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

Cynthia A. Challener

Global government regulatory agencies are paying increasing attention to the contract manufacturing space, with increased inspections particularly of overseas contract manufacturing/contract development and manufacturing organizations (CMOs/CDMOs) supplying the US market. At the same time, most pharmaceutical companies are focusing on supply chain diversity as a risk management/mitigation strategy. The increasing complexity of APIs and drug delivery technologies is also leading sponsor firms to seek service providers with demonstrated expertise in complex chemistry, high-potency API production, and small-volume manufacturing. Manufacturers of APIs are crucial links in the pharmaceutical industry supply chain. Selecting the right API supplier has become essential for the success of any new drug development or commercialization project.

	Before the selection of API suppliers begins, it is important to conduct an internal needs assessment in order to understand the expertise needed to support a company’s entire API portfolio, according to Janel Firestein, life-sciences lead at Clarkston Consulting. “Understanding the technologies your project requires is a good first step,” agrees Eric W. Smart, president of Fountainhead Pharmaceutical Consulting. “If there are special capabilities required, for example the ability to handle a potent compound or perhaps energetic reactions, it is best to seek out companies that specialize in that technology,” he says.

	In addition to having the right technical capabilities and resources to support production needs both today and in the future based on the pharma company’s organizational strategy, the right supplier will be able to demonstrate compliance, flexibility, and costs for any existing, established APIs it produces, as well as have a proven track record for hitting regulatory milestones successfully, according to Firestein. She adds that the ideal CMO/CDMO will also have the ability to partner in support of other portfolio and pipeline projects, have innovative technical capabilities in early-phase formulation development, and have developed a roadmap that shows commitment to keeping their facility compliant and efficient.

	Smart uses web searches, but also seeks advice and recommendations from people he trusts. “Just because a company lists a capability online, doesn’t necessarily mean they are good at it or easy to work with,” he says. He also finds it useful to create a fairly detailed request for proposal (RFP) that includes the project objectives, quantity, timeline, process description, etc. “The more detailed you can make the RFP, the more consistent the resulting proposals will be (if you get that far with a particular supplier), and the easier it will be to compare multiple proposals,” Smart explains. Compliance history should be gauged through review of recent inspections and their outcomes.

	The selection process, according to Firestein, should include a self-evaluation questionnaire, interviews, an onsite evaluation, and a thorough review of any supporting documentation. With regard to on-site audits, Smart usually advocates waiting until a supplier has been chosen, because it is a time-consuming process for both the supplier and the pharma company. Proposal acceptance can be made contingent upon a successful audit.

	The criteria by which API suppliers should be judged can vary depending on the requirements of each project. For instance, Smart notes that if difficult or specialized chemistry is involved, finding a supplier with these capabilities should be the focus. If the chemistry/technology requirements are of a more general nature, then he recommends focusing on compliance and whether the supplier appears to communicate well and will be easy to work with. “While it can be hard to assess in advance of beginning work, matching a pharma company’s project management expectations with the CMO’s way of doing things is important,” he observes.

	Firestein points to six key considerations, including manufacturing quality, capacity, culture/compatibility, cost (accuracy of the cost estimate, approach to cost-containment), data integrity, and facilities (protocols, location of raw material receiving, sampling, testing, etc.). Product quality can be gauged by comparing the CMO’s/CDMO’s regulatory history against industry standards. The percentage of clients that are repeat customers also gives an indication of client satisfaction, according to Firestein. The number and types of molecules a company has produced-and at what scale-gives an indication of manufacturing sophistication and supply chain diversity.

	Data integrity is increasingly important due to the greater emphasis being placed by FDA on this performance aspect, according to Firestein. “Data integrity issues will inevitably create regulatory challenges, but there are also impacts to communication and integration,” she notes.

	Smaller sponsor firms should also assess the CMO’s/CDMO’s roster of active clients and consider asking potential suppliers how smaller projects are not orphaned as resources are allocated to bigger-budgeted projects.

