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

Cynthia A. Challener

The small number of new drug approvals in 2016-only 22 (1)-may have been an anomaly. As of Nov. 14, 2017, FDA’s Center for Drug Evaluation and Research (CDER) has approved 38 new drugs (2) and is on track to achieve numbers similar to the 41 approvals in 2014 (3) and 45 approvals in 2015 (4). The approved drugs include a number of firsts in terms of both drugs for untreated diseases and new modes of action. Nearly two-thirds were approved under one or more accelerated pathways and just over one-third were designated as orphan drugs.

	Given the return to record-level FDA approvals, it is not surprising that most industry analysts predict strong growth in the market for APIs. Markets and Markets, for instance, predicts the global API market, including chemical and biologic branded and generic-drug substances, will expand at a compound annual growth rate of 6.3% from $157.95 billion in 2016 to $213.97 billion in 2021 (5). Market research firm Grand View Research predicts the value of the global API market will reach $239.8 billion by 2025 (6).

	Growth is attributed to the aging of the world population with a concomitant rise in age-related diseases and an increase in lifestyle-induced conditions and cancer. Small-molecule APIs account for the greatest share of the market (6), which reflects the rate of approvals for drugs based on chemical and biologic APIs; in 2017 nearly 75% of the approved drugs as of November 14 were formulated with small-molecule APIs (2). Captive manufacturers held the greatest market share, but due to increased outsourcing of API manufacturing, contract manufacturers are expected to expand their share more rapidly in the coming years. Demand for generic APIs is also increasing rapidly (6).

	Manufacturers continue to leverage the four expedited review and approval programs-Fast Track and Breakthrough Therapy Designations and Accelerated Approval and Priority Review processes-made possible with passage of the FDA Safety and Innovation Act (FDASIA) in 2012. FDA under Commissioner Scott Gottlieb is also committed to accelerating the approval of new drugs (7). Nearly two-thirds (24 out of 38, 63.2%) of the drugs approved in 2017 through mid-November were filed under at least one of these four programs. Of those 24 drugs, just over one-third qualified for two programs, and nearly 16% for three. Of the four programs, 22 drugs were approved under Priority Review, 14 as Breakthrough Therapies, eight with the Fast Track designation, and six with Accelerated Approval.

	The Orphan Drug Act (ODA) was passed in January 1983 to encourage the development of drugs to treat rare diseases. Drugs intended to prevent, treat, or diagnose a disease/condition that occurs in less than 200,000 patients in the United States may be designated as an orphan drug. Developers also can receive tax credits for clinical research expenses and seven years of marketing exclusivity upon FDA approval. In the 10 years prior to passage of the ODA, the pharma industry commercialized only 10 products for rare diseases; since 1983, more than 450 orphan drug products have been approved for more than 600 indications (8). In addition, 60% of the 87 Breakthrough Therapies approved from January 2013 to Sept. 15, 2017 are indicated for rare diseases and accounted for 25% of the orphan drug approvals. Nearly 75% of orphan drugs received Priority Review.

	In 2017, 13 of the 38 new drugs approved through November 14, or 34%, were classified as orphan drugs.

	Of the types of diseases targeted by the 38 new drugs approved by FDA in 2017 through November 14, cancer accounted for the largest proportion. Drugs were approved for leukemia (9-11), urothelial carcinoma (12), mantle cell lymphoma (13), and lung (14), skin (15), breast (16-18), follicular lymphoma (19), and epithelial ovarian, fallopian tube, and primary peritoneal (20) cancers. Seven of these drugs are kinase inhibitors.

	Nerlynx (neratinib maleate) is the first extended adjuvant therapy, a form of therapy that is taken after an initial treatment to further lower the risk of breast cancer returning. Two of the drugs were approved for treatment of acute myeloid leukemia (AML) with companion diagnostics. Idhifa (enasidenib), which is for treatment of adult patients with relapsed or refractory AML who have mutations in the IDH2 gene, was approved for use with the RealTime IDH2 Assay (9). Rydapt (midostaurin) from Novartis, a treatment for adult patients with newly diagnosed AML that have the FLT3 gene mutation, was approved for use with the LeukoStrat CDx FLT3 Mutation Assay (10).

	Bavencia (avelumab), a monoclonal antibody (mAb), is the first treatment for metastatic Merkel cell carcinoma (MCC), a rare aggressive form of skin cancer (15).

	A number of the new drugs approved in 2017 through November 14 are firsts in the treatment of rare diseases. Benznidazole is the first drug approved in the US for the treatment of Chagas disease, or American trypanosomiasis, a parasitic infection caused by Trypanosoma cruzi that can lead to serious heart illnesses and affect swallowing and digestion (21). Radicava (edaravone) is the first new treatment approved in the US in many years for the treatment of myotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease (22).

	Two drugs received the ninth and tenth rare pediatric disease priority review vouchers issued by FDA. Emflaza (deflazacort) is a corticosteroid for the treatment of Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness and the first treatment approved for a wide range of patients with DMD (23). Brineura (cerliponase alfa), an enzyme replacement therapy, is the first FDA-approved treatment to slow loss of walking ability in symptomatic pediatric patients three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency and a form of Batten disease (24).

