Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

	There is growing demand for “CDMOs” in both pharmaceutical product development and manufacturing. Several major trends are driving this growing demand-small and specialty companies with limited infrastructure are playing a bigger role in innovation and early stage product pipelines. Big and mid-sized Pharma continue to tighten their focus on core discovery and commercialization activities, and thereby align with external partners to advance their promising compounds. Patient-centric and more specialized medicines are driving the need for more complex formulation and processing capabilities. These trends translate into increased need for not only external partners, but those will capabilities that can help advance today’s drug development and manufacturing challenges.

	Outsourcing continues to be an important aspect of drug development and manufacturing. This year (2017) was marked by major acquisitions involving huge transactions in billions of dollars, such as 

acquisition of Patheon by Thermo Fischer Scientific

. A notable trend is the expansion of CDMOs to become full-service providers that offer end-to-end capabilities. While Big Pharma remains the least penetrated, with only 20% of their new drug applications (NDAs) being outsourced, most small companies are already outsourcing 80% of their activities, said Jim Miller, president of PharmSource, a GlobalData company, in his presentation at the 2017 CPhI Preconnect Congress (1).

	“Business models are changing,” says Christian Dowdeswell, senior director of commercial development at Lonza, who notes a change in client base in pharma. “Small specialty companies are increasing in numbers, and they need a development and manufacturing partner, especially given the increasing complexity of molecules with solubility and bioavailability challenges as well as APIs that are highly potent. These molecules require specialized formulations, but drug development needs to be phase appropriate.”

	“It is crucial to start with understanding the molecule and what the target profile is,” explains Jim Coward, global head, market development, Bio/Pharmaceuticals, Lonza. “Designing appropriate feasibility studies requires depth in technology in order to develop a formulation that is fit for purpose.” Time to market is a crucial factor, but Coward points out that speed is not just about getting it fast. “The goal is to achieve optimal design, so that you reduce the need for rework,” he says. 

	Coward observes that the oral solid-dosage form market continues to grow, specifically, the multiparticulates because they offer flexibility for the different populations, such as paediatrics and geriatrics. “There is a demand for more patient-centric formulations, and multiparticulates are advantageous as they can be developed into fixed-dose combinations, or designed to have controlled-release profiles. You can also do drug layering or taste masking,” he adds. Coward notes that existing molecules are also being reformulated for new indications and to offer convenience. “Repositioning existing molecules using the FDA NDA 505(b)2 pathway or equilavent in Europe makes up approximately 40% of approvals,” he says.

	According to Miller, the contract manufacturing space continues to see strong performance in 2017, with APIs leading the way, driven by the high-value products and broad outsourcing activities (1). For Saneca Pharma, business is growing in the opiate division, says Anthony Sheehan, chief executive officer of the Slovakia-based CDMO. Saneca currently manufactures 15 opiate API products under cGMP. “We are looking to launch new drug master files (DMFs) and certificates of suitability (CEPs) in the near future,” Sheehan told 

	Saneca is also moving into custom synthesis of APIs, driven by the growth in the company’s API business. “API manufacturing is moving back to Europe from Asia,” Sheehan observes. “Eastern Europe, in particular, is a growing market.” He adds that Saneca is also expanding its finished dosage forms development services, starting with non-sterile liquids. “What we notice is that customers want regulatory support and support with tech transfer,” says Sheehan. “Tech transfer can be a challenge, especially with old products, which in some cases, may have to be reformulated, or perhaps the process has to be optimized.”

		J. Miller, “Contract Manufacturing Outlook,” presentation at CPhI Preconnect Congress (Frankfurt, Germany, October 2017). 

Articles

Pharma trends translate into increased need for not only external partners, but those will capabilities that can help advance today’s drug development and manufacturing challenges.

Small and Specialty Companies Shape Pharma’s Evolving Outsourcing Landscape

	The advantages of orally disintegrating tablets (ODTs) as a patient-centric dosage form are well recognized. “Because of their convenience and ease of administration, ODTs are ideal for pediatric, geriatric, and psychiatric patients,” says Ralph Gosden, head of product development at Catalent’s Swindon, United Kingdom site. “They dissolve in the mouth without water, thereby addressing the problem of difficulty in swallowing. It has been reported that 25–45% of children have swallowing difficulties and 30–40% of elderly institutionalized patients suffer from dysphagia.” He adds that ODT formulations reduce the overall cost of care, citing a study that showed children receiving orally disintegrating ondansetron tablets for the treatment of gastroenteritis had less vomiting, increased oral hydration, and reduced need for intravenous hydration (1). ODTs demonstrated economic value through cost savings from reduced length of hospital stay. The authors of the study noted that the ODT was easy to administer, had few side effects, and was safe and effective, making it a useful therapy in the emergency department for children with vomiting and mild-to-moderate dehydration as a result of gastroenteritis (1). 

	According to Gosden, speed is an important parameter with ODTs. “The requirements for an ODT is to have fast dispersion rates,” he explains. “Rapid dissolution enables effective buccal and sublingual delivery, which may enable pre-gastric absorption, rapid onset of action, and reduced side effects by avoidance of food effects and first pass metabolism.” He adds that other desired critical quality attributes of ODTs include appearance, palatability, potency, physical/chemical stability, and physical strength to withstand packaging, shipping, and patient handling. 

