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

Cynthia A. Challener

Although not pharmacologically active, excipients have a direct impact on the performance of formulated drugs, and their quality and purity are equally important to assuring drug product safety. Because excipients are seldom pure compounds, consistent composition is of utmost importance, asserts Irwin Silverstein, president of IBS Consulting in Quality. Conformance to good manufacturing practices (GMP) is also important so that the customer can rely on the excipient manufacturer’s certificate of analysis (CoA). The wide variety of compounds approved for use as excipients in pharmaceutical formulations, however, creates challenges for sourcing.

	Pharmaceutical excipients are typically multifunctional chemistries not exclusively designed and formulized for the pharmaceutical industry. As a result, these molecules often originate from other applications and industries and are later utilized within the pharmaceutical industry, according to Jessica Cansler, a senior quality management specialist with BASF. “The initial manufacturing and quality standards of these molecules were focused more to the requirements of the original application areas and industries, not to the manufacturing and quality requirements of the pharma industry,” she says.

	It is incumbent upon pharmaceutical manufacturers to understand the full excipient supply chain and have in-depth knowledge about selected suppliers. Recognizing that risk cannot be avoided but must be mitigated is equally important.

	The challenges to excipient sourcing vary according to the type of supplier from which the manufacturer is purchasing the material. “Lack of transparency about manufacturing locations and the entire excipient supply chain can provide challenges,” notes Fernanda Onofre, technical service manager for pharma solutions at DuPont Nutrition & Bioscience.

	One of the biggest challenges, perhaps, is that many industrial-scale manufacturers make products in multi-application plants, and the volumes produced for the pharma industry are typically only a fraction of the total production, making it difficult to fulfill pharmaceutical industry expectations (GMP, quality, etc.), according to Cansler.

	It can also be challenging to trace back the source of the original materials and understand the quality level of the ingredients, as many are ‘tested up’ to monograph standards rather than produced under the appropriate guidelines, she notes. In some cases, it can be difficult for drug manufacturers to find an appropriate excipient manufacturer fulfilling pharma quality expectations, particularly for legacy products; sometimes drug manufacturers must make compromises and accept what is available on the market.

	When the excipient is shipped directly from the excipient manufacturer to the drug manufacturer, there should be no misunderstanding as to the source, according to Silverstein. “However,” he observes, “purchasing through a distributer, broker, or trader may raise a challenge, especially where the excipient has been packaged from bulk or repackaged from discrete packages. Tracing the excipient back to the source relies on having confidence in the packager or repackager and receiving the excipient manufacturer’s certificate of analysis.”

	Issues in the past, according to Chris Moreton, principal with FinnBrit Consulting, have related to the sourcing by a distributor of excipients from multiple manufacturers without notifying the customer, which had only validated one source of supply, as well as the switching of plant species from which excipient starting materials have been derived, impacting excipient performance in the manufacture of the finished drug product. Distributors, Moreton says, must inform their customers of the manufacturing sites for every delivery of an excipient. The pharmaceutical customer must also confirm that the manufacturing site is on their approved list, adds Silverstein.

	The excipient manufacturing process can also provide challenges. “This information is often proprietary, yet drug manufacturers need to understand the raw materials and processes that can impart variability in excipients,” Onofre notes. Regardless of the source, therefore, pharma manufacturers must be willing to invest the time and effort in establishing monitoring systems based on the use of advanced spectroscopic methods, notably for plant-derived excipients, in order to detect unexpected changes in impurity profiles from a single supplier or variations in profiles from different suppliers of the same excipient, according to Moreton. “The difference in levels of concomitant components may impact the performance (manufacture, in-use and/or stability) of the finished pharmaceutical product,” he explains.

	Pharma companies should also be sure to conduct supplier qualifications to ascertain the necessary details about excipient suppliers, a process that can provide challenges as well, according to Onofre. “Thorough qualification requires an on-site audit of the excipient supplier, either by the pharma company themselves or by a trusted third party,” she says.

	The first step, Onofre adds, is for pharma companies to fully engage with their excipient suppliers, asking for clarity on the excipient’s entire lifecycle. “Even in the instances where information may be proprietary, much can be clarified after a discussion with the supplier,” she comments. Detailed discussions under a confidential disclosure agreement (CDA) can also help in understanding excipient variability and how that can affect the formulation and process. “Such discussions aid in excipient risk management and the formulation of robust drug products,” Onofre states.

	Drug makers should also insist that the manufacturing site of the excipient be identified on each lot of the excipient received at the product manufacturing site, Moreton asserts. The International Pharmaceutical Excipients Council (IPEC) CoA guide (1) establishes that the site of manufacture should be disclosed on this document, according to Silverstein. “Ideally, the batch numbering system of the excipient should be site specific, such that a change in the format of the batch number would act as a check for the site of origin,” Moreton adds. Any change in sourcing of the excipient starting material sourcing should also be included as part of the change notification requirements in the quality agreement or in a commercial agreement, with change notification completed per the IPEC significant change guide (2).

	On-site audits conducted by the pharma company itself or via a third party, such as EXCiPACT- an international consortium of excipient, chemical, and quality organizations-should be conducted to gather as much information as possible about the supplier and the excipient, Onofre says. If a third-party has been used for the audit, Silverstein adds that it is important to obtain a copy of the audit report to help assure the validity of the audit conclusions concerning production of an excipient in conformance to GMP.

	To verify the source of the delivered excipient, whether in the original manufacturer’s container, packaged from bulk, or repackaged, Silverstein comments that the user should verify the authenticity of the excipient label, package, and tamper-evident seal.
	Overall, the best approach is to source excipients from excipient manufacturers that clearly commit themselves to the pharmaceutical market and the expectations of the pharmaceutical industry, Cansler asserts. “Usually these excipient manufacturers are appropriately certified to pharmaceutical industry quality standards (e.g., NSF/IPEC/ANSI 363 and/or EXCiPACT),” she says.

