Exploring New Possibilities with 3D Printing of Pharmaceuticals

Exploring New Possibilities with 3D Printing of Pharmaceuticals

February 23, 2024PAO-02-24-CL-11

Additive manufacturing, commonly known as 3D printing, is reshaping pharmaceutical manufacturing. Unlike traditional oral solid dose (OSD) manufacturing, 3D printing offers unparalleled flexibility in designing drug prototypes, final dosage forms enabling precision dosing and the creation of complex release kinetics. This technology is especially valuable during early R&D, for creating innovative dosage forms and streamlining the supply of clinical trial material. MilliporeSigma’s SAFC® raw materials portfolio plays a leading role in the 3D printing space, establishing collaborations and developing products to realize the potential of additive manufacturing. In this Q&A, MilliporeSigma’s Thomas Kipping, Ph.D., Head of 3D Printing and Solubility Enhancement, SAFC® Portfolio,­ sheds light on the evolution, current state, and future prospects of 3D printing in pharma, in conversation with Pharma’s Almanac's Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): To start off, can you give us an overview of the potential that additive manufacturing or 3D printing presents in pharma?

Thomas Kipping (TK): Much of the potential of additive manufacturing stems from the higher degree of flexibility that it offers in manufacturing. With traditional oral solid dose (OSD) manufacturing like tableting, the final geometry is ultimately very limited by the machine tooling. Even creating prototypes often requires extensive, complex modifications to the tooling and dedicated formulation development to match target release kinetics. In contrast, additive manufacturing offers maximal flexibility in designing and creating prototypes, and it has been extensively used in many other industries for that purpose.

In pharmaceutical manufacturing, this degree of flexibility is invaluable for a range of target applications — especially during early R&D, the development of new dosage forms, and clinical trials supply. In the early phases of pharmaceutical development, there is often a need to modify the final dosages and the corresponding release kinetics of these dosage forms. 3D printing allows you to individually fine-tune not only the drug concentrations but also to design how rapidly a drug can dissolve or to define the target location in the gastrointestinal system where it is released.

Another important point is that 3D printing enables us to design the 3-dimensional objects via computer software, creating different structures and then evaluating the results. Combining smart design technology with modern pharma 4.0 approaches or machine learning tools can create feedback loops that optimize the design and accelerate the creation of the best prototypes for your target application.

This also creates a lot of opportunities for industrial applications. When you can optimize and streamline development in an industrial setting, it allows you to get to your final dosage form much faster. In the past, you needed more than six months to get to the right formulation for your drug product. Using additive manufacturing, you can streamline that process by printing multiple predefined designs and then evaluate them in parallel, which saves a lot of time during the development process getting to the final drug product.

In the future, you may use additive manufacturing to facilitate decentralized manufacturing approaches, allowing you to react to certain demands in individual target countries or regions and move rapidly into localized on-demand production. Today, most manufacturing is very centralized manufacturing in one big plant but supply needs to be assured, and the global supply chain is getting more and more complex. Establishing a larger number of manufacturing hubs can significantly improve the availability for patients and potentially circumvent shortages.

DA: Along the same lines, additive manufacturing can potentially enable one of a long-sought goal in pharma: truly personalized dosing, wherein a customized tablet is manufactured specifically for an individual patient, correct?

TK: Absolutely. Drug developers are exploring a lot of different concepts with respect to the personalization of medication. We see a fast evolution, especially in the field of biosensors and other tools that can measure the extent of certain diseases and give a feedback loop directly to determine the required dose. Some diseases must be treated very delicately. For some compounds, there is a high tolerance between the effective dose and potential toxic levels, but some have a very tiny tolerance level and need to be precisely adjusted. This has very real effects on patients, because if you underdose, you don’t have the therapeutic effect of the drug, but if you overdose, you have adverse side effects or toxicity. Reliably delivering the optimal dosing level prevents potentially toxic side effects, and that in turn improves the patient’s perception of the medication, which ultimately improves the patient’s compliance rate and the patient’s quality of life.

DA: How have pharma companies embraced the possibilities that 3D printing offers, and how is MilliporeSigma helping to enable that?  

TK: We see a range of different positions across the industry. Aprecia has emerged as one of the big players. They introduced the first 3D-printed tablet on the market Spritam but since then there has been a bit of a lag time without any new 3D printed drugs getting to market. In the meantime, Aprecia has continued to work in the background to evolve their technology and broaden the application range of their 3D-printing platform. We have been working together with Aprecia to create additional value, by combining our solubility enhancement platform with their additive manufacturing technology.