	Gosden, however, notes that drawbacks of ODTs include the requirements for taste masking and the drug loading capacity. Catalent’s Zydis Ultra technology was developed to address those limitations, he says. Zydis Ultra is the same basic formulation as Catalent’s Zydis ODT, which is a lyophilized oral solid-dosage form that dissolves in the mouth in less than three seconds. A lyophilization process is used to make the ODT. The API is formulated into a solution or suspension, which is then filled into blisters and passed through a specially designed cryogenic freezing process to control the size of the ice crystals and subsequent pore formation during freeze drying. After the drying step, the blisters are sealed to protect the product. 

	Gosden explains that Zydis Ultra includes a dry coating process for taste masking. “Micronized polymer agglomerates, through the action of acoustic vibration and particle–particle interaction, are used to coat the host API. Particle collisions deform the deposited polymer to create a continuous coating layer,” he says. “No solvent is involved in this process; it is a completely dry process. It has the ability to coat small particles of approximately 100 µm and the potential for much higher API potency in the coated material.” 

	Zydis Bio offers opportunities for the sublingual or buccal delivery of biologics, such as peptides, proteins, allergens, and vaccines in an ODT formulation, Gosden highlights. He adds that there are no extreme pH exposure or proteases in the oral cavity and this route avoids the harsh environment of the gastrointestinal tract. “For vaccines, Zydis Bio offers the potential to eliminate cold-chain storage. Zydis vaccines are suitable for mass immunization programs and emergency response,” says Gosden. For stability, he explains, Zydis Bio uses a lyophilization process with low processing temperatures, and there are formulation options to optimize in-process stability such as through matrix component selection or pH adjustment. He adds that the dried product has low water activity to ensure long-term stability. Acceptable room temperature storage has been demonstrated for multiple peptide and protein compounds, according to Gosden. 

	Catalent’s Zydis Bio technology enabled Danish pharmaceutical company ALK-Abelló A/S to successfully launch Grazax as a patient-friendly allergen immunotherapy for the treatment of grass pollen-induced allergic rhinitis (2). Grazax is a registered trademark of ALK-Abelló A/S. Patients previously had to make monthly visits to the clinic for their subcutaneous injections. The convenience of being able to administer a daily sublingual dose of the medication at home improved patient experience and increased patient adherence. 

Case Study-Zydis Bio Technology, Grazax & Grastek: Revolutionizing Allergy Therapy,


	Vol. 41, No. 11
	November 2017
	Page: 18

	When referring to this article, please cite it as A. Siew, “ODTs Dissolve Drug Administration Challenges," 

Ralph Gosden, head of product development at Catalent’s Swindon, United Kingdom site, explains the opportunities of orally disintegrating tablets as a patient-centric dosage form. 


ODTs Dissolve Drug Administration Challenges

	Oral drug delivery continues to be the preferred route of administration because of its convenience and patient acceptance. The vast majority of marketed products today are tablets, observes Gretchen Bedford, global market research analyst at Colorcon. “As medicine advances, so do specialized solid-dosage forms with drug combinations and layered, extended- and immediate-release tablets, as well as enteric-coated tablets and capsules,” she says. 

	Charlotte Miller, film coatings manager, Colorcon EMEA, notes that the number and variety of medicines available are increasing. “Patients are now taking multiple medications and living longer,” she says. “Administering medicines may be carried out by several healthcare professionals, and communication failures can lead to mistakes.” Miller points out that medication errors are reported to harm 1.5 million people every year, some of which result in sickness, injury, and death (1). “It is estimated that between 2–14% of patients are admitted to hospitals due to medication errors, and approximately 1–2% of those patients are harmed as a result (2),” she continues, adding that these numbers are alarming considering that most, if not all medication errors could be prevented. “Further, these statistics only include those medication errors that have actually been reported,” she says, but highlights that awareness and better reporting have resulted in the increased number of recorded medication errors. “Many of the regulatory authorities have issued guidance or directives (3, 4) to ensure that any errors, no matter how small, are captured, as well as to ensure learnings are made to prevent reoccurrence of incidents.”

	Miller notes that FDA and EMA have published guidance for industry to minimize the risk of medication errors (5, 6). “These guidances aim to address the design of drug products to promote the safe and correct use and minimize or eliminate hazards contributing to medication errors at the product design stage,” she says. “The FDA guidance conveys the current thinking about how a safety-by-design approach to new product development can be an effective tool in reducing the unintentional medication errors that result in 44,000–98,000 deaths in the United States each year (7). Recommendations include, but are not limited to, the adequate distinction between immediate-release and extended-release or delayed-release products, differentiation between multiple dosage strengths, and inclusion of clear, legible imprints to help identification. The size, coating, and palatability of the tablets should also be considered to ensure tablets are easy to swallow, safeguarding patient compliance.”

	According to Miller, manufacturers have a duty to ensure the medicines they develop are well differentiated, especially between dosages of the same product. “Medication is more easily identified if it has a distinctive appearance, and single or multiple visual indications are a defense against swallowing the wrong tablet,” she says. “For many, not just the elderly and their caregivers, color alone can serve as that great safety net, an easy way to help reduce potential errors. For those who take multiple medications, the drugs can be safely commingled in a pill-sorting container where patients or caregivers rely on color or other visual clues. Familiar colors, shape, and size also help patients remember proper dosing.” 

	Miller adds that differentiating tablets does not have to be costly, but it does require the right resources at the right time. “Colorcon’s unique tablet design service, BEST, enables pharmaceutical companies to explore options and evaluate tablet shapes and sizes for ease of swallowing, as well as color for differentiation,” she says. “Risk assessment studies using the proposed tablet(s) to simulate in-use testing can also be conducted with patients, pharmacists, and caregivers to identify any difficulties in identification of the product.”

