Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Today, FDA expects drug formulators to not only consider patients outcomes when developing new products, but to also focus on the overall patient experience. Four main factors address the patient experience, according to Sarath Chandar, chief science officer with SPI Pharma: convenience, compliance, safety, and efficacy. Orally disintegrating tablets (ODTs) and other fast-dissolving oral dosage forms address the first two factors-and to some extent efficacy as well- from the standpoint of sublingual delivery, which can lead to increased bioavailability for poorly soluble APIs.

	Convenience is increased with ODTs and fast-dissolving products across all patient populations. “Pediatric patients benefit from this group of products because they dissolve faster than what they are able to spit-out and can also be mixed with foods for easy administration. These products can also be taken without water, so they are also amenable for adults on the go,” says Krizia Karry, global technical marketing manager at BASF Pharma Solutions.

	The fact that ODTs do not need to be washed down with water provide additional benefits as well. ODTs are, for instance, attractive to those who do not want to swallow liquids or hard tablets because they are feeling nauseous, adds Ralph Gosden, head of product development at Catalent Swindon. They are also useful when there is a need for rapid drug release, such as to relieve a headache, according to Torkel Gren, science and technology officer for Recipharm. “Orally disintegrating products are an ideal platform for delivery of active ingredients for the treatment of pain, allergies, diarrhea, Parkinson’s disease, travel-related illness, and other indications where rapid dosing and absorption is required,” he observes.

	In addition, ODTs can help patients who have an aversion to swallowing a tablet or capsule, and those who find it extremely difficult to take standard tablets because they may have dysphagia or other problems with swallowing (e.g., the elderly and infirm), Gosden notes. “Patients suffering from mental impairments can benefit as well,” he adds, “as they will sometimes deliberately avoid taking medications or pretend to have swallowed a standard tablet or capsule by hiding it in their mouth to spit out later-a practice referred to as ‘cheeking’. This tactic is nearly impossible with an ODT as it disintegrates quickly and completely.”

	Other benefits of orally disintegrating products in some cases are higher bioavailability and the fact that faster drug uptake can be achieved, according to Gren. “Instantaneous disintegration allows the drug to be dissolved and absorbed more rapidly, and for drugs that can be absorbed via the mucous membranes within the oral cavity, it can help to avoid the harsh environment within the gastrointestinal tract and bypass first-pass metabolism by the liver.”

	Orally dissolving products include tablets, granules, and films. “For tablets, the most common manufacturing technology is direct compression into tablets or minitablets,” Karry asserts. The use of 3D printing is also being explored for the production of ODTs, Gosden notes. “Granules are mostly produced via fluid bed granulation/drying and twin-screw granulation to ensure adequate size control. On the other hand, films are cast and dried on moving Teflon membranes from solutions or suspensions of APIs and soluble polymers,” Karry comments. More advanced technologies are often protected by patents, which may restrict competition, according to Gren. “In addition,” he stresses, “a more complex technology should not be used if it does not result in significantly better product properties.”

	Thin film strips are a delivery technology that can be used for both systemic and local delivery by oral, buccal, and sublingual routes, according to Gosden. “Although they dissolve rapidly in the mouth and are considered self-administrable, the application of thin-film strips is somewhat limited as the maximum dose that can be formulated for delivery via the digestive tract is only in the 20–50 mg range,” he says.

	In addition, Chandar adds that FDA has not approved many thin-film products for pharmaceutical applications because the strips can stick together, resulting in the patient taking multiple doses at once. This challenge has been addressed by individually packaging the oral strips, according to Karry.

	The distinguishing properties between orally dissolving products are the form factor and drug delivery methods (e.g., sublingual, buccal, oral, etc.). “The form is selected taking into consideration the target population and the API solubility. For example, a drug dissolved in a polymeric matrix in the form of a fast-dissolving film may avoid first-pass effects through buccal drug delivery and thus show higher bioavailability due to the design of the drug product,” Karry says.

	To be successful, orally disintegrating formulations must have certain features. The most important property is rapid-within 30 seconds or less-disintegration or dissolution in the oral cavity with or without water, according to Chandar. Because they are placed in the mouth, they also ideally should have a pleasant mouth feel that is creamy rather than chalky. An attractive taste is also ideal, which requires taste masking if the API is bitter, which many are.

	Excipients: The most important component

	Excipients are the most important part of orally disintegrating/fast-dissolving products, according to Karry, because they ensure good sensory properties and adequate technical performance. “When developing conventional tablets, the drug developer will focus on a limited number of characteristics that are easy to measure quantitatively, such as hardness, friability, disintegration, and 

 dissolution. When working with ODTs, several parameters that are difficult to measure are affected by the excipient,” Gren explains.

	“Examples include creating a clean mouth feeling, or creaminess and overall good palatability, as opposed to grittiness and lingering bad flavors, all the while leading to tablets with high tensile strength, low friability, and fast disintegration,” Karry says. She also points out that the interplay between tensile strength and disintegration is particularly important, because the stronger the tablet, the lower its porosity and the slower it disintegrates. “In this case, having both an efficient binder and a super-disintegrant is necessary for good performance of the drug product,” she comments.

	Compressed tablets require super-disintegrants, which either swell or wick up saliva, disrupting the tablet’s structure and encouraging dispersion, according to Gosden. Other important excipients include binders and fillers, according to Karry. Numerous other excipients can also be added to impart specific properties, such as lubricants, sweeteners, colors, and flavorings. “However,” Gosden notes, “some of the additional ingredients that may be required to manufacture the tablet can impede its disintegration. For example, if high levels of lubricant are necessary, the particle size must be carefully considered. If the particle size is too large, then the tablet may give a gritty and unpleasant mouthfeel as it disperses.”

	Certain excipients also enhance the bioavailability of poorly soluble APIs (e.g., Biopharmaceuticals Classification System [BCS] II and IV) by helping to increase the dissolution rate, according to Chandar.

	The type and amount of excipient needs to be carefully selected in order to get the right balance between a number of technical characteristics, including stability, flavor, and mouthfeel, Gren comments. It is particularly important to choose the right filler(s), he says, because the filler is often present in large quantities and has a significant impact on the taste and mouthfeel of the product. “A judicious use of quality-by-design and multivariate methods are helpful here,” notes Gren.

	Some excipients found in orally dissolving products such as sweeteners and flavoring agents are not normally used in conventional tablets, according to Gren. “Here it is extremely important to work in close collaboration with the marketing professionals when selecting the type and amount of all excipients, but especially the flavoring agents. The taste of the product should be developed in order to suit the intended patient population,” he says. “In my experience, sugar alcohols, mannitol in particular, are extremely useful in orally disintegrating products; they provide sweetness and pleasant mouthfeel and also have relatively favorable technical properties,” Gren observes.

	The most important excipients are those that ensure adequate technical and sensorial performance, notes Karry. She lists binders to give strength to the formulation, super-disintegrants to ensure fast hydration and disintegration, taste-masking polymers to decrease the interaction between the bitter or acidic drugs and tongue receptors, and flavors, which are used as needed based on the target population and to stimulate saliva secretion. Strawberry and apple flavors stimulate more saliva than cinnamon, for example.

