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

Cynthia A. Challener

Continuous processing is attracting attention in the manufacture of both small-molecule drugs and biopharmaceuticals. In small-molecule manufacturing, flow chemistry has many advantages, including increased development speeds, improved product and process consistency and thus product quality, greater process safety when employing hazardous chemistries, the opportunity to perform reactions that cannot be run under batch conditions, and reduced capital investment and operating costs. 

	Continuous downstream processing operations offer many similar advantages, and there has been more focus on integrating continuous downstream processes with continuous flow synthesis. While many downstream processes can be readily adapted to run continuously, such as extraction, phase separation, and distillation, others-particularly those related to solids handling-present greater challenges.

	Several research groups supported by industry have focused on continuous crystallization. The Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization (CMAC), for instance, has support from founding members such as GlaxoSmithKline, Novartis, and AstraZeneca and is developing continuous processes for all stages of crystallization that are efficient, cost-effective, scalable, sustainable, and precisely control the form, size, shape, purity, surface structure, and functionality of crystallized drug intermediates and APIs. Researchers at the Novartis-MIT Center for Continuous Manufacturing have investigated methods for the direct crystallization of APIs on polymer excipient surfaces and the incorporation of continuous crystallization processes within an integrated continuous manufacturing pilot plant, which requires careful selection of appropriate process analytical technology (PAT).

One of the advantages that can be realized by implementing integrated continuous processing is reduction of the number of processing steps typically required for completion of the same process in batch equipment. For crystallization processes, direct crystallization of a pharmaceutical intermediate or API on the surface of a polymeric excipient can lead to the simultaneous separation of impurities and formation of a drug-excipient composite. This result may cause the elimination of several solid-handling steps that are typically required for the downstream processing of solid products, according to Bernhardt L. Trout, the Raymond F. Baddour professor of chemical engineering at MIT and director of the Novartis-MIT Center for Continuous Manufacturing. “If crystallization can provide a product with the appropriate physical properties, it is possible to eliminate the need for milling, granulation, and other processes,” he says.

Importance of heterogeneous nucleation
	

Heteronucleation involves the formation of crystal nuclei at a solid-liquid interface and can be employed to control nucleation and, potentially, polymorphism, which is important for the production of APIs with stable forms (1). There is some evidence, according to Trout, that the surface morphology of the solid affects the crystallization process. “In particular, the use of nano-patterned substrates can affect not only the nucleation kinetics, but phase stabilization, polymorphism, and the orientation of the resultant crystals,” he adds.

Heteronucelation of a single compound using different polymeric substrates can provide access to a wide range of polymorphs for that compound, because the different surface morphologies of the polymers result in different interactions at the polymer-crystal interface (1). Nanoimprinting of polymers provides a way to impart specific surface geometries that can be used to influence nuclei formation and ultimately polymorphism, according to Trout. “Our supposition was, therefore, that nanoimprinting of polymers that already provide favorable surface-solid interactions to create surface geometries that lead to nanoconfinement should allow for control of crystallization behavior,” he comments. It should be noted that the functionality of the polymer and whether it is more hydrophilic or hydrophobic determines the interactions between the solute and the polymer surface, and thus the crystallization process.

	Trout and his colleagues examined a range of polymer types to determine their effects on this templated crystallization process. To create the engineered polymer surfaces, a rigid, flat silicon mold with nanometer-sized and mono-dispersed pillars of varying angles was fabricated using interference lithography. Negatives of the mold were then transferred to polymer films using nanoimprint lithography. “With this method, it is possible to create both hydrophobic and hydrophilic polymer surfaces with nanopores of many different shapes and sizes. By considering the structure of the API, it may therefore be possible to choose a specific polymer and nanopore structure that will result in crystallization of a specific polymorph of the API, even metastable forms,” Trout notes. For example, favorable interactions can be observed by matching the surface geometry angles with the angles between dominant faces of the desired polymorph of a compound, according to Trout. Enhanced nucleation rates and alternation of the polymorph distribution can result.

	Initially the biocompatibility of the polymers was not considered; eventually the researchers focused solely on polymers that have generally-recognized-as-safe (GRAS) status given that these polymers can be used as excipients in final drug formulations, says Trout. The processability and solubilities of the polymers were also considered. Pharmaceutically acceptable organic solvents were also screened to find an appropriate crystallization solvent.