	1. The National Academies of Science, Engineering, and Medicine, “Medication Errors Injure 1.5 Million People and Cost Billions of Dollars Annually,” Press Release, July 20, 2006.
	2. L.L. Leape, 

Journal of the American Medical Association (JAMA)

, 272 (23) 1851–1857 (1994).
	3. MHRA, Stage Three: Directive-Improving Medication Error Incident Reporting and Learning (March 2014).
	4. EMA, 

Streamlining EMA Public Communication on Medication Errors

Guidance for Industry: Safety Considerations for Product Design to Minimize Medication Errors

Good Practice Guide on Risk Minimization and Prevention of Medication Errors

 (November 2015).
	7. L.T. Kohn, J.M. Corrigan, M.S. Donaldson, eds. 

To Err Is Human: Building a Safer Health System

 Institute of Medicine, National Academies Press, Washington DC, 2000, accessed Oct. 4, 2017.


	Vol. 41, No. 11
	November 2017
	Page: 20

	When referring to this article, please cite it as A. Siew, “Reducing Medication Errors," 

Experts from Colorcon share insights on how manufacturers can play a role in minimizing the risk of medication errors by ensuring that the medicines they develop are well differentiated, especially between dosages of the same product.


Reducing Medication Errors

Pharmaceutical companies today face higher hurdles than ever before in getting products to market. The patient, as the end-user, is now a force to be reckoned with as governments, payers, and healthcare providers around the world place increasing emphasis on patient outcomes. With this new emphasis on patient centricity, the pharmaceutical industry has been quick to realize the importance of embracing the patient.

	“The industry continues to move toward a system where the value of care determines a drug’s market success, as can be seen with outcomes-based management programs targeting drugs for cancer, obesity, and pulmonary diseases,” observes Elizabeth Hickman, director of sales and marketing, Catalent Pharmatek. “Improving patient outcomes and patient experience is a growing trend,” she says. “And companies are looking at ways to achieve this through better drug design-such as bioavailability enhancement to improve therapeutic effect at lower doses, making drugs last longer with extended-release profiles to reduce dosing frequency, delivering drugs through less invasive methods, simplifying complex regimens with combination drugs, and customized dosage forms for specific patient populations and/or indications.” 

	Hickman cites a study by MarketWatch, which showed that patient noncompliance costs the pharmaceutical industry approximately $330 billion annually (1). Noncompliance could be due to dose burden, size and quantity of dosage, or patient acceptance, she notes and highlights that aging and pediatric populations often present unique challenges to achieving compliance. “Dosage forms that improve swallowability, palatability, and dosing convenience, as well as reduce the pill burden can lead to better compliance, experiences, and outcomes for aging and pediatric populations,” Hickman explains. “These factors can also support better product differentiation, which can lead to improved product lifecycles and sales.” 

	Patient-centric drug development considers the end-user from the start of the formulation process through to the selection and design of the dosage form and finished product. The evolving regulatory reforms in Europe and the United States (2–6) reflect the increasing drive toward patient-centric formulation development to ensure that drug products adequately meet the needs of end-users in all target patient populations. Developing a dosage form for geriatrics or pediatrics requires special considerations. In the elderly, factors such as age, morbidity, co-morbidity, multiple drug use, and reduced organ function have an effect on pharmacokinetics. The pediatric population, on the other hand, experience rapid and continual growth, development, and maturation; as a result, there are distinct physiological differences between neonates, infants, children, and adolescents. The most significant compliance challenge in older adults is polypharmacy and the pill burden, whereas for children, taste is often the biggest barrier. 

“The pharmaceutical industry acknowledges the special requirements for geriatric patients,” says Ravinder Kodipyaka, senior director and head of formulation R&D, Dr. Reddy’s Custom Pharmaceutical Services. However, he notes that product design and development for the elderly is complex because of the interplay of various factors. Geriatric patients often have concomitant conditions and according to Kodipyaka, pill cocktails for their multiple diseases have very limited clinical data available. “For those with cognitive problems, remembering multiple doses, multiple drugs, and their administration schedules can be a challenge. In addition, the reduced physical strength of the patient affects his/her ability to open packs, break tablets along the break-mark, or swallow tablets,” he adds. 

	Although there are programs and companies focusing on addressing the needs of older patients, Kodipyaka believes that there is scope to do much more. “We find that most of the drugs for chronic indications and/or that have age-related prescription potential are being developed as single-dose packs, push-pull packaging designs, and fixed-dose combination (FDC) products. Target population is a key factor that needs consideration in a product development program. A holistic approach considering patient age, drug indication, and duration of therapy among others, needs to be adopted for systematic geriatric product development,” he says. 

Kodipyaka acknowledges that in terms of work that is done and being done for special populations, the pediatric population is one of the most progressive ones. “The pharmaceutical industry has actually developed and commercialized suitable products for children; for example, orodispersible dosage forms, orally disintegrating tablets, solutions, suspensions, powder for suspension, and drops for anti-retroviral, anti-tuberculosis, and anti-malarial products,” he says. An important driving force, he notes, has been the focus and support of regulatory bodies, non-governmental organizations (NGO), and global agencies such as the World Health Organization (WHO), which have gathered huge data points on what is required for pediatric patients. Despite these efforts, there are still unmet needs, according to Kodipyaka, “particularly with challenges of taste masking; the risk of suboptimal dosing due to spitting/vomiting by children; high dose drugs, where administering large volumes of liquid medications has practical challenges for the child and the drug administrator; and dosing accuracy with liquids.” The measuring cups or spoons routinely used with liquids may have residual volumes and most administrators either add overfills or the dose is administered less, he explains. Kodipyaka sees ample opportunities to develop more patient-centric, innovative drug-delivery systems and packaging systems that could address the specific needs of children. 