	When considering different excipient suppliers, there are some warning signs that could indicate potential issues for pharmaceutical manufacturers. For Moreton, a top red flag is not naming the site of manufacture because that precludes physical audits. “Reliance on the distributer’s paper audits or third-party audits for and on behalf of the distributer-and in which the excipient user has no control and is not consulted ahead of time-should not be acceptable,” he says.

	The claim that an excipient will meet the United States Pharmacopeia (USP) monograph when tested is a key warning sign for Silverstein. “This language may indicate that the excipient was not produced under ‘appropriate’ GMP as required by USP. Refusal to share non-compendial test methods is another red flag; a good supplier wants to facilitate the proper testing of their excipient, he says.
	Pharma manufacturers should also be wary of excipient suppliers that are not aware of current issues, concerns, and trends in the industry they serve, or have to custom-make standard documents, according to Cansler.

	Suppliers that are not known in the pharma industry or only have a small presence, as well as those that are unable to provide the required qualification documentation, historical manufacturing trend data under CDA, and support manufacturing location audits raise concerns as well, adds Onofre. Finally, Moreton points to suppliers that are unwilling to enter into quality/change notification agreements as raising red flags.

	Be on the lookout for positive attributes

	On the flip side, reliable excipient suppliers exhibit a number of recognizable attributes that should be sought. Most importantly, reliable excipient suppliers are open, albeit under confidential disclosure agreements, according to Moreton. They will allow either customer audits or certification to excipient GMP by a recognized accreditation body or certification scheme, adds Silverstein.

	These excipient suppliers recognize the importance of the pharma market to their business profitability and participate in appropriate trade associations and meetings. They also have deep knowledge of their products and can provide technical support for their use in drug formulations and provide products with reliable excipient quality, consistent composition, documentation in order, and an established quality management system at the excipient manufacturing site that complies with pharma excipient GMP requirements and expectations, according to Cansler.

	“Highly reputable companies in the pharma market, with consistently good performance and proven experience over the years tend to strive for customer satisfaction and fulfillment through the reliability of their own services and products provided,” Onofre concludes.

	In addition to an initial onsite audit, pharma manufacturers should closely evaluate several aspects of excipient supplier performance during the selection process. Identification of the GMPs to which the supplier intends to conform is paramount, according to Silverstein. Standard quality, regulatory, and technical documentation for the excipient should be readily available and complete, coupled with a point of contact to ask questions, Cansler observes. Evidence of the supply chain, quality, and services being offered by the supplier should also be provided, along with in-depth information on the manufacturing locations, notes Onofre.

	Access to multiple excipient samples from different campaigns and different raw material lots for qualification is also important, adds Cansler. Excipient suppliers should also sign quality/change notification agreements as part of the overall supply or quality agreement, says Moreton.
	Finally, once a supply agreement is in place, Moreton and Silverstein both note that an effective monitoring program at the excipient user site should be implemented to assess the quality and technical characteristics of the excipient.

	Excipient grades are typically differentiated based on a certain physical characteristic (e.g., particle size, molecular weight, degree of substitution, or viscosity). A change in grade means a change in that physical characteristic. For some formulations, a change in grade may not impact product performance, but for others it could be detrimental to the finished product, according to Moreton.

	“Different grades allow for flexibility in formulation and process design to address various technical challenges in other raw materials or processes used to manufacture the final dosage form,” Onofre explains. She adds that different grades are also critical for optimizing the right process, which can help in cost-saving efforts in areas from wet granulation to direct compression.

	If a specified excipient grade is important to the quality attributes of the drug product, then the formulator should demonstrate in what manner the grade is important, adds Silverstein. “In this case, the homogeneity of the excipient lot for that attribute becomes critical to drug product quality, and the excipient manufacturer should be asked about homogeneity within each lot,” he says. In addition, a change in grade most likely would necessitate a revalidation and a notification under the scale-up and post-approval change (SUPAC) rules, Moreton comments.
	Choosing the right excipient grade used to be at the personal preference of the formulator, but with quality by design widely implemented today, properly designed and executed design of experiments studies give support to the choice of excipient grade, according to Moreton.

	In addition to information provided by excipient suppliers, pharma companies may also conduct grade-differentiating testing when establishing excipient specifications. Talking to the excipient technical experts and sharing the intended use for the excipient and the issues to be addressed in the designed formulation can also help in grade selection, according to Onofre. “Based on the API, the formulation, and the intended process, the excipient supplier can recommend the right excipient and the right grades,” she says.

	Assuring receipt of the right excipient grade starts at a minimum with identification testing and testing against the CoA/monograph listed tests and parameters, according to Cansler. Services such as infrared scanning flaps/windows in packages, whenever possible, can help reassure the customer about the accuracy of the product and reliability of the supply, adds Onofre.

	It is also important to confirm product labeling and product documentation and compare them with the purchase request, Cansler observes. “The excipient specification at the drug maker should clearly link to the excipient supplier’s specification for the grade, and the purchase order should also clearly delineate the grade as it will appear on the excipient package label and CoA,” Silverstein explains. In some cases, he notes that it may also be necessary to discuss with the excipient manufacturer the recommended test method for the parameter that designates the grade and that the accuracy and precision are sufficient to confirm the grade.

	As with all excipients, conducting due diligence when approving an excipient supplier and ensuring quality and supply agreements are in place should result in the right product being sent, according to Onofre. Auditing the site of manufacture and the supply chain are important, agrees Moreton. “Testing of the excipient upon receipt at the customer site is often necessary as well because the grade is critical for the particular application, and formulators would be well-advised to test each lot,” he states. Having a sampling plan based on lot homogeneity is also recommended by Silverstein.