	“The absolute most important excipient for these products, in my opinion, are disintegrants,” Karry says. “As a patient, I can accept having a bad tasting medicine-there are many out there already-but what I cannot accept is having a bad taste in my mouth for minutes or hours. Disintegrants help to ensure this does not happen. They enable complete drug product disintegration in the mouth so that the small particles can be swallowed, and if designed right, they clean our mouth as well,” she explains.

	Karry notes that studies have shown that both particle size and shape play an important role in mouthfeel. Hard irregular particles are perceived as larger than soft and smooth particles (1), while particles of 100 µm in size are perceived as creamy or fatty and thus activate salivary secretions and swallowing (2). “These studies demonstrate that a systematic science-based approach is needed when formulating orally disintegrating products,” Karry concludes.

	For lyophilized ODTs, Gosden says the most critical excipients are those that form the porous structure, specifically gelatin and mannitol. “While the freeze-drying process is under way, it is important to ensure that all of the mannitol remains crystalline, or there will be a risk that the finished dosage form will collapse during storage,” he explains.

	Chandar notes that for poorly soluble APIs, surfactants and plasticizers are used for bioavailability enhancement. He stresses, though, that no excipient should be used unless there is a demonstrated need and each ingredient in an ODT formulation should be justified.

	It is also worth noting, according to Gosden, that some excipient suppliers have developed proprietary blends of excipients in ready-to-use form (i.e., co-processed excipients) for the creation of compressed ODTs.

	Co-processed excipients based on microcrystalline cellulose (Prosolv ODT from JRS Pharma) and mannitol (Ludiflash from BASF and Pharmaburst from SPI Pharma) have been increasingly used in orally disintegrating/fast-dissolving products owing to their ease of use and overall particle characteristics, according to Karry. “In particular,” she observes, “those containing mannitol have the advantage that this alcohol sugar has a negative heat of solution and upon dissolving in the mouth imparts a cooling effect with a sweet taste. Mannitol is also amenable for ketogenic diets (important for epileptic patients) and diabetics (due to the low carbohydrate count).”

	Co-processing, unlike simple blending or mixing, of different excipients, enables the enhancement of functional performance, according to Chandar. “Whether via spray drying, granulation, congealing, or other methods, co-processing-when done effectively-creates synergies between the excipients involved, leading to unique properties and functionality not achievable any other way,” he states.

	As an example, Chandar points to SPI Pharma’s latest addition to the Pharmaburst line (500), in which the excipients are subjected to a three-step process that includes spray drying and granulation. “The result is a microplate structure of the combined excipients that exhibits a 30–40% improvement in compactability compared to simple, physical mixing. This higher compactability opens up a broader design space for formulating robust ODTs by providing a much higher API carrying capacity of up to 500–600 mg,” he remarks.

	Catalent has developed Zydis Ultra, a next-generation ODT technology that provides better taste-masking properties in a lyophilized ODT combined with an increased drug loading capacity, according to Gosden. A coating is applied to the outside of micronized API particles (as small as 100 µm in diameter) using a dry-coating process.

	“Gelatin forms the overall polymeric structure of the tablet, while mannitol increases robustness and makes the tablet look aesthetically elegant. Both ingredients dissolve readily in saliva, giving a quick-acting, melt-in-the-mouth experience for the patient,” Gosden says. In addition, he observes that unlike compressed ODTs, they are not reliant on the use of super-disintegrants to provide rapid dispersion. Instead, the rapid disintegration results from the way in which lyophilized ODTs are manufactured as well as the formulation of excipients.

	BASF, meanwhile, has developed Kollidon CL-SF, a superfine disintegrant with unique properties for ODTs, according to Karry. “This super-fine version of crospovidone was specifically designed to provide formulators a disintegrant that generates upon hydration smooth particles that are less than 100 µm for a non-gritty, melt-in-your-mouth feeling,” she explains.

	Separately, Karry notes that many companies in South America and Europe are moving to twin-screw granulation methods for manufacturing fast-disintegrating granules. “Twin screw allows for better control of granule size and is easily converted and integrated into continuous manufacturing processes,” she says.

	Regardless of the technology, the advantageous properties of new and more advanced excipients should be balanced against the higher costs that are often associated with them, asserts Gren. “For example,” he comments, “a more expensive excipient may allow you to avoid complex process steps and hence reduce manufacturing costs. As a result, the overall costs must be considered.”

	Compatibility and flexibility are important

	As with any formulation, one of the biggest challenges to developing orally disintegrating/fast-dissolving products is ensuring API-excipient compatibility. “Even though the majority of the excipients are pharmacologically inert, sometimes physical and chemical interactions between the API and excipients can occur that affect the stability, safety, and efficacy of the drug,” Gosden explains.

	For fixed-dose combinations involving two or more APIs, the question of whether the APIs are chemically compatible or prone to interact when combined must also be considered. Catalent addresses this issue when using its Zydis technology by using two or more homogenous formulations that are dosed sequentially under different conditions prior to freeze-drying. “This approach addresses issues of incompatible APIs/excipients and temperature-sensitive APIs,” says Gosden.

	ODT formulators should also prioritize exploring the relationship between tensile strength, friability, and disintegration, according to Karry. “Tensile strength is lower for ODTs compared to regular tablets due to fact that you need higher porosity for solvent uptake and core hydration. Similarly, disintegration tests are decent 

 predictors of palatability as patients prefer dosage forms that do not linger in their mouth for too long,” she adds.

	Given the wide range of APIs and the drive to develop more patient-centric formulations including orally disintegrating fast-dissolving products, it is also important for formulators to have access to broadly flexible platform technologies that can be used for multiple drugs, Chandar asserts. “An antiretroviral drug may require a very high dose, while a cardiovascular therapy may need minimal loading. A universal excipient platform that can be used for both types of formulations and generate robust tablets that don’t apart when the patient opens the package dramatically simplifies the process,” he comments.

	Chandar goes on to note that excipient technologies that provide rapid dissolution and can also aid in enhancing bioavailability are particularly attractive given than nearly 75% of pipeline candidates fall in BCS Class II or IV. In addition, ODT excipient technologies if designed appropriately may even be able to facilitate the oral delivery of some smaller biologic drugs- notably peptides-by enabling sublingual dosage forms that dissolve under the tongue in just five seconds, avoiding first-pass metabolism in the liver.

, online doi.org/10.1111/j.1745-4603.2005.00022.x. (Sept. 19, 2005),
	2. J. R. Stokes, M. W. Boehm, and S. K. Baier, 

Vol. 44, No. 6
	June 2020
	Pages: 20–23, 60

	When referring to this article, please cite it as C. Challener, “Formulating for Convenience and Compliance," 

Articles

The correct mix of excipients is crucial to the success of fast dissolving/orally disintegrating dosage forms.

Formulating for Convenience and Compliance

Ensuring the quality of data in process monitoring and control systems starts in process development phases. Maintaining data integrity during scale up and technical transfer phases is crucial. Building quality features into data management systems is a recommended strategy.