	“Ultimately, pharmaceutical companies should be looking for CMOs/CDMOs that will treat their molecules as though they were their own,” Firestein asserts. Smart adds that while geographic proximity, price, and the like can sometimes play important roles, in his experience they take a back seat to technical competence and the ease with which the sponsor can work with the supplier. 

	To an extent, the same criteria should be continuously met throughout the lifecycle of the sponsor/supplier relationship, according to Firestein. “There should be a partnership scorecard established and shared on both sides of the relationship that measures key performance criteria (e.g., on time delivery, number of deviations, batches right-first-time, etc.). It may also include volumes that need to be tracked each year, such as consumption for Drug Enforcement Administration controlled substance licenses,” she observes.

	Evaluation of CMO/CDMO performance should be ongoing, with the pharmaceutical company providing honest and timely feedback throughout a project, according to Smart. “Suppliers may not always like what they hear, but they should appreciate it because it is not in anyone’s interest for clients to be unhappy. If feedback isn’t provided, particularly when it is negative, it is hard for a supplier to improve its performance,” he says. 

	Changing suppliers is usually difficult, because institutional knowledge tends to be lost in the process. Sticking with one supplier all the way through clinical trials and into commercial production is not always possible, but is a good goal, according to Smart. “Even if a project doesn’t go smoothly, a supplier will usually learn important lessons every time a given product is manufactured,” he notes.

	Due to the costs and timelines required to onboard a new CMO/CDMO, Firestein adds that establishing a long-term partnership is advantageous. “We advise our clients to catalogue partners’ capabilities, determine partnership goals, regularly review partner results, and continuously evaluate opportunities to invest to extend the value of the partnership. These partnerships are especially beneficial in building out multi-year contractual minimums, where you can agree to dollar minimums across multiple APIs with the ability to rebalance needs as demand fluctuates.”

	While switching is difficult, in some cases a project outgrows a supplier’s capacity. In fact, some CMOs/CDMOs aim to serve only clinical needs, while others only work on commercial products. “Shifting from a clinically-focused CMO to a commercial supplier is a pretty easy decision when its necessary. If it is a decision being made because of poor performance, that can be more difficult,” Smart says.

	Clarkston Consulting clients have switched in the past due to supply or quality issues with their current CMOs/CDMOs. Others have made a change after reevaluating their supplier bases, making the decision to move from tactical to more strategic relationships with a select group of preferred partners, according to Firestein. “When pharmaceutical companies perform a risk assessment of their entire supply chain for a given product, they often discover that the risk profile is too great for their CMO/CDMO. In addition, as government agencies continue to tighten regulations across the globe, more and more CMOs/CDMOs are finding it difficult to meet the more stringent regulations, so we’re seeing more audit findings (i.e., 483s), which creates risk for pharmaceutical companies and often causes them to pursue new partners,” she observes.

	When sponsors do choose to make a change, it is important to get a good technology transfer package put together and, if possible, the assistance of the previous supplier, according to Smart. The practicality of achieving this goal often depends, however, on the circumstances surrounding the need for the change.

	CMOs/CDMOs can take steps to make themselves attractive to potential clients. First, according to Firestein, they can differentiate around a core competency in the increasingly consolidated industry, whether through quality, flexibility, or a proprietary expertise. Demonstration of a commitment to the future of their facilities is also important. “Suppliers should make it clear how they will remain compliant and efficient while leveraging industry best practices and new technologies,” she says. CMOs/CDMOs can also prove their dedication by acting as extensions of their clients’ strategic imperatives and showing that their organizations will be aligned through good times and challenges.

	For suppliers looking to establish new relationships, the sales team plays an important role in conveying what it would be like to work with them, according to Smart. “Some CMOs/CDMOs never really get a chance at a new project if their business functions aren’t easy to work with,” he observes. Smart also believes it is important for CMOs/CDMOs to get key technical personnel involved during the early phases of the sales process in order to provide prospective clients a good window into their organizations. “Being perceived as a company that is easy to work with and responsive to client needs is, all other things being equal, a key factor in the selection process,” he concludes.

