Category: OSD

Oral solid dose (OSD) form medications remain the industry juggernaut. Though biopharmaceuticals continue to grow and evolve, offering new and unique treatment options, small-molecule drugs maintain their dominance with OSD medications leading the charge.

Considering OSD drugs date back to 1,500 B.C., the industry has had time to perfect the form factor, improve manufacturability and enhance the efficacy of one of the most portable and easily ‘packageable’ dosage forms.¹

Despite this long-held dominance, however, challenges in the manufacture of effective OSDs remain — in particular, the gradual decline in aqueous solubility of small molecules coming out of discovery. Hence, there continues to be a strong focus on enhancing the bioavailability of these substances.

Solubility issues are typically the most common hurdles to achieving ideal bio- availability, and these can be divided into molecules that are poorly soluble and those that are just too slow to dissolve. Approximately 80% of the drug candidates in the R&D pipeline exhibit poor solubility in water.² Drugs with solubility/dissolution-related issues and those falling into class II and IV of the Biopharmaceutical Classification System (BCS)² and class IIa, IIb, and IV of the Developability Classification System (DCS)³ typically exhibit  poor  or  varying   bioavailability, effectively canceling out some of the convenience offered by OSD. For molecules falling in class IIb and IV of the DCS, oral absorption is limited by solubility in the gastrointestinal tract. The molecules will not be completely dissolved in the three- hour transit time of the small intestine (where most drugs are absorbed). For molecules falling into DCS class IIa, complete solubility of the drug is feasible, but the OSD needs to ensure that the drug is freely able to disperse and dissolve. In these cases it may be critical to control particle size, surface area, wettability or all three of these factors.

As manufacturers of OSDs look for ways to successfully provide poorly soluble molecules within the dosage form, there is a growing demand for the application of so-called enabling  technologies, i.e., those that can mitigate the poor solubility of the API. Particle engineering approaches, such as micronization and comicronization, remain as simpler, lower-cost options that could be utilized for DCS IIa drugs, and while not likely to solve all the challenges of a DCS IIb drug, could be a cost-effective option for those that are close to being a DCS IIa. Particle-size engineering and analysis require specialized equipment and expertise, leading many pharmaceutical companies to turn to a reliable contract development and manufacturing organization (CDMO) partner.

With more than 25 years of experience handling particle engineering and analysis, Catalent is one such CDMO. After the company made the decision to acquire Micron Technologies in 2014, Catalent has become a leader in particle engineering and analytical services. With a thorough understanding of which approach is needed for each specific API, Catalent can help manufacturers avoid costly trial and error and better direct efforts to produce bioavailability-enhanced products that ultimately offer an improved patient experience. 

As manufacturers of osds look for ways to successfully provide poorly soluble molecules within the dosage form, there is a growing demand for the application of socalled enabling technologies, i.e., those that can mitigate the poor solubility of the API.

Understanding Particle Engineering

The goal of particle engineering is to first gather quantitative data that can help guide improvement efforts for the drug. More specifically, particle characterization should, at a minimum, not only con- sider the mean particle size, particle-size distribution and shape of the particles (both API and nonactive ingredients) in the formulation, but may also consider other factors.⁴

Due to the complexities involved in selecting and conducting the best analytical method for this type of research, it is not surprising that the 2017 Nice Insight Contract Development and Manufacturing Survey found access to specialized technologies to be the number one rea- son for engaging with a CDMO partner.⁵ With particle analysis in particular being a costly field, a CDMO partner with experience in characterization can help select the most accurate method(s) while also offering analytical guidance throughout the process. Catalent has over 350 analytical scientists and over 25 years’ handling hundreds of APIs, allowing them to pro- vide numerous particle-size testing options for both stand-alone particle analysis and more complete processes.