	The mAb Ocrevus (ocrelizumab), which acts as a direct factor Xa inhibitor, is the first treatment approved for primary progressive multiple sclerosis (25). Bevyxxa (betrixaban) is the first treatment to prevent the development of deep vein thrombosis and pulmonary embolism blood clots in adults hospitalized with acute illnesses for extended periods of time (26). Ingrezza (valbenazine) is the first drug approved by FDA for the treatment of tardive dyskinesia a neurological disorder characterized by repetitive involuntary movements, usually of the jaw, lips, and tongue that is seen in patients that have been taking antipsychotic medications for schizophrenia, bipolar disorder, and depression for long durations (27).

	In many cases, the new drugs approved in 2017 are the first treatments commercialized for diseases in 10 or more years. Tymlos (abaloparatide) is the first new bone building agent for postmenopausal women with osteoporosis in the US in nearly 15 years (28). Prevymis (letermovir) is the first new medicine for the prevention of cytomegalovirus infection and disease in adults receiving allogeneic hematopoietic stem cell transplants to be approved in 15 years (29). Austedo (deutetrabenazine) is the first new treatment option in nearly a decade for chorea associated with Huntington’s disease, a rare and fatal neurodegenerative disorder (30). Parsabiv (etelcalcetide) is the first therapy approved for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease on hemodialysis in 12 years and the only calcimimetic that can be administered intravenously by the dialysis healthcare team at the end of the hemodialysis session (31).

	Two of the approved drugs operate by new mechanisms of action. Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%) is the first prostaglandin analog with nitric oxide as a metabolite to be approved for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension (32). Solosec (secnidazole) is a next-generation 5-nitroimidazole antibiotic and the first and only single-dose oral therapy for bacterial vaginosis in adult women (compared to twice-per-day dosing for seven days) (33).

	Although not approved by CDER and thus not appearing on its list of novel approved drugs (2), FDA, through the Center for Biologics Evaluation and Research, has approved gene therapies for the first time in 2017.

	The first, Kymriah (tisagenlecleucel) from Novartis, was approved in August and is a chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (34). Kymriah was approved under Priority Review with the Breakthrough Therapy designation.

	At the same time, FDA expanded the approval of Actemra (tocilizumab) from Genentech for the treatment of patients two years of age or older with cytokine release syndrome that occurs with CAR T-cell therapy. Because of the risk cytokine release syndrome (CRS) and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified and trained to recognize and manage CRS and neurological events.

	The second, Yescarta (axicabtagene ciloleucel), is also a CAR T-cell therapy, but for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment (35). Yescarta was approved under Priority Review and had both Breakthrough Therapy and Orphan Drug designations. Yecarta was approved with a similar REMS.

	Other diseases targeted by novel drugs approved by FDA in 2017 include chronic hepatitis C virus (two different products), complicated urinary tract infections, acute bacterial skin and skin structure infections caused by gram-positive and gram-negative pathogens, eczema, plaque psoriasis (two products), Parkinson’s disease, carcinoid syndrome diarrhea, chronic idiopathic constipation, opioid-induced constipation, rheumatoid arthritis, and asthma.

	FDA approved a record number of abbreviated new drug applications (ANDAs)--763 approvals and 174 tentative approvals--in fiscal year 2017 (36), compared with 639 ANDA approvals and 183 tentative approvals in fiscal year 2016 (37). Not only were more ANDAs approved in 2017 compared to 2016, a much higher number of ANDAs was received as well.

	In addition, as of Nov. 28, 2017, FDA had approved 65 first generics (38)-or products that are the first generic competitors to their branded counterparts--and looks to be on track to meet or exceed last year’s figure of 73. The increased rate of approvals is attributed to an increase in FDA personnel by nearly 1000 as a result of funds collected through the Generic Drug User Fee Amendments. FDA has also prioritized the approval of generics to help reduce drug costs.

CDER Approved Many Innovative Drugs in 2014

,” FDA Voice, Jan. 14, 2015.
	4. FDA, “

.”
	5. Markets and Markets, Active Pharmaceutical Ingredients/API Market by Type (Innovative, Generic), Manufacturer (Captive, Merchant), Synthesis (Synthetic, Biotech), Product (mAb, Hormone) Drug (OTC, Rx), Therapy (Diabetes, Oncology, CNS, CVD) - Global Forecast to 2021, January 2017.
	6. Grand View Research, “API Market Size Worth USD 239.8 Billion By 2025,” Press Release, January 2017.
	7. B. Norman, S. Karlin-Smith, and B. Griffiths, “

