January 28, 2022
Thomas Briel (TB): Pharmaceutical manufacturing often requires handling of multi-ton quantities of raw materials, such as buffers, salts, and stabilizing chemicals, ideally in as little time as possible. Any delays in handling lead to unwanted delays in production. For solid raw materials, handling issues arise if the material tends to cake together or solidifies and becomes difficult to dispense out of the primary container/packaging, to weigh accurately, and to flow properly through processing machinery, which impacts manufacturing efficiency and potentially leads to process interruptions and quality deviations. To address these issues, operators will often manually de-cake solidified materials using hammers or other tools, but this attempt is time consuming and usually creates high risks of injury to the workers.
Moritz Beck‑Broichsitter (MBB): Ideally, the material should be able to be transferred easily from the primary packaging (e.g., bag or container) it arrives in directly into the process. Any additional work, particularly if it is labor-intensive and hazardous for operators, should generally be avoided. It really is all about processability of the raw material — whether the material is caked/solidified or does not easily flow, the overall issues are the same: it does not allow for fast and simple handling.
TB: Dust formation is another handling issue that presents safety concerns, especially in terms of worker exposure. Special equipment is necessary to manage dust formation and protect workers and the environment, but of course the more dust formation that occurs, the more difficult it becomes to manage.
MBB: And, of course, the more hazardous the material, the greater the precautions that must be taken. But even if materials themselves are not considered hazardous, for example sodium chloride, permanent exposure to their dust still can present significant health risks to the operators.
TB: Given the handling and processability issues, as well as safety concerns associated with operator de-caking of solidified raw materials and dust formation, pharmaceutical manufacturers are seeking solutions that address or avoid these problems.
TB: Apart from manual de-caking of solidified materials with hammers, there are also automated crushing machines that can be used. However, such equipment is very expensive. Regardless of the method, the need to break up solidified raw materials adds an extra process step and increases the time for each manufacturing run. In addition, none of these approaches address the root cause of caking.
A possibility would be to avoid caking on a chemical level by adding anti-caking agents or other chemicals to improve the flowability. This is, however, not an option for pharmaceutical raw materials due to regulatory hurdles and as extremely high purity of raw materials is needed throughout.
TB: First of all, granulation addresses the root causes associated with problematic solid raw materials. Second, there are different techniques that can be used, such as dry and wet granulation. There is a caveat on this benefit, however. Wet granulation requires the use of water or other fluids that have the potential to change the chemical characteristics of the utilized raw materials. As a solely mechanical process, dry granulation is therefore the best solution: no water or other additives are needed, and it does not impact the purity or chemical characteristics of the material.
MBB: Dry granulation is also attractive from a process efficiency point of view. It is a high-throughput technique that enables the physical nature of a large quantities of material to be changed fairly rapidly.
MBB: In our SAFC® raw materials portfolio at MilliporeSigma, we granulate raw materials using roller compaction. It is much faster, for instance, than preparing tablets on a rotary press and then breaking them into smaller pieces and eventually particles. The powder is fed through a funnel into a mixing device that pushes the material toward the roller compaction zone, which comprises two rollers that press against each other to compact the material. The compressed material exits in the compaction zone as plates that are slightly thicker than paper. The plates are then ground in a mill to generate granules of a desired particle size. Lastly, the granules are passed through a sieve to remove any fine particles, which are recirculated and combined with the bulk raw material to be reprocessed again.
This approach gives us flexibility with respect to the final particle size of the granules. There are, of course, some technical limitations based on the milling equipment. It is not possible to generate very small or very larger particles, but that is not the goal of the granulation process for raw materials. It usually makes no sense to produce particles below one millimeter in diameter or larger than a centimeter in diameter.
MBB: The properties of the material and its intended application can dictate the desired particle size of the granules. For instance, if the material will be used in a process that requires dissolution in water, and its dissolution is dependent on the particle size, a particle size for the granules is needed that will afford the appropriate dissolution rate. For instance, particles that are “too” large will dissolve “too” slowly, while those that are “too” small will likely present handling issues, as observed for the bulk material. It is therefore important to target the sweet spot so that the material will not cake and is freely flowing but will still provide a dissolution time similar to that of the bulk material.
MBB: For materials that can be granulated, we have not seen any materials for which granulation did not afford desirable product properties. In fact, our method of granulation is suitable for heat- and moisture-sensitive materials. In addition, we generally achieve only minimal differences in the dissolution kinetics for the granulated products and their corresponding bulk materials.
Of course, there are some materials that cannot be granulated due to their inherent material properties or because of specific performance requirements.
TB: Due to this fact, granulation is not a one-fits-all solution for all raw materials. Examples are very “sticky” chemicals that stick to the machinery and clump, thus not forming granules. Or chemicals with no self-cohesion that remain powders even after passing through the roller compactor.