Vol. 42, No. 4
	April 2018
	Pages: 26–29

	When referring to this article, please cite it as C. Challener, "Unlocking the Best Solution for API Sourcing" 

Articles

CMOs/CDMOs that are easy to work with, have demonstrated performance track records, and plan for the future are preferred.

Unlocking the Best Solution for API Sourcing

The switch in emphasis in the pharmaceutical industry from the development of blockbuster drugs to therapies that treat rare diseases and smaller patient populations has led to the need for small-volume current good manufacturing practice (cGMP) API manufacturing capabilities. These APIs must meet the same regulatory requirements as larger-volume drug substances, except at smaller scale and with less-but much higher value material-available for analytical testing, and often under accelerated timelines. In addition, the APIs used to formulate these products are typically highly complex, requiring multi-step syntheses using unusual reagents. Managing multiple projects can be a challenge for contract development and manufacturing organizations (CDMOs).

	CDMOs often manage at any one time numerous small-volume API development projects involving a wide range of chemicals targeting a broad array of therapeutic indications. As a result, they must deal with many different challenges simultaneously. “These molecules tend to by highly complex, and most have never been synthesized before except perhaps at small scale in the laboratory. They also typically require the application of specific, sophisticated technologies, some of which must be engineered for the first time,” says Ed Price, president and CEO of PCI Synthesis.

	Practical syntheses must be developed that can be transferred to cGMP processes that consistently meet quality requirements. Even though commercial processes for these APIs involve smaller volumes than those of APIs intended for blockbuster drugs, scale-up issues must still be addressed. Understanding critical process parameters (CPPs) and their impact on critical quality attributes (CQAs) is essential to understanding the process and conducting risk evaluations for unit operations and equipment to ensure “right-first-time” technology transfer, according to Shyam Vispute, general manager of tech transfer at Neuland Labs.

	Analytical methods must also be developed and validated, which can be challenging due to the complexity of the molecules. In addition, given the small quantities of high-value material being manufactured even at commercial scale, minimizing the quantity of material consumed in these activities is important. “Alternative protocols may need to be developed in some cases to allow for use of reduced quantities of these costly APIs,” Vispute says.

	The complex molecules being developed as drug candidates today require sophisticated technology for their production, such as advanced chromatography systems and specialized isolation techniques like tangential flow filtration, according to Price. PCI Synthesis has seen the need for low-temperature chemistry grow significantly. “Doing cryogenic chemistry is manageable at the lab scale but is much more challenging at the 1000-gallon scale,” he says.

	Often it is necessary to design suitable hardware for use in the laboratory and then transfer the technology to plant scale, according to Vispute. In some cases, existing equipment can be modified, but in others new systems must be purchased.

	Scale-up and optimization of small-volume processes can be challenging because for many there is little information available in the literature. “It is essential to consider all of the various process parameters-temperature, pressure, mass transfer, etc.-upfront,” Vispute observes. Risk analyses for each unit operation-reaction and purification (extraction, distillation, crystallization, filtration, etc.), drying, and powder processing-should be conducted to avoid problems at plant scale.

	Joshua Hoerner, senior director of research and development at Noramco Athens, notes, however, that solution mixing, pressure, and temperature challenges may actually be reduced on a small-volume basis due to the smaller surface areas involved.

	In some cases, the batch scale, which is determined from the dosage strength of the final formulation, will impact the choice of technology used in a synthesis. When developing peptides, for example, researchers must determine whether solid-phase, solution-phase, or hybrid technology is most appropriate, according to Partha Pal, head of custom manufacturing solutions and business development for Neuland Labs.

	Because most of these molecules have not been synthesized on any appreciable scale before, it is also necessary to develop practical purification strategies, according to Price. Poorly soluble compounds falling in Biopharmaceutical Classification System (BCS) classes II and IV can be particularly challenging. “Exploring all available techniques to improve solubility and bioavailability, such as employing suitable techniques to modify the physicochemical properties or increase the specific surface area of the API powder particles, is often necessary,” notes Girish Kavishwar, associate vice-president of R&D at Neuland Labs.