Gottlieb Signals Priorities for FDA, Including Drug Pricing

Insights into Rare Disease Drug Approval: Trends and Recent Developments

,” presented at the NORD Rare Diseases & Orphan Products Breakthrough Summit, Oct. 17, 2017.
	9. FDA, “FDA Approves New Targeted Treatment for Relapsed or Refractory Acute Myeloid Leukemia,” Press Release (Silver Spring, MD, Aug. 1, 2017).
	10. FDA, “FDA Approves New Combination Treatment for Acute Myeloid Leukemia,” Press Release (Silver Spring, MD, April 28, 2017).
	11. FDA, “FDA Approves New Treatment for Adults with Relapsed Or Refractory Acute Lymphoblastic Leukemia,” Press Release (Silver Spring, MD, Aug. 17, 2017).
	12. FDA, “Durvalumab (Imfinzi),” www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930.htm.
	13. FDA, “FDA Approves New Treatment for Adults with Mantle Cell Lymphoma,” Press Release (Silver Spring, MD, Oct. 31, 2017).
	14. Takeda Pharmaceutical Company, “Takeda Announces FDA Accelerated Approval of ALUNBRIG (brigatinib),” Press Release (Cambridge, MA, April 28, 2017).
	15. FDA, “FDA Approves First Treatment for Rare Form of Skin Cancer,” Press Release (Silver Spring, MD, March 23, 2017).
	16. Novartis, “Novartis Kisqali (ribociclib, LEE011) Receives FDA Approval as First-Line Treatment for HR+/HER2- Metastatic Breast Cancer in Combination with Any Aromatase Inhibitor,” Press Release (March 13, 2017).
	17. FDA, “FDA Approves New Treatment for Certain Advanced Or Metastatic Breast Cancers,” Press Release (Silver Spring, MD, Sept. 28, 2017).
	18. FDA, “FDA Approves New Treatment to Reduce the Risk of Breast Cancer Returning,” Press Release (Silver Spring, MD, July 17, 2017).
	19. FDA, “FDA Approves New Treatment for Adults with Relapsed Follicular Lymphoma,” Press Release (Silver Spring, MD, Sept. 14, 2017).
	20. FDA, “FDA Approves Maintenance Treatment for Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancers,” Press Release (Silver Spring, MD, March 27, 2017).
	21. FDA, “FDA Approves First US Treatment for Chagas Disease,” Press Release (Silver Spring, MD, Aug. 29, 2017).
	22. FDA, “FDA Approves Drug to Treat ALS,” Press Release (Silver Spring, MD, May 5, 2017).
	23. FDA, “FDA Approves Drug to Treat Duchenne Muscular Dystrophy,” Press Release (Silver Spring, MD, Feb. 9, 2017).
	24. FDA, “FDA Approves First Treatment for a Form of Batten Disease,” Press Release (Silver Spring, MD, April 27, 2017).
	25. FDA, “FDA Approves New Drug to Treat Multiple Sclerosis,” Press Release (Silver Spring, MD, March 29, 2017).
	26. Portola Pharmaceuticals, “US FDA Approves Bevyxxa (betrixaban) First and Only Anticoagulant for Hospital and Extended Duration Prevention of Venous Thromboembolism (VTE) in Acutely Ill Medical Patients,” Press Release (South San Francisco, June 23, 2017).
	27. FDA, “FDA Approves First Drug to Treat Tardive Dyskinesia,” Press Release (Silver Spring, MD, April 11, 2017).
	28. Radius Health, “FDA Approves Radius Health’s TYMLOS (abaloparatide), a Bone Building Agent for the Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture,” Press Release (Waltham, MA, April 28, 2017).
	29. Merck & Co., “Merck Receives FDA Approval of PREVYMIS (letermovir) for Prevention of Cytomegalovirus (CMV) Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients,” Press Release (Kenilworth, NJ, Nov. 9, 2017).
	30. Teva Pharmaceuticals, “Teva Announces FDA Approval of AUSTEDO (deutetrabenazine) Tablets for the Treatment of Chorea Associated with Huntington’s Disease,” Press Release (Jerusalem, Israel, April 3, 2017).
	31. Amgen, “FDA Approves Amgen’s Parsabiv (Etelcalcetide), First New Treatment in More Than a Decade for Secondary Hyperparathyroidism in Adult Patients on Hemodialysis,” Press Release, Feb. 7, 2017.
	32. Valenat Pharmaceuticals, “Bausch + Lomb and Nicox Announce FDA Approval of VYZULTA (Latanoprostene Bunod Ophthalmic Solution), 0.024%,” Press Release (Thousand Oaks, CA, Nov. 2, 2017).
	33. Symbiomix Therapeutics, “FDA Approves Symbiomix Therapeutics’ Solose (secnidazole) Oral Granules for the Treatment of Bacterial Vaginosis in Adult Women,” Press Release (Newark, NJ, Sept. 18, 2017.
	34. FDA, “FDA Approves tisagenlecleucel for B-cell ALL and Tocilizumab for Cytokine Release Syndrome,” Press Release (Silver Spring, MD, Aug. 30 2017).
	35. FDA, “

FDA Approves CAR-T Cell Therapy to Treat Adults with Certain Types of Large B-cell lymphoma

,” Press Release (Silver Spring, MD, Oct. 18, 2017).
	36. FDA, “

Activities Report of the Generic Drug Program (FY 2017)

Vol. 42, No. 1
	January 2018
	Pages: 24–33

	When referring to this article, please cite it as C. Challener, " FDA Ramped up Approval Rate in 2017," 

Articles

FDA looks to achieve near-record level of new drug approvals following slowdown in 2016.