	Controlled-release formulations to reduce dosing frequency

	The shift to personalized medicine and an increasing focus on geriatric and pediatric applications is creating a demand for specialized dosage forms, observes Paul Spencer, head of the Oral Excipients Business at Evonik Health Care. “Controlled-release formulations, including once-daily applications, can improve patient adherence and enhance therapeutic success,” he says. “In an aging society, where there is an increasing number of people with multiple morbidities, who need to administer several drug products every day, controlled-release formulations offer significant advantages. They provide constant plasma levels over a desired timeframe, optimized bioavailability, minimized side effects, and reduced dosing frequency. Such factors help to increase patient quality of life and improve compliance. There are multiple chronic conditions where controlled-release formulations are being used, for example, cardiovascular diseases, diabetes, and diseases of the central nervous system, such as Alzheimer’s.” 

	Fixed-dose combination to reduce pill burden

	With polypharmacy and compliance being a huge problem, especially in the geriatric patient population, Anil Kane, global head of Technical and Scientific Affairs at Patheon, part of Thermo Fisher Scientific, points out that FDCs offer the possibility of combining several drug candidates into a single pill. “FDCs could benefit patients from the potential increase in efficacy, synergistic effect, and a potentially lower dose, leading to higher convenience in administration and compliance,” he says. 

	Kane explains that several drugs in the same category of therapeutic effectiveness have been combined for synergistic effects. “Specific examples include elvitegravir, emtricitabine, tenofovir disoproxil fumarate, cobicistat (Stribild, Gilead) for the treatment of HIV/AIDS; metformin combinations with glipizide, glimepiride, pioglitazone, rosiglitazone, and many other gliptins for diabetes; and amlodipine, valsartan, and hydrochlorothiazide (Exforge HCT, Novartis) for hypertension,” he says. Citing an article (7) that listed the top 10 drugs that registered the maximum growth in global sales over 2015, Kane observes that interestingly, three of the 10 drugs are FDCs as highlighted in the following:

		Epclusa (sofosbuvir and velpatasvir), a new launch by Gilead, brought in $1752 million in sales in 2016. Approved by FDA in June 2016, the FDC was Gilead’s third sofosbuvir-based regimen, but it marked the first and only all-oral, pan-genotypic single tablet regimen for chronic Hepatitis C virus infection. 

		Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) by Gilead recorded sales of $1484 million in 2016, compared with $45 million sales in 2015. The FDC demonstrated a better safety profile when tenofovir alafenamide was added to the combination. Genvoya has been the most successful HIV treatment launch since the introduction of the first single-tablet regimen, Atripla.

		Triumeq (abacavir, dolutegravir, and lamivudine) by GlaxoSmithKline had sales of $2151 million in 2016 versus $905 million in 2015. Triumeq was the company’s first once-daily, single-pill FDC tablet combining dolutegravir, an integrase inhibitor, with the nucleoside reverse transcriptase inhibitors abacavir and lamivudine.

	From a development and manufacturing perspective, Kane says that various types of drugs have been successfully combined into a single unit of a solid oral dosage form, including low- and high-potency drugs; low- and high-dose drugs, and immediate- and controlled-release profiles for individual drugs based on the site of absorption and efficacy. “Based on the chemical and physical stability of each active drug in the FDC, the dosage form can be developed as a simple monolithic tablet or a blend of actives with some excipients in a capsule,” he explains. “With molecules having stability challenges, we could develop dosage forms such as bilayer, tri-layer, tablet-in-tablet, or multi-particulates of each active in a bead/pellet form and filled into capsules. The techniques and technology have developed enough to achieve a good shelf life for a combination pill in one of these dosage form options.”

	Palatability and taste are crucial parameters for oral dosage forms because they have a significant impact on patient compliance, especially for the pediatric population. Several approaches have been used to mask the taste of bitter APIs, such as the addition of flavors and sweeteners, modification of the API to minimize its solubility in the oral cavity, complexation with cyclodextrins, or the application of a coating to form a barrier between the drug and palate.

	User-friendly dosage forms to improve patient experience and adherence

	User-friendly dosage forms are increasingly popular with patients and consumers and are becoming more widely available on the market. “User-friendly dosage forms are orally administered formulations that are designed to make taking medication as convenient and trouble-free as possible for end-users,” explains Martin Koeberle, head of Analytical Development and Stability Testing at Hermes Pharma. “These formulations, which include instant drinks, effervescent tablets, orally disintegrating tablets/granules (ODTs/ODGs), chewable tablets, and lozenges, overcome many of the difficulties commonly experienced with conventional tablets and capsules. As well as being easy to swallow, they can be formulated to offer a more pleasant taste and mouthfeel than traditional solid oral dosage forms. Some forms can be taken without any liquid, enabling consumers to conveniently integrate them into their daily routines.”

	Koeberle notes that traditional oral dosage forms such as tablets and capsules pose a significant challenge for large number of people. A consumer survey, conducted in the US and Germany by Hermes Pharma and the Spiegel Institut Mannheim, found that more than half of the respondents from all age groups and genders experienced difficulties swallowing tablets and capsules (8). Various reasons were cited, but the most frequent were related to the pill being too large to swallow, becoming stuck in the throat, or having an unpleasant taste or odor. “As a result of these swallowing issues, some individuals reported not taking their medicine as intended (such as by crushing tablets or dissolving them in water), or worse still, not taking them at all,” Koeberle says. “For patients with chronic diseases or the elderly, who may need to take multiple medicines daily, this poses a significant problem.” He adds that because user-friendly dosage forms simplify administration and are more convenient to take, they can significantly improve patient compliance and treatment efficacy, as well as improve quality of life.