	The most important concept to grasp when dealing with the excipient supply is “Caveat emptor: let the buyer beware!” asserts Moreton. “There are no certainties, and there is always a risk that something may go wrong. However, the risk can be reduced to an acceptable level, but only by acquiring as much knowledge as possible about the excipient and using a combination of site and supply chain auditing, quality/change notification agreements, and an effective monitoring program for all excipient deliveries to the site of use,” he states.

	In addition to risks associated with manufacturing processes for excipients, there is risk associated with the distribution and supply chain of excipients globally, notes Cansler. She points to risks associated with the intermediate storage and transportation of excipients. “Trending topics including fraud and adulteration within the supply chain are of serious concern. In addition to raw material qualification, appropriately established supply-chain traceability and supply-chain security processes should be in place,” she observes.

	The IPEC excipient qualification guide (3), according to Onofre, provides details on recommendations for building a robust supplier qualification process. “Building customer-supplier relationships that are transparent and provide robust information-sharing opportunities is the foundation for success,” she concludes.

Certificate of Analysis Guide for Pharmaceutical Excipients

Significant Change Guide for Pharmaceutical Excipients

Qualification of Excipients for Use in Pharmaceuticals 

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	Vol. 44, No. 2â¨
	February 2020
	â¨Pages: 22–26

	When referring to this article, please cite it as C. Challener, “The Search for Transparency in Excipient Sourcing," 

Articles

Researching excipient grades and sources, as well as screening suppliers and materials, form the basis of programs to mitigate risk.

The Search for Transparency in Excipient Sourcing

Effective analytical methods are essential for the successful development and commercialization of both small- and large-molecule drug substances and drug products. As the complexity of both biologic and chemical drug substances increases, analytical methods must evolve as well.

	“Faster, more efficient techniques will give companies an advantage as their products move through the pipeline,” asserts Robin Spivey, director of analytical research and development, Cambrex High Point. Techniques that are more sensitive and more accurate will, she says, better position a company for regulatory acceptance as long as they are willing to help pioneer the techniques. In addition, such companies will be seen as being at the forefront of the industry.

	Some of the most noteworthy advances in analytical methods involve the application of mass spectrometry (MS) for process development and product release of both biologics and synthetic drugs, the enhancement of chromatographic techniques, particularly liquid chromatography (LC), microcrystal electron diffraction, and techniques designed for use as process analytical technology (PAT).

	For biopharmaceuticals, MS was initially limited to use for protein characterization to provide supplemental information for regulatory filings, according to Amit Katiyar, director of analytical and formulation development for bioprocess sciences at Thermo Fisher Scientific. Process release/stability testing continues to largely depend on conventional analytical methods such as LC, capillary gel electrophoresis (CGE), imaged capillary isoelectric focusing (iCIEF), and enzyme-linked immunosorbent assays (ELISA) due to their simplicity and wide adoption in quality control (QC) labs.

	Inclusion of biosimilars, complex non-monoclonal antibody proteins (e.g., fusion proteins), bispecifics, and combination products in the product pipeline, however, is presenting challenges due to the inability to gain a thorough understanding of these molecules using platform methods. “Most of the time, platform methods may not be able to provide the information required to develop and commercialize complex biomolecules. In these cases, MS-based methods are being used for process development and as identity and release/stability indicating methods,” Katiyar observes.

	In addition to using peptide-mapping principles in multi-attribute methods (MAMs), major biopharmaceutical companies are now using MS-based identity methods to release biologic drug substances and drug products. “This approach will provide the opportunity to gather more information on the performance of MS instruments in QC labs that can then be used for implementing MS technology for process development, release, and stability testing,” says Katiyar. The current approach for regulatory filing, he adds, is to use a combined package of conventional methods and MS methods to gain more confidence from health authorities and be able to present a future case for submissions based only on MS data.

	For Da Ren, process development scientific director at Amgen, MAM is probably the most important emerging analytical technology that has been used in process development and release and stability testing of therapeutic proteins. “MAM is an LC/MS-based peptide mapping assay. Unlike profile-based conventional analytical assays, which focus on whole or partial proteins, MAM can identify and quantify protein changes at the amino acid level and can provide more accurate information on product quality related attributes,” he explains. Notably, MAM is capable of replacing four conventional assays including hydrophilic interaction liquid chromatography for glycan profiling, cation exchange chromatography for charge variant analysis, reduced capillary electrophoresis-sodium dodecyl sulfate for clipped variant analysis, and ELISA for protein identification, according to Ren.

	In the case of small-molecule drug development and commercialization, MS detection systems are no longer considered just research tools and are becoming more widely used for routine QC testing, for example determining extremely low level impurities such as genotoxic impurities/potential genotoxic impurities, according to Geoff Carr, director of analytical development in Canada with Thermo Fisher Scientific.

	“These advances are very likely in response to new regulatory guidelines issued by agencies such as FDA and the European Medicines Agency, but also as a result of specific problems that have occurred in the industry, such as recent concerns regarding observations of N-nitrosamine residues in sartans,” Carr explains.

	Chromatographic-based analytical procedures continue to be the most widely used technologies for small-molecule API and drug product analyses and most advances are likely in this area. For the most part, procedures based on high-performance liquid chromatography (LC)/ultra-high-performance LC (HPLC/UHPLC) coupled with ultraviolet detection are most widely used, according to Carr.

	Notable advances in this area, Carr says, include improvements in HPLC/UHPLC column packing chemistries designed to provide better resolution between sample components and greater robustness, such as resistance to particularly high or low pH conditions for mobile phases.

	Advances in crystallography are also important for small-molecule API analysis. Microcrystal electron diffraction, also known as micro-ED or cryo-EM, for instance, can be used for structure determination by electron diffraction using micron-sized crystals. “Typically, millimeter-sized single crystals are necessary to achieve unambiguous determination of the absolute structure of an API using single-crystal X-ray crystallography,” explains Heewon Lee, director of analytical research and quality systems in chemical development US for Boehringer Ingelheim Pharmaceuticals.