Effective continuous crystallization in an integrated process
	

Continuous crystallization techniques in the pharmaceutical industry are typically developed as stand-alone processes, but in many cases, the goal will be to develop a fully integrated continuous process involving flow chemistry, purification, and final formulation. In such a setting, the crystallization process can be affected by events that occur upstream, and careful control of the crystallization conditions is required to ensure that all critical material attributes and critical process parameters are met on a continual basis.

	Trout and several colleagues at MIT have investigated the implementation of continuous crystallization in the pilot plant developed at the Novartis-MIT Center, which is designed for integrated continuous manufacturing (ICM) of pharmaceutical compounds (2). “The most significant result of this study, which involved the two-stage continuous crystallization of aliskiren hemifumarate as part of an ICM pilot plant, was the determination that the use of a combination of different PAT tools and automated control loops was sufficient to maintain operational performance within specifications for extended periods of time,” Trout states. In fact, the continuous reactive crystallization was performed for more than 100 hours in the integrated process, providing product with a purity >99% and a yield of 91.4% (2).

1. V. Lopez-Mejías, A. S. Myerson, and B. L. Trout, 

, 13 (8) 3835−3841 (2013).
	2. H. Zhang et al., 


	When referring to this article, please cite as C. Challener, “Considering Continuous Crystallization,” 

Articles

An integrated pilot plant tests heteronucleation and continuous crystallization.

Considering Continuous Crystallization

	For many reasons-from ease of administration to dosing accuracy to manufacturing efficiency-pharmaceutical manufacturers prefer to formulate their APIs as solid dosage drugs, and particularly tablets. There is significant room, however, for improvement of tableting processes.


	Lubricants (commonly magnesium stearate) affect the tableting process and the finished tablet. They not only reduce the compression force during tableting, but also prevent product buildup on tablet press tools and give the tablet a smooth surface. Too much lubricant can, however, reduce the hardness of the tablet to an undesired level, according to Sharon Nowak, business development manager with Coperion K-Tron Food & Pharmaceutical Industries. Traditionally, lubricants have been mixed with the solids used to form tablets, but this approach often leads to non-uniform distribution of the lubricant. To compensate, excess lubricant is used, which can negatively affect tablet properties.
	
	Recently, equipment has been developed that allows for spraying of the lubricant onto the tablet press tooling, allowing for significant reduction in the quantity of lubricant required. Original systems sprayed powdered lubricants on to the tablet press tooling to prevent sticking of the powder to the tool and die of the tablet press, according to Nowak. Importantly, these applications were done primarily volumetrically, with no measurement of the actual weight of the lubricant delivered. Magnesium stearate does not flow well, which can cause high variations in the feed rate with volumetric feeders because of inconsistent filling of the twin screws. As a result, there has been an increased demand for automated tablet press lubrication systems with highly accurate gravimetric feed designs, according to Nowak.

	“High accuracy twin-screw gravimetric feeders quantitatively deliver a specific amount of lubricant to the tablet. They also allow accurate determination of the amount of lubricant delivered to each tablet, even though the quantity of lubricant that ends up in the tablet granulation formulation is significantly decreased,” she observes. As a result, not only are the material handling properties of the granulation process improved, the overall dissolution rates of tablets can be increased. The lower quantities of lubricants required for tableting have also led to a need for lower and lower feed rate deliveries, according to Nowak. “For this reason, automated lubricant feeding systems today require highly accurate, specialized low-rate feeding,” she says.

	Coperion K-Tron’s solution uses patented load cell technology that continuously measures the weight of the lubricant and maintains a constant mass flow (weight per unit of time) by adjusting the speed of the twin-screw feeder. As a result, according to Nowak, the unit can be validated for a steady and uniform feed of lubricant to the tablet press. In addition, because the lubricant is delivered to the tools in a fraction of a second, the short-term accuracy is high. “With a nearly constant feed rate, it is possible to achieve uniform coating of the tablet tools and eliminate sticking problems, all with reduced stearate consumption and lower overall operating costs,” Nowak states.
	