FDA Ramped Up Approval Rate in 2017

Taste masking is a method used to improve not only the taste of bitter APIs in formulated drug products, but also mouth feel (smooth vs. gritty) and the overall acceptability of medications to patients. It can be achieved in various ways. Common methods include changing the API to a different form (e.g., drug freebase, salt, or pro-drug) that is less bitter; using sweeteners, buffers, taste modifiers, or aromas to reduce aversive sensory attributes; and complexing the API to prevent its interaction with taste receptors, such as with cyclodextrins and ion exchange resins. The API can be physically encapsulated through application of a coating (or coatings) to a drug particle or tablet, the use of barrier membranes, or the formation of solid dispersions via spray drying or hot-melt extrusion. Another potential method involves blocking of taste receptors directly or along the signaling pathway.

	Taste masking is important because poor patient adherence often leads to worsening health and poor outcomes, along with increased costs across the healthcare system. A broader range of taste-masking technologies is required for the growing number of different dosage forms and drug-delivery approaches in use and under development today to meet the unique and specialized needs of different patient populations. Pediatric patients consist of subgroups from babies to teenagers, each with its own requirements. Geriatric patients may have difficulty swallowing. Patients with neurological conditions may resist taking medications if the drug product is not easy to take. Excipient manufacturers and service providers focused on taste masking are overcoming a range of challenges--from regulatory hurdles to an ability to accurately predict and measure taste-masking performance--to develop technologies suitable for the growing range of dosage forms and delivery systems.

	The use of taste-masking technologies is driven by a number of factors that can be classified as regulatory, economic, demographic, and philanthropic, according to Jeff Worthington, president and founder of Senopsys. Regulations in the United States and European Union both require the development of pediatric medicines and the submission of detailed plans that outline the studies to be conducted as part of the pharmaceutical and clinical development programs. Unless a waiver is granted, pharmaceutical companies are required to develop pediatric formulations suitable for patients from birth to adolescence requiring age-appropriate dosage forms, such as liquids, orally dissolving films, fast dissolving tablets, granules (sprinkles), and mini-tablets, Worthington reports. 

	Tablets and capsules effectively bypass the taste receptors in the oral cavity, but most of the pediatric (and geriatric) dosage forms have residence times in the oral cavity, meaning the drug active can be perceived. Palatability, however, is essential to dosing compliance and adherence; therefore, regulatory agencies require that companies demonstrate the palatability of drug products in pediatric patient populations as part of the pharmaceutical and clinical development program. “Because many drug actives are bitter or have other aversive attributes including trigeminal irritation, malodor, and texture (e.g., grittiness), taste masking is required to ensure successful dose administration,” Worthington explains.

	Non-governmental organizations also support the development of pediatric dosage forms for use in developing countries. Solid-dosage forms that permit flexible dosing (e.g., granules and mini-tablets) are preferred due to a variety of factors, including lack of potable water, complex logistics, and lack of refrigeration, according to Worthington.

	Geriatric patients present additional adherence challenges. “This demographic group is often taking multiple medications and dosages provided by their caregivers; they also have a greater degree of challenges with swallowing and handling. Taste-masking is just one element that has to be considered,” according to Ali Rajabi-Siahboomi, vice-president and chief scientific officer of Colorcon.

	Dosage forms other than conventional tablets and capsules-which may be difficult for older patients to swallow-need to be developed, adds Don Barbieri, technical product manager at SPI Pharma. He points to chewable tablets, dispersible powders, and orally disintegrating tablets as alternate dosage forms that can be administered to address swallowing difficulties. With orally dispersible products, however, there is a need for taste masking so that these dosage forms have acceptable palatability with little or no bitterness.

	On the economic front, many of the growing number of drug candidates being developed to target orphan diseases, including many pediatric medicines, are often financially attractive due to premium pricing opportunities, market exclusivity, and priority regulatory reviews among other benefits; however, the formulations require taste masking, according to Worthington. 

	A number of hurdles must be overcome when developing taste-masking technologies that are effective. Top among them is achieving the necessary balance between preventing release of the API while the drug product is in the mouth but allowing for release once the medicine is in the stomach, according to Rajabi-Siahboomi. “The pharmacodynamics and pharmacokinetics (PK) cannot be effected by the taste-masking technology,” he says. The taste-masking technology must be appropriate for the extent of bitterness of the API, its solubility, and dosage level, as well as the dosage form (coated tablet, liquid, or granules to be distributed on food, etc.). In some cases, adding a sweetener or flavor is sufficient; in others, some type of barrier membrane must be used. Taste maskers that sequester the API from taste receptors (e.g., particle coating, adsorption, complexation), however, may adversely affect PK, leading to effective taste-masking but reduced bioavailability, according to Worthington.

	Developers of taste-masking technologies also often work with APIs that have been incompletely or inaccurately characterized with respect to their aversive taste attributes because many APIs have multiple aversive taste attributes--such as bitter and sour basic tastes with trigeminal irritation--each of which may require a different mitigation approach, according to Worthington. In addition, he notes that the absence of a robust measurement system to provide quantitative data on the intensity and duration of aversive taste attributes makes optimization of taste-masking technologies difficult.

 taste models (e.g., the electronic tongue with human data) often results in sub-optimal taste-masking and palatability issues, according to Worthington. There is also increasing regulatory pressure to reduce the number of excipients used in pediatric formulations, leading to the availability of fewer tools and lack of regulatory clarity on how specifically to approach pediatric formulation development. “For the most part, agencies have adopted a ‘propose-and-justify’ approach, rather than ascribing a defined process,” Worthington comments.