As you know, within our SAFC® portfolio, we have designed many technologies in-house, and one focus for us has long been solubility enhancement. One product we have developed that is ideal for 3D printing is a Parteck® SLC. Parteck® SLC consists of many tiny nano pores, which gives it a very high surface area; to put it in perspective, a few grams of this mesoporous silica is equivalent to the surface area of an entire football field. During the powder-based 3D-printing approach, we can then use this in a powder bed to load the tiny pores of this mesoporous silica with drug substance solubilized in an appropriate solvent. Then, the solvent is evaporated, and the drug substance stays in the pores, but the pores are so tiny that the drug substance cannot crystallize and instead remains in an amorphous form. In a combined step, we can apply a binder liquid to create the 3-dimensional structure out of the powder bed. With this kind of system, we can either print a tablet using prefilled silica or load the silica with the drug substance or API (active pharmaceutical ingredient) during 3D printing on the fly. Our work with Aprecia is further enhancing the value that you can create using either technology by combining solubility enhancement and 3D printing to create our SoluPrint manufacturing technology.

While solubility is clearly a pressing need, there are many other applications that are beginning to be explored, which will probably become more common as 3D printing technology evolves. Not only can you modify doses and release kinetics with more precision than ever before, but you can also handle compounds that simply could not have been handled using classical manufacturing. We can provide new opportunities for these compounds, which makes a strong case for the industry to also revisit some types of molecules that were previously out of reach.

We are also working closely with Triastek — they’re another of the bigger players in the industry and very advanced in the realm of melt-based 3D printing systems. They are using polymer melts, which they deposit using a melt extrusion deposition technology, which is similar to hot melt extrusion. Within our SAFC® portfolio, we have been actively exploring excipients and applications for hot melt extrusion, so we are able to provide a lot of expertise and work together with Triastek to help them evolve this technology. They are currently evaluating our Parteck® MXP platform to create these 3D printed tablets.

This approach transforms amorphous solid dispersion (ASD) technology into a super versatile downstream. Traditionally, you would perform hot melt extrusion of your drug substance and a polymer, mill it all down, mix it with other ingredients, and then potentially granulate it and build a tablet from there a lot of individual process steps. Now, you can directly perform the melt extrusion step and deposit the melt to create the final form, which only takes a few seconds, making it possible to produce more than 100,000 tablets per day with one machine line.

Triastek has filed three IND (investigational new drug) applications and are close to having products on the market soon. With their strong expertise in GMP manufacturing and PAT technology, we are confident that we will soon have another big player entering the field, which will help further drive the adoption of 3D printing across the industry.

DA: What do you see as the primary drivers of adoption today?

TK: Functionality will probably continue to be the biggest driver of adoption, but in many cases that will require one big player to blaze a trail and create dedicated technologies for each application. Aprecia remains focused on immediate and dedicated release technologies. They are also rapidly widening the application space, also adding more functionality by incorporating multiparticulate designs, as well as in-blister printing technologies, while Triastek is differentiating themselves with a dedicated release technology that enables precise targeting of where the drug substance is released. These are all examples of functionalities that really weren’t possible before 3D printing.

Another major driver will be sustainability, especially in R&D or early clinical stages. When you have only a small amount of compound available, the synthesis is often rather complex, and process steps are not optimized compared with later stages, when you must reduce the amount of solvent, streamline the process, and optimize your drug substance production.

Production is never optimized in the early stages, so it can end up costing up to €10,000–100,000 for just a few grams of drug substance. Streamlining R&D development with a dedicated 3D printing approach would enable you to consume less of the API for the first formulation trials, which would have a big impact on reducing the amount of drug that you need to produce through all of the complex synthesis steps. This would have a good impact on sustainability in addition to cutting down on the development cycle either way, saving both time and resources that could be used later.

DA: I’d like to circle back to what you were discussing in terms of the solubility enhancement potential of combining 3D printing with the Parteck® SLC mesoporous silica. Can you expand a bit on how and why solubility is a growing problem in drug development and the extent to which conventional approaches are inadequate?

TK: The overall drug development pipeline is evolving toward increasing numbers of drug substances falling into biopharmaceutical classification system (BCS) Class 2 or even BCS Class 4. In general, the molecules are getting larger and more lipophilic, largely because these molecule target receptors, which are themselves are often rather lipophilic. This trend is not quite as significant as it was predicted back in the early 1990s, in part because pharma companies have limited the types of molecules they will even attempt to formulate, but the trend can still be observed. Providing more and better solutions for lipophilic molecules will also enable the development of more kinds of APIs, broadening the availability of new compounds.

Nonetheless, BCS Class 2 molecules are in high demand and will continue to be so, and they pose a big challenge for formulators in the future. Solubility enhancement can involve solutions at every level. The first is the molecule itself: is it possible to create a salt? If that doesn’t work, micronization is another option, but that path is often limited by performance.

