How to tackle hard-to-clean residues with targeted cleaning
Abstract
Cleaning in pharmaceutical manufacturing is not a routine task; it is a critical process for product quality, regulatory compliance and, ultimately, patient safety. At IMA Active, we integrate advanced cleaning strategies into equipment design and validation support to help manufacturers overcome residues such as cellulose derivatives, methacrylic acid polymers, iron oxides, titanium dioxide and stearates. This article outlines best practices for cleaning these hard-to-remove materials, based on process development studies and real applications validated on IMA equipment in collaboration with partners such as Ecolab.
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1.Introduction
In pharmaceutical production, cleaning is not merely an operational step; it is a cornerstone of quality assurance. Regulatory frameworks, such as EU GMP Annex 15, require validated cleaning processes to prevent cross‑contamination and ensure compliance. However, achieving effective cleaning is complex, particularly when dealing with residues that strongly adhere to equipment surfaces or exhibit low solubility.
The effectiveness of any cleaning process depends on four critical parameters, commonly represented in the Sinner Circle:
• Time
• Temperature
• Chemical action[th1.1]
• Mechanical action
Optimising these factors requires a systematic approach supported by cleaning process development studies. These studies identify the most effective cleaning agents, temperature ranges, and cycle durations for specific residues.
IMA Active Competence Center conducts cleaning studies with leading partners (e.g. Ecolab) to define chemistry selection, temperature windows and cycle durations, integrating these strategies into granulators, coating systems and tablet presses with a focus on efficiency, sustainability and compliance.
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2. Understanding Cleaning Dynamics
Ecolab’s development approach combines solubility assessment, coupon studies and, when needed, beaker studies, to select the right chemistry and parameter set points.
For example, temperature can play a more significant role than detergent concentration in driving cleaning efficiency. However, this relationship varies depending on the residue type and is therefore making customisation of the cleaning process essential.
In Figure 1 it is evident that for this example, the temperature drives cleaning effectiveness much more than the concentration of the cleaning agent. This is because thermal energy accelerates residue solubilisation and improves chemical reaction kinetics.
However, for other products, the critical parameters can differ substantially. This variability underscores the importance of bespoke cleaning strategies based on residue characteristics and process constraints. To illustrate this, the following sections present practical examples of residues frequently encountered in pharmaceutical manufacturing and outline the best practices for their removal.
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3. Case Studies: Strategies for Hard-to-Clean Residues
3.1 Cellulose and Derivatives
Cellulose, including derivatives such as HPMC and HPC, are widely used in tablet formulations and coatings. Residues can be found in granulators, coating equipment and tablet presses. The cleaning approach for cellulose residues can vary depending on the specific type of cellulose. However, process development studies have shown that the most effective method combines hot water with acidic detergent, such as CIP 72. This combination promotes residue solubilisation, ensuring effective removal of all contaminants.
Our recommended procedure is to apply the cleaning solution through an automated system, which guarantees uniform coverage across all contact surfaces. Follow with a thorough rinse cycle to remove any remaining detergent, preventing contamination risks.
This strategy secures complete removal of cellulose residues while maintaining compliance with cleaning validation requirements.
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3.2 Methacrylic Acid Polymers (Eudragit®)
Eudragit coatings, designed for gastro-resistance or controlled release, are highly durable and difficult to remove. In general, it is important to avoid hot temperatures, as the coating can become soft and pliable if exposed to excessive heat. For example, a validated cleaning cycle developed for a coating pan in which EUDRAGIT S-100 was present include a solution prepared with a basic detergent (such as CIP 96) at 2%, which works effectively to break down and remove the residue.
Figure 2 shows there are multiple types of Eudragit coatings. Some can be effectively cleaned using solutions that provide a specific pH range, while others, such as sustained-release formulations, require specialised cleaning agents like COSA PUR 81, and additionally also hot temperatures for effective cleaning. COSA PUR 81 was designed specifically for these sustain-release cleaning applications.
Cleaning Eudragit residues often occurs at elevated temperatures. However, process development studies have shown that effective cleaning can also be achieved at lower temperatures (around 30 °C), offering a valuable starting point for optimisation focused on sustainability. Nevertheless, although this approach reduces energy consumption, it may not be suitable for all formulations.
When low-temperature cleaning is not possible, higher temperatures identified during process development studies remain essential for achieving complete residue removal. This variability reinforces the need for tailored cleaning strategies based on coating type and process constraints.
3.3 Iron Oxides
Iron oxides are widely used as colorants in solid oral dosage forms due to their stability and strong pigmentation. However, their high adhesion to stainless steel surfaces makes them one of the most persistent residues in pharmaceutical cleaning.