	Some isolated intermediates and APIs may be oily liquids, which can create handling and stability challenges, according to Hoerner. “Managing active ingredients that are predominately viscous oily liquids is a significant challenge, both from a handling and stability perspective. Noramco is working on dosage form solutions to help improve the processability of such substances while also enhancing their commercial shelf-life,” he notes.

	Crystalline powders, on the other hand, may have different polymorphs and crystal habits that can impact drug product manufacturing robustness and the bioavailability of the API, Hoerner adds. “Identifying and stabilizing the appropriate polymorph requires special skills and should be performed early on in the process to avoid problems late in the development cycle,” agrees Pal.

	Handling cytotoxic and highly potent compounds is yet another issue. Appropriate facility and equipment design is required for handling such compounds, and appropriate disposal facilities are also required based on their occupational exposure limits. Automation of process operations is also important for reducing the exposure of operators and the environment to hazardous chemicals, according to Pal. “A process hazard analysis (PHA) should always be conducted prior to implementing a small-volume cGMP synthesis to systematically identify and mitigate hazards that arise from innate chemicals or chemical reactions,” Hoerner asserts.

	One of the key technical and operational challenges associated with cGMP manufacturing of small volumes of intermediates and APIs is difficulty in obtaining reliable reaction yields and consistent quality, according to Hoerner. Noramco tackles this issue with thorough process development efforts to maximize process knowledge and understanding. In-process controls for monitoring reaction completion, crystallization, drying, and other critical steps are also used to ensure completion.

	“Overall, we emphasize a company culture that focuses on the patient/customer and ensures our products are of optimal quality and produced in a safe and compliant manner,” Hoerner comments. From a technical perspective, Noramco begins at the R&D stage, selecting and developing a phase-appropriate route and evaluating critical raw material sources, reagents/solvents, equipment, and analytical controls to ensure robust delivery of cGMP material. In addition, Hoerner says that scale changes between development and cGMP supply are modeled with advanced software; process analytical technology (PAT) or advanced offline analytical technologies are applied to synthetic steps that are highly complex or have significant risk to impact product quality.

	Neuland uses quality-by-design (QbD) and design-of-experiment (DoE) approaches beginning at the development stage to identify relevant process parameters and identify the design space that will have minimal variations at the plant scale, according to Vispute. Use of simulation software, such as for scale up and mixing behavior studies, allows the evaluation of equipment performance prior to actual experimentation in the plant, leading to reduced costs and development times for Neuland. PAT tools are used for real-time measurement of CPPs, such as focused-beam reflectance measurement (FBRM) probes for particle size distribution, particle vision and measurement (PVM) probes for particle shape and polymorph determination during crystallization processes, infrared (React IR , Mettler-Toledo) for monitoring the real-time progress of reactions, and near infrared (NIR) probes to perform drying profile studies for determination of desired polymorphic forms of temperature-sensitive products.

	The internal protocol at PCI Synthesis places emphasis on doing a good job at building a practical process early on in a project. “Once the chemistry and analytics are locked in, if any changes are needed, a tremendous amount of work will need to be repeated. That is why it is so important to take the time upfront to choose the right raw materials (considering cost and availability), really understand the process, and build into the early stage chemistry what will be required down the road,” Price observes. Process optimization using a DoE approach allows efficient yet thorough exploration of the design space. Method development for in-process and final product testing and confirmation of process robustness and reliability at larger scale are then performed before moving to GMP production.

	Small-volume cGMP chemistry is clearly an area that can pose significant challenges. “The first focus should always be on safety and compliance during manufacturing and ensuring robust production of high-quality intermediates and active ingredients,” Hoerner says. That cannot be achieved if small-volume API manufacturing is treated as a commodity business, according to Price.