Amorphous solid dispersion technology offers another powerful option. By using methods like hot melt extrusion or spray drying, you can create an amorphous solid dispersion, where the drug substances are stabilized in their amorphous form longer, so there is no need to overcome the energy of the crystal to dissolve and release.

All these technologies hot melt extrusion, spray drying, and silica loading with Parteck® SLC have their individual advantages, which is good because overcoming solubility challenges requires a full toolbox. In some cases, you will not be able to progress with hot-melt extrusion because of sensitivity of the API to temperature. Spray drying is only possible if you can find the right solvents. If your drug substance is a very weak glass former and cannot be stabilized in its amorphous form via classical approaches, Parteck® SLC is a very important alternative because then we can load the API into the silica and stabilize the amorphous form of the API via nanoconfinement in its unique porous structure.

One major advantage of Parteck® SLC and the SoluPrint technology is that the technology itself is rather independent from the particle requirements. We can either load the powder directly on the run or use the preloaded system, and in both cases, you’re independent from the properties of the particle. This is very different from conventional tableting, where you need to always think about the compression behavior and deformation characteristics of your pre-mix. Those are all things you need to fine-tune during formulation development.

With our SAFC® SoluPrint technology, you can use any API, and you don’t need to think about the particle properties how compactible or compressible the API is. You’re eliminating critical process factors from your requirements and streamlining development, because you don’t need to mix additional excipients to match a certain manufacturing profile, related to classical compression approaches. That is an advantage at this stage that I think is currently underestimated.

DA: What about the converse: are there any types of molecules that aren’t suitable for use of Parteck SLC?

TK: The most important step is that you need to find the right solvent, which requires a good knowhow of what kind of solvent and solvent mixtures work together with the drug substances. Solvent removal and the drying process are important. But given an appropriate solvent, the approach isn’t limited to any dedicated structures.

DA: With 3D printing, you’re able to combine the loading and tableting steps, which streamlines production. But is it also possible to begin packaging by printing directly in primary packaging?

TK: Yes, and that’s an important point — to create the forms directly into the final packaging can really avoid common challenges you have with more classical powder bed printing. For example, if you end up losing a lot of powder and premix, then you would need to address a lot of parameters in order to be able to reuse them. Additionally, homogeneity of the mixture needs to be assured.

Aprecia has been working on creating in-blister printing systems, where you then can directly create the dosage form in the blister and just have a dedicated amount of powder for individual blisters. It also definitely streamlines the whole production process because you can directly move into packaging afterward, and the final form is already available.

The choice of whether to print in-blister largely comes down to things like throughput and, to a lesser extent, on batch sizes and the stability of your powder. The classical approach is faster and is suited for higher volumes by providing higher throughput rates, whereas in-blister printing brings clear advantages in terms of fast printing, fast final packaging, and fast closure of the system.           

DA: How straightforward is it to accommodate Parteck® SLC in those two printing systems?

TK: We have a very close and strong collaboration with Aprecia surrounding the SoluPrint technology. We evaluated our technology in our laboratories through proof-of-concept studies to confirm that this kind of technology is applicable. Then, we worked close together with Aprecia, to set up the manufacturing process in a GMP environment and to ensure a potential scalability to support early capability phases up to later mass production.

Together, we have performed preliminary evaluations, and the synergy of our two technologies looks very promising. Currently, we are fine-tuning technical settings, but overall, we are very pleased with the results. Later, we hope that we can bring it to a technical standard, where it can be used as a platform technology within the pharmaceutical industry.

DA: Will you be exploring other possibilities in the 3D printing space within the SAFC® portfolio?

TK: Looking forward, our priority is to enable these technologies to mature. Looking at the technical landscape, we see a fast evolution of technologies. Currently, we do not observe a great deal of competition among companies exploring 3D printing; different companies are following rather individual approaches it’s more a case of matching different niches with technologies with different advantages. We bring in a lot of knowhow on the excipients the polymers, for example but also on how to utilize the processes, and we are doing our part to evolve different pharmaceutical printing steps into an applicable technology.

We are exploring the space very broadly: ranging from powder-based systems to melt-based systems. Together with universities and companies in the field, we’re exploring concepts like selective laser sintering approaches, where you use the energy of a laser in order to agglomerate the powder particles rather than granulating the particles via binder jetting or solvent systems.

Each technology has certain advantages, so it’s really important to collaborate with multiple stakeholders in the field to see what technology is best suited to each application. We’re in close contact with R&D departments, universities, industrial partners, and clinics, because each has their own view on how to apply the technology. Their everyday struggles are also driving a need for point-of-care manufacturing, as well as some of the other drivers I mentioned earlier: the need to speed up development times and to reduce the amount of API needing during formulation.