	According to Koeberle, Hermes Pharma has developed a range of user-friendly combined calcium and vitamin D3 products for several international pharmaceutical companies. “These products are designed for osteoporosis patients, with doses ranging from 500 mg to 1200 mg calcium and 200 IU to 2000 IU vitamin D3. Our own versions are sold under the Calcimed brand, and include effervescent and chewable tablets as well as ODGs,” he says. “Many aspirin products are available on the market as effervescent and chewable tablets, instant drinks, and ODG formulations. With these user-friendly formulations, aspirin is often combined with other active ingredients such as phenylephrine, caffeine, and paracetamol.” Koeberle also highlights that in Germany, the most widely used formulation for mucolytic cough remedies containing acetylcysteine are effervescent tablets. “This user-friendly dosage form is more popular than other formulations, including syrups and conventional film-coated tablets,” he says. 

	Kodipyaka sees a growing focus on patient-centric product developments. “In addition to safety and efficacy, patient compliance, convenience, and cost effectiveness are recognized as important elements for the commercial success of a drug product,” he says. Previous misconceptions that a business model focused on putting the patient first will not generate sufficient profits to satisfy shareholders are now being reconsidered; most pharmaceutical executives are beginning to see that patient centricity holds the key to sustainable profitability.

		E. O’Brien, “The Cost of Not Taking Meds as Prescribed: $330 Billion,” MarketWatch, Sept. 17, 2017. 	

		EMA, “EMA Encourages Tailored Development of Medicines for Older People,” Press Release, Aug. 1, 2017. 	

Studies in Support of Special Populations: Geriatrics E7 

Guidance for Industry: E7 Studies in Support of Special Populations: Geriatrics-Questions and Answers 

Chemical Entities Shine in the Top 10 Fastest-Growing Drugs of 2016

Market Study Summary-A Hard Truth to Swallow


	Vol. 41, No. 11
	November 2017
	Page: 16–23

	When referring to this article, please cite it as A. Siew, “Patient Centricity Takes Center Stage,” 

Pharmaceutical companies are increasingly adopting patient-centric formulation development to ensure that drug products adequately meet the needs of end-users in all target patient populations.


Patient Centricity Takes Center Stage

	The pharmaceutical industry is under tremendous pressure to make drug development faster and cheaper. “There is a need for better treatments that show real-world efficacy, but the price has to be acceptable to payers and at the same time offer good returns to the developing company,” says Will Downie, Catalent’s senior vice-president of Global Sales & Marketing. “However, R&D budgets are tight and failures are costly.” He further points out that the majority of molecules in the pipeline are increasingly complex, thus presenting development challenges. 

	“There are a number of pitfalls in drug development that can stall, stop, or require you to rework your program,” observes Julien Meissonnier, vice-president of Science & Technology at Catalent. “More than 40% of new chemical entities in late-stage discovery are insoluble in water (1). Only one in 10 new molecules in active clinical development are readily bioavailable (2). The rate of attrition is high, with many drugs failing between first toxicity study and Phase I, and the likelihood of approval for Phase I candidates is 9.6% (3),” he says, highlighting the need for early formulation and dose form design. Downie explains that applying the right formulation strategy using structured and rigorous science can help avoid costly failures and re-starts, but it’s important to start from an early stage. The key, according to Meissonnier, is to select an appropriate formulation technology and dose form based on the needs of the molecule in development. 

	Stephen Tindal, director of Science & Technology & Technical Support for Catalent’s OptiForm Solution Suite, US, notes that the transition from high throughput screening (HTS) to traditional formulation development requires a significant amount of expertise. “Early on, it is useful to be able to screen thousands of samples at very small scale, to narrow down the sample set to the best few. Whether that can be done effectively will of course depend on the API sample set in question, on the validity/variability of the analytical method, and the screening criteria that are applied, and the ability to manage the amount of data generated,” he says. “Done well, HTS can deliver a small set of ‘most viable’ samples for further evaluation using laboratory techniques at a higher scale, with better validity and less variability. Optimistically, it may even be possible to develop software that performs 

 predictions to reduce the laboratory work further.”

	Tindal observes that the screening criteria can vary from company to company. “At Catalent, during a first meeting with a customer, we see very few molecules for which sufficient data has been collected to make an informed decision on which formulation development technology to use,” he says. “Most companies pursue simpler formulation options, which are often appropriate only for drugs with good solubility. This is inconsistent given what we know about the prevalence of poorly soluble molecules in development pipelines.” According to Tindal, Catalent’s OptiForm Solution Suite platform helps address this issue. “We evaluate the API’s challenges and consider the technologies that are needed for improving the API profile. We consider salt form, conventional technologies (e.g., powder in capsule), and enabling technologies such as amorphous dispersion, lipid-based formulation, and micronization in parallel, depending on solubility and other data. This saves time and money, and gives a higher chance of success for the estimated 90% of drugs in development where solubility is a problem,” he says. 

	In July 2017, Catalent announced the expansion of its OptiForm Solution Suite platform to include support at an earlier stage of drug development. The expanded service includes 

 and formulation screening tools to select the most viable candidate; molecule characterization to identify development challenges, parallel screening to determine the feasibility of multiple bioavailability-enhancing technologies; formulation development for good laboratory practice (GLP) toxicity studies; and a dosage form strategy and cGMP materials for Phase I studies (4). 