	

Multi-tipped tooling and advanced coatings


	The key drivers in tablet manufacturing are the need to increase yield and capacity while reducing manufacturing costs and minimizing the space used and the time spent setting up each press, and increasing productivity has always been a challenge in modern tablet production, according to Steve Deakin, owner director of I Holland. That is why he believes the widespread use of multi-tipped tooling and the continued development of punch-and-die treatments and coatings have been great advances in the pharmaceutical industry.
	
	“Our ongoing development of multi-tip tooling is specifically driven by the desire to assist our customers in increasing productivity and capacity,” he says. Multi-tip punches allow the number of tablets per turret rotation to be multiplied by the number of tips on the punch. They also require less floor space, because more tablets can be produced with fewer tablet presses, leading to a reduction in overall plant running costs. “The development of a technology like multi-tip tooling is beneficial to many end users,” says Deakin.

	With respect to treatment and coating technologies, I Holland categorizes them based on their function: improving wear resistance, improving corrosion resistance, and improving anti-stick properties. “Treatments and coatings with these properties can help preserve the life of our punches and increase productivity for our customers,” Deakin comments. “The overall result is reduced press downtime and increased productivity, which is what every company wants,” he adds.


	Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology. Read the complete article by Cynthia Challener, with additional discussion of continuous manufacturing, systems integration, and modeling, in the 

Learn More from Sharon Nowak and Others at Interphex

 will host solid dosage manufacturing experts on the Innovation Stage. Come hear Sharon Nowak, Business Development Manager, Coperion K-Tron Food & Pharmaceutical Industries, speak about 

Optimization of Feeding and Conveying Technologies for Difficult Flowing Pharmaceutical Powders; 

Martin Hack, vice-president and general manager, L.B. Bohle, speak about 

Fluid Bed Technologies for Improved Processing; 

and Fred Murray, president, Korsch America, speak about 

Innovations for tablet tooling and presses improve quality and productivity.

Specialized Equipment Improves Tableting

	In September 2011, the US Government Accounting Office (GAO) published a report on the challenges that FDA faced in assuring the safety of the API supply chain given that reliance on APIs produced by foreign manufacturers has risen dramatically and the complexity of the global pharmaceutical supply chain has increased significantly over the past two decades (1). The report found that while FDA had increased inspections of foreign API manufacturers (up 27% from 2007 to 2009, for example), its rate of inspection for foreign establishments was still far below that for domestic manufacturers. In addition, most foreign inspections were scheduled far in advance, conducted under controlled circumstances, and typically occurred during much shorter time frames. GAO also determined that FDA still lacked important information about foreign API manufacturers (1).

	On a positive note, GAO recognized that FDA had begun to implement initiatives designed to improve its oversight of the drug supply chain, including increased training by overseas offices, the development of programs for control of APIs and other drug products entering the United States, and a push for risk-based inspections rather than a set schedule (1). The GAO concluded, however, that FDA needed to implement changes more rapidly to better assure the safety of drugs on the US market (1).

	Since that report, new legislation has affected FDA ‘s ability to schedule and conduct inspections of API manufacturers. As a result, inspections of foreign manufacturers have increased dramatically--along with warning letters--while inspections of domestic manufacturers have decreased.


	The most important piece of legislation affecting FDA ‘s ability to improve the safety of the pharmaceutical supply chain is the Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012. The Generic Drug User Fee Amendments (GDUFA), included as part of FDASIA, instituted a Generic Drug User Fee Program that was agreed to by FDA and the generic-drug industry, specifically the Bulk Pharmaceutical Task Force (BPTF) of the Society of Chemical Manufacturers and Affiliates (SOCMA), the European Fine Chemicals Group (EFCG), and the Generic Pharmaceutical Association (GPhA).

	The user fees are intended to provide additional funding for FDA ‘s drug approval and inspection efforts with the goal of increasing the safety of generic drugs and the ingredients used to produce them, increase the speed of the drug approval process, and the transparency of the industry. One of the main goals of GDUFA is to ensure that foreign facilities are inspected at a rate equal to that of domestic facilities. The fees raised through GDUFA have enabled FDA to hire approximately 1000 additional employees, making it possible for the agency to complete more inspections and speed up the approval process for abbreviated new drug applications (ANDAs) and the review of drug master files (DMFs).