	 “We work with many different small companies, each with its own business model, culture, internal resources, and level of experience. Each project they bring us is unique, involving vastly different raw materials, equipment, and chemistry. Flexibility and the ability to respond to the different needs of our customers and their projects are crucial to success. We must be able to bring a significant number of differing resources to bear to create custom-tailored solutions to complex problems,” Price concludes.

Vol. 42, No. 3
	March 2018
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, " Small Volumes, Big Challenges" 

Highly complex APIs developed to treat rare and orphan diseases present big technical questions for contract developers.

Small Volumes, Big Challenges

Excipients are crucial ingredients in final drug formulations with potential impacts on product quality, stability, tolerance, release profiles, local distribution and availability, and thus overall efficacy and safety. Recent regulations have increased the requirements for drug manufacturers and excipient suppliers with respect to ensuring the quality and safety of excipients. The emphasis continues to be on the use of risk assessments and the growing recognition that excipient producers and pharmaceutical companies have shared responsibility for ensuring excipient safety.

	Excipients are becoming a top priority among regulatory agencies. Regulatory bodies in the United States, European Union (EU), and Japan, as well as those in the ‘BRICK’ (Brazil, Russia, India, China, and Korea) countries, are modifying existing and/or introducing new regulations for finished pharmaceutical products that specifically address excipients, either directly or indirectly. Many of these regulations have an impact beyond domestic production of drug products, according to Priscilla Zawislak, global regulatory affairs advocacy manager with Dow Pharma Solutions. National pharmacopeias are also placing a greater emphasis on standards for excipients.

	Regulations on excipient risk assessment were issued by the European Medicines Agency (EMA) in 2015 (1) with implementation required by March 21, 2016. An update of the annex to the European Commission’s guideline on excipient labeling by EMA on Oct. 9, 2017 (2) included the expansion of safety warnings for 10 excipients and the addition of five new excipients to the list, according to Mario DiPaola, senior scientific director at Charles River Labs.

	“Recent draft guidance documents issued by FDA, such as the 

 guidances, are examples of why drug product manufacturers must have a better understanding of what’s needed to comply,” adds Zawislak. “Open communication with suppliers about the composition, functionality, and performance of excipients in a drug product is essential. Excipients are no longer regarded as inactive and it is no longer sufficient to simply provide excipient specifications in an investigational new drug application (ANDA). FDA now requires drug product manufacturers to tell the full story about the role and interaction of the excipients with the API in final drug products,” she continues.

	In China, “Bundling Review” requirements were included within the 

 2015 standards (3) and will be retained in its future 2020 version.

	Industry has also been active in updating voluntary guidelines on ensuring excipient quality and safety. The updated International Pharmaceutical Excipients Council (IPEC) 

 (4) by the IPEC Federation was issued in November 2017. Earlier in the year, the group also published updated guidelines on both excipient good manufacturing practice (GMP) (5) and good distribution practice (GDP) (6), as well as excipient risk assessments (7), according to DiPaola.

	Regulatory proliferation driving communication

	The proliferation of regulations in many different countries and regions around the world has resulted in different excipient requirements that are often not fully aligned with one another. Global excipient suppliers must work with customers to find ways to meet these challenges across multiple regions, sometimes for one particular type of application, according to Zawislak.

	 “More diligence is required when excipients fall under drug or API regulations,” she says. For example, she notes that Brazil and India have requirements for a specific amount of remaining shelf life for imported drug products, which includes excipients, APIs, and finished drug products. Defining a shelf life in this case is different than for APIs and drug products imported into other countries. “Open communication between raw material suppliers and formulators is particularly important here, because without knowledge of the end use, suppliers cannot help ensure that formulations are in compliance,” Zawislak states.

	With the proliferation of more regulations for excipients in the BRICK countries and in emerging countries, Dow Pharma Solutions is also initiating dialogue with regulatory agencies as well as customers to address some of these differences. “We see this situation providing a good opportunity, because it opens lines of communication and leads to greater awareness of the key role excipients have in pharmaceutical products,” asserts Zawislak.