	Micro-ED enables the same level of structure determination using micrometer-sized crystals, eliminating the need to grow larger single crystals, which can be challenging. “This capability is very useful for process development, as understanding impurity formation is a critical step to optimize processes,” Lee says.

	Other advances include applications such as near infrared and Raman spectroscopies in support of process analytical technology to enable monitoring of manufacturing processes and the quality of resulting products on-line. “Developments in these areas are in response to regulatory encouragement for the application of quality-by-design approaches for manufacturing drug products,” Carr notes. He adds that this type of technology is more likely to be applied by companies that manufacture their own products and less likely in a contract manufacturing environment.

	Changes in analytical workflows have the potential to impact productivity and efficiency but may also create challenges depending on the nature of the modifications. These changes may also originate as the result of new technology or new processes and approaches.

	As an example of the former, Heewon Lee, director of analytical research and quality systems in chemical development US for Boehringer Ingelheim Pharmaceuticals, points to material identification using Raman spectroscopy as a technique that has impacted analytical workflows associated with small-molecule API manufacturing. “This technique is now mature, and several companies have launched products that are user-friendly and GMP [good manufacturing practice]-compliant. Benefits are gained because this method can be used to identify raw materials, intermediates, and APIs in the process area. QC personnel can then release batches based on the Raman data acquired, streamlining the analytical workflow,” she explains.

	For biologics, using MAM through process development and release and stability testing is a revolutionary analytical workflow, according to Ren. “The continuous monitoring and control of product quality attributes at the amino acid level during product and process characterization as well as release and stability testing enhances the understanding of biotherapeutic products and processes,” he asserts.

	One driver leading to changes in analytical workflows is the desire to achieve greater efficiencies and thereby reduce operating costs, according to Carr. One approach that many pharma companies have taken, he notes, is to implement operational excellence initiatives within laboratory operations.

	Regulatory pressures for improvements in the scientific understanding and quality of drug product is also leading to an evolution in analytical workflows. “We are seeing increasing guidelines focused on analytical development, such as a [Brazilian Health Regulatory Agency] ANVISA guideline on conducting forced degradation studies that is very demanding,” Carr observes.

	There are also initiatives within the International Council for Harmonization (ICH) and the US Pharmacopeial Convention (USP) focused on replacing the traditional development-validation-transfer approach to management of analytical procedures to one based on lifecycle management. “This approach,” asserts Carr, “requires rational development/validation coupled with a process of performance monitoring that leads to continuous improvements.”

	These changes relate to an important development noted by Katiyar; the adoption of phase-appropriate analytical workflows combined with increasing harmonization of workflows across sites and with external partners, such as contract research and development organizations.

	Phase-appropriate development and manufacturing can help pharma companies better handle their expanding product pipelines by enabling the supply of safe clinical materials while maintaining flexibility in manufacturing operations, according to Katiyar. He does note, however, that while ICH guidelines are defined for late-stage development, there is a lack of clarity on the qualification of analytical methods for early phase development.

	“Harmonization using a platform approach to method development and qualification for early and late-stage projects and method validation for late-stage projects, as well as forced-degradation, research comparability, and formal comparability studies and specification setting has provided the opportunity to engage process development, analytical development, operations, quality, and regulatory organizations earlier in the development cycle,” Katiyar says. “The harmonized approach creates a well-defined roadmap for process development and operations teams to execute the program timelines in an efficient manner,” he adds.

	The details of each harmonization approach vary from company to company. In some cases, the harmonized templates may contain specific experiments and acceptance criteria to ensure a successful platform approach, according to Katiyar. In other cases, high-level harmonization guidance provides flexibility during development.

	“Pre-approved generic templates for draft methods, qualification plans, and forced degradation/comparability protocols result in higher productivity due to time savings resulting from a shorter review process for every program,” Katiyar observes. While there may be a need to modify the templates as reflected by the development data, he notes that such changes can be incorporated in the molecule-specific methods/plans, and protocols and subsequent changes can be reviewed by appropriate stakeholders for quality and regulatory compliance.

	Some of the most important advances in sample preparation tools include increasing application of automation and robotics. Quality-by-design (QbD) approaches to analytical testing can often lead to multiple sampling and testing to  achieve a more accurate assessment of the total batch rather than testing one or two samples per batch.

	An example given by Carr is stratified sampling for solid oral dosage forms whereby samples are taken at approximately 20 time points during tablet compression or capsule filling and tested for drug content, and three units from each time point are tested. “In circumstances such as this one, there are huge benefits in having automation available in the lab for the preparation of the analytical samples from the 60 individual tablets that require testing,” he explains.

	Automation of sample preparation for low throughput methods is also critical to improve turn-around times to support process development activities, adds Katiyar. In general, he notes that automation of all in-process methods for biologics-including size-exclusion chromatography, CGE, iCIEF, n-Glycan content and residual host-cell protein, DNA, and Protein A-to support process development activities is crucial for meeting fast-to-first-in-human trials/quick-to-clinic timelines.

	In the field of biologics sample preparation, Process Development Scientific Director Jill Crouse-Zeineddini at Amgen sees acoustic droplet ejection for potency assays as an important advance. Acoustic droplet ejection uses acoustic energy instead of tips to transfer a fixed amount of liquid sample from a source to destination plates freely with excellent accuracy and precision, she explains. “The significance of this technology resides in its superb dispensing performance at a very low sample volume. This technology performs direct dilutions instead of serial dilutions and prepares each dose independently, improving assay precision and throughput,” Crouse-Zeineddini observes.

	Robust aseptic sampling and automated sample preparation for the purification, desalting, and digestion of protein samples, meanwhile, enables many different product quality analyses. “This technology not only significantly improves operational efficiency, but also eliminates potential contamination and mistakes during manual sampling handling,” states Gang Xue, process development scientific director at Amgen.