	Several other aspects of the FDASIA legislation have also impacted the API and formulated-drug supply chain. For instance, FDASIA requires FDA to identify facilities involved in the manufacture of generic drugs and associated APIs. “Prior to FDASIA, FDA didn ‘t know how many facilities were producing formulated drugs or APIs in the US, let alone how many companies around the world were manufacturing APIs and formulated drugs and exporting them to the US,” says John DiLoreto, executive director of BPTF. Before the self-registration process began, the industry estimated that there were 1700-2000 manufacturing sites around the world. After the registration process was complete, that number was reduced to approximately 1300. DiLoreto believes that some consolidation of manufacturing plants occurred as companies looked to reduce the GDUFA fees they would have to pay by consolidating operations.

	In the most recent report on foreign and domestic drug establishments issued by FDA (2), the agency identified a total of 12,949 registered drug establishments in 2014, including 9330 domestic and 3619 foreign (slightly up from 12,613 in 2013. Of those 12,949 facilities, 4383 were registered as finished drug product (FDP) establishments, and 1495 were registered as API establishments. (If a site produces both finished drug products and APIs, it is placed in the FDP category.) The remaining 7071 establishments fell into the “other” category, which includes facilities that produce, compound, or process medical gases, medicated feed, and some biologic drugs.

	FDASIA also grants FDA the authority to confiscate and destroy unsafe APIs and drug products being imported into the US. With its increased ability to track the manufacturing activities and inspection histories of API and drug manufacturing sites, the agency can determine if APIs or finished drug products were produced at a facility that has not been FDA-inspected or is not in compliance. The agency has also published guidance on what conduct it considers as delaying, denying, limiting, or refusing inspection, actions that can result in determination of a drug to be adulterated. In addition, under GDUFA, all drugs produced in an unregistered facility or in a facility for which the GDUFA fees have not paid are considered “misbranded.”

	“Together, these new capabilities of the agency make it possible for potentially unsafe APIs and drug products to be removed from the marketplace completely,” DiLoreto says.

	FDA is also using the information on establishments to prioritize them according to the level of risk each represents. Rather than inspect facilities on a set schedule as was the case in the past-typically once every two and one-half years on average for domestic facilities and once every 10 years or more for foreign manufacturing sites-the agency now determines which facilities to inspect based on the overall level of risk they pose, which is determined using a model that takes into account inherent risk, outbreaks, recalls, adverse events, and compliance history (3). This move has led to a dramatic increase in foreign inspections and a concomitant decline in domestic inspections.

	In fiscal year (FY) 2014, the total number of foreign and domestic high-risk human drug inspections by FDA was 918, which exceeded the agency ‘s target of 750 (3). In FY 2013, 443 domestic and 365 foreign high-risk establishments were inspected (total of 808); 43 GMP-based warning letters were issued as a result of those inspections (4). Overall in FY 2013, FDA conducted 967 domestic and 604 foreign GMP inspections (3). In FY 2014, those numbers were 780 and 757.  FDA estimates that in both FY 2015 and 2016, there will be 591 domestic and 843 foreign inspections.

	Both the agency and the industry are adjusting to the risk-based inspection approach, according to DiLoreto. “When FDA first indicated that it would be decreasing domestic inspections so significantly, BPTF was initially concerned that domestic facilities would not be receiving inspections often enough, particularly those exporting to Europe, because the European Medicines Agency (EMA) requires pharmaceutical manufacturers importing products into the European Union to have had an inspection within the previous three years,” notes DiLoreto. The agency has addressed those concerns and established an agreement with EMA. “One of the primary goals of GDUFA was to achieve inspection parity between foreign and domestic facilities, but the change to a risk-based program allows FDA to better utilize resources,” he adds.


	An additional step in the right direction was made in December 2014 when FDA Commissioner Margaret Hamburg signed an agreement with Chinese officials to collaborate on inspections in China that builds on an initial agreement signed in 2007 (5). China also finally agreed to provide additional visas for more FDA inspectors, which will allow the agency to boost its number of employees from 13 to 33.

	FDA is working with EMA on joint inspections and trying to establish mechanisms for sharing of inspection data, according to DiLoreto. BPTF would like to eventually see EMA and FDA inspections results considered to be equivalent. There are, however, concerns on the part of some manufacturers about how confidential business information can be adequately protected under such a scenario.