	“To optimize early-stage development of oral doses, it is necessary to select the best few viable candidate API forms that have been identified during early R&D,” explains Ronak Savla, scientific affairs manager at Catalent. “A comparison of the APIs’ properties needs to be undertaken, and those with poor chemistry eliminated, before looking to achieve a reasonable level of oral bioavailability in animals to study drug metabolism and pharmacokinetic (DMPK) properties,” he says. “Where a drug is poorly soluble, there are opportunities to enhance its solubility. It is also necessary to characterize available polymorphic forms to select the most stable form. At this stage, doses are formulated as liquids rather than finished dose units.” 

	Savla observes that early API characterization and solid-state optimization is typically undertaken by an API supplier and/or preformulation services supplier, and then transitioned to a contract development and manufacturing organization for formulation development activities. “But animal dosing of poorly soluble APIs poses unique challenges requiring a fast, flexible, and cost-effective service, so it’s our belief that companies with broad capabilities are better placed to do this work,” he says.

	Reliance on formulation to solve suboptimal pharmacokinetics of Development Classification System (DCS) Class IIb lead compounds-where the main challenge is the solubility of molecules-has been shown to increase timelines by approximately two years (5). “Instead of pursuing a powder-in-capsule formulation for Phase I, screening for other potential options that maximize a molecule’s bioavailability and solubility profile should be investigated if delays in later development are to be avoided,” Tindal explains. 

	Catalent’s OptiForm Solution Suite platform was used to assist in the formulation of a drug candidate developed by a London-based pharmaceutical company, Trio Medicines. “The compound, TML-001, had undergone initial clinical trials that indicated poor bioavailability,” Tindal says. “An acetylated prodrug was developed, and screening showed that it falls into the Biopharmaceutics Classification System (BCS) class IIa category, where the molecule’s dissolution rate was more of a problem than its solubility. Further tests suggested issues with permeability.” 

	Catalent presented Trio with four alternative candidate formulations: a micronized form, a lipid-based formulation, and two amorphous dispersions created by hot-melt extrusion. “The most promising was the micronized API, which was simple to manufacture and showed good chemical and physical stability,” says Tindal. “The amorphous dispersions were ranked as the riskiest because they showed greater degradation, possibly as a result of thermal action during processing. In addition to being relatively difficult to process, a crossover study in healthy humans showed that the solid dispersions offered no improvement over the original formulation, and were, therefore, dismissed. In contrast, the other formulations demonstrated enhanced performance, marking a good starting point for further trials, which could be further adjusted to offer improvements to bioavailability later in development.”

	“Catalent’s OptiForm Solution Suite has been designed to help drug developers start early and start smart. It provides a fast and efficient path from candidate selection to Phase I by selecting the right candidate, presented in the right API form, delivered in the right formulation and right dosage form,” Meissonnier sums up. 

	1. K.T. Savjani, A.K. Gajjar, and J.K. Savjani, 

, online doi: 10.5402/2012/195727, Jul. 5, 2012. 

www.ncbi.nlm.nih.gov/pmc/articles/PMC3399483/

 16 (3) 10–16 (2013).
	3. D. Thomas, “Clinical Development Success Rates 2006–2015,” presentation at BIO International Convention (San Francisco, CA June 2016).
	4. “Catalent Launches New OptiForm Solution Suite,” Press Release, July 17, 2017.  
	5. M.M. Hann and G.M. Keseru, 


	When referring to this article, please cite it as A. Siew, “Starting Early is Key to De-Risking Drug Development,” sidebar to “Formulation Strategies in Early-Stage Drug Development," 

The pharmaceutical industry is under tremendous pressure to make drug development faster and cheaper. Applying the right formulation strategy using structured and rigorous science can help avoid costly failures and re-starts, but it’s important to start from an early stage.

Starting Early is Key to De-Risking Drug Development

Improving R&D productivity continues to be a key challenge for the pharmaceutical industry. There is increasing pressure to speed up drug development and make it more cost-effective. Companies want to ensure that their most promising drug candidates eventually hit the market. But while speed to market is a crucial element, applying a structured approach starting at an early stage can help de-risk the drug development process and avoid costly late-stage failures. 

 During the early stages of a drug development program, time is of the essence, notes Torkel Gren, general manager at Recipharm Pharmaceutical Development. Establishing proof of efficacy and safety is the top priority, and formulation development is often left to later stages. Gren finds it strange that such an important activity as formulation development is often overlooked and started too late. “But I see it all the time,” he says. “Of course, there is no point starting formulation development before we have selected the drug candidate. The API has to be manufactured in sufficient quantities before formulation development can begin. However, to a certain extent, you can start formulation development with small quantities of non-GMP material. This approach is, no doubt, risky because solid-state properties of different batches can vary considerably at this stage. Nevertheless, especially with simpler formulations, useful information can often be collected from work with early batches.” 

	The rate of attrition is high during clinical trials with only 10% of new drug candidates making it to market, according to Rob Harris, chief technical officer at Juniper Pharma Services. “Therefore, there is a natural reluctance within the industry to invest in the development of a robust dosage form until there is some confidence in the safety and efficacy of the drug.”   

 Anil Kane, executive director and global head of Technical and Scientific Affairs at Patheon, observes that once a molecule has been selected as a potential candidate, all efforts tend to focus on proving that the drug substance gets absorbed in an animal species before a first-in-human Phase I study. “Typically, a formulation is prepared by simply suspending the drug in a hydroxypropyl methylcellulose suspension, with or without a surfactant, which is then dosed to an animal so that an absorption profile can be established,” he says. “In a similar manner, the first dose format prepared for a quick Phase I study is usually a neat API in a capsule.” 