	Another important point, according to Carr, concerns the reliability of the sample preparation procedure. “This issue is not a new one, but it is becoming more apparent as we apply QbD approaches to our analytical procedures. While the greatest emphasis has been applied to chromatographic parameters, we now realize that the sample preparation stage is at least as important and also needs to be developed using QbD,” he comments.

	For Lee, a specific technology development that has improved sample preparation is once again material identification by Raman spectroscopy for small-molecule drug substances. “Using this technique simplifies sample preparation, because it allows identification of compounds without any physical contact with the sample. Depending on the container material, it is even possible to acquire Raman data through the container without the need to withdraw a sample,” she says.

	Such capability for biologic drug substances has yet to be developed, however, and simplified identity methods to support release and establishing post-shipment identity of bulk drug substance are still required, according to Katiyar. Currently, peptide mapping and binding ELISA are used as identity methods, but they have long turnaround times. Raman spectroscopy has been evaluated for biologics, but it has not yet been adopted by the industry for release of drug substances and drug products. “Simplification using scan-based methods with better specificity and faster turnaround times would be highly beneficial for biopharmaceuticals,” he says.

	When integrated with analytical instruments, aseptic sampling and automated sample preparation has the potential to move in-process and product release testing from offline QC labs to the manufacturing floor, either in-line or online, according to Xue. In addition to enabling real-time monitoring of not only cell growth, but also the critical quality attributes of therapeutic proteins themselves, the technology is beneficial for providing much more granular insights into the conventional batch process and products in-flight, he notes. “More importantly,” Xue states, “it could in the future be crucial for lot definition, process variation detection, and material segregation as required for continuous bioprocessing.”

	For small-molecules, Lee would like to see the widespread adoption of x-ray fluorescence (XRF) for metals testing because it would also reduce turnaround times. “XRF is a powerful method for detecting metals used as catalysts in API manufacturing. Compared to inductively coupled plasma-MS, XRF does not require sample dissolution and digestion, facilitating easier sample preparation and faster turnaround times,” she explains.

	Carr, meanwhile, expects to see increasing us of LC–MS for routine analytical testing. “This technology is widely applied in chemical drug development labs for various purposes and is also used for biopharmaceutical analytical testing, but less for release testing of products and for testing stability samples. The technology has advanced considerably over recent years, and while these instruments were previously only applied in R&D, they have now become highly suitable for use in routine testing labs,” he remarks.

	There are a number of challenges to the adoption of advances in analytical techniques, some of which vary according to the development phase. Adhering to compressed program timelines is the key challenge in getting advances in method adoption for early stage development, according to Katiyar. “Fast-to-first-in-human (FIH)/quick-to-clinic program timelines have been introduced in almost every pharmaceutical organization to provide clinical material for Phase I studies, and these timelines have shrunk from 18 months to less than 12 months during the past five years,” he says.

	The shorter timelines are met by relying on platform approaches developed based on knowledge generated over years with multiple molecules. “For new molecules that fit the platform methods, there is no scientific justification to explore new technologies,” Katiyar states. When working in a lab that is operating in a high-efficiency environment, there is often resistance to the introduction of new methods and approaches due to concerns about meeting delivery targets, agrees Carr.

	Once programs move to late-phase development, organizations are hesitant to introduce any change in the control strategy unless it is absolutely needed. This reluctance is particularly strong if a filing has been made to a regulatory agency and/or if significant data have been collected using the older technique, according to Spivey.

	“To be adopted for measuring product quality measurement, the performance of new analytical methods must be equivalent to or better than the methods they replace, and there must be clear evidence that they are reliable and robust across a wide range of operating spaces,” states John Harrahy, director of process development in pivotal attribute sciences with Amgen. The adoption of new technology in the middle of a program, adds Katiyar, requires significant effort to develop the new method, perform bridging studies, requalify the method, perform technology transfer (if outsourced), perform retrospective testing, and define new specifications. Bridging studies cost the sponsor additional money and time, and there is always the risk that a bridging study may show that the methods or techniques are not comparable, adds Spivey.

	There is also often a reluctance on the part of drug companies to be the first to make a submission to FDA with a new technique due to the possibility of the validity of the technique being questioned, Spivey notes. “They don’t want the burden of having to defend the technique to FDA or other regulatory agencies,” she says. There can be some risk with introducing new technologies that have had limited regulatory exposure, adds Harrahy, particularly considering the different regulatory expectations and change control requirements from different regulatory authorities worldwide.

	“With that said,” Harrahy comments, “evaluating innovative technologies is a vital component to ensuring product quality and value to patients, and the ultimate risk of not evaluating new technologies greatly outweighs remaining stagnant.”

	The ideal solution, Katiya argues, is to explore new technologies as part of improvement initiatives without associating them with any programs. This approach provides the flexibility to explore new technologies without putting the program timelines at risk. “Once proof of concept is established and the method is ready to be adopted, a platform approach can be used to implement the new technology,” he comments.

	Senior leadership in large organizations, according to Katiya, must provide guidance to their teams to push innovation without risking program timelines. In addition, it is also important to apply thorough training practices to ensure that scientists really understand the new approaches, says Carr. Continuity of data must also be addressed. “Trend analysis is a widely used tool for monitoring pharmaceutical product quality, and the introduction of new and ‘better’ methods may be perceived to interfere with this trending process,” Carr observes, even though it is more important to apply continuous improvement and accept possible breaks in trends.

	In addition to evaluating new analytical methods separately from specific drug development programs, there are several other strategies that can be used to facilitate the adoption of advances in analytical techniques.

	The best strategy for adopting a new analytical method in a quality setting, according to Harrahy, is to start with the end in mind. Does the proposed method fit the analytical target profile? Is the method sufficiently capable for the product or products that it will measure? Does the methodology require modification to the available GMP/QC environment?

