Granulation: evolving slowly but surely

Guia Bertuzzi. Granulation Product Manager at IMA ACTIVE. Granulation is the most crucial step in the manufacture of solid dosage forms because it provides the main physical modification to the product bulk that affects the rest of the production downstream and, of course, the characteristics of the final form. There are three main types of granulation: direct compression, dry granulation and wet granulation.

Direct compression is a process that is becoming more and more important, and is the first choice of every technologist developing a new product because it requires simpler industrial equipment and allows productivity to be improved. However, not all formulas can be processed in this way because excipients for direct compression, known as diluent-binders, need to have good flowability, excellent compressibility and a specific particle size distribution to ensure uniform mixing.

Dry granulation creates granules by roller compaction of the powder blend with low pressures. The compacted material is then broken and sized gently to produce agglomerates. This process is often used when powders are sensitive to moisture or heat. Dry granulation is a simpler process than wet granulation in terms of process flow and room layout, which reduces manufacturing costs. However, dry granulation requires drugs or excipients with cohesive properties to help the formation of granules and so may not be suitable for all formulations. Additionally, it may sometimes produce a higher percentage of fine granules, which can compromise tablet quality or create other issues.

In wet granulation, a liquid binder is used to agglomerate the powder particles into granules using a high‑shear mixer granulator. The amount of liquid must be properly controlled because over-wetting will cause the granules to be too hard while under-wetting will cause them to be too soft and friable. Wet granules are sized through a mill and then dried in a fluid bed or oven. In most cases, further sizing of the dry granules is required.

Wet granulation is the most widely-used technology for granulation, even though it consists of many steps and product transfer, which increases production costs. It is the most flexible granulation technology available because it can handle the majority of formulations and it is also very suitable for multi-production. Wet granulation can also be conducted as a single‑pot process (granulator-dryer), involving a fluid bed with liquid spraying system. This process is especially suitable for high productivity or high‑shear mixer vacuum dryers and is highly recommended for the handling of high potency formulas.

The problems with change

Because granulation is such a critical manufacturing step, pharmaceutical companies seldom take any risk of technology change, especially for existing proven products, even when there may be opportunities for process improvement.

The pharmaceutical industry is always hesitant to introduce innovative systems into the manufacturing sector. One reason for this that is often cited in the pharma field is regulatory uncertainty, which has resulted from the perception that the regulatory system is rigid and unfavourable to the implementation of innovative systems; for example, several manufacturing procedures, including granulation, are often treated as static procedures and process changes are managed through regulatory submissions.

Nevertheless, pharmaceutical manufacturing has continued to gradually evolve with increasing interest in science and engineering principles. The most recent innovations concerning granulation technologies do not directly involve granulation principles; instead, they take into account aspects related to regulatory issues and safety and toxicity concerns that are becoming ever more stringent.

In 2004, the FDA issued the PAT initiative aimed at developing an integrated approach to regulate pharmaceutical product quality. One of the recurrent themes of the initiative was “quality by design” — “quality cannot be tested into products; it should be built in or should be by design”.¹This document starts from the axiom “quality by design” and tries to articulate the aforementioned stringent instances expressed by drug manufacturers.

Significant innovation in process control has been brought about by introducing the latest generation of sensors (NIR, FRBM, acoustic detectors, etc.) for better process understanding and the detection of process end-point to comply with the latest regulatory guidelines, based on risk analysis and the PAT approach.

Meanwhile, with regards to safety and toxicity concerns, more attention has been paid to process containment to minimise operational exposure level and cross contamination by rationalising the room layout or introducing new product transfer systems, which can achieve OEB 5 when working in containment. Additionally, more sophisticated CIP devices, such as self‑cleaning stainless steel filters for fluid bed and self-cleaning sampling devices, have helped reduce cleaning time and improve cleaning reproducibility.

Future needs

The pharma industry puts high pressure on equipment manufacturers to reduce manufacturing costs (both directly and indirectly) and time to market. Direct costs are referred to as equipment management or operating costs, while indirect costs come from out‑of‑specific products and set‑up activities. According to Benson and McCabe,² pharmaceutical companies lose approximately $90 billion/year worldwide because they are not able to achieve “world class” production efficiencies.

As reported by Werani et al.,³ tablets represent the majority of dosage forms sold worldwide. Often, tablets are made of granules and, consequently, granulation processes play a major role in the production of high-quality medicines. Several multinational pharmaceutical companies are actively involved in identifying alternative tablet manufacturing technologies, which would give significant advantages over traditional equipment characterised by capacities of 200–1000 L.

When it comes to manufacturing equipment, pharma companies demand flexibility, reliability, lower capital costs, lower operating costs and the ability to easily expand capacity. I believe that future innovations in granulation will look towards flexibility as a priority; manufacturing equipment must be capable of producing different amounts of final products, it must be able to adapt to multi-product manufacture and must also be easy to scale up. At first sight, these requirements could seem difficult but they are absolutely reasonable. In particular, if we consider the rising interest in continuous processing at all stages of the pharmaceutical manufacturing chain, continuous granulation won’t be far behind.

In the future, continuous manufacturing will probably be introduced for new products; however, batch manufacturing will remain for existing products, but will have a greater focus on process understanding and control to implement quality by design.

References

1. D.C. Hinz, Anal. Bioanal. Chem., 384(5), 1036–1042 (2006).

2. R.S. Benson and J.D.J. McCabe, Pharmaceutical Engineering, 24(4), 26–35 (2004).

3. J. Werani et al., Powder Technology, 140(3), 163–168 (2004).