Resolving drug manufacturing issues early on is crucial to successful up-scaling

The process of applying coatings to pharmaceutical tablets is complex, involving many variables – and any problems in the process have the potential to impact the quality of the end product. 

While some formulation issues can be obvious to spot, such as sticky tablets in your coater, others may be hidden and only become apparent afterwards when characterizing the final coated product. Taking a proactive approach to preventing and resolving problems that emerge is essential to ensure your process is fully optimized.  

Troubleshooting follows a systematic approach, and involves exploring potential issues within the substrate, equipment set-up, process parameters or environmental conditions. Through thorough inspection, optical defects, tacking tendencies, blocked nozzles and spray drying as well as storage issues can be identified and linked to the categories mentioned. 

During drug characterization, manufacturers can experience out-of-track results, out-of-specification results, higher levels of variation and other quality diminishing aspects. Especially during scale ups or if the coating process requires many layers to achieve the desired functionality such issues might occur. So, while the formulation runs perfectly on one piece of equipment, it may not necessarily work when scaled up to full-scale production.  

It is important to take prompt action to amend problems as soon as they arise and in the case of hidden issues - such as cracked coating or the development of sedimental talc – analyzing your product with a scanning electron microscope is a convenient way to detect the majority of process related problems.  

It is essential to understand that all elements of the process are connected and changing one can have an impact on the whole outcome. Therefore, the process should be, first of all, fully understood and secondly be monitored to ensure the overall result of the product is not negatively impacted. 

When troubleshooting issues arise in the manufacturing of solid oral dosage forms, it is important to follow a systematic approach, starting with the quality of the used drug and excipients itself. If the substrate – the foundation by which the product is made – has an issue, the domino effect  comes into play and eventually affects the quality of the final product.  

The three most important topics to consider with substrate quality are: mechanical stability, particle size distribution, shape and surface area, and batch-to-batch variations.  

If the particles or substrates come in different shapes, sizes and surface areas, it can be very problematic. While a spherical shape is often unproblematic, sugar-based cores may tend to break and there is an increased risk of sticking tendencies in the beginning of a coating process. Needle shaped and longish forms of substrates have an increased tendency to break during the whole coating process and have poor flow properties even without being coated – leading to agglomeration tendencies and lump formation in the coating process. Meanwhile, dry compacted granules and cubical to plate-like structures can result in abrasion, friction, breaks and agglomeration tendencies.  

The size of the to be coated substrate determines the type of coating process. If the substrate is easy to handle, like round, convex tablets the coating process normally bears not many challenges. The same is true for spherical, stabile, small substrates in the range of 0.5 mm to 1.2 mm. The narrower the particle size distribution the better. What needs to be considered is the smaller the size of the substrate the greater the surface area, which results in an increase in the amount of polymer necessary to obtain film functionality.  

The primary issues around coating formulations and suspension preparations are the coagulation of aqueous systems, the particle size and porosity of the solids (which can later affect the performance of the film coating) and the maintenance of keeping solids within the spray suspension in flow. If a mistake was made during formulation design, it can result in chemical incompatibility of the excipients and might require a high neutralization grade to overcome these issues. Additionally, important factors are, for example, the solid content of the spray suspension, as this might influence the film formation and thus the functionality of the coated dosage form. Also, high shear forces should be avoided when working with aqueous latex dispersions as they are one of the main reasons for coagulation. 

One common issue can arise from the equipment that is used. For example, breakdowns require immediate attention and can slow down the scaling-up process. If solids, like pigments, are being used in the coating formulation, spray guns can become partly to fully blocked and consequently alternating the spray beam, eventually requiring the process to be halted for cleaning of the guns and lines.  

Another key factor to consider is the conditions present in the coating equipment the oral drug product is produced in. Product temperature is one of the most crucial control parameters that needs to be monitored during the coating process, as both high and low temperatures can negatively impact the product. For example, a temperature that is too high can result in spray drying effects and leading to rough surfaces of the substrate up to inferior film qualities. Those spray drying effects will increase even more if inlet air volumes are too high. Therefore, ensuring the inlet air, product bed and exhaust air are at the optimum temperature will help to ensure the coating formulation is successful applied onto the substrate.  

Once the product is ready and packaged, the job is not over; it still needs to be closely monitored as sticking tendencies can occur if the storage conditions are not ideal and lead to an increased moisture uptake. This can lead to unexpected changes in the release profile or create unwarranted interactions or degradation effects that were not picked up during the manufacturing process.  

Another important point is curing of aqueous formulated sustained release coatings. Curing means that the film formation is not yet completed after the coating process ends. To bring this to an effective stop and reach the final release profile, a curing process under controlled conditions, mainly heat and humidity, should be carried out. If curing tendencies are neglected the coated dosage from is prone to cure in an uncontrolled way during storage, which eventually will result in a drop of release profile over an unidentified amount of time.  

 Following a systematic troubleshooting approach based on understanding and a troubleshooting toolbox provides an effective framework to identify and rectify errors in the drug manufacturing process quickly and efficiently. Considering all factors that impact the end-product, it is important to ensure you optimize every step of the process and take a proactive approach at the first sign of a problem.