Several different methodologies and technologies may be used for characterization. As with any analysis, it  can be helpful to use more than one method, especially when a test is not specific. In addition, more specific, complex methods may provide more information, but a simpler method may be more cost-effective for fast access to data over a large number of samples. For example, while scanning electron microscopy provides more information about particle form, optical microscopy and laser diffraction are still more commonly used for run-of- the-mill samples. 

The goal of particle engineering is to first gather quantitative data that can help guide improvement efforts for the drug.

The Path to Improved Bioavailability

The solubility and oral absorption of DCS Class IIa drugs is limited by their dissolution rate. Based on the Noyes-Whitney equation, dissolution rate is directly proportional to surface area of the drug particles. In micronization, an increase in particle surface area is achieved by reducing particle size. DCS includes a proposed equation to calculate target particle size (D90). If the D90 is below this value, oral absorption of the drug is not limited by the dissolution rate, even in sink conditions.

The micronization process is a simple and well-established method that offers a consistent particle-size distribution with- out the use of solvents and without producing excessive heat.⁶ Traditional mechanical techniques such as hammer, pin and conical milling may not produce the de- sired particle-size distribution suitable for specialized applications, such as those intended for pulmonary delivery. Jet mills rely on impact and attrition of the API particles themselves to reduce particle size and, for solid-dose medications, are one of the most common and effective forms of micronization.⁶ High-velocity particle collisions cause larger particles to break down, and by careful design, centrifugal forces separate larger particles and ensure they linger in the mill, while the newly created small particles are able to escape into the collection system. This self-regulating process helps ensure a consistent result.

Additionally, when improved control is desired, or when working with highly potent compounds, there are more enhanced micronization options; for example, cryogenic micronization, which is similar in principal to jet milling but performed at temperatures as low as -50°C. This is becoming increasingly popular for micronization of compounds that have low brittleness or are tacky at ambient temperature. The colder temperatures help increase brittleness and friability of the compounds resulting in a finer particle size. Another option is to use a multiprocessing classifier mill, like that housed in Catalent’s Dartford, U.K. facility, which simultaneously micronizes and classifies powder substances and can be especially valuable when a narrow particle size range is required. Catalent has a range of different air jet mills at various scales including those that can micronize 250 mg or less of API, which may be suitable for companies looking at micronization during early development. Further, Catalent has achieved full containment in order to handle potent compounds. Micronization of potent drugs is difficult due to dust, which is a part of the milling process and has historically made the process inside containment impossible at larger scales.

Co-micronization, in which a small percentage of an excipient is blended with API prior to micronization, is an advancement on the traditional process. Compared with micronization followed by blending, the comicronization process promotes enhanced interactions between API and excipients. The potential advantages include decreased agglomeration, avoidance of dry blending, enhanced hydrophilic character and solubility, enhanced dissolution rate, and better flow properties. By increasing rate of dissolution and/or solubility, co-micronization can improve bioavailability of poorly soluble molecules, where particle size reduction alone may not be sufficient.

Though equipment considerations remain important, however, equipment alone cannot satisfy cGMP guidelines and deliver consistent results. When scientists are looking into particle engineering services it is best to seek existing expertise from a company that not only uses specialized equipment, but also offers support for any custom protocol development that may be required depending on the potency of the API, validation, execution and, of course, reporting.

Conclusion

OSD medication, being the preferred dosage form for in-house manufacturing, continues to be the dosage form of choice. Enabling technologies such  as particle   engineering will continue to have a place in drug product development for poorly soluble APIs. Particle characterization and engineering can identify optimal particle size, provide a more thorough understanding of the drug, and point to bioavailability enhancement options through particle reduction processes — a simple, elegant solution to a modern-day dissolution-rate issue.

Ultimately, if the goal is to ensure robust and consistent bioavailability with the most cost-effective OSD, then micronization and co-micronization have a case for being the ideal solution. Catalent has many other enabling technologies in their portfolio, and are ideally placed to advise companies about which data need to be collected to make an in- formed decision about whether particle engineering is right for a given molecule. In addition, Catalent has capability all the way from preclinical development to commercial supply. Catalent now integrates particle engineering capabilities with its existing expertise in characterization, giving customers options for molecule to phase 1 OSD materials with a fast turnaround.