	Modifying existing APIs through complexation to ionic exchange resins, while effective for taste masking, can present regulatory challenges, according to Barbieri. “In the United States, over-the-counter (OTC) monographed drugs can be marketed without further FDA approval. When an OTC monographed drug is attached to an ion-exchange resin, however, FDA considers the complexed drug to be a new compound that requires regulatory approval,” he explains. 

	Getting novel excipients of any kind approved for use in prescription medicines is also challenging because there is no separate approval pathway for excipients. A new excipient must be approved along with a formulated drug product, and often drug developers are hesitant to take on the added risk of using an excipient that has not already been proven acceptable to regulators.

	On the production side, Barbieri notes that the use of solvents for the application of taste-masked polymer systems is an issue. “Aqueous systems are definitely preferred to avoid the additional testing that is required to quantify residual solvent levels and the added cost of handling and disposing of solvents,” he says.

	Recent innovations in established taste-masking approaches have been incremental rather than breakthrough or novel technologies, according to Worthington. As an example, he notes that in particle coating there have been advances in barrier coatings used for taste masking that are better at balancing the need to maintain the target PK profile while minimizing particle size to minimize grittiness. 

	Senopsys applies expertise in sensory and formulation science garnered from the food industry to the development of palatable, patient-accepted drug products for its clients. These efforts include advances in the company’s quantitative FlavorMetrics Taste Assessment and FlavorOpt Taste Masking platforms and the development of methods for assessing the ease-of swallowing multi-particulate dosage forms (granules and mini-tablets), and a science-based approach to screening age-appropriate dosing vehicles for multi-particulate products. The company also is focused on the development of novel dosage forms to address unique dosing challenges, such as bars, chews, gummies, and ready-to-use puddings for high drug loading applications, according to Worthington.

	SPI Pharma has developed a gelatin coacervation process as a new approach to taste masking of APIs. Originally introduced to manufacture carbonless copy paper, the process is performed in water without the need for solvents. The gelatin coating provides an excellent taste-masking barrier, and the resulting hydrogel film around the particle provides great mouth feel with smooth sensation and improved swallowability, according to Barbieri. “Interest in acetaminophen and ibuprofen taste masked with coacervated gelatin has increased significantly and, worldwide, more products are planned for introduction in the next one to two years,” he observes. Given the continuing increase in both interest and sales, SPI is actively evaluating other APIs that would be good candidates for taste masking via a coacervation process, according to Barbieri. 

	In addition to offering its established barrier membrane technology (Surelease/Opadry combination) and ion exchange resin (using DowDuPont AMBERLITE and DUOLITE) taste-masking solutions, Colorcon is working with BASF on the application of that company’s Kollicoat Smartseal, a novel, reverse enteric polymer that is highly stable in saliva and specifically soluble in gastric juice. It is being evaluated by Colorcon for inclusion in a film-coating system to simplify and accelerate coating operations and provide new options for taste masking of drug particles and granules. Colorcon also recognizes the industry need for a pigmented taste-masking solution to address the issues of differentiation and patient recognition. “However, because the polymer is a novel excipient, there is a real challenge to get it approved. We are working with some branded pharmaceutical companies who are evaluating its use in their formulations,” Rajabi-Siahboomi says.

	As demand for taste masking increases further, the industry will look for ways to improve coating efficiency, reduce processing time, reduce waste, and maximize product yields, according to Barbieri. “Excipient manufacturers can be of benefit here by providing to pharmaceutical manufacturers a selection of different substrates for bead coating in a range of different particle sizes. The various core beads can be made to target specific particle size specifications and narrow particle size ranges. In this way, manufacturers can select the most appropriate seed product for their process without having to perform additional screening steps to sort out the inappropriate size beads, thereby facilitating manufacturing and reducing waste,” he comments.

	To better support the application of its new taste-masking technologies and offerings, Colorcon is developing new methods for in-vitro testing using artificial saliva that will be truer tests and resemble what occurs within the body. They will be intended for use in conjunction with conventional dissolution testing. “There needs to be a mechanism for confirming that formulated products are indeed taste masked. Current dissolution testing methods don’t accurately model what is in the mouth,” says Rajabi-Siahboomi.

	Worthington expects to see advances in barrier coatings in which these systems are combined with smaller particles to yield further improvements in palatability and swallowability. He also notes that further advances in 3D-printing may provide additional opportunities for taste masking as well as enable on-demand production of custom drug products.

	Receptor disruption as a long-term solution?

	Humans have approximately 30-40 known bitter taste receptors (many more than for sweet, sour, or salty); different compounds activate different sets of receptors. Efforts are underway to identify compounds that block bitter perception. Because individual compounds activate different sets of receptors, the prospect would appear greater for interrupting the common signaling pathway rather than a multiplicity of receptors, according to Worthington. “Regulatory agencies might consider these to be biologically active components at either the receptor or signaling pathway level, however, meaning that the bitter blockers would be regulated as drugs--or at best novel excipients--either way impeding adoption by industry,” he states. It is possible though, that basic research in taste perception may lead to future advances in taste-masking technology.