	In addition to focusing on excipient quality in recent years, regulatory agencies have strengthened their positions on preventing drug adulteration of both APIs and excipients by enacting a number of new regulations, ultimately requiring tighter control of the manufacturing processes and testing, according to DiPaola.

	 “A major area of concern in excipient quality is contamination from a number of potential sources, including viruses; microbial and endotoxin/pyrogen contaminants; transmissible spongiform encephalopathy; and impurities resulting from raw materials, byproducts generated during processing, and product degradants. Lack of sterility for excipients deemed sterile is also a potential issue,” DiPaola says.

	These problems can occur for a number of reasons ranging from the lack of dedicated equipment and/or facilities for the manufacturing of excipients; poor environmental control during manufacturing; and/or inappropriate storage and shipping conditions, among others.

	Given this sizeable list of concerns, regulatory bodies have begun to expect excipient users (e.g., drug manufacturers) to perform extensive risk analyses and implement mitigation plans for situations deemed to be high-risk. “Such mitigation strategies may require more testing of excipients for the presence of contaminants or require more control of the manufacturing process and distribution,” notes DiPaola.

	One example is the EU guideline that became effective in 2016. It requires more formalized risk assessments to be conducted on a regular basis. This approach is not limited to the EU, however, according to Zawislak. “We have seen risk assessments become more of a standard globally as a tool in managing raw material and supplier qualification,” she says.

IPEC-PQG Good Manufacturing Practices (GMP) for Pharmaceutical Excipients 2017

 (5), which was published in May 2017, was updated partly in response to the increased requirements for drug manufacturers to perform risk assessments for excipients to determine the appropriate level of GMP that should be used to produce them. It also takes into account third-party standards (EXCiPACT and ANSI) “against which excipient suppliers can be certified to provide assurance that they are operating in conformance with excipient GMP,” according to an IPEC news release (8).

	With increasing regulatory and business demands, the relationships between excipient suppliers and medicinal product manufacturers have never been so important, according to Dominik Odenbach, director, global regulatory and external affairs, Pharma & Human Nutrition, BASF. “A mutual understanding of what is appropriate to ensure the safe and reliable supply of high quality excipients is essential, and it is in the quality agreement that these expectations can be defined,” he explains.

 (4) reinforces the fact that the business of ensuring excipient safety is a shared responsibility between excipient users and suppliers, according to DiPaola. “The quality agreement enables the drug manufacturer and the excipient supplier to establish a partnership through which all quality requirements and responsibilities are clearly delineated. This legally binding agreement provides a process by which costly product quality issues can be minimized and ensures that the drug manufacturer can meet its regulatory expectations and requirements,” he explains.

	“We have found that use of the IPEC QA templates published in 2009 significantly facilitate and accelerate the negotiations between excipient suppliers and customers and, hence, reduce the workload related to the review and discussion of quality agreements for all parties involved,” adds Odenbach. “BASF strongly promotes the use and further optimization of standard templates.”

	The major change incorporated in this latest version of the 

 is the addition of the Manufacturer’s Statement. The original version of the guide addressed the need to have a quality agreement between the excipient manufacturer and its direct customer (e.g., the drug product manufacturer or distributor) and between the distributor and its customer.

	In recent years, customers who buy from distributors have been requesting quality agreements with excipient manufacturers as well. However, because there is no direct business relationship between the excipient manufacturer and the distributor’s customer, formalizing a three-way company agreement would be necessary-and complicated, according to Zawislak.

	The Manufacturer’s Statement addresses this gap. It is written by the excipient manufacturer to define its quality responsibilities for manufacturing the excipient through its lifecycle (e.g., maintenance of a quality management system, adherence to GMPs, change notification, etc.). The Manufacturer’s Statement is signed and dated by the manufacturer and can then be attached to agreements between distributors and their customers.

	“It is important to note that the Manufacturer’s Statement is not a full quality agreement between three companies or a stand-alone document. It is, however, a signed statement from the excipient manufacturer regarding its quality responsibilities, which are generally the same regardless of the end-use customer. As a result, the need for a three-way quality agreement is eliminated, yet each party is protected with respect to quality assurance,” Zawislak observes.