References

1. Mestel, Rosie. “The Colorful History of Pills Can Fill Many a Tablet.” Los Angeles Times. 25 Mar. 2002. Web.
2. Löbenberg, Raimar, Gordon L. Amidon. “Modern Bioavailability, Bioequivalence and Biopharmaceutics Classification System. New Scientific Approaches to International Regulatory Standards.” European Journal of Pharmaceutics and Biopharmaceutics 50.1 (2000): 3-12. Web.
3. Butler, James M., Jennifer B. Dressman. “The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development.” Journal of Pharmaceutical Sciences 99.12 (2010): 4940-54. Web.
4. Tong, Henry, Albert Chow. “Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications.” Pharmaceutical Research 24.2 (2007). Web.
5. The 2017 Nice Insight Contract Development and Manufacturing Survey.
6. Markarian, Jennifer. “Need for Particle Engineering Increases.” Pharmaceutical Technology. 17 Sep. 2004. Web.

Originally published on PharmasAlmanac.com on March 8, 2017.

Developing robust processes from the outset by building broad and fundamental process knowledge minimizes future validation and revalidation work for drug substance manufacturing. Open communication between development and production teams also minimizes loss of process knowledge, streamlining process validation and reducing time to market.

Demonstrating Control

Process validation is a requirement of regulatory authorities that involves demonstration of process control. Both branded drug manufacturers filing new drug applications and generic drug companies seeking approval for off-patent products must complete process validation to clearly show that their processes are reproducible and produce batch-to-batch consistent product that meets all specifications set for the starting materials, intermediates, the drug substance, and the final product. Key to this demonstration is the application of the correct and appropriate control strategies across all steps in the overall process for detection of relevant impurities.

Three-Part Process

Process validation today comprises three phases: process design, process qualification, and continued process verification (CPV). Process design involves side-by-side process and analytical development to establish an optimum process and matching control strategy. Process qualification involves executing a certain number of batches at production scale to show that the process is reproducible and delivers in-spec material.

CPV is the newest aspect of process validation and is performed after the process qualification exercise. The intent is to ensure that the process remains under control by making validation an ongoing activity. As long as a drug product is on the market, the production process used to manufacture it must be assessed on a regular basis to confirm that it remains in a validated state.

CPV Freedom

There is a great deal of freedom in how to demonstrate that a process is maintained under control. The guidance is designed to allow each manufacturer to implement an optimum system best suited for its products and processes. The drug manufacturer has the final responsibility to perform CPV and must defend the adopted approach during any future regulatory inspection.  

In particular, the drug manufacturer must decide what data is needed to demonstrate CPV. The data collected should also enable ongoing process improvement. Smart companies choose data that will support annual product quality reviews as well, which are a separate regulatory expectation. In essence, forward-thinking manufacturers collect a set of data capable to support multiple internal programs while also meeting multiple regulatory requirements.

At Fareva Excella, formal assessments are performed at least annually for products that are produced infrequently. If issues are encountered during a production campaign, an assessment is also performed after the batch run is complete to determine if the issues can impact process validation. For products that are manufactured frequently, assessments are performed after each production campaign.

Process Validation and QbD

The need during process validation to demonstrate that processes are reproducible and robust can only be assured if an effective process development approach is taken. Such an approach must take into consideration external variations in raw material quality and address from the outset potential scalability issues across the entire process design space. Leveraging quality-by-design (QbD), it is possible to assess the relevant variables that can influence process quality and consistency and the risk each bears. Information gained through this process can be used to design processes and establish effective control strategies that avoid or at least minimize those risks, leading to a more stable and robust process.

Managing Changes within Validated Processes

Changes to validated processes can present significant challenges to drug manufacturers. Some changes can be managed within the CPV process, while others require demonstration through comparability studies that the product has not been affected and is still equivalent to the original product produced using the original process.