	“The robustness, reliability, and value of introducing any new method must be clearly demonstrated, which is often best accomplished by taking a staged approach: determining the method operable design space in a development laboratory, piloting the method in a development/phase-appropriate setting to monitor ‘real-world’ method capability, performing bridging studies vs. the older method, staging its implementation in QC, and continuously monitoring method performance,” he says. In addition, for regulatory acceptance of novel technologies, early partnered engagement with health authorities is strongly recommended, for example, participating in FDA’s emerging technology platform when the new technology has the potential to improve product quality.

	The most important strategy, agrees Spivey, is to provide ample data demonstrating that new methods are reliable and robust and that there is little or no risk to implementing the technique in a regulated environment. Advances that offer significant advantage over corresponding currently accepted techniques will also have greater likelihood for acceptance. However, Spivey stresses that the advantage would need to be significant enough to be worth the time and money needed for it to be implemented. “Ideally,” she says, “the owner of the technique would perform some preliminary legwork with the regulatory agencies demonstrating the capabilities of the technique. The sponsor would then have some assurance that the agencies would accept their data and make it a less risky approach for them.”

	Another approach, depending on the nature of the old and new/improved methods, is to run both in parallel for a period of time in order to develop an understanding of how their performance and the resulting data compare, Carr suggests.

	For Lee, the key to new analytical method adoption is the sharing of use cases between pharmaceutical companies combined with the publication of white papers and communication with regulatory authorities. Katiyar agrees that sharing knowledge and gaining the feedback of peers and regulatory authorities in timely manner is essential. “Peer-reviewed publications, conference presentations, and Biophorum Operations Group-like forums are the best places to share information and exchange ideas to improve and adopt new technologies on a global scale,” he comments.

	That information sharing should occur between all stakeholders, including contract research, development and manufacturing organization, testing laboratories, biopharmaceutical companies, regulatory authorities, and instrument/equipment vendors.

	“Innovators and service providers need to be open to new ideas and be willing to invest the time and money to implement new techniques. Service providers also, rather than waiting for clients to request a technique before investing in it, should advocate for the use of new methods with their clients,” Spivey asserts. In addition, Katiyar believes innovator companies working with service providers should form an external working group to share new methods and technology to eliminate knowledge gaps caused during technology transfer of methods. “Most of the time,” he remarks, “innovator companies are not willing to share new methods and technologies and thus delay the adoption of new technologies throughout the pharmaceutical industry.”

	Regulators also need to be open to new ideas and willing to work with pharmaceutical companies to ensure that new methods and techniques are acceptable for use in a regulated environment, according to Spivey. It is important for pharma companies and regulatory authorities to remember they have a common goal in identifying new methods and technologies for monitoring and quantifying critical quality attributes that may impact the safety and efficacy of the molecule throughout the lifecycle of the program, adds Katiyar. He points to MAMs as an example where health authorities have accepted data packages consisting of results obtained using conventional approaches supplemented by those obtained using MS-based approaches.

	Instrument/equipment vendors, meanwhile, should be prepared to demonstrate that a new technique is sufficiently better than the currently accepted technique to be worth investing in and worth any potential regulatory risks, asserts Spivey. The dilemma here, according to Carr, is how stakeholders all link together.

	“If a new analytical technology comes up, it will not be accepted by industry/regulators unless the equipment that is required to use it becomes widely available. Maintenance, qualification, and repair services must also be widely available and reliable. Typically, however, a vendor will not set establish this level of availability unless there is a level of confidence that sales targets will be achieved. I think that this is the area where conferences, exhibitions, and publications provide a really valuable platform to get the information from innovators and suppliers circulated to end users,” he says.


	Vol. 44, No. 2
	February 2020
	Pages: 16–21

	When referring to this article, please cite it as C. Challener, “Biopharma Analysis Benefits from New Technology and Methods," 

Analytical solutions are improving for raw material testing, drug product release process development, and more.

Biopharma Analysis Benefits from New Technology and Methods

Viral vectors must be free of viral contaminants, both adventitious agents introduced via raw materials and those generated during processing. Because conventional viral clearance treatments would degrade or destroy many viral vectors, assessment of the potential risk for contamination and the implementation of prevention and control strategies are essential. Detection can be an issue, too. Multiple analytical methods must be used, many of which have performance limitations, adding to the challenge.

	Regulatory authorities require testing to be performed at every stage of the manufacturing process. Cell substrate banks, viral seed banks, raw materials of animal origin, bulk harvests, and the batches of the final manufactured clinical product all have to be tested, according to Francesca Vitelli, head of process development, for viral vectors at Lonza. Both adventitious viral agents and replication-competent viruses are a concern, adds Tony Hitchcock, technical director with Cobra Biologics.

	While there are no regulations solely dedicated to the viral safety of viral vector products, several guidance documents from various agencies provide relevant information on ensuring the viral safety of biological products. There are also guidance documents specifically for cell and gene therapies, according to Karen Tiano, spokesperson for MilliporeSigma, and some do mention that testing for adventitious viruses is expected. Select guidelines for viral contamination testing are listed in 

			Table I. Select international guidelines for viral contamination testing. ICH is International Council for Harmonization.			

Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines
					of Human or Animal Origin

Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) 

Characterization and Qualification of Cell Substrates and Other Biological Materials Used
					in the Production of Viral Vaccines for Infectious Disease Indications, Guidance for Industry

 5.2.3 Cell Substrates for the Production of Vaccines for Human Use

 2.6.16 Test for Extraneous Agents in Viral Vaccines for Human Use

, The Rules Governing Medicinal Products in the European Union, Volume 4,
					Good Manufacturing Practice, Guidelines on Good Manufacturing Practice Specific
					to Advanced Therapy Medicinal Products (Effective May 2018)

					FDA Draft Guidance
					for Industry

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy
					Investigational New Drug Applications (INDs)

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up 

	Many viral contaminants may be present in viral vector products. The risk for specific contaminants is dependent on the raw materials and the process, according to Lorraine Borland, product manager for regenerative medicine–cell and gene therapy in the cell line, media, and testing solutions business of Sartorius Stedim Biotech.