	Pharmaceutical Technology
	eBook: Biologics and Sterile Drug Manufacturing, May 2020
	May 2020
	Pages: 4–9

	When referring to this article, please cite it as C. Challener, “Building Data Quality In Generates Quality Data Out,"

 Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

Ensuring the quality of data in process monitoring and control systems starts in process development phases. 

Building Data Quality In Generates Quality Data Out

The concept of bioconjugation has been recognized for many decades, as has the specific idea of antibody-drug conjugates (ADCs). Technology for the production of ADCs did not advance sufficiently until the late 20th century. Even then, the first ADC approved by FDA-gemtuzumab ozogamicin (Mylotarg) from Pfizer in 2000-was voluntarily withdrawn in mid-2010 due to its association with the serious liver condition called veno-occlusive disease.

	Gemtuzumab ozogamicin was ultimately re-approved in 2017 at a lower recommended dose and schedule in a different patient population. There are now six additional FDA-approved ADCs on the market: brentuximab vedotin (Adcetris, Seattle Genetics/Takeda); (ado-) trastuzumab emtansine (Kadcyla, Genentech/Roche); inotuzumab ozogamicin (Besponsa, Pfizer); polatuzumab vedotin-piiq (Polivy, Genentech/Roche); Fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo and AstraZeneca); and Enfortumab vedotin (Padcev, Astellas Pharma/Seattle Genetics), the latter of which received approval in February 2020. And, there are approximately 80 ADC candidates undergoing nearly 600 clinical trials (1).

	Why have more not already been approved? The issue of toxicity has been a challenge, as has the complexity of ADCs and the consequent manufacturing challenges.

	Finding the right target, protein, linker, and payload all belong to the discovery phase. “This phase is very challenging, as the correct definition of the drug is key to move it into the clinic successfully. ADCs represent a product class that is also highly complex and difficult to predict,” comments Iwan Bertholjotti, director of commercial development for bioconjugates with Lonza. It is, in fact, one of the key questions in the development of ADCs since the rules are still being written, as data from clinical trials are used to guide ADC technology improvements, according to Steve Coats, global project leader at AstraZeneca.

	Finding the right targets and crafting an effective molecule has proven to be much more difficult than many researchers had expected at the outset of ADC research, adds Justin Sweeley, senior technology manager, biologics at Novasep. “It was initially understood that finding a good target antigen for an ADC-based compound would require a target with rapid internalization once it had reached the cell,” he notes. “The result,” he says, “was that in many cases targets that were ineffective for monoclonal antibody (mAb) therapies because of rapid internalization became perfect targets for ADC therapies.”

	This picture became much more complex upon the addition of payloads to these mAb candidates, however. This issue can be seen most clearly in the fact that the clinical trial landscape includes well over 50 different payload candidates, but only seven have successfully made it into commercial production, according to Sweeley.

	“As a result, there has been a recent shift in the industry to recognize that when trying to predict ADC effectiveness, researchers must take into account the target epitope, the physical attributes of the payload on the mAb once conjugated, and also the effect of the payload mechanism of action on the specific kind of cancer being targeted,” Sweeley observes.

	AstraZeneca takes an empirical approach to target and payload selection, keeping the patient population top-of-mind, using data from clinical trial results and non-clinical data to help validate target and payload selection. “With potency being driven by the strength of the warhead, we optimize the therapeutic index of our molecules by selecting the most favorable drug-to-antibody ratio (DAR) in designing our ADCs,” Coats says. “We believe,” he adds, “that establishing target rationale and strategy early on are key to determining the right payload.”

	Site-specific conjugation is looked at as the second generation of ADC conjugation techniques. “The homogeneity of these molecules allows for much tighter control at both the manufacturing and characterization levels,” Sweeley explains. Better definition for an ADC means that its therapeutic index can be further improved, adds Bertholjotti.

	Additionally, the technology allowing for site-specific conjugation has evolved dramatically from the Thiomab concept piloted by Genentech to current techniques allowing site-specific conjugation with any native mAb, such as Synaffix’s glycogen modification techniques or Ajinomoto’s AJI-cap technology, Sweeley remarks. Many of the ADCs in preclinical and clinical stages are based on site-specific conjugation technology of one form or another, Bertholjotti adds.

	On the other hand, Sweeley notes that even though more site-selective ADCs are expected in the future, ADCs with stochastic conjugation can still be successful. Coats agrees that site-selective conjugation does not seem to demonstrate significant differences in terms of clinical activity and safety when compared to classic non-site-selective conjugation. In fact, the seven commercially approved ADCs are not based on site-specific conjugation.

	It is possible, according to Sweeley, that the lack of a commercially available site-specific conjugated molecule is just a result of the head start that stochastic conjugation has had, but it is also possible that simplicity in manufacturing and homogeneity in analytic testing methods doesn’t directly result in better outcomes for patients.

	Finding an ADC that is better than standard therapy or that provides a solution to an unmet need definitely represents a challenge, just as with other drugs based on different approaches, according to Bertholjotti. The linker chemistry is an important component of ADC and has a significant impact on performance.

	“Linker chemistry plays a critical role in 

 stability, but initially was assumed to have a passive role with the exception of either being stable or labile in the acidic cytosolic cellular environment,” observes Sweeley. More recently, however, he notes that there has been growing recognition that the linker plays an active role in conjugate hydrophobicity and therefore stability of the ADC as a whole.

	The technology, according to Coats, has advanced and matured during the past 20 years to a point where linker technology is stable and molecules in development demonstrate low levels of deconjugation in patients. Both protease cleavable and non-cleavable linkers are in development and on the market.

	Classic conjugation chemistry approaches include maleimide and N-hydroxysuccinamide-ester moieties (Seattle Genetics, Roche, and Pfizer). There are also various newer technologies for linkers, with some, Bertholjotti comments, at the proof-of-concept stage and others already in preclinical evaluation.

	An example pointed out by Sweeley is the use of non-natural amino acid-based click-chemistry (Ambrx and Sutro). “To my knowledge, these technologies have clearly simplified the conjugation process, but have not shown a clear improvement in product effectiveness in the clinic,” he states.

	ADCs are designed to be more selective than traditional chemotherapy agents. The mAb enables targeting of cancer (or other disease) cells where the payload is delivered with high selectivity, thus reducing the systemic toxicity in comparison with standard chemotherapeutic drugs.

	Unfortunately, undesired immune responses have presented a problem that has been difficult to overcome. These responses are largely due to the massive number of variables being examined and the relatively small number of clinical trials going on, according to Sweeley. “Many of the warheads being investigated for ADCs induce immunogenic cell death, which may enhance anti-tumor immunity,” adds Coats. He also observes that there are recent examples demonstrating clinical activity with a combination of an ADC with PD-1 inhibition.

	“In the process of taking any ADC through the approval process, it is necessary to look at the mAb, the linker, and the payload chemistries individually, the ADC as a whole, and the payload and linker residues after the ADC has been internalized and digested within the cell. The end result is that for each ADC trial, researchers must monitor all of the normal undesired immune responses that occur during any oncology trial, but then try to attribute the cause of any that are observed to one of the five different potential sources,” Sweeley explains.