	Despite the numerous advances that FDA has made in addressing concerns about APIs and formulated drugs manufactured overseas, there are still many challenges facing the agency. Some foreign governments still do not welcome the agency, and inspections of foreign facilities still suffer from many restrictions. DiLoreto does believe, however, that the situation is improving in many countries, as indicated by the recent agreement in China.

	There is also the issue of the dramatic increase in warning letters issued to foreign manufacturers that has occurred along with the rise in foreign inspections. DiLoreto expects these problems to be resolved once these manufacturers have been educated about GMP requirements and become familiar with the expectations of FDA. “It is not surprising that issues are being found at facilities that are being inspected for the first time. These facilities will implement the required improvements, and the number of citations will decline as more effective quality programs are put in place,” he observes.

	It is also important to remember, according to DiLoreto, that many of the FDA inspectors now on the job are still quite new. “It takes at least two years for an FDA inspector to be fully trained, because it take time for him/her to gain the practical experience needed for the job,” he says. “A large percentage of current FDA inspectors don ‘t have that two years of experience yet, and while new inspectors are on the learning curve, issues can arise,” DiLoreto continues. These difficulties, however, should also be resolved in the next few years, he notes.

, “Drug Safety: FDA Faces Challenges Overseeing the Foreign Drug Manufacturing Supply Chain,” Sept. 14, 2011 (Washington, DC).
	2. FDA, 

2015 Annual Report on Inspections of Establishments in FY 2014

, January 2015 (Rockville, MD).
	3. Department of Health and Human Services, 

Fiscal Year 2015 Food and Drug Administration Justification of Estimates for Appropriations Committees

, February 2014 (Washington, DC).
	4. Department of Health and Human Services, 

Fiscal Year 2016 Food and Drug Administration Justification of Estimates for Appropriations Committees

, Jan. 30, 2015 (Washington, DC).
	5. M. Mansour et al., “United States: FDA And China Agree To Collaborate On Inspections,” 


	When referring to this article, please cite as C. Challener, “FDA Steps Up Foreign Inspections,” 

New legislation and changes in policy at FDA are leading to better control of the API supply chain.

FDA Steps Up Foreign Inspections

Innovative equipment, analytical techniques, software, and modeling systems are improving the tableting process.

Advances in Tableting

					Thinkstock Images/Stockbyte/GETTY IMAGES

	The market for formulated drugs based on highly potent active pharmaceutical ingredients (HPAPIs) is growing at a rapid pace, largely due to the development of highly targeted therapies based on antibody-drug conjugates, which can include cytotoxic small-molecule components. The manufacture of this expanding field of HPAPIs is challenging and requires specific know-how, facilities, equipment, and procedures designed to mitigate the risk associated with producing and handling potent compounds. Standards and technologies are continually changing, and HPAPI manufacturers must remain vigilant and prepared to adopt and implement the latest designs, equipment, training, and procedures to reduce the risks posed by HPAPIs.


	Although many challenges exist for high-containment API manufacturing, the variability and uncertainty associated with each compound present the greatest risks, according to Waldo Mossi, general manager of Helsinn Advanced Synthesis. “The importance of occupational exposure limits (OELs) is widely neglected in discovery research and early development,” he states. He explains that many companies use a one-size-fits-all approach to handling and managing the containment of bulk drug substances. Each individual process, however, offers different challenges, and no two new chemical entities (NCEs) are alike. The situation is aggravated by the lack of universally accepted definitions for various compound types, such as highly active, highly potent, and cytotoxic agents, which can lead to confusion between sponsor companies and custom-manufacturing organizations (CMOs), according to Mossi.

	To manage the variation and address the uncertainty associated with new substances, Helsinn continues to strive for design of toxicology testing and safety evaluation from the early stages of process development. The company also uses a comprehensive, science-based OEL evaluation approach from the start of an HPAPI project, and works with experienced industrial hygienists to assign initially conservative OELs to each potent compound that will enter its facility. “Since a certain level of risk will always exist when working with HPAPIs, it is important to foster a strong company culture of excellence in protecting employees, products, and the environment. Our comprehensive approach to process and compound evaluation helps to clearly define the needs and objectives in handling each process step,” Mossi observes. 