	“The highest risk pathways for introduction of adventitious viruses are typically raw materials used in the upstream portion of the manufacturing process,” asserts Morven McAlister, senior director of regulatory and validation consultancy at Pall Biotech. “Raw materials such as cell-culture media and trypsin typically cannot be autoclaved and so represent the highest risk of entry of these viruses. This risk is heightened with the use of serum. The cell line is also a potential source of adventitious viruses. To reduce the risk associated with the cell line, it must be very well characterized and both the master and working cell banks thoroughly tested,” she adds.

	“The manufacturing process, if not carried out in a closed system, may also have multiple aseptic process steps where breaks in the process or transfer of the intermediate material may increase contamination risk,” Borland notes. For instance, Hitchcock notes that producer cells and viral seed stocks can also become contaminated when used. The generation of replication-competent viral vectors during the manufacturing process is also a key concern.

	For raw materials, McAlister adds that contaminants can be placed into two categories: adventitious viruses that enter the viral preparation inadvertently through raw materials or poorly characterized cell lines and helper viruses such as baculovirus, adenovirus, or herpes simplex virus, which are deliberately used to stimulate expression of the virus of interest (generally adeno-associated virus [AAV] produced via transient routes).

	Efforts to control for the presence of viral contaminants have focused on testing for retroviral contamination and species-specific viruses when animal-derived raw materials are used, according to Vitelli. Examples include bovine or porcine adventitious agents and species-specific viruses such as rhabdovirus, polyomavirus SV40, and arboviruses for other animal and insect cells.

	“Where bovine serum or porcine trypsin has been used in the process, there is a risk of introducing bovine and porcine viruses such as bovine polyomavirus and bovine and porcine circovirus,” notes Borland. “Minute virus of mice and vesivirus are viruses that have emerged in recent years as contaminants of bioreactors, and screening for both is now included as standard for rodent cell lines.”

	Detection is more complicated with viral vectors compared to antibodies, according to McAlister, because human cell lines are generally used for their manufacture. A typical panel for a human cell line could include herpes simplex virus, HIV-1, hepatitis A virus, porcine parvovirus, and possibly encephalomyocarditis virus. “When working with human cell lines-for example HEK293 cells-besides standard viral safety issues, special precautions should be taken because this cell line is susceptible to infection by human viruses,” she observes. Other human viruses that may need to be tested for include cytomegalovirus, human T-lymphotropic virus, Epstein-Barr virus, hepatitis B virus, human papillomavirus, and hepatitis C virus.

	It is easier to identify residual helper viruses such as baculovirus, adenovirus, and herpes simplex virus because they have been deliberately introduced and are also usually present at much higher concentration, according to McAlister. Due to that fact, however, the challenge becomes removal rather than detection, she comments.

	In addition to raw material and process risks, the facility, equipment, utilities, and people involved in the manufacturing the process are all potential sources of viral contamination, according to Borland.

	“The facility itself may be a point of entry for rodents, providing a pathway for viral and bacterial contamination to transfer to the process stream. If using stainless-steel bioreactors, the cleaning and sterilization regimes must be validated to ensure no cross-contamination of product. Such a risk is driving the movement to sterile, single-use systems. Water systems and non-sterile gas systems must also be taken into consideration,” Borland says. In multi-product facilities, there can also be opportunities for cross contamination by adventitious agents, according to Hitchcock.

	Operators, Borland asserts, may present the biggest risk to the process. “Viral manufacturing processes require aseptic manipulation within cleanrooms to controlled standards. People provide perfect reservoirs of bacteria, mycoplasma, and viruses, and therefore, the controls around people working on the processes must be to the highest standards,” she explains.

	One of the biggest challenges to assuring that viral vectors contain no viral contaminants is the fact that traditional viral clearance steps such as filtration and treatment with heat or strong acids cannot be used with many viral vectors such as enveloped viruses (e.g., lentiviruses), because they are too fragile and cannot withstand these processes. AAV is one exception; it is a relatively robust virus and so typically tolerates standard virus hold strategies to eliminate unknown adventitious agents in the preparation, according to McAlister.

	Neutralization of viral vector products without impacting the viral contaminants is also difficult, Hitchcock says. As a result, detection of unknown viral contaminants present at low levels is highly challenging.

	The range of potential viral contaminants and numerous sources, meanwhile, creates the need for a holistic approach to viral contaminant detection using a combination of methodologies including both general and specific assays, observes Vitelli. Examples are adventitious agent tests, usually non-specific tests capable of detecting a broad range of viruses; species-specific assays designed to detect the presence of identified potential contaminants (e.g., specific bovine or porcine viruses in serum or trypsin, respectively, or murine viruses in mouse cells); and tests for retroviruses.

	The limitations of the testing methods provide a huge challenge to the industry, Borland agrees. “Traditional 

 methods are broadly specific and will detect viruses that infect a range of cell types but may not detect viruses that do not cause cytopathic effects (CPE). Molecular methods such as real-time polymerase chain reaction (PCR) are more specific and have the ability to target those viruses that do not cause CPE in cell culture; however, they are limited by the fact they are specific. Methods such as [transmission electron microscopy] TEM, which is used to detect retroviruses, are limited by their sensitivity,” she explains.

	There are few tools available for accurate, efficient, and reliably precise assays to determine the activity of residual viruses, agrees Vitelli. “Generally, the limit of detection for these assays tends to be low, and more sensitive methods such as PCR-based assays can sometime result in false positives. In addition, risks are posed by potentially unknown viral contaminants that may be undetectable using current analytical tools,” she states.

	Borland notes that next-generation sequencing has been applied for general viral detection in biologics; technology advances and validation of this technique may bring it into routine testing use.