	“Factoring these additional considerations into the normal variables of any trial, such as the specific cancer type, patient population, and level of pretreatments, etc., the picture becomes incredibly complex. Even after 20 years of clinical testing, the issue is still not fully understood,” he concludes.

	The primary issue affecting ADC approvals today, according to Sweeley, is the lower-than-expected therapeutic window of these therapies. “If the therapeutic window of ADCs were as large as people expected when ADCs first came to light, then many more approvals would already be on the market,” he asserts. This window has proven to be much more complicated than originally hoped, however, and therefore the clinical impact less significant than originally imagined.

	Here again, the complexity of ADCs themselves is the main problem. For instance, Sweeley notes that if an innovator company wants to test a new conjugation method, they might choose a mAb and payload pair that have already shown success in the clinic. Similarly, a mAb company with a new antigen target is likely to use an established conjugation approach (e.g., that for Adcetris) to lower their risk. “The best molecule, however,” Sweeley explains, “might be a combination of multiple new technologies that are too risky to investigate for a small company with a limited budget.”

	The supply chain for ADCs is highly complex as well. ADCs are unique in that their manufacture is an amalgamation of classical small-molecule production and traditional mAb manufacturing with the added complexity of highly potent drug manufacturing. “All three characteristics are complex on their own, and combining them brings the complexity to a level where it is no surprise that the vast majority of ADCs are manufactured by outsourcing partners,” Sweeley says.

	For the most part, he notes that innovator companies treat the manufacturing of an ADC as three separate processes:

		mAb manufacturing using traditional mAb techniques

		Payload synthesis using traditional highly potent synthesis techniques

		ADC conjugation using specialty contract manufacturing organizations capable of both working with both biologics and highly potent payloads.

	“Taken individually, all three of these steps are actually defined quite well and have been orchestrated successfully for a long time. But because ADC manufacturing requires all three to happen together, any delays or issues in one process will necessarily affect the other two. The reality, therefore, is that ADC supply-chain management is one of the most complex processes in the pharmaceutical industry and must be managed by an experienced team who can mitigate risks whenever possible,” observes Sweeley.

	Bertholjotti agrees. The supply chain for ADCs is complex and requires specialized companies to manage different steps in a safe way and with the necessary quality. “If the supply chain is not properly managed, delays and supply issues may arise. Therefore, compromises related to the supply chain can result in critical impacts on timelines and costs to bring a drug to market,” he asserts.

	FDA has shown willingness to work closely with sponsors to ensure that ADCs that truly benefit patients are brought to market expeditiously, says Coats. For example, he comments that AstraZeneca’s ADC Enhertu (developed in collaboration with Daiichi Sankyo) demonstrated significant benefit in a high unmet-need cancer population. FDA approved Enhertu four months prior to the FDA goal date for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting. Enhertu is manufactured using site-selective conjugation and contains a cleavable linker technology that releases a warhead with bystander activity. It has also shown encouraging clinical activity in other HER2-driven cancers.

	Over the past decade, awareness of these issues has increased dramatically, leading to the development of more optimized molecules. Even so, Sweeley emphasizes that the complexity of the space means that it is still prudent to go slowly and only tackle one challenge at a time. “Progress is therefore slow, but continually happening. Each success creates a new platform for companies to reach out a little bit farther. And as the industry matures, the rate of success will increase, just as it has in every other area of pharmaceuticals,” he asserts.

	Novasep has strong expertise in highly potent compound synthesis and for the past three years has brought this expertise into the realm of ADC conjugation, Sweeley notes. “Our focus has always been on producing the highest quality materials by developing the simplest possible procedures and coupling them with world-class analytics. The end result of these efforts is a simplification of the payload synthesis and conjugation steps along the supply chain, enabling rapid development of the two most complicated parts of the manufacturing of ADCs,” he states.

	Since 2006, Lonza has been establishing a center of excellence for the development and manufacture of ADCs. Today the company offers an integrated solution, which helps to reduce the challenges presented by such a complex supply chain, according to Bertholjotti. “Integrated offerings such as that offered by Lonza represent a competitive advantage. They afford ADC developers with better predictability of timelines and costs, along with substantially reduced complexity and supply risk,” he says.

	AstraZeneca is developing novel ADCs and building a library of payloads using its antibody engineering expertise for site-specific conjugation and next-generation ADCs. “ADCs form one of AstraZeneca’s key oncology scientific platforms, along with immuno-oncology, DNA damage response, and tumor drivers and resistance mechanisms. Within these platforms, multiple technology and scientific options offer great potential to yield effective medicines for cancer patients,” Coats says.

	As more ADCs are approved commercially, Sweeley believes a roadmap will be established for other companies to follow, leading to more success in the near future. “In the last 12 months alone, the number of approved ADCs on the market has more than doubled, and I would expect that this track record will be followed by a sizable increase in the amount of research being put into the molecule discovery and preclinical trial stage,” he observes. “With the healthy increase in candidates being brought into the preclinical stage, it is only a matter of time until some of those candidates make it through the rigorous demands of clinical testing and reach the market in the not-so-distant future,” Sweeley concludes.

	The increased number of ADC candidates in the pipeline in combination with ever improving knowledge and the further development of new conjugation technologies will result in an increased rate of approvals, agrees Bertholjotti. Lonza expects that the number of ADC molecules will in fact rise at a 10% compound annual growth rate until 2029.

Vol. 44, No. 5
	April 2020
	Pages: 22–27

	When referring to this article, please cite it as C. Challener, “Formulating an ADC Development Solution," 

Many antibody-drug conjugate therapies are in the pipeline; however, only a handful have been approved. What are the bottlenecks? 

Formulating an ADC Development Solution

Technology transfer of bioprocesses, while common in the biopharmaceutical industry, can be complex and present numerous challenges. Projects with accelerated development timelines that also involve multiple contract service providers have the potential to magnify the difficulties. Both contract manufacturing organizations (CMOs)/contract development and manufacturing organizations (CDMOs) and sponsor companies can facilitate the process using pragmatic approaches that mitigate risks and ensure cooperation between all parties involved.

	Material, specification, and change-management issues

	When transferring a bioprocess to a CDMO, manufacturers often face multiple challenges that can include meeting the material demands of their clinical or commercial strategy and achieving aggressive timelines. These constraints must be met while accommodating the facility fit and scale-up needs determined by both the established process and the CDMO’s platform, equipment, and capabilities, according to Frank V. Ritacco, director of scientific and technical affairs for pharma services at Patheon, part of Thermo Fisher Scientific.

	Abel Hastings, director of process sciences at Fujifilm Diosynth Biotechnologies, adds there are some themes that often slow the progression of sponsor projects, including materials challenges, specification ambiguity, and challenges with historical change management. “The implications of an ill-selected material can linger and hinder manufacturability. Once selected, materials dogma can be difficult to unpick because of the fear of the unknown,” he notes.

	With respect to specifications, Fujifilm splits them into two general categories: safety/efficacy and manufacturability. It is important, according to Hastings, to convey the known safety/efficacy limits as early as possible and communicate what events might cause specifications to change. “As a CDMO, our primary goal is often to adjust the process design to reliably meet these specifications, and knowing the status of specifications up-front helps us guide our clients,” he explains.