It’s critical to be closely connected to the industry so you can get the right input to know where you need to be active. Where is the gap or pain point? Why is the technology not evolving as fast as it could be? There are definitely roadblocks going forward. But we’re very active in different consortia and working closely with industrial partners to identify the roadblocks and develop workarounds to advance the technology.

DA: Looking forward, where do you ultimately see 3D printing existing in the continuum of pharma manufacturing? Will it become the gold standard for certain types of APIs or products, while conventional manufacturing remains for generics, for example?

TK: It’s an interesting question. That might be true in a general sense, but even for more classical products ibuprofen or paracetamol for example there is sometimes room for improvement and the evolution of new products. While most stick with the standard tablet, for such classical substances, a constant evolution can be also observed in terms of line extensions. Formulations are reworked and optimized, for example, to act faster. If you have a headache, you want it gone now; you don’t want to wait 15 minutes for the drug to take effect. If additive manufacturing can add value, I think we will even see it being applied for traditional medications. But for sure, the initial focus of this technology will be laid on enabling drug delivery of new chemical entities and challenging molecules, as well as the personalization of medications.

Ultimately, 3D printing has the potential to disrupt the supply chain and the current manufacturing model. We are very used to centralized distribution. But if you imagine a very disruptive change to the supply chain, even the classical and generic compounds may be affected. How often do you need a medication for headache? Hopefully not too often. It could be manufactured in an additive way, so you get the exact dose that you need. If you know more about your metabolism or your biometric details, you could get the exact dosage that would confer the therapeutic effect and minimize side effects for you. Once this new, decentralized supply chain is established, it would be a missed opportunity not to take advantage of it.

DA: I would imagine that 3D printing can also create opportunities for life cycle extensions, and refreshing patents. Do you see that as a major driver?

TK: We don’t really see that as a major driver yet, probably because the industrial setting isn’t quite there yet, but once we see more industrial acceptance, I think we will see companies exploring that. Why not? It can be a great opportunity for life cycle extension. It makes it also easy to fine-tune your dosage form and match certain release kinetics to possibly create a specific bioequivalent in your compound.

An important consideration is going to be PAT (process analytical technology) control: How do you certify that the system is producing exactly the right 3D printed forms? There needs to be very strong collaboration with PAT experts for successful development and matching the pharmaceutical industry’s needs with digitalization. As it is a fully digital process, you can really start with a 3D design at the computer and move further if you have the right process controls, like the ability to take images of each layer. There are already PAT sensors established that can measure the drug content per layer and things of that nature. I would say the PAT technology is pretty much there now. The GMP manufacturing technology is there. Combining the technology status with the recently seen tremendous evolution in machine learning algorithms, we are close to bringing these technologies to the final level.

Now it is on us to put the pieces together so that we obtain good regulatory acceptance and we can assure the safety of patients. For immediate release forms, it will be easier at the beginning, because the full dose is there for direct release. Sustained or delayed release formulations are much more challenging because you really need to match certain kinetics; otherwise, you have dose dumping or very fast dissolution of the compounds that you sought to prevent. Safety will need to be established empirically, but the fundamental technology individually is already here.

At first, we will see a fast evolution for the pioneers in additive manufacturing like Aprecia and Triastek who are working at a larger scale, since at the industrial environment it makes it more realistic to establish the very expensive controls needed at the end to really demonstrate and assure the performance and safety. But for immediate release formulations, there isn’t such a high risk; it could also be easily done in a decentralized concept. Companies like FabRx are here at the forefront of designing rather personalized solutions that may be deployed in hospitals of pharmacies.

DA: I know that products within the MilliporeSigma SAFC® portfolio, especially innovative products like this, are typically paired with a service element where you help customers to begin using the product. Is that the case with Parteck® SLC for 3D printing?

TK: We support customers in setting up the Parteck® SLC loading process for their drug. Our SAFC® products are further supported by application service labs, so the customer can ship samples to us, and we can set up a dedicated loading process for them. Since we have already spent a lot of time optimizing Parteck® SLC loading and processing, it makes the most sense for customers to approach us for support. And we can work together with Aprecia to ensure that they develop a GMP process. We are also very experienced in other solubility-enhancement technologies like spray-drying and hot melt extrusion. Under our SAFC® brand, we provide a dedicated portfolio of excipients and technical solutions where we also offer strong support via our application service labs worldwide.

DA: To what extent do you think the industry understands how advanced this technology is?

TK: A lot of people still see this as something that will happen in the future and are astonished to see how advanced the technology is already. I think it’s important for people especially for formulators in early stages to know that additive manufacturing is an option that can really benefit their formulation development. I think that people who have begun to explore it will see real advantages in their delivery formulation. So, 3D printing is something that everyone should have on their radar to consider integrating into early-stage research activities. The technology needs to be implemented now to ensure future innovations. Don’t get left behind.



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