We encountered this challenge in a pilot-scale high shear mixer granulator, where iron oxide III was a major component of the formulation. After production, reddish stains were visibly left on the internal surfaces of the granulator, particularly in joints, gaskets, and other hard-to-reach areas. These residues proved resistant to standard cleaning cycles, highlighting the need for process optimisation.
To address this issue, an acidic detergent specifically designed for iron oxide removal, such as CIP 77, was introduced. This detergent chemically breaks down the oxide layer, significantly improving cleaning efficiency. This focused approach improved the overall effectiveness of the cleaning process by removing all the residues.
As shown in Figure 3, when cleaning is unsuccessful, iron pigments can create a continuous coloured film on equipment surfaces. In some cases, re-deposition of pigments onto clean surfaces occurs, particularly when alkaline cleaning solutions and long cleaning cycles are used. This phenomenon results from pigments separating from the product matrix and adhering strongly to stainless steel.
To prevent this, process development studies recommend multiple short cleaning cycles instead of one prolonged cycle when iron pigments are involved. The most effective approach is a two-step process:
1. Remove the main residues.
2. Perform an acid cleaning step using COSA CIP 77 to eliminate all iron oxide residues.
This strategy ensures complete removal of iron oxide contamination and minimises the risk of pigment re-deposition, maintaining compliance with cleaning validation requirements.
3.4 Titanium Dioxide
Titanium dioxide is widely used in coating processes due to its unique functional properties as a whitening agent and opacifier. These characteristics not only improve the appearance of the final product, but also protect light-sensitive active ingredients.
The challenge with titanium dioxide lies in its extremely low solubility in water and its strong tendency to adhere to metal surfaces. Over time, it can form chalky films that are highly resistant to removal, especially when drying occurs before cleaning begins. In our experience, the most effective approach involves the use of an acidic detergent which helps to break down and loosen the residue, facilitating its removal from equipment surfaces.
A key element in the cleaning strategy is timing: starting the cleaning cycle shortly after production helps prevent drying and adhesion of the coating residue.
Moreover, using designed spray systems ensure that all areas prone to accumulation are adequately treated. In this case, a high-pressure system (up to 5 bar) helps detach particles from surfaces, hitting the target thanks to its mechanical action.
Successfully removing it requires a tailored approach that combines appropriate chemical action with controlled process parameters to prevent build-up and ensure compliance with cleaning validation standards.
Excessively hot cleaning cycles can cause the formulation to break apart, leading to white staining or film formation as shown in fig.4. Similarly, very long cleaning cycles can result in pigment separation from the product matrix, causing strong adhesion to equipment surfaces, similar to what occurs with iron oxides.
Therefore, the preferred approach is to use the most effective detergent at temperatures below 65 °C and apply short cleaning cycles. This combination ensures efficient removal of titanium dioxide residues while cutting energy consumption and avoiding re-deposition issues.
3.5 Stearates
Stearates are widely used as lubricants in tablet and capsule manufacturing. However, due to their waxy and hydrophobic nature, they tend to adhere to equipment surfaces, forming residues that are difficult to remove with water or general-purpose detergents.
We tackled this issue by using hot temperature washing cycles, combined with an alkaline detergent. Using a product like CIP 92 (or a similar high-performance alkaline cleaner) will be suitable as it can emulsify and break down these types of residues. In this case, a pre-rinse with hot water could be useful to soften and loosen residues. Then, we apply an alkaline cleaning solution allowing sufficient contact time. Even in this case, mechanical action given by water pressure is the key to success. In the end, a final rinse with demineralised water is needed to remove all detergent residues.
Figure 5 shows that stearate residues are often visible as white powder on equipment surfaces. Another indicator is the formation of water droplets on cleaned surfaces, signalling persistent hydrophobicity.
The most effective cleaning strategy combines hot temperatures with an appropriate cleaning agent containing surfactants. This approach ensures complete removal of stearate residues and compliance with cleaning validation standards.
5. Conclusions
With all the examples discussed, it becomes clear that cleaning activities in pharmaceutical manufacturing are rarely straightforward. Each contaminant poses unique challenges, and every piece of equipment requires a tailored approach to ensure effective cleaning and compliance with regulatory standards.
The case studies presented are not merely a list of cleaning methods — they represent real-world challenges, and the solutions developed to overcome them, from laboratory-scale to large-scale production equipment. These experiences highlight a fundamental principle: understanding the properties of each material and customising the cleaning process is key to success.
Cleaning is not just a regulatory requirement; it becomes a strategic advantage when combined with IMA Active’s process expertise. By integrating advanced cleaning protocols into our equipment design and collaborating with leading partners like Ecolab, IMA Active delivers solutions that maximise cleaning efficiency and sustainability while ensuring robust and reproducible results.