Formulation and excipient advances address taste masking concerns to improve medication adherence in pediatric, geriatric, and other special patient populations.

Improving Taste to Enhance Medication Adherence

Flow chemistry is no longer a novel technology largely relegated to drug discovery laboratories. Most pharmaceutical companies and some contract manufacturers have embraced continuous manufacturing to some degree for both drug substance and drug product manufacturing. Several factors are considered when determining whether batch or flow production methods are warranted.

	The switch from batch to flow chemistry is often driven by the need to perform hazardous reactions, according to Matthew M. Bio, president and CEO of Snapdragon Chemistry. “Flow chemistry is an excellent way to deal with gas/liquid reactions and reactions that are run under high pressures, at high temperatures, or that involve unstable intermediates that require low temperatures,” he says.

	At Hovione, the hazard source is first identified. In addition to the above examples, highly exothermic reactions and reactions with highly toxic/corrosive reactants are also good candidates according to Rui Loureiro, director R&D process chemistry development with the company. “Reactions that involve hazards that cannot be easily controlled under batch conditions are typically performed using flow chemistry,” he says.

	Loureiro does note, however, that not all hazardous reactions are automatically switched to flow chemistry. “Many catalytic hydrogenations and hydrolysis reactions have been performed in batch for a long time in a safe manner. In such cases where safety is not compromised, the decision to move to flow should consider the required throughput versus the investment in time and costs,” he observes.

	Reactions that involve suspensions are also often a challenge in flow chemistry, particularly during the development stages using smaller equipment, according to Filipe Ataíde, team leader of Hovione’s continuous manufacturing group. “Such processes often must be studied at much lower concentrations, which can make it difficult to define the benefits of flow versus what can be achieved in the batch process,” he comments.

	The reaction time/rate is usually the primary indicator as to whether the reaction is practical in flow, according to Bio. Long reaction times would result in tubular or continuous stirred-tank reactors that are quite large. For these slow reactions, however, flow chemistry still presents opportunities. “With the expanded processing windows available in flow (e.g., pressure, temperature), many reactions that at first glance would appear as poor candidates for flow can be successfully developed as continuous processes,” he asserts.

	Knowing the process kinetics also helps convert batch processes to flow, since the equipment can be designed to fit the kinetics, agrees Rudi Oliveira, an R&D chemist in Hovione’s continuous manufacturing group. “The decision to use flow chemistry in a process should be taken as soon as possible, however, and preferably at the start of process development so reactors can be designed early and delays be avoided,” he notes.

	Designing the equipment setup is key in flow conditions, according to Loureiro. While the equipment must be assembled to obtain the best performance out of the process, it should also mitigate the different hazards. “One example is a very fast reaction (< 1 sec) that produces a significant exotherm. The equipment designed for this process must be dimensioned to perform the reaction in the appropriate time, but it should also be capable of removing the heat generated efficiently,” he explains.

	Loureiro also notes that a variety of engineering solutions have been developed over the years to make it possible to perform certain hazardous processes safely in flow and avoid the use of expensive reagents or long synthetic routes that in batch would be required to work around those issues. Ataíde points to tube-in-tube technology for gas/liquid reactions, which provides a different type of control at the interface between the two phases than is possible when simply bubbling a gas into the liquid phase, as an example.

	“The evolution of flow chemistry is highly dependent on the engineering solutions that are developed,” adds Loureiro. The arrival of 3D-printed reactors is a good step towards the required flexibility to better address the various chemistries.

	From a larger perspective, according to Bio, as flow chemistry has successfully moved from a laboratory curiosity to an actual production technology, there are opportunities to use continuous manufacturing not just as a tool to address a single problematic step, but as a technology that allows new opportunities, both technical and economic, when an entire process end-to-end can be done in flow.

	He also notes that while the cost of developing a commercial batch process need not be paid until late in development, the cost of flow processes is generally paid up front, but in the long run can be significantly lower. “Flow provides unique opportunities in automation that promise to greatly reduce the cost of development,” Bio says. Snapdragon is currently building an autonomous flow chemical development platform that promises to dramatically speed the discovery and development of flow processes.

	Flow chemistry is typically safer for hazardous reactions due to downsizing of the reactivity zone, which also provides increased heat and mass transfer, and higher precision in controlling process parameters, according to Oliveira. “A flow system will always have a much smaller volume of reactive stream and thus is intrinsically safer than batch,” Bio explains. Flow systems are also typically small footprint reactors, so containment for highly potent APIs is much easier.

	Flow typically also provides much greater control over the process variables that could impact product quality, even if the quality of the input material is variable, which can result in improved product quality relative to batch, adds Bio.

	From an economic perspective, flow systems typically have significantly lower capital costs than a comparable batch reactor and are readily automated, resulting in lower operating costs, according to Bio.

