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

Research groups supported by industry tackle the challenges of continuous crystallization and process analytical technology.

Advances in Continuous Crystallization

	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,” 

FDA steps up inspections of foreign API manufacturers, thanks to new legislation and changes in policy.

Better Control of the API Supply Chain?

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 

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Specialized Equipment Improves Tableting

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.