	Kane cautions that while these methodologies or procedures are simple and fast, hence, allowing pharmacokinetic assessments and safety studies to be performed, the results obtained are not always promising. “In many instances, it’s found that the drug was not properly suspended, due to hydrophobicity and poor wettability. In Phase I clinical programs, the results can show that the API was not absorbed sufficiently to obtain the desired plasma levels and there was not enough exposure,” he says. Gaining speed by deferring formulation development to a later stage has, in many instances, not met the goals of early development, Kane observes. 

	Aaron Goodwin, principal investigator, Internal Research and Development, Capsugel, now a Lonza company, shares a similar view. He agrees that preclinical formulation development is generally focused on achieving a desired pharmacokinetic response in a translatable animal model while minimizing formulation development time and cost. Goodwin, nonetheless, points out that this can be challenging for molecules with poor bioavailability or a narrow therapeutic window given that 

 relationships are often not straightforward and, therefore, require additional time and cost to establish. “It’s tough to justify the additional cost and timing given the low probability of success for a preclinical API especially for a new mechanism of action,” he says. “However, if not addressed adequately, the drug product can be at risk of reformulation or even fail to demonstrate clinical efficacy in late stage when the stakes are much higher.”

	Giving an example, Goodwin explains that adequate exposure at an initial dose may be achievable in preclinical studies with a crystalline or perhaps a micronized suspension; and progressing a simple, conventional formulation may be the quickest way to the clinic. “But if the compound properties suggest that oral absorption may be solubility limited at high doses, and this is supported by preclinical 

 data, advancing a simple, conventional formulation may risk not reaching a maximally effective exposure,” he says. “Advancing an amorphous form might take a bit longer to get to the clinic, but even if not optimized, it would likely circumvent this risk as well as reduce exposure variability.”

	Kane emphasizes that formulation development, based on a systematic drug substance characterization and material properties, is required to avoid such failures or loss of time, investment, and opportunity in early development. 

 One of the main challenges in developing formulations for new drugs is the poor solubility of many of the compounds emerging from drug discovery, notes Harris. He estimates that 80% of new drug candidates are classified as poorly soluble, and points out that oral bioavailability will be compromised if the drug is not completely dissolved in the gastrointestinal tract. 

	Karl Werner, senior director, Finished Product Development, Midas Pharma, concurs that the number of Biopharmaceutics Classification System class II and IV compounds has increased tremendously. “There are challenges when trying to formulate these drugs into an oral dosage form,” he says. “Poor solubility or bioavailability will result in incomplete or variable absorption, higher impact of pH and food on drug absorption, and poorly controlled pharmacokinetics.” In such cases, it is extremely important to develop a formulation that maximizes the chance of good exposure even if doing so requires additional time and cost, Gren stresses. But he also points out that in some situations, it is worth asking if formulation development is really the right solution to a solubility/bioavailability problem or if modifying the molecule may be a better way to develop a successful drug product.  

	For weakly acidic or basic drugs, salt formation is often the preferred method for improving solubility because it is simple and effective. Other methods that have been widely used to address solubility issues in early development include particle size reduction by micronization or nanomilling to increase the dissolution rate, the use of surfactants or cosolvents, and complexation with cyclodextrins. But with the solubility of new molecules becoming more demanding, Harris notes that the application of more advanced solubilization technologies, such as lipid-based and self-emulsifying drug-delivery systems and amorphous solid dispersions, in early development is becoming more prominent. 

 “Formulation strategies in early-stage drug development entirely depend on the complexity of the molecule and its critical nature and behavior,” says Kane, noting that some molecules may exhibit polymorphism, for example. “It is, therefore, important to understand the different polymorphic forms, their stability and properties, and potential to convert from one form to another,” he explains. “The formulation strategy would then be based on preventing the conversion of the selected polymorph and ensuring its stability throughout the clinical stability or shelf life of the product.” 

 Uncertainty over the dose range to be administered is another complication during early development, according to Harris. “A formulation strategy suitable for a 5–50 mg dose range is unlikely to be appropriate for a 100–1000 mg dose range and vice versa,” he says. “However, there are modeling software tools, such as GastroPlus, which can be used to predict an appropriate human dose based on physicochemical and animal pharmacokinetic data for the drug substance.”   

 “Early-stage drug development is a balance between minimizing time to clinic and developing a progressable formulation that meets pharmacokinetic targets while at the same time has minimal pharmacokinetic variability,” says Goodwin. “This can be remarkably difficult when there is limited API for development.” In such cases, he recommends using API-sparing 

 tests to assess what types of formulations are likely to achieve clinical pharmacokinetics targets.

	“Only minimal amounts of API are necessary to measure the neutral crystalline solubility as a function of pH, micelle partition coefficient, and amorphous solubility along with precipitation propensity. These values, along with estimates of permeability, can be input into simple models such as a maximum absorbable dose and dose number and dissolution rate models to get a basic understanding of absorption potential,” Goodwin explains. According to him, these basic models lack a high degree of accuracy, but they are useful for identifying the limiting factor for absorption and providing an initial estimate of an absorption dose response. “Ultimately, these estimates can be used to determine if a drug-delivery technology is needed to achieve the target pharmacokinetic profile,” Goodwin says. “And if an enabling technology is required, the information can indicate whether simple particle size reduction would work; or if the compound is ionizable, whether a high-solubility polymorph or salt form is likely to be adequate; or whether an amorphous form or lipid solution is necessary. This type of methodology decreases development time and API use by reducing the number of prototype formulations and 

 studies to nominate a proof-of-concept formulation for first-in-human studies.”