	Barriers to switching from batch to continuous

	Despite the fact that flow chemistry can enable hazardous reactions to be performed on a commercial scale that cannot be safely conducted under batch conditions, barriers to the advancement of flow chemistry do exist. “The biggest barrier is the lack of expertise needed by process development chemists. To truly develop robust and scalable flow processes, practitioners need to have a good understanding of physical chemistry and reaction design, skill sets not widely available,” says Bio. Electrical engineering and computer programming expertise are also needed for effective implementation of automation and real-time analytical technologies, also skills that many process development professionals do not have. Bio also notes that collaboration is needed between chemists, engineers, and analytical scientists.

	From a technical standpoint, Bio notes that the laboratory tools available for flow chemistry development today typically don’t easily translate to pilot or commercial scale, which inhibits adoption of the technology. To address this issue, Snapdragon has developed laboratory platforms that directly translate to pilot-scale platforms to facilitate a rapid design to delivery cycle. More analytical tools specifically designed to work with flow systems are also needed. “It is through these analytical tools and the integration of them into the process control strategy where the true power of flow over batch is to be realized,” Bio states.

	Real potential for supply chain improvements

	The combination of small footprint and low capital and operating costs allows for new ideas in supply-chain management and supply risk mitigation, according to Bio. “Multiple flow plants can be built and deployed to ensure robust supply chains. The low cost also means that there is minimal penalty for over building production capacity, which can eliminate the risk of drug shortages.”

	In addition, Bio says that process development chemists should strive to eliminate hazards where ever possible, and flow chemistry can be a critical tool. Rather than storing hundreds of tons of temperature-sensitive intermediates on site for use in batch processes, small flow reactors can be used to convert stable, non-hazardous precursors to the required intermediates on-demand.

	“An on-demand flow system is an intrinsically safer situation where no explosion can occur,” Bio says. This approach would also eliminate the need for trucks and rail cars to carry hazardous materials around the country. “The supply chain for most, if not all, of these materials could be re-imagined in terms of on-demand, point-of-use manufacture. Not only would this greatly reduce the human, environmental, and national security risk, but also create resilient supply chains able to tolerate local disruptions,” he continues.

	“The question really should be, why do we need to run hazardous chemistry in batch; flow should be the default,” Bio concludes.


	Vol. 41, No. 12
	December 2017
	Page: 20–21

	When referring to this article, please cite it as C. Challener, “Hazardous Chemistry: Choosing Batch or Flow," 

For many processes involving hazardous chemistry, running in flow mode has safety and economic advantages.

Hazardous Chemistry: Choosing Batch or Flow

Established vaccine manufacturing technologies are complex, often highly customized, and typically require dedicated facilities. Development and approval times can be lengthy, presenting hurdles for medical professionals seeking rapid response to pandemic diseases.

	Standardized vaccine manufacturing platforms that can be deployed across different vaccines and vaccine types, could speed the delivery of vaccines and enable manufacturing in emerging economies. Technical and funding challenges must be overcome to bring the advanced manufacturing potential to reality.

Pharmaceutical Technology and BioPharm International

Vaccine Development and Manufacturing 2017

	When referring to this article, please cite it as C Challener, " Accelerating Vaccine Development and Manufacturing," 

Pharmaceutical Technology and BioPharm International Vaccine Development and Manufacturing 2017 eBook

The use of approved platform technologies can reduce the time and cost required to generate new vaccines.

Accelerating Vaccine Development and Manufacturing

	When referring to this article, please cite it as C. Challener, “Growing Demand for Taste-Masking Technologies," 

Taste masking increases drug acceptability and medication adherence in pediatric, geriatric, and other special patient populations.

Growing Demand for Taste-Masking Technologies

The global market for highly potent APIs (HPAPIs) is growing at a healthy rate. According to market research firm Markets and Markets, demand for HPAPIs will expand at a compound annual growth rate of 8.5% from $16.02 billion in 2016 to $24.09 billion in 2021 (1). Rapid growth in the markets for oncology treatments (including generics) and antibody-drug conjugates is driving this expansion. 

	The manufacture of HPAPIs requires specialized facilities, equipment, and skills to ensure the safety of operators and the environment. As such, the bulk of HPAPIs are produced by contract development and manufacturing organizations (CDMOs) with these specialized capabilities. One of the challenges for CDMOs when accepting new projects, particularly those involving new chemical entities (NCEs), is identifying the level of potency, or biological activity, in order to establish appropriate safety and handling procedures.

	There are two parts to an assessment of an NCE with respect to potency or biological activity. The first part, according to Simon Edwards, vice-president of sales and business development at Cambrex, is a risk assessment that produces an exposure “limit” or an exposure “range” (i.e., occupational exposure limit [OEL] or occupational exposure band [OEB], respectively). The limit or range is in units of mass per volume air (micrograms per cubic meter, mg/m

). The second part of the assessment is risk management, which involves establishing actions or preventive steps to keep exposures below the limit or range determined by the risk assessment. This work is undertaken through a collaborative effort between toxicology, safety, and engineering departments.