	Issues can arise, however, if sponsors establish specifications that are rooted in manufacturability too early, and then the process performance changes in the development stage or when moving a program from one site to another. Establishing expectations for process performance with limited data can, Hastings says, often over-constrain the development team, leading them to necessarily forego improvements in order to achieve a manufacturability specification. 

	Change management during process development, meanwhile, can challenge both sponsors and CDMOs as they work to expedite processes. “In this day and age of accelerated processes and ever-changing team members, capturing rationale for change becomes increasingly important to guard against knowledge loss as team members leave a company and to help guide development in an unemotional manner,” Hastings asserts. 

	While commercial processes typically have robust quality and change-control systems, earlier-phase projects can often change quickly and with limited traceability. “We recommend taking a balanced approach in order to capture pertinent information while not hindering development,” comments Hastings. Some sponsors use iterative risk assessments or failure mode and effects analysis tools to quickly capture changes and build catalogs of development and lifecycle changes. “This approach allows the user to both convey historical details and to project forward-looking risks in order to steer development in a planned way,” Hastings observes.

	The overall challenge in tech transfer is to ensure that the sponsor’s process will be reproduced in a similar, robust, and compliant way. Manufacturing product in the quality and quantity in the defined timeframe are indicators of a successful transfer of the manufacturing process to the CMO/CDMO, according to Andrew Bulpin, head of process solutions at MilliporeSigma. “This overall challenge,” he says, “is mainly linked to the process itself, but it also relates to the capacity to transfer the process knowledge built for several years to the CMO/CDMO that will be integrated to ensure a successful tech transfer.”

	It often also varies depending on the development phase of the bioprocess being transferred. Sponsor companies’ early-phase programs are typically challenged by transferring processes that do not fit into their external partners’ platform operations, according to Emily Schirmer, senior director of process development at Catalent Biologics. “Those partners that can offer a high level of flexibility and unit operation expertise are more successful in accommodating unique or non-traditional processes,” she remarks. 

	In addition, as programs progress through clinical stages, process transfer becomes more difficult because there is less inherent flexibility allowed and process changes or adaptations become more challenging to justify, Schirmer adds. Bulpin agrees that the process parameters in Phase I or II can be slightly adapted or adjusted to ensure a successful tech transfer, while in Phase III the process is more locked with defined critical process parameters, critical raw materials, and designated critical quality attributes (CQAs). Thus, any changes in Phase III should be assessed, justified and, if necessary, validated.

	Scale-up, equipment, and parameter adjustments

	Adding in a scale-up element when transferring a process increases the overall risk for project success and comparability. “It is difficult to discern the differences observed from facility to facility and any disparities that can be observed on scale up independently,” Schirmer says. “These risks,” she notes, “can be minimized by having a good depth of knowledge of the facility’s specific equipment and well-established scaling models.”

	Variations in equipment and material handling at facilities can complicate the tech transfer process, agrees Bulpin. “If the target facility uses different equipment, the raw materials must be compatible with that equipment,” he explains. In addition, to ensure a successful scale up, it is critical that raw materials are available at large scale and equipment capacity is evaluated. “The scale-up strategy of the CMO/CDMO, as well as its expertise in various process types, molecules, and innovative process methods-including perfusion, precipitation, and single-pass tangential flow filtration-is also key,” asserts Bulpin.

	For cell-culture processes in particular, scale up can be challenging because scaling to larger volume is not linear, and multiple engineering parameters must be optimized to match process performance developed at the bench scale and confirmed at pilot to manufacturing scales of 2000 L and beyond, according to Ritacco. Harvest and downstream purification processes also need to be scaled up to match product quality and impurity profiles, and sometimes adapted to address differences in product titer and impurity profiles observed at larger scale.

	Even if projects don’t involve scale-up, generally they still require a thorough investigation of which parameters need adjustment to fit best within the CMO/CDMO facility and equipment constraints without impacting specifications, Hastings observes. “In our view, scale changes and facility-fit adjustments are not complications but rather just part of what we do,” he says.

	Many new biologic drug candidates are awarded some form of accelerated approval designation. While accelerated approval designations may allow a faster path to the clinic or to commercial approval for breakthrough therapies, the time it takes to develop a bioprocess that will be robust, scalable, and reproducibly deliver target product quality remains significant, according to Ritacco. “Fast-tracking the timeline and schedule without compromising product quality and patient safety is an additional challenge,” Bulpin says.

	While some product development steps can be reduced, Bulpin insists that risk analysis and decision justifications should not be underestimated. “Sufficient understanding of the process is necessary to ensure control of operating parameters to consistently deliver safe and efficacious product to patients, and achieving this on an accelerated timeline requires a skilled team leveraging well-established processes and methods, as well as past experience to streamline development and avoid pitfalls,” adds Ritacco.

	It is also extremely important for sponsor companies to work with a partner who has extensive experience with tech transfer and scale up into commercial launch, according to Schirmer. “A typical program with an external partner is designed to have a process-acquisition phase, which includes a paper transfer followed by establishing the process at a small scale. Then the scale up occurs within the facility infrastructure. These scale-up activities can, however, be minimized by performing the process acquisition at the manufacturing scale to meet accelerated timelines,” she says.

	Fujifilm often observes three particular challenges with accelerated programs: prioritization, collaboration and communication, and planning. Most sponsors with accelerated designations greatly reduce timelines, Hastings says, by focusing on refining their processes to reliably achieve CQAs, often at a cost to the yield. “The most successful projects have a cross-functional team that is clear on their priorities and what success looks like. Ensuring all members of the team work together to settle on the right balance of yield and CQA reliability will ensure teams aren’t derailed by conflicting priorities,” observes Hastings.

	One problem Hastings has observed, however, is that as teams turn attention to accelerating development timelines, they have a tendency to unintentionally reduce the circle of communication. “The most successful teams, however, enlarge their circle to engage all functional areas, allowing everyone to be part of the process of building the best balance of speed, reliability, and risk,” he asserts.

	Planning for an accelerated designation project, meanwhile, requires a balance of creativity, dedication, and pragmatism, according to Hastings. “Teams need to be able to challenge their platform expectations to strike a balance to improve timelines. This planning cannot be done once,  but rather needs to evolve as the scientific understanding of the process grows and teams need to be aware that any new data might require an adjustment to the project plan,” he adds.

	Engaging with multiple outsourcing partners

	For many projects, it is necessary to transfer a bioprocess from one CMO/CDMO to another. Regardless of the reason, it is essential that everyone involved does not overlook the complexities associated with leveraging previous data and maintaining technical continuity, according to Hastings. 

	To proactively address this issue, Fujifilm identifies new, unique, or difficult (NUD) elements, such as process-specific factors that depend on equipment idiosyncrasies that may not be fully evident to a sponsor while the process is running at a CDMO. “When a process is moved from one CDMO to another, the receiving site rarely has access to complete equipment-specific details, which can make interpretation of previously generated data challenging and incur risk,” Hastings says. 

	“At Fujifilm, we work hard to identify NUDs as early as possible and then categorize them as equipment-specific versus equipment-agnostic. This approach allows us to suggest studies that may improve facility fit,” he adds.

