant to chemicals, display low adsorption affinity for hydrogen peroxide during fumigation and also its rapid desorption during aeration in order to speed up the production process [12].

Kraemer et al. [19] researched on clean ability test of a robot contamination with a water-based fluorescing test contamination. The researchers mixed riboflavin in ultra-pure water which was then allowed to dry onto the manufacturing surfaces. On inspection under UV light before ultra and after manual wipe cleaning with a pre wetted polyester knitting cleanroom wipe using ultrapure water, they observed areas that were difficult to clean because of the use of the fluorescing pigment riboflavin. This included depressions, indentations and edges.