The first consideration is the ranges for different parameters covered in the validation exercise. If a change in one of these parameters goes outside of the validated range, then additional validation activities are likely warranted. A change in the material of construction for process equipment must also be taken into account. There can be unexpected effects if a process originally performed in stainless steel is then carried out in a Hastelloy reactor or even a glass-lined reactor, and, if this factor was not evaluated during process development, such a change could be significant.

Changes within the supply chain are a third potential issue. For example, if a supplier has two production facilities and uses comparable equipment, the same raw material suppliers, and identical processes to produce a starting material at each facility, it would be a small change if the supplier switched production from one plant to the other, because the impurity profile would be expected to remain the same. It would be a large change, however, if the supplier used different synthetic routes to the raw material at each facility, and additional assessments would need to be performed.

Finding the Right Development Balance

One of the biggest challenges to achieving successful process validation comes during the process development stage. It can sometimes be difficult to find the right balance between doing too much and too little process development. The more process knowledge that is available, the lower the probability that problems will occur during process validation. There has to be a balance, though, or products would never be commercialized. It is essential to determine the level of process development work that is actually needed to ensure that the validation exercise will be successful.

Fareva Excella, in this instance, benefits from the integration of process and analytical development and production activities at one facility. Knowledge about raw material suppliers, equipment materials of construction, vessel geometries, and other parameters are readily available to the process and analytical development experts from the outset of a project. Those constraints help drive the QbD approach and accelerate process development efforts while still ensuring that processes will be robust, reproducible, and validatable at commercial scale. In addition, the production team is kept abreast of the process development efforts as the project progresses. As a result, there is continuous knowledge flow from development through final production, including intermediate scale-up.

In many larger pharmaceutical companies and CDMOs, the development site is located in a separate part of the world far away from the manufacturing facility or facilities. The process development team may not even know initially to which production site the product will ultimately be transferred. A separate technology transfer team manages the process transfer to the production team, which has no knowledge of the development efforts other than provided through documentation. Even if the process is well designed at the beginning, the loss of knowledge flow during such a transfer exercise can lead to real issues during process validation.

A Few Validation Challenges

In general, the process validation approach is systematic regardless of the process to which it is applied — whether it has three or 10 synthetic steps and whether those steps involve heating, cooling, or pressurization. Difficulty tends to increase when the equipment being used is pushed to its limits, such as a heating or cooling rate at the top of the equipment’s established range.

Reactions run in heterogeneous mixtures may also pose validation challenges, because performance depends on several factors, like heat and mass transfer, as well as adequate mixing. Further on, mixing can vary significantly in small lab- and large commercial-scale equipment. Different mixing conditions can, for instance, result in lower yields, greater by-product formation, or the generation of particles of a size outside the specified range.

The scale and type of mixing is an important factor with impact on validation during scale-up. The performance of a reaction strongly depends on the type of mixing, causing unexpected scale effects if not taken into consideration. The Bourne protocol is used to judge the impact of the mixing type (micro-mixing, mesomixing, and macro-mixing).

Mixing issues can be exacerbated when the heterogeneous mixture includes a complex, special catalyst for which availability may be a problem and quality may be variable. Furthermore, for hydrogenation reactions, additional precautions must be taken to avoid poisoning the catalyst, which halts the reaction.

Finding the Right CDMO for Process Validation

The job of a CDMO is to adapt a client’s process in an ideal way to the equipment that the CDMO has and to finally produce the drug substance using a validated process. The optimum CDMO has the capabilities to perform almost all needed tasks at one site without the use of numerous external laboratories.

An ideal CDMO partner also has the ability to meet the specific needs of each client. For clients that have their own process validation knowledge, the CDMO must be able to work with the client’s team to establish an appropriate strategy for performing the validation, addressing any issues that might arise, and assessing the results. For virtual pharma customers with little internal process validation resources, the CDMO should have not only development and process validation knowledge, but also onsite regulatory expertise to support the initial product filing.