	Differences in equipment throughout the process, as well as differences in scale, require optimization of multiple engineering parameters to match process performance in cell culture, harvest, and downstream purification processes between facilities, Ritacco agrees. He also points out that analytical methods have to be transferred, established, qualified, and ultimately validated to assure consistency in analytical results between manufacturers.

	Hastings also notes that some processes include historical elements that are difficult to translate into and out of batch records. “In some cases, sponsors deal with this issue by maintaining some of the same staff throughout transfers to minimize the chances that so-called tribal knowledge is lost,” he observes.

	Transparency between all team members, adds Schirmer, can actually be the catalyst to a successful development, scale up, and tech transfer of a drug with an accelerated approval designation. “Whether the process technology transfer occurs between the sponsor company and the external partner, or between two external partners, the importance of transparency is the same. Communication is also critical. If all parties are aligned and understand the path forward, it is much more likely that the transfer will be a success,” she comments.

	The general constraints are the same for any tech transfer process, including those between outsourcing providers, although the confidentiality becomes more marked and the training process can be slightly different. “The aim remains the same,” Bulpin says. “In addition, any process, analytical, equipment, raw material, and/or regulatory gaps should be listed and mitigated to meet specifications and ensure a successful tech transfer.”

	Technology transfer introduces additional risk to the development and commercialization of biopharmaceuticals, so minimizing risk is fundamental to successful technology transfer of bioprocesses. 

	A clear project plan with milestones that are mutually agreed upon sets the stage for a successful program, Schirmer observes. “Risks should be identified at the onset of the project and continuously re-evaluated to determine effectiveness of mitigations and any additional risks,” she says. In addition, risk assessments should be backed by scientific reasoning and process data.

	The main strategy, according to Bulpin, is to consider tech transfer-with or without scale up-as an entire project with dedicated subject matter experts, communication flow, clear responsibilities, and planning. Dedicating one individual to the management of one CMO/CDMO group helps with this approach, except for quality assurance and regulatory topics, which Bulpin says should be managed globally to ensure process compliance.

	The preparation and review of thorough process descriptions, facility fit, and tech transfer documentation, with appropriate quality review and oversight, go a long way toward achieving a successful tech transfer, adds Ritacco. The experience and expertise of the teams involved is also critical. “A highly skilled and experienced team will anticipate potential challenges and leverage their deep understanding of bioprocess development, tech transfer, and manufacturing to achieve the desired process performance and product quality in a new facility, even when the timeline may be challenging,” he asserts.

	It is also important, according to Hastings, for everyone involved in a tech transfer project to recognize up-front that priorities may change during the development cycle for biologics with accelerated approval designations. Risk-based tools can be used to segment process characterization into two or more phases and to design the process to prioritize CQAs over yield. “Using this approach, it is possible for sponsors to start their process performance qualification (PPQ) in parallel with some process characterization work, thereby shortening the timeline from clinical manufacturing to PPQ,” Hastings observes.

	On the other hand, it can result in post-approval yield fluctuation, which makes business-planning difficult. Fujifilm see this issue as an opportunity to move through a natural transition point. “Purposefully pivoting from biologic license application-enabling activities to business-enabling process improvements at the optimum time will allow programs to benefit from both accelerated PPQ and long-term commercial pay-back,” he concludes. 

	Cynthia A. Challener, PhD, is a contributing editor to 


	Vol. 44, No. 5
	May 2020
	Pages: 56–58

	When referring to this article, please cite it as C. Challener, “Ensuring Smooth Tech Transfer of Bioprocesses to Outsourcing Partners,” 

Experience, communication, collaboration, transparency, planning, and prioritization contribute to success.

Ensuring Smooth Tech Transfer of Bioprocesses to Outsourcing Partners

Human coronaviruses (HCoVs) in the past were considered to cause nothing more than the common cold in healthy people. That changed with the advent of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in the past decade. The latest coronavirusâ2019-nCoV, since renamed by the World Health Organization as COVID-19âemerged in December 2019 in Wuhan, China. As of late February 2020, it had sickened tens of thousands and killed nearly 3000 people.

	Four of these large, enveloped, positive-strand RNA viruses are endemic globally and thought to cause 10–30% of upper respiratory tract infections in adults (1). They possess a surface spike (S) glycoprotein that binds to host cell receptors, and the nature of this protein is believed to determine the main properties of each coronavirus. SARS-CoV was the first coronavirus to jump from animals to humans; MERS-CoV and COVID-19 have as well.

	The genetic sequence for COVID-19 was released to public databases on Jan. 10, 2020 by the Shanghai Public Health Clinical Center & School of Public Health (1). The three-dimensional (3-D) structure of the spike protein suggests that it binds more tightly to human cell surface receptors than SARS-CoV, a possible reason that this coronavirus exhibits greater infectivity (2).

	Platform diagnostic methods have been rapidly adapted to include COVID-19 for early identification of cases. Several academic and industrial researchers have also focused on applying novel vaccine development and manufacturing platforms to the accelerated development of a COVID-19 vaccine.

	In terms of vaccine development and protection against dangerous viral pathogens, there is nothing particularly unique about coronaviruses, according to Eric von Hofe, chief scientific officer of NuGenerex Immuno-Oncology. “All of the recent potentially pandemic viruses, including SARS and MERS and two flu viruses (avian and swine flu), have the common feature that they simply had never been seen before by the human immune system. That said, we now know a lot about how the human immune system protects against viral infections and can rapidly identify the critical parts of a new virus to target for vaccine development,” he says.

	Traditional vaccines, like the seasonal flu vaccine, are made by growing up large quantities of the virus and in some way killing or inactivating it so that it can be used safely as a vaccine. This approach is an old technology from the middle of the past century, according to von Hofe. “The main problem here is the time it takes to produce the vaccine, which is at least a year and can be several. Ideally, we’d have a platform technology that could be used to produce a vaccine in a few months,” he observes.

	Such technology platforms should be flexible enough to respond to any new viral threat. “We would like to have a simple ‘plug-and-play’ setup where the critical components of a new virus required to make the vaccine can be determined by rapid computer analysis and plugged into the platform to generate a vaccine,” von Hofe notes. “Getting all of the critical components produced and structured in a way that perfectly models the vaccine is the big challenge,” he adds.

	The best way, von Hofe says, is to follow a reductionist strategy to identify key viral components that alone produce complete protection in a safe vaccine that can be manufactured rapidly and in a cost-effective manner. “Clearly this is a tall order, but we’re making good progress in that direction,” he asserts.

	As an example, he points to the development of subunit vaccines that rely on recombinant DNA to encode a critical subunit of the vaccine that generates a response. There are additional challenges to this approach, however. “While responses can be produced, the protection may be short-lived, as there is no guarantee that immunological memory will be generated as is possible with a whole virus vaccine,” von Hofe comments.

	San Diego-based Inovio Pharmaceuticals is one company developing a DNA-based vaccine against COVID-19. The biotech was the first to advance a vaccine (INO-4700) against MERS-CoV into human testing and is currently preparing to initiate a Phase II trial for INO-4700 in the Middle East. This vaccine, however, cannot be used against COVID-19 because the two coronaviruses are too different.