	Fortunately, as an HPAPI project proceeds through the development lifecycle and into clinical trials, the understanding of the risks associated with the potent compound increases and risk mitigation generally becomes less difficult, according to Patrick Klipstine, director of SAFC’s Madison, WI site. “During the development process, SAFC pursues ongoing internal evaluations and works with third parties to bolster this process. As the definition of potency becomes better defined during the development cycle, our process engineers and environmental, health, and safety (EHS) representatives can make appropriate modifications to the manufacturing engineering controls,” he notes. 

	Manufacturing and process continuity are also crucial during scale up to ensure that risks are minimized, according to Mossi. “Laboratories and small-scale GMP equipment should be designed so that they are aligned with the large-scale equipment used for commercial production in order to ease the transition and reduce uncertainty and risk during scale up,” he says. At Helsinn, the risk associated with scale up is reduced through facility design and investigated during early design of experiment (DOE) analyses.


	In any chemical manufacturing plant, the protection of operators is a top priority. In facilities producing HPAPIs, providing operator protection is absolutely critical and the top priority, according to Klipstine, which means that appropriate engineering controls are in place and personal protective equipment is available. In addition, every unit operation must be considered with regard to both the chemistry and potential occupational exposure. “Chemical processing steps are evaluated on their merits with regard to sound chemical process hazard criteria, and then each process is developed to allow for the safest execution of the process within the identified equipment train, taking into consideration compatibility with materials of construction, thermal output, gas evolution, waste stream management, etc.” Klipstine notes. With these considerations taken into account, SAFC then applies engineering controls for containment to mitigate the risk for occupational exposure. Specifically, the company has adopted a risk-minimization strategy that is systematically constant, but allows for different outcomes depending on the chemistry and potency of each API.

	“Each opportunity that turns into a project goes through a defined risk assessment process, with experts in our process development, EHS, and process engineering groups closely collaborating to provide a robust process from both a chemical engineering and process engineering standpoint. One of SAFC’s first principles is that all processing of powders and liquids are conducted in closed systems that have been verified to be effective for the prevention of occupational exposure. Second tier to these systems are robust training programs that have been designed for specific unit operations,” he adds.

	Helsinn also emphasizes the use of fully closed systems and isolation to avoid or mitigate areas of greatest risk. The company fosters the approach of contained chemistry, which means that equipment for each individual process (e.g., balances, rotary dryers, pressure filter dryers, and slurry vessels) is installed inside an isolator that has been qualified for occupational exposure levels down to nanogram levels according to the International Society for Pharmaceutical Engineering’s (ISPE) Standardized Measurement of Equipment Particulate Airborne Concentration (SMEPAC) methodology. The use of such an approach, according to Mossi, was made possible by a clean atmosphere design supported by accurate general ventilation using double-pass, high-efficiency particulate arrestance (HEPA) filtration. 

	It should also be noted, according to Mossi, that in addition to variable chemistry, operational risk depends greatly on several factors, including the company culture, personnel training, proper operational execution, and the design and engineering of the facility. In general, the greatest challenges are typically associated with operations such as sampling, loading/unloading of the reactor, and transfer of the material. “Powder handling presents the highest probability for potential worker exposure, and it is important to carefully study optimal methods for minimizing and, wherever possible, removing powder handling operations from an HPAPI process,” he states. At Helsinn, if powder handling is necessary, effective and consistent safeguards are factored in with redundancies to mitigate the risk even further. 

	SAFC handles both liquid and powder HPAPIs under a defined set of unit operations to minimize the potential for occupational exposure. “By using one common system defined appropriately for scale to ensure containment, our chemists can be assured that the processes they are executing are appropriately identified for the defined potency,” Klipstine explains. To reduce risk, all large-scale isolation of powders is conducted in jacketed filter dryers where solids can be filtered and dried without the necessity for discharge from the drying unit operation. Once dry, the HPAPI is discharged using glove-box containment techniques directly into predefined drug-substance packaging using ILC Dover continuous liner technologies, according to Klipstine. As a best practice, Helsinn investigates each manufacturing process step for hazard and safety together with the aid of an outside industry expert as part of its DOE analysis. 