With respect to process validation itself, trained and knowledgeable personnel — combined with open and transparent communication between development and production teams — is also essential so that as little knowledge as possible is lost during transfer from one to the other.

Similarly, open and transparent communication between the CDMO and client is necessary to ensure that potential problems can be identified early on and preempted and that any issues that do arise can be rapidly resolved. Clear timelines and good project management are also important.

Process validation is a significant endeavor. It starts with development, moves to the first validation batches, and then continues throughout the life cycle of the product. Good project management and transparency with the client are critical for ongoing success.

Taking a Holistic Approach at Fareva Excella

At Fareva Excella, we have a complete process development unit as well as a development laboratory with access to all of the instruments and methods typically used in the pharmaceutical industry today to establish sound scientific specifications. These groups are located at the same facility as our commercial production area, making it possible to smoothly transfer processes from development to production. Our development colleagues attend the production runs and provide advice and training. Production personnel also follow the development process and provide input as needed. As such, there is excellent communication with no loss of process knowledge.

Furthermore, when a client transfers a process into Fareva Excella, we not only run the process in the development lab as provided, but also explore a wider design space. This approach is important for creating knowledge and understanding about the process and potential events that could lead to deviations — information that should not be discovered during the validation exercise.

Fareva Excella also has the ability to run a wide variety of different analytical methods and therefore can support many different experimental runs in our development labs with the right analytical techniques. In addition, access to such a wide range of methods allows for effective control strategies for many different processes run in the various types of equipment we have in the manufacturing facility. Our analytical scientists are also well-positioned to support the resolution of unexpected issues during the performance of validation batches. 

Overall, Fareva Excella has performed more than 100 process validations during the last 30 years. We recognize that developing robust processes from the outset by building broad and fundamental process knowledge minimizes future validation and revalidation work. We also realize that the more substance we add to our process validations, the better we understand our processes. That greater understanding enables us to help our customers extend their product life cycles, because we are positioned to support a product across its entire lifetime. This capability is a critical advantage for our customers.

Originally published on PharmasAlmanac.com on March 15, 2022.

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.

Originally published on PharmasAlmanac.com on February 23, 2024

Virtual pharma companies (VPCs) account for a growing percentage of the pharmaceutical market. With few internal resources and limited knowledge and expertise regarding regulatory expectations across drug development and commercialization activities, VPCs rely heavily on outsourcing partners. To maximize the benefits of outsourcing, however, they must choose the right partners.  Tedor Pharma Services does not view our clients as just numbers – they are valued partners. Tedor Pharma Services has the flexibility, responsiveness, transparency, and appropriate organizational fit, combined with extensive knowledge and experience in oral solid dosage (OSD) formulation and manufacturing to support programs from phase II clinical through commercial stages and help VPCs decrease their time to market with highly differentiated products.

The Rise of Virtual Pharmaceutical Companies

The biopharma industry has been experiencing significant transformation in recent years, including the rising contribution of virtual drug companies to the growth of the sector. This trend has been underway and accelerating for more than a decade.

A significant fraction of VPCs were founded by experts that left large international firms due to downsizing or because they wanted to strike out on their own. They often have ideas on how to leverage known molecules — either via new delivery mechanisms or new dosage forms or in new application areas. Others come from academia and seek to commercialize novel technologies, including new molecule types with new mechanisms of action. Both have minimal overhead. The former has highly experienced leadership and the latter has unique and differentiating technologies. In both cases, these small, emerging firms are attracting investment dollars from private equity and big pharma alike.¹

Many VPCs are focused on early-stage drug discovery and seeking help to rapidly take their ideas from concept to clinic and ultimately marketing approval.² The key to their success is the establishment of a clear outsourcing strategy and partnerships with reliable, high-performing third-party providers for all non-core activities. If executed properly, development costs and times can potentially be reduced by 25% and 50%, respectively.³

Biopharma Outsourcing Trends

According to BioPlan Associates, the value of the global biopharma outsourcing market was $14 billion in 2022 and expanding at a healthy rate.⁴ Growth is being driven by a combination of factors. Top on the list is the need to increase efficiency and productivity, reduce cost, and gain access to specialized, advanced technologies. The increasing number of small and virtual companies is also a driver, as these firms need support for both development and manufacturing activities.