	To develop a new vaccine, Inovio first converts the virus’ RNA into DNA and identifies short sections that will, according to computer simulations, generate the greatest immune response. The plasmids are then produced in large quantities using bacteria. The overall development and approval timeline is thereby significantly reduced.

	Inovio began animal testing of INO-4800, its COVID-19 vaccine candidate, in February 2020 and is aiming to begin human safety testing in early summer 2020. The company will conduct tests in both the United States and China, the latter in collaboration with Beijing Advaccine Biotechnology Co. (3). Work in the US is supported by a $9-million grant from the Coalition for Epidemic Preparedness Innovations (CEPI). The collaboration with Beijing Advaccine is anticipated to accelerate developed on INO-4800 in China by providing access to not only its vaccine expertise, but also its relationship and experience with Chinese regulatory authorities and clinical trial management in the country.

	Two companies, both also supported by grants from CEPI, have developed platform technologies based on messenger RNA (mRNA). Cambridge, MA-based Moderna-which has developed numerous prophylactic mRNA vaccines with positive Phase I clinical readouts and also has a fully integrated clinical-material manufacturing site-is progressing its COVID-19 vaccine candidate (mRNA-1273) into the clinic (4,5). The Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), collaborated with Moderna to design the vaccine. NIAID will conduct investigational new drug-enabling studies and a Phase I clinical study in the US.

	Moderna’s mRNA vaccines can contain multiple mRNAs coding for different proteins and mimic natural infection, thus stimulating a more potent response, according to the company. Only the coding region of the mRNA must be changed for each new vaccine. The rapid discovery approach and the manufacturing agility of mRNA vaccine design and production also make it an effective platform technology.

	Just 42 days after sequence selection, Moderna shipped the first batch of mRNA-1273 to NIAID for use in a planned Phase I clinical study in the US. The mRNA vaccine encodes for a prefusion stabilized form of the COVID-19 S protein.
	
	German biotech CureVac also has an mRNA platform technology for vaccine development and manufacturing suited for rapid response to viral outbreaks, it says (6). Using an extensive in-house nucleotide sequence library, CureVac is able to identify optimum sequences for any given vaccine target and eliminate the need for chemical modification, shrinking the development timeline.

	The company has also developed specific carrier molecules for its mRNA products, including lipid nanoparticles (LNPs), developed in partnership with Acuitas Therapeutics and Arcturus Therapeutics). It is developing 

, a mobile, automated production unit for rapid supply of LNP-formulated mRNA vaccine candidates.

	A fourth group receiving funding from CEPI for application of a vaccine platform technology to accelerated development and manufacture of a COVID-19 vaccine is located at Australia’s University of Queensland (UQ) School of Chemistry and Molecular Biosciences (7). Its rapid response technology relies on molecular clamp technology, an approach developed by UQ researchers and patented by UniQuest.

	The molecular clamp technology is used to create subunit vaccines against class I and III enveloped viruses by stabilizing the pre-fusion form of viral fusion proteins, thus mimicking the protein conformation found on live virus and generating a strong immune response. A polypeptide is used to maintain the pre-fusion structure and prevent the protein from folding after entry into the cell.

	The platform technology, which does not require prior knowledge of a protein’s quaternary structure, therefore facilitates the expression of recombinant viral glycoproteins without loss of native antigenicity (8). It has previously been used to produce chimeric polypeptides that mimic the pre-fusion conformations of several enveloped viruses. The goal is to complete preclinical development within 16 weeks and then progress directly to Phase I clinical trials, with completion of that step in 10 weeks, followed by large-scale production of more than 200,000 doses in eight weeks.

	For its COVID-19 vaccine, the UQ researchers created a first candidate in the laboratory in just three weeks (9). This work confirmed that the engineered vaccine candidate is readily recognized by the immune system and triggers a protective immune response. Plans for preclinical testing were underway as of late February, and the researchers hope to begin clinical testing by mid-2020.

	NuGenerex Immuno-Oncology is focusing on what von Hofe refers to as the smallest and simplest fragments of the virus needed to produce an immune response. These short fragments of proteins are identified by a computer algorithm and can be made rapidly by entirely synthetic means. They are modified to ensure that they activate immune cells that are key in producing immunological memory. “While these virus fragments may not produce as complete a response as whole inactivated viruses, they basically produce a ‘memory’, so when a person treated with our vaccine does encounter the virus, he or she is more prepared to mount an effective response,” von Hofe explains. The technology is also a platform approach because it can be applied to virtually any virus that may emerge as a threat.

	While these smaller biotechs have generated attention for their accelerated development platforms, Big Pharma companies have also been actively working on COVID-19 vaccine candidates. Both Johnson & Johnson and Sanofi are collaborating with the US Department of Health & Human Services (HHS).

	Johnson & Johnson’s Janssen Pharmaceutical Companies unit is collaborating with the HHS’ Biomedical Advanced Research and Development Authority (BARDA) to rapidly advance the initial stages of Janssen’s COVID-19 vaccine development program, which is based on its AdVac and PER.C6 platform technologies (10). BARDA is funding accelerated development of a candidate into Phase I clinical trials, while Janssen is upscaling its manufacturing capacities.

	Sanofi Pasteur, the vaccines global business unit of Sanofi, is also collaborating with BARDA, using its established recombinant DNA technology platform to accelerate the development of a potential COVID-19 vaccine (11). This technology produces an exact genetic match to proteins found on the surface of the virus, which are then expressed using Sanofi’s insect (baculovirus) expression platform. The technology is used for Sanofi’s licensed recombinant influenza vaccine and a SARS vaccine that has been shown in non-clinical studies to be immunogenic and afford partial protection in animal challenge models.

	1. C. I. Paules, H. D. Marston, and A. S. Fauci, 

, online, doi:10.1001/jama.2020.0757 (Jan. 23, 2020).
	2. T. Hesman Saev, “To Tackle the New Coronavirus, Scientists Are Accelerating the Vaccine Process,” 

, Feb. 21, 2020.
	3. Inovio, “Inovio Collaborating with Beijing Advaccine To Advance INO-4800 Vaccine Against New Coronavirus in China,” Press Release, Jan. 30, 2020.
	4. Moderna, “Moderna Announces Funding Award from CEPI to Accelerate Development of Messenger RNA (mRNA) Vaccine Against Novel Coronavirus,” Press Release, January 23, 2020.
	5. Moderna, “Moderna Ships mRNA Vaccine Against Novel Coronavirus (mRNA-1273) for Phase 1 Study,” Press Release, Feb. 24, 2020.
	6. CureVac, “CureVac and CEPI extend their Cooperation to Develop a Vaccine against Coronavirus nCoV-2019,” Press Release, Jan. 31, 2020.
	7. University of Queensland, “Race to Develop Coronavirus Vaccine,” Press Release, Jan. 24, 2020.
	8. K. Chappell, D. Watterson, and P. Young, “Rapid Response Pipeline for Stabilized Subunit Vaccines,” Presentation at the Vaccine Technology VIII Conference (June 2018).
	9. University of Queensland, “Significant Step in COVID-19 Vaccine Quest,” Press Release, February 21, 2020.
	10. Johnson & Johnson, “Johnson & Johnson Announces Collaboration with US Department of Health & Human Services to Accelerate Development of a Potential Novel Coronavirus Vaccine,” Press Release, Feb. 11, 2020.
	11. Sanofi, “Sanofi Joins Forces with US Department of Health and Human Services to Advance a Novel Coronavirus Vaccine,” Press Release, Feb. 18, 2020.