	Of significance to HPAPI producers is having a thorough understanding of the cleaning procedures required to meet allowable carryover limits for multipurpose equipment, according to Klipstine. “Controlling cross-over contamination mitigates any potential risk to patients,” he asserts. Mossi agrees that safety cleaning verification at each stage of a manufacturing process and GMP cleaning validation is crucial. SAFC’s philosophy is to apply a continuous improvement mentality so that its systems will exceed current industry standards. Even so, one challenge the company faces regularly as a CMO with a multipurpose facility relates to servicing customers ranging from virtual biotechnology firms to large pharmaceutical manufacturers that have a wide range of expectations regarding handling and cleaning verification.


	Another challenge for CMOs that offer HPAPI manufacturing services is the continual evolution of industry standards and technologies. “Companies that want to participate in this market must adopt these newer technologies,” Klipstine asserts. SAFC, for example, had to transition to more robust analytical technologies with improved sensitivity and detection levels that allow for the determination of potential API carryover at part-per-billion levels.

	On the other hand, as the industry continues to mature, consultants and innovative equipment manufacturers can help design state-of-the-art engineering controls to better suit specific facility containment requirements, according to Mossi. He notes that Helsinn’s recent facility expansion was custom-designed to support workflow, ergonomics, and safety, while containing several unit operations within only a few isolators.


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

: When referring to this article, please cite as C. Challener, “Minimizing Risk during HPAPI Manufacture,” 

Protecting workers, patients, and the environment requires advanced technologies.

Minimizing Risk during HPAPI Manufacture

	The vast majority of new small-molecule drug candidates are chiral, and methods must be identified for obtaining the desired enantiomer in high purity. A common approach is to separate the enantiomers of a racemate. Certain chemo- and biocatalysts mediate transformations that provide chiral chemicals with high enantioselectivities; however, in most, both the desired and undesired enantiomers are obtained. Diastereomeric resolutions via salt formation, kinetic resolution, and chiral chromatography are techniques commonly used at commercial scale. All of these methods have drawbacks, and pharmaceutical companies are always seeking alternatives that carry lower costs and can be completed in shorter times


	Many compounds with bioactivity exist in two forms; enantiomers only differ by the way in which they rotate light. These enantiomers have identical chemical and physical properties, but interact differently with other chiral molecules, including many important biochemicals. Therefore, when a new candidate API is identified, a synthetic route that produces only the correct enantiomer must be developed.

	Finding efficient methods for the production of chirally pure APIs is a continually important topic in the pharmaceutical industry, according to Robert Hof, chief operating officer of contract research organization Syncom, based in Groningen, The Netherlands. Chiral racemates remain one of the major sources for the single enantiomers required for chiral APIs and drugs. “Resolution is absolutely necessary for separating enantiomers,” asserts R.M. Kellogg, a cofounder of Syncom. Fortunately, he notes that striking advances have been made in diastereomeric resolutions, kinetic resolutions (stoichiometric, catalytic, and parallel), and chromatographic techniques. “The availability of many different methodologies allows the selection of the best methodology for a particular compound,” Kellogg says.

	Chiral resolution by either diastereomeric salt formation or biocatalysis remains one of the most applied technologies due to its relative simplicity and scalability, according to Hof. “In particular, when racemization loops or-even better-dynamic kinetic approaches can be implemented for compounds with racemization-prone functionalities, 100% yield with 100% enantiomeric excess (pure enantiomer) can be achieved,” Hof adds.

	Resolution by diastereomeric salt formation is often applied to amines and acids because they have reactive groups that can form salts with chiral resolving agents. Alcohols are often resolved using biocatalysts. For apolar compounds including alcohols, many amines, thiols, and sulfides, biocatalysis, sometimes combined with organometallic catalysts, can be the method of choice, according to Kellogg.


	When a racemate is separated via diastereomeric salt formation, the two enantiomers react with a single enantiomer of a chiral compound that will form a salt with both enantiomers. Because each component of the salt is chiral, the product has two chiral centers and is considered to be a diastereomer. Unlike enantiomers, diastereomers have different physical properties and often can be readily separated from one another via crystallization.

	While there are well-established, inexpensive basic (e.g., cinchonidine and phenethylamine) and acidic (e.g., tartaric and camphor-1-sulfonic acids) resolving agents that are available on a large scale, efforts are continually being invested in the development of novel resolving agents that can be produced cost-effectively in quantities required for the production of commercial APIs. Syncom, for example, has developed strongly acidic chiral phosphoric and sulfonic acids. Others have also developed more economical, scalable routes for the production of older resolving agents that previously were not cost-effective for commercial API synthesis.