Companies of all sizes are focusing on core competencies and turning to outsourcing partners as a means for optimizing resources.⁵ At the same time, they are potentially benefiting from additional regulatory support, gaining access to new markets, and expanding capacity while reducing risk. To maximize their outsourcing activities, many are shifting from tactical to strategic outsourcing, forming long-term relationships that contribute to better communication and transparency and help increase the security of supply.⁶ Such strategic partnerships can further improve efficiency and productivity and reduce development timelines owing to strong integration between the contract service provider and its customers, particularly for contract development and manufacturing organizations (CDMOs) that offer end-to-end services from development through commercial production.⁷

Advantages of Pharma Outsourcing

Outsourcing has several benefits beyond the reduction of costs and timelines and access to specialized technologies. The use of top-level CDMOs with state-of-the-art equipment and emerging technologies allows drug companies to bring their processes up to date.⁸ Often, working with multifunctional teams at contract service providers also improves similar collaboration within sponsor firms.⁹ CDMOs that have pursued digital transformations can also help simplify regulatory compliance and quality management, among other activities.

The use of CDMOs and contract research organizations (CROs) also provides access to greater capacity and enables expansion into new geographies without the need for upfront investment in facilities and equipment.⁹ Furthermore, outsourcing to multiple partners can significantly reduce risk and help ensure security of supply.

To maximize the advantages of biopharma outsourcing, it is essential to select the right service providers. Typically, options include larger CDMOs that offer a comprehensive suite of services supporting early-phase development through commercial production or smaller CDMOs that tend to specialize, either in a technology or development phase.

Service providers should have a demonstrated record of success with respect to on-time, in-full delivery, as well as a long history of achieving high quality and regulatory compliance.¹⁰ Open and transparent communication, flexibility in contract agreements, capacity (small to large volumes); technologies, appropriate expertise, and a similar working culture are also very important.

Benefits of Full-Service CDMOs

For virtual and emerging biopharma companies, a simplified outsourcing strategy can be very beneficial. One approach is to work with CDMOs that offer integrated services from early-stage development, including an understanding of the Investigational New Drug (IND) application process, through both early- and late-stage clinical material manufacturing and on to filing of New Drug Applications (NDAs) and/or Biologic License Applications (BLAs) and ultimately commercial production.

This strategy eliminates the need to manage multiple outsourcing partners and supply chains. It also eliminates the need for technology transfer from one CDMO to another, reducing timelines, cost, and risk. By choosing CDMOs that provide detailed and accurate quotes, clearly value each and every customer, and have open lines of communication combined with flexibility, stability, technical expertise, and a commitment to continued improvement and ongoing investment, these benefits can be further magnified, particularly for virtual and emerging pharma companies.

True End-to-End Support from Tedor

Tedor Pharma Services is a CDMO that can support projects from phase II clinical stage through formulation development and regulatory submission to commercialization — and anywhere along that path. We have extensive experience in analytical method development, formulation development, stability studies, and commercial manufacturing for oral dosage forms, including projects based on ANDA, 505(b)(2) pathways, or NDAs. For companies looking to purchase ANDAs, Tedor can also help identify potential pitfalls with those purchases. Once those clients are ready to move forward, we have the technology transfer expertise to seamlessly bring onboard relevant analytical methods and implement commercial final dosage form manufacturing processes.

With Drug Enforcement Agency (DEA) licenses, Tedor can support projects from the development stage through commercialization from Schedule II to Schedule V controlled substances.