Within our SAFC® portfolio, we specifically evaluate candidate raw materials and identify those that can technically be granulated. For positively evaluated materials, we then determine the optimum parameters for different granulation processes so that our granulated materials provide the highest possible benefits for our customers.
TB: The granules we produce as part of our SAFC® portfolio are subjected to extensive evaluations to confirm that they are stable when exposed to harsh mechanical stresses. The integrity of our granules is excellent, and they do not undergo any significant abrasion during shipment or storage. As a result, there are very little fine or smaller particles present in the product that could potentially affect re-caking behavior or flowability of the material.
So far, we have received very good feedback regarding the elimination of both dust formation and flowability issues. Customers have even reported benefits beyond reduced caking and dust formation. The granulation process, regardless of the properties of the starting material, generates granules with comparable flowability properties. Having all raw materials with similar flowability increases the simplicity and efficiency of processes.
In addition, granulation helps to reduce re-caking events during long-term storage. Internal studies of SAFC® granulated products demonstrate that re-caking can be reduced by 90 % or greater when raw materials in granular form are stored under proper conditions. For chemicals where minor re-caking does occur upon long-term storage, small clumps form — rather than complete solidification — that can be easily broken. Our customers confirm those results as well.
MBB: Our customers have not had any issues with processing machinery when switching from bulk materials to granulated materials. That is because the size of the granules is within the standard processing dimensions. From a technical point of view, therefore, there is really no resistance in the market. As we discussed earlier, dissolution rates can be slightly different, but MilliporeSigma takes special care to deliver good quality in that regard. We are able to provide granules with particle sizes that have dissolution properties very similar to their corresponding bulk materials.
MBB: That is one of the charms of granulation. We are essentially following a particle engineering approach, and only the physical shape of the material is changed. The composition and chemical properties of the material are not affected. Accordingly, the granulated material is the same from a regulatory perspective. Of course, certain specific parameters of the granulated material, such as particle size, must be tested and confirmed, but these analyses are routine and easily performed.
TB: And, as all our SAFC® granulated pharmaceutical raw materials are multi-compendial, we meet the very strict requirements for the respective pharmacopeial testing that must be met by all pharmaceutical-grade excipients.
MBB: Within its SAFC® portfolio, MilliporeSigma has decades of experience in granulation processes for the production of pharmaceutical products that we have been able to tap into. With respect to dry granulation of excipients in particular, we have about seven years of experience. For each raw material, development takes time, because each material has different physical and chemical properties and different application requirements.
TB: Beyond this, MilliporeSigma has also offered a portfolio of dry granulated cell culture media for many years now. Our efforts with excipient and raw material granulation also greatly benefited from the experience we gained in that space.
TB: The current materials we offer in granulated form are urea, glycine, and potassium chloride. These materials in bulk form have very strong tendencies to cake and thus serve as high pain points for our customers, which is why they were the first granulated products to be introduced.
We have plans for additional products and will further expand our SAFC® portfolio in the upcoming years, always with the goal of eliminating processing challenges for our customers. We welcome input from pharmaceutical manufacturers regarding the experiences they have with challenging raw materials within their production environments so that we can develop granulated products that will provide significant impact and added value.
TB: Even though cake formation and dust generation have been problems since the pharmaceutical industry was first established, granulation of raw materials is still not an often-used approach, with only a few offerings on the market. We therefore see very good opportunities here to meet the needs of customers and provide significant benefits with granulated products that can solve real pressing issues.
MBB: The three products we currently offer have very different chemistries: two organic molecules and one inorganic salt. Despite the wide range of properties for these different molecules, our dry granulation technique leads to materials with much better properties than their bulk counterparts. In addition, although the materials have very different chemistries, the granules have similar particles sizes, mechanical stabilities, and flowability properties. And, as a plus, our SAFC® granulated products are part of our Emprove® program.
TB: Products within the Emprove® Program always come with very broad documentation, which is important to customers to meet regulatory requirements. That includes deep information on quality parameters, test methods performed, manufacturer and supply-chain information, stability studies, and so on.
There are also grades of products within the Emprove® program. Products that are Emprove® Expert grade are typically intended for higher-risk applications, generally parenteral pharmaceutics. For these raw materials, it is particularly important to have low endotoxin and bioburden levels, and they are therefore subjected to even broader testing.
All of our SAFC® granulated products are Emprove® Expert grade, and thus our highest-grade products offered in this space.
Thomas Briel is a Strategic Marketing Manager at Merck KGaA, Darmstadt, Germany and responsible for a broad portfolio of excipients for liquid formulation. He has more than six years experience in pharma and biopharma industry with different positions in the field of pharmaceutical formulation. Thomas holds a Ph.D. in Biology from the Technical University of Munich. In parallel to his Ph.D. and industry roles, Thomas acquired a bachelor's degree in economics with focus on marketing.