	Standardized approach, but no standard system

	This general approach to risk assessment is reasonably well-standardized, but the way the results are displayed varies greatly because the application of uncertainty factors differs depending on the individual risk assessor. The standard approach, according to Cambrex, is incorporated into the International Council for Harmonization (ICH) guidance on impurity assessment (2), which is used by the American Conference of Governmental Industrial Hygienists (ACGIH) in a manner similar to the way FDA and the European Food Safety Authority (EFSA) conduct food ingredient risk assessments and EPA undertakes environmental risk assessments.

	There is no standard system, however, because there are no regulatory compliance requirements for occupational exposure limits. “Having discussed this in depth with expert consultants, we feel that it is very unlikely that there will ever be a collaborative effort to establish a common system unless a regulatory mandate is introduced,” says Edwards. 

	This lack of a standard classification system is not a hindrance for CDMOs, however, according to Ramesh Subramanian, vice-president of strategic marketing with Piramal Pharma Solutions. “The actual nomenclature is not as relevant as the OELs themselves. So despite using various classifications, the industry is able to move forward with minimal issues, as the OELs provide the clarity that is needed to establish containment solutions,” he observes. 

	Because there are many possible pharmacophores and toxicity endpoints, Edwards stresses that risk assessment/risk management of NCEs takes a great deal of experience and chemical intuition. “Managing the potential exposure in manufacturing is not prescriptive either, as it is facility- and equipment-specific, and requires experienced engineers and safety people to implement correctly in order to protect employees, the facility, and the surrounding environment,” he states.

	The key, according to Vivek Sharma, CEO of Piramal Pharma Solutions, is having an established potent compound category policy that defines the level of containment required depending on OELs or other toxicity data (e.g., LD50) and having predefined default criteria for containment in the absence of such data. “Quality CDMOs tend to default to a higher OEL when in doubt to ensure operator and staff safety,” he says. “Achieving a strong track record of safe HPAPI manufacturing also requires an understanding of the systems that are required to minimize the risks associated with potent compounds.” Sharma notes that proper facility design and engineering, including the heating, ventilation, and air-conditioning (HVAC) system, barrier isolation, and gowning/degowning areas are key considerations. “Appropriate facilities, engineering controls, and safety protocols are, in fact, increasingly imperative as newer HPAPIs under development have ever declining OELs,” he comments.

	During early development stages, many drug sponsor companies do not have the toxicity data needed to ensure that their compounds are handled safely. The challenge for CDMOs then becomes ensuring that the right level of safety measures is implemented and followed when handling the molecule and the associated chemistry, according to Vince Ammoscato, site head-Riverview at Piramal Pharma Solutions. In the absence of any data, many companies default to a potent designation Category 3 (10µg/m

	“The responsibility for containment rests with the CDMO since they are responsible for the safety of their employees. Having environmental, health, and safety (EHS) best practices with an excellent chemical hygiene program, which includes a potent compound handling policy that has been vetted through testing of the engineering controls and procedures, is paramount to ensuring NCEs are handled safely regardless of whether the potency levels have been established,” Ammoscato asserts.

	There is the additional challenge, however, of the tendency by chemists and operators to make “dread”-based decisions on handling and how to respond to incidents, according to Edwards. “This type of response is really not necessary if the appropriate risk assessment is performed,” he notes.

	The most common strategy when a CDMO is presented with a project involving an NCE, according to Edwards, is to initially ask the drug sponsor for available data, as this information should be available because the results-probably 

-have led them to move forward in the development of a NCE. 

	“In instances where the OEL of the molecule is unknown, there is no one common strategy for NCEs, but most CDMOs use some form of standard operation procedure,” Edwards says. “For either an NCE or synthetic intermediate, qualitative, or quantitative structure activity- and reactivity assessment-related data coupled with read-across and 

 data are used at Cambrex. These data are all important and come from many sources. The amount of data available depends on novelty of the pharmacophore,” he explains. Cambrex also calculates an OEL even when the sponsor has provided one.

	Ramesh from Piramal adds that firms may use substructure- or chemotype-based OEL estimations that include consideration of the therapeutic class for guidance. “One approach involves comparison of the API’s properties to those of similar substances with known toxicities and assumption of a similar level of risk,” he notes. Some CDMOs have in-house categorization systems for determining the required safety measures. 

	“Regardless of the method, if there is any uncertainty, it is best to assume a compound is potent, despite the potential higher costs incurred,” Ammoscato states. “Frequent communication between the sponsor and the CDMO is then essential to ensure that necessary data can be generated and an appropriate decision on the potency of the compound be reached as early as possible,” he adds. The CDMO should also be prepared to respond as needed if additional toxicity data are developed indicating that reclassification is warranted. Furthermore, CDMOs should perform additional risk assessments as an HPAPI project moves through different stages of development and commercialization to ensure the implementation of optimal procedures and practices that both protect operators and the environment but are also practical and cost effective, according to Ammoscato.

	1. Markets and Markets, “High Potency API /HPAPI Market by Type (Innovative, Generic), Synthesis (Synthetic, Biotech (Biologic, Biosimilar), Manufacturer (Captive, Merchant), Therapy (Oncology, Glaucoma, Hormonal Imbalance)-Global Forecast to 2021,” January 2017.
	2. ICH, 

M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk

CDMOs sharpen skills for identifying API potency risks and establishing safety and handling procedures.