Transparent, Detailed, and Accurate Quotes with Controlled Costs

Cost pressures for generic products have been consistently rising for many years. Profit margins have been continuously squeezed, making control of drug development and manufacturing costs essential. Often, clients developing generic products are looking for guaranteed commercial production costs from the outset, even if the timeline for development or tech transfer of a commercial process is 18 months.

Having previously been a developer and manufacturer of generic drugs, Tedor understands how critical it is for our clients to have a clear understanding of project costs and to avoid any creep in scope. We are committed to avoiding scope changes. Huge price increases in projects do not occur because of our extensive experience and knowledge about what is required by regulatory authorities. We provide extremely detailed project quotes that take into account all potential scenarios and possible regulatory compliance requirements, many of which other CDMOs will leave out in order to be more competitive, knowing that once a client is committed it is very difficult for them to switch to another provider.

We begin all projects with a discussion between our technical and quality team members and representatives from the client organization. We carefully review the aspects of the proposed project and ask numerous questions, often about issues the customer has not considered. One increasingly common challenge is the need to demonstrate that certain types of products that comply with nitrosamine impurities regulations. Elemental impurities must also be addressed for all projects. Generally, however, the questions we raise are project-specific and depend on the nature of the API, route of administration, and the ingredients use in formulation.

Ideal Outsourcing Partner for VPCs

Tedor is a small, cutting-edge CDMO with 20 years of experience helping clients meet their OSD manufacturing needs in a very personalized manner. Knowledge, capability, and caring comprise the fundamental pillars of our company. Our leadership team possesses critical information and a unique perspective, facilitating the development of differentiated products and the rapid resolution of development and manufacturing challenges.

Our goal at Tedor is to help clients achieve their goals by serving as an extension of their business. Indeed, we offer a unique set of capabilities and knowledge around the redesign of drug product formulations across all development cycles. Clients also benefit from our transparent quoting process and experience with generics and controlled substances.

Tedor has capabilities well-suited to meeting the needs of VPCs across the phase II clinical to commercialization spectrum. We have agility and flexibility combined with deep industry knowledge and the perfect organizational fit. As a smaller CDMO offering one-stop-shop services, we provide a level of access and responsiveness that larger CDMOs with end-to-end service portfolios cannot achieve.

In summary, Tedor Pharma Services does not view our clients as just numbers — they are valued partners. We work diligently to understand the specific needs of each of our customers and provide tailored solutions designed to ensure their success.

References

“The Future of Outsourcing: CPhI Report Predicts a Shift in Outsourcing Strategies.” CHEManager. 19 Oct. 2022.

“Virtual Pharma Companies: The Future is Now.” Drug Development & Delivery. Accessed 8 Aug. 2023.

Cliffe, Rachel. “Virtual pharmaceutical companies: Effective communication in a dynamic information network.” Torx Software Blog. 27 Jan. 2021.

Naylor, Stephen and Kirkwood A. Pritchard, Jr. “The Reality of Virtual Pharmaceutical Companies.” Drug Discovery World. 6 Aug. 2019.

Khanna, Smita. “2022 Outsourcing Trends In Biopharmaceutical Manufacturing.” Outsourced Pharma. 15 Jun. 2022.

Chaudhary, Kshitij. “Pharmaceutical outsourcing trends and key drivers: How can pharma companies strategically engage global outsourcing?” Current Trends in Biopharma. 28 Mar. 2023.

“Trends in Outsourcing for Pharmaceuticals.” Zenvision Pharma. 1 May 2023.

Krämer, “An evolution in pharma outsourcing.” Chemistry World. 29 Sep. 2022.

“New outsourcing trends take shape across the pharma industry.” PharmaLex. 7 Nov. 2022.

Jain, Avijeet. “Why are Pharma Companies Outsourcing Production?” Innovare Academics Blog. 30 Aug. 2022.

Originally published on PharmasAlmanac.com on January 11, 2024