Vol. 44, No. 4â¨
	April 2020
	Pages: 22–26

	When referring to this article, please cite it as C. Challener, “Can Vaccine Development Be Safely Accelerated?" 

Biopharma companies responding to the COVID-19 outbreak think accelerating the development of vaccines is safe.

Can Vaccine Development Be Safely Accelerated?

Fixed-dose combination (FDC) drugs offer a number of benefits to drug manufacturers, patients, and caregivers. These medicines contain two or more active ingredients in a defined composition or fixed ratio. The greater focus on patient centricity and improving patient medication adherence has led to a growing interest in FDC formulations.

	In the past five years, approximately 43 fixed-dose combinations were approved in the United States, according to Anil Kane, global head of scientific and technical affairs at Thermo Fisher Scientific. The majority were treatments for cardiovascular, metabolic disorder (including diabetes), and infectious diseases (including HIV). Most are solid, orally delivered drugs.

	FDC medicines, because they contain multiple APIs, provide advantages for patients and opportunities for manufacturers. From a patient perspective, according to Torkel Gren, senior director and science and technology officer at Recipharm AB, FDC products can be consumed quickly and easily because fewer tablets need to be taken. “By altering and controlling API release rates through the combination of multiple drug products into a single carrier, treatment is ultimately more efficient and straight-forward for patients,” he says. “To this end, FDCs have helped to improve patient compliance and by extension the overall treatment of diseases,” Gren adds. FDCs also have the potential to offer patients increased efficacy and synergistic effects that may enable the need for lower doses, according to Kane.

	For manufacturers, Gren notes that formulating FDCs has enabled the introduction of new products with improved properties and with significantly lower development costs. “Reformulating and combining drugs that have been proven to be safe and effective into FDCs represents an essential strategy for drug development companies to realize maximal commercial potential returns in a faster way than developing new molecular entities, which can be a lengthy, expensive, and high-risk endeavour,” agrees Kane.

	Lifecycle management, Kane observes, is in fact one of the major strategies used in the pharmaceutical industry in response to several significant trends, including patent expiry of major blockbuster drugs in the coming 5–10 years, stiffer competition in the market due to the presence of generic players, and a drought in the pharmaceutical R&D pipeline. Combination drugs also offer an opportunity for intellectual property and exclusivity.

	Developing an FDC formulation that offers these benefits and challenges can be difficult, however. Because many active ingredients are incompatible-meaning they are less stable in the presence of each other-selecting excipients and processes that reduce the degradation rate of the active ingredients and afford the optimal composition and process parameters increases in difficulty as the number of active ingredients increases, Gren notes. In fact, the main challenge to fixed-dose combination development usually involves product formulation and manufacturing strategy to address stability, dose differential, and analytical method development issues, according to Kane.

	The APIs in an FDC must be physically and chemically compatible with one another and all of the excipients used in the formulation and not generate any new impurities or raise any new drug-drug interactions. “The physicochemical properties and stability of each of the APIs in an FDC will define the formulation approaches to maintain stability during the shelf life of the combined drug product. As an example, the hygroscopicity of one active drug substance can influence the stability of the other drug in a combination product unless they are completely separated by way of multiple techniques,” explains Kane.

	Dosage size is another challenge experienced during pharmaceutical development, according to Gren. For example, if several high-dosage drugs are combined, the resulting target may be too large to be consumed by the patient. Differentials in individual drug doses are another issue. “The particle size distribution of a low-dose drug and the distribution of a second high-dose drug can impact the content uniformity of the former and the flow and processability of the latter in a single two-layer tablet,” Kane observes.

	From an analytical chemistry standpoint, it may be challenging to develop an analytical method that can quantitate all of the active ingredients and their degradation products, according to Gren. New analytical methodologies are often required to be developed for these innovative formulation strategies to accurately assess the product potency of multiple ingredients, as well as potential degradation products and their quality parameters, Kane agrees. “One alternative,” says Gren, “is to apply several analytical methods. However, the employment of multiple analytical methods will increase quality control costs and subsequently impact the cost of goods,” he notes.

	Finally, Kane observes that the packaging of a fixed-dose combination product may need to be re-considered based on the criticality of the multiple actives and their stability profiles in combination.

	The best way to overcome these challenges, Kane asserts, is for formulators to fully evaluate/understand the individual drugs that need to be combined in FDC products with respect the API characteristics, forced degradation and stability profiles, site of absorption and pharmacokinetics, potential for drug-drug interactions and chemical compatibility, and the individual doses required to have an optimal therapeutic effect. “A thorough pre-formulation assessment of the combination and generation of critical data is the key to a successful formulation development strategy,” he concludes.

	Clarity around the stability of the APIs to be formulated into an FDC product can be gained through retrieved literature data and experimental work, notes Gren. “Gathering information and knowledge around the specific patient population and other market conditions, combined with an understanding of stability issues, will allow for a clear development strategy to be outlined and implemented,” he states.

	Where the APIs in FDCs are known to be incompatible in the presence of each other, formulation in a single pill can be achieved using a number of different options. Kane identifies multilayer tablets, compression-coated tablets, multi-particulates in capsules, and combinations of coated and uncoated beads and pellets of one active placed with a powder of another active as common technologies.

	A suitable way to manage incompatibilities is by separating the different active ingredients with multilayer tablets or by including one of the drug substances in the coating and another at the core of the tablet, Gren notes. Formulation of different actives into separate pellets that can then be mixed into a capsule or tablet can make it easier to vary the doses of each API, he adds. For modified-release formulations, the pellets are typically coated.

	It is important to note, however, that although pellet technology has broad applications in oral FDCs, it is not a universal tool. “While some drug substances can be readily combined in a conventional tablet without any problems occurring, liquid or semi-solid formulations are often required for some indications and administration routes,” Gren comments.

	In general, therefore, the strategy for developing FDCs is entirely dependent on the individual active ingredients in the combination, their dose, stability profile, target release profile, sight of release, and other factors, Kane asserts.

	Looking to the future, 3D printing has recently been introduced as a manufacturing method for pharmaceutical products and may enable contract development and manufacturing organizations to effectively customize combination drugs for individual patients, according to Gren. He notes that it could also potentially facilitate the separation of different drug substances to reduce incompatibility issues.

	The first approval of a product manufactured using 3D printing (Aprecia Pharmaceuticals’ Spritam) was granted by FDA in 2015. “There are, however, several quality assurance and regulatory issues that need to be solved before this technology can be employed across the industry on a larger scale,” Gren says.


	Vol. 44, No. 3â¨
	March 2020
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, “Characterizing APIs is Essential for Combo Drug Formulations," 

Formulating fixed-dose combination drugs proves more complex than simply adding one ingredient to another. 