	One challenge with the diastereomeric salt approach, however, is that the resolving agent must be relatively cheap or readily recyclable, according to Hof. “Large-scale manufacturing is all about process simplicity and a low cost of goods. For chiral resolution, therefore, the key is identifying a relatively cheap or easily recyclable resolving agent and, ideally, racemization conditions for the unwanted isomer,” he says.


	An alternative approach is to find a way to separate enantiomers without the need to form diastereomeric salts. In fact, there are many types of chiral compounds that cannot form salts or for which it is difficult to do so due to steric hindrance, reduced reactivity, or other reasons.

	For these compounds, Syncom has focused on attrition-enhanced deracemization, or Viedma ripening, in which chiral compounds that are conglomerates (i.e., the enantiomers crystallize separately) are resolved efficiently without the need to use a chiral resolving agent. The separation is achieved by grinding the solid racemate of a conglomerate under racemizing conditions. Separation of the enantiomers occurs because in a conglomerate, each enantiomer has a greater affinity for the same enantiomer and ultimately the two enantiomers will crystallize separately to form a mechanical mixture. This process is accelerated by creating very small crystals for more rapid dissolution and when performed under racemizing conditions provides a pure, single enantiomer in high yield.

	Because few organic compounds are conglomerates, it is necessary to form derivatives of most substances to obtain conglomerates suitable for attrition-enhanced deracemization. A demonstration of this technique is an alternative synthesis of clopidogrel developed in the Syncom laboratories (1). “This need has stimulated search techniques for conglomerates (second harmonic generation techniques) and also more profound studies of crystallization behavior in order to predict the formation of conglomerates,” notes Kellogg.

	In addition, Syncom is working with various partners to develop standard pharmaceutical multipurpose manufacturing equipment for performing commercial-scale, attrition-enhanced deracemization. The company is also working to develop attrition-induced resolutions of non-racemisable conglomerates, and recently reported the resolution of a salt of omeprazole, a drug for treatment of the symptoms associated with gastroesophageal reflux disease (GERD) and other conditions caused by excess stomach acid (2). 

Enantiospecific cocrystallization in solution


	Researchers at Université Catholique de Louvain (UCL) in Belgium have developed another new resolution technology that does not require the use of chiral resolving agents. This approach is based on the fact that one enantiomer of a chiral compound will form a cocrystal with only one of the two enantiomers of a chiral coformer, allowing the resolution of a racemic mixture via enantiospecific cocrystallization in solution (3). 

	The technique was demonstrated using an enantiomeric mixture of 2-(2-oxopyrrolidin-1-yl)butanamide. The S-isomer is an API (levetiracetam) for the treatment of epilepsy that must be separated by chiral chromatography because no effective chiral resolving agent has been found. A structure-based cocrystal screen was performed to identify coformer candidates, and then ternary-phase diagrams were constructed for different temperatures to identify the ideal coformer and conditions for enantioenrichment. Notably, after just one cocrystallization step, 70% of the S-enantiomer was separated. 

	This approach to chiral resolution is attractive because it does not require the use of resolving agents and can be applied to compounds that do not readily or cannot form diastereomeric salts, many of which would require separation via chiral chromatography. The coformer technique is more cost-effective than chiral chromatography and can be performed using typical crystallization equipment (3). Syncom also participates in a project funded by the Dutch National Science Foundation in which co-crystallization together with attrition-induced deracemization is used to resolve commercial products, such as Naproxen.


	Even with these attractive alternative technologies, the search for improved chiral resolution methods is far from over. “Nature sometimes separates enantiomers for us. Roughly 10----15% of chiral organic compounds are conglomerates for which the enantiomers crystallize separately from one another. Could we imitate nature and learn how to crystallize compounds in a single step as single enantiomers and at the same time separate them? This scientific challenge remains as yet unanswered and is waiting to be met,” Kellogg asserts.

 13 (6), 1195-1198 (2009).
	2. R.M. Kellogg, et al., 

 17 (6), 946-950 (2013).
	3. G. Springuel and T. Leyssens, 

When referring to this article, please cite it as:
	C. Challener, " Chiral Resolution with and without Resolving Agents," 

Resolution technologies remain crucial for commercial-scale chiral API production.