	Aside from variations in the regional regulations designed to ensure excipient safety, a key challenge for the pharmaceutical industry is the lack of integrity and transparency within the excipient supply chain and variability in the quality of excipients, according to DiPaola.

	Significant test method variability is another issue for Ann Gulau, a quality assurance scientist at Dow Pharma Solutions. “This variability should be considered when setting monograph and specification limits. Currently, there are many tests that have much higher variability than the monograph specification limits. As a result, significant amounts of material are discarded as unsuitable for pharmaceutical use, despite no real safety or quality concerns,” she explains.

	Further issues for DiPaola are the limited amount of testing currently performed for excipient release and the lack of robust stability data.

	Updated and harmonized monographs needed

	Most current excipient testing is conducted according to pharmacopeia methods, which like excipient regulations, vary on a regional basis.

	“It is not value-added to measure essentially the same properties with different methods to satisfy all regional requirements. There are frequently minor regional test differences in various pharmacopeia that require additional testing or studies to prove equivalency. This additional testing does not improve product quality or patient safety,” asserts Barbara Serr, business analytical leader for Dow Pharma Solutions.

	For instance, despite the global pharmacopoeial harmonization efforts in the US, Europe, and Japan, the 

) develops individual excipient monographs with separate requirements, according to Odenbach. “For an excipient manufacturer, higher analytical efforts and costs to release globally used materials are necessary to introduce products to the Chinese market, if possible at all. These stringent Chinese requirements create new hurdles to trade, restricting choice, and raising costs, also for pharma manufacturers or consumers,” he says.

	Complicating this particular issue is the lack of timely availability of an official-and therewith binding-English translation of the 

 compliance, analytical method set up and validation work must be performed in the release labs of the excipients manufacturers, for non-Chinese speaking lab personnel an impossible task. In addition, from a technical and testing point of view, several excipient monographs require technically non-achievable limits and/or demand the performance of technically non-feasible methods. Furthermore, scientific cooperation with the Chinese Pharmacopoeia experts in advance is difficult and protracted,” Odenbach states.

	Many of these methods also are in need of modernization. “Current methods tend to be highly time consuming, frequently lack appropriate sensitivity, and generally rely on older analytical technologies,” observes DiPaola. Adds Serr: “Continuation of old limit tests to satisfy some regional pharmacopeia is unwarranted and unnecessary testing. Additionally, some test items may simply be historic without any real relationship to patient safety. Monographs should be updated with a focus on items that are real safety concerns instead of simply continuing historical practices without real purpose.

	One recent example of an improvement is the conversion from old wet chemical methods to the use of inductively coupled plasma-mass spectrometry for elemental impurity determinations. “Using this advanced analytical technique has revealed that many excipients do not contain any of the elements of concern,” Serr notes.

	DiPaola would like to see more use of mass spectrometry for the detection and characterization of impurities/contaminants and newer ultra-high-performance liquid chromatography technology with high-resolution columns.

	Ultimately, according to DiPaola, pharmaceutical manufacturers are held accountable for the overall quality and safety of pharmaceutical products. They are thus applying more pressure on excipient suppliers for greater control of the quality and safety of their excipients, as well as tighter control of excipient distribution.

	At the same time, regulation in the pharmaceutical industry is a dynamic situation, according to Zawislak. “Patient safety is the ultimate goal and often requires development of regulations and standards to achieve that goal in an ever-changing world. Regulations also need to keep pace with emerging technologies and innovations in drug development,” she observes.


	Vol. 42, No. 2
	February 2018
	Pages: 36–41, 61

	When referring to this article, please cite it as C. Challener, “Managing Risk in a Complex Excipient Supply Chain," 

Regulations and industry guidelines focus on ensuring excipient safety by specifying risk assessments and shared responsibility.

Managing Risk in a Complex Excipient Supply Chain

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," 

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.