	Before selecting a formulation strategy, one needs to have a thorough knowledge of the physicochemical properties and biological attributes of the drug substance, in particular its solubility and intestinal permeability characteristics, Harris explains. Knowing what dose to administer is also important, he adds, because this information allows the formulator to select the most appropriate formulation strategy for the compound. 

	Kane agrees that a systematic understanding of the molecule, its properties and challenges, and a sound, phase-appropriate formulation development strategy that addresses those challenges is key to success in early development. “For example, solid dispersions or lipid-based formulations can be used to address poor bioavailability challenges,” he says. “For molecules that are unstable, there are various ways of stabilizing the molecule through a detailed understanding of its forced degradation profile, ensuring early- and late-stage drug product stability.” 

	Drug structure and physiochemical properties can also be used to assess formulation risks, according to Goodwin. “Melting point and glass transition temperature are examples of two physiochemical properties that are very informative for advanced drug-delivery technologies and easily measured with small amounts of API,” he says. “For example, an API with a low glass transition temperature would suggest that it may be difficult to achieve a stable amorphous form with high API loading in the drug product. A high melting point would suggest that it will likely be challenging to have a practical solubility in a lipid vehicle unless the dose is quite low. Although these are just a few examples, these physiochemical properties provide the basis for a preclinical risk assessment when evaluating enabling technologies for 

 performance, drug product stability, and manufacturability.”

	Another objective of early-stage development is to ensure the formulation and process developed in Phase I can be transitioned into a scalable, manufacturable process in late-stage development, Kane points out. “The objective of late-stage development is to scale up the early-stage clinical formulation and process to a larger-scale product that can be commercialized, while ensuring and establishing its shelf life to be commercially viable. Keeping an eye on and envisioning a larger-scale process early on will help address challenges early in development. Designing robust processes with a thorough understanding of critical processing parameters that impact drug quality and defining the control strategies at a reasonable scale will ensure a robust manufacturing platform in late-stage development,” he says. 

	Werner stresses that the risk of failure of a molecule is not only related to its pharmacological and pharmacokinetic properties or its toxicity, but also to its manufacturability. With reference to Midas Pharma’s systematic screening process for “difficult to formulate” drugs, he recommends including such technical considerations at an early development stage. He cites a project where solubility enhancement was achieved for a molecule, but pilot bioequivalence testing failed because it was found that higher scale production significantly changed the physicochemical behavior of the formulation. “This resulted in a substantial increase in development costs and an extended timeline, which likely could have been avoided by an earlier testing of the robustness of the formulation in terms of its scalability,” he says. 

	Keeping in mind the required commercial viability streamlines the development of new drug products and significantly decreases the risk of failure at later stages, according to Werner. In another example involving a highly potent and poorly soluble compound, he explains how applying the right methodology can help avoid scale-up issues. “The bioavailability of the compound had to be improved and at the same time, become less variable with regard to food effects,” he says. “Several technologies were applied, including size-reduction (nanozation), spray-drying, and hot-melt extrusion. The nanoparticles agglomerated, and the first animal trial displayed highly variable adsorption rates. Application of amorphous suspensions, either prepared by solvent-based method (spray drying) or temperature-based method (hot-melt extrusion), showed more promising results. However, manufacturing trials revealed that the yield of the spray-drying process was substantially lower and the use of an uncommon organic solvent was required, which negatively affected the intended commercial viability. Hot-melt extrusion, on the other hand, not only enabled the desired positive effects on bioavailability and variability, but also helped to avoid the dust formation typical for a spray-drying process (dust formation is undesirable for highly potent drugs).” Hot-melt extrusion proved to be superior in this case.

	Early-stage formulation strategies should not only focus on developing a dosage form that can be manufactured using simple and cost-effective processes but also one that offers a high probability of clinical success. “A sound formulation strategy is one that is ‘phase-appropriate’ and not over-engineered to a large commercial-scale in early development,” says Kane. “When developing a new drug, the chemistry, manufacturing, and control (CMC) strategy should involve a systematic drug substance characterization upfront to understand the molecule, its material properties, physical and chemical stability issues, and addressing these early in a phase-appropriate formulation development strategy.” Kane explains that this approach ensures a significant advantage by not needing to go back and address one or more challenges as they appear in the development process. 

	According to Goodwin, efficient drug product development can be accomplished using a risk-based approach to formulation design based on fundamental- and mechanistic-based models. The identification of high-risk areas provides a basis for initial formulation selection and optimization. Harris also stresses that risk mitigation is crucial throughout the whole drug development process. “For early stages, it is vitally important to understand as much as possible about the attributes and behavior of the drug substance. This allows for selection of a formulation strategy that gives the compound the best chance of success in clinical trials,” Harris says. 

	One future prospect that is already showing potential in dramatically reducing the amount of API and time necessary for drug product development is machine learning, Goodwin observes. “If trained on a wide diversity of data, these types of algorithms have the potential to predict drug-delivery technologies and processes that have the highest probability of successfully delivering an API-all based on a few simple API-sparing 

 measurements and calculated properties of the molecule,” he says. “In the past decade, this approach has gained a lot of recognition for predicting absorption, distribution, metabolism, elimination, toxicity attributes such as permeability, transporter and metabolism substrates, and estimates for clearance and volume of distribution.” Goodwin believes this methodology has huge potential in advancing drug development because of the high degree of prediction accuracy.

	When referring to this article, please cite it as A. Siew, “Formulation Strategies in Early-Stage Drug Development," 

Applying the right formulation strategies early in the drug development process can help avoid costly late-stage failures.