	Another concern for McAlister is the time required to test for the absence of viruses. “Current methods are laborious and may require more time to perform than the actual product is stable for. This issue is one of the biggest drivers for the development and acceptance of rapid alternative microbiology methods to allow testing within the shortest timeframe possible,” she comments.

	Once adequate testing is established, Vitelli notes that another substantial challenge is obtaining enough purified viral material for use in formal viral clearance studies, which is costly and time-consuming to generate. “These tests also typically require purified material that must be redirected from other potential uses that are critical to the product development cycle and timeline,” she observes.

	Tiano adds that there is only a finite amount of sample available for testing, which creates challenges, particularly when material is required for cytotoxicity pre-studies and viral interference testing in addition to virus spiking studies. “Reduction of the sample size for pre-studies is being made possible, however, with the development of sensitive molecular assays useful for testing cells, virus stocks, and raw materials used in the production of viral vectors,” she notes.

	Prevention, detection, and maybe removal

	The traditional approach to assuring that no viral contaminants are present in biologic products involves prevention, detection, and removal. Prevention involves ensuring that only high-quality, pure, contaminant-free raw materials are purchased from reliable suppliers, detection involves verification of the absence of contaminants in raw materials and process intermediates, and removal involves steps to remove or inactivate any potential viral contaminants that may be present.

	Because the latter step cannot be performed for many viral vector products, a risk-based approach must be taken, according to Borland. “Performing a detailed and relevant risk assessment is key to ensuring that an appropriate and comprehensive virus control strategy is employed,” adds McAlister. She also notes that because few viral vector processes have been performed at large scale, knowing how to do this risk assessment can be a challenge. “The good news is,” she observes, “that many years of experience have been developed in closely related processes such as monoclonal antibodies and vaccines, and this experience can be leveraged for these processes.”

	In addition, Hitchcock believes the best strategies clearly rely on understanding the vector design; selection of the appropriate producer cell line and manufacturing process, including the use of closed manufacturing systems, especially with regards to the production of replication-competent vectors; implementation of a stringent quality system and management of suppliers to ensure that the required control measures are in place to minimize the risks of adventitious viral contamination and for multi-product areas/facilities, adoption of procedures for prevention of cross-contamination and that demonstration of the removal of previously manufactured product from the cleanroom facility and shared equipment.

	“The over-arching requirement,” states Vitelli, “centers on good facility design, process design, material control, and strict compliance with good manufacturing practices to ensure safety and success. Fundamental facility controls are typically established during the facility design phase, such as the segregation of personnel, material and waste flows, and selection of cleanable materials of construction, and are propagated by validated facility management practices to include robust environmental monitoring, product changeover, and visual inspection.”

	Following the general viral safety strategy that incorporates prevention through safe sourcing, detection, and removal has resulted in safe biological products for many years, says Tiano. “Cell and gene therapies is an exciting and rapidly developing area. Although the therapies may be new, using this strategy for guaranteeing viral safety will help ensure that these new therapies are as safe as more traditional biological therapies.”

	There are limited options for viral clearance other than extensive testing of materials going into the process. Many of the same strategies used to inactivate/remove contaminating viruses can impact the quality/potency of the final viral gene therapy product. Manufacturers can look to adopting viral removal steps into their raw material entry points, Borland suggests. She points to next-generation virus filters that have been developed to offer a cost-efficient strategy for media filtration but notes that this technology is not yet adopted throughout the entire industry.

	Techniques such as nanofiltration, ultraviolet-treatment, gamma irradiation, and high temperature, short-time treatment can also be used to ensure that no viruses are present in starting materials, according to McAlister. She stresses, though, that it is important to ensure during process development that subjecting raw materials to these techniques does not affect their performance.

	Viral clearance technologies that are used in the manufacturing process for viral vectors that can withstand them are engineered into the manufacturing process and are most commonly heat inactivation and the use of viral retentive filtration, according to Vitelli. In some cases, such as for AAV products, affinity chromatography and exposure to acidic pH conditions (< pH3) may be employed.

	For removal of helper virus, McAlister notes that nanofiltration works well because there is a large difference in diameter between the virus of interest and the contaminating virus. She notes, however, that direct-flow filtration is not well adapted for the removal of viruses at high concentration. “It is generally recommended, therefore, that an initial virus removal step that can remove significant amounts of the helper virus, such as membrane chromatography, be performed first.”

	Some chromatography steps that are used in the purification of non-enveloped viral vectors may contribute to viral clearance for the vector as well, according to Tiano. “These steps may include an affinity resin or an anion exchange resin, which are optimized to purify the viral vector product and coincidentally may remove potential viral contaminants. Since the chromatography steps purify the vector product, viral clearance is only achieved when there is a difference in partitioning between the vector and potential viral contaminants,” she explains.

	Lonza’s R&D group is evaluating chemical additives and exploring different lysis reagents that have viral inactivation capabilities without risking impact on the quality of the viral vector product.

	As next-generation processes move toward commercialization, there has been a general shift away from adherent cell-culture processes in open, manual-intensive, flatware systems that are difficult to scale to automated, suspension cell-culture processes in closed bioreactors that are more efficient and readily scalable. This shift is also enabling the use of sterile, disposable systems, which is in turn enabling improved risk-mitigation strategies, according to Borland.

	Hitchcock notes that as viral vector manufacturing processes are scaled, the likelihood of the generation of replication competent viruses increases, which poses challenges for purification.

	Improving overall process yield will be an issue, in fact. McAlister points to downstream processing yields, typically around 30%, for AAV as an example. “Nanofiltration, if not done properly, can further reduce this yield. Appropriate filterability trials must be performed to ensure that a scalable scheme for virus control is designed,” she observes. Vitelli adds that as the per-dose demand for viruses increases, notably AAV, vendors of viral-retentive filters should continue to work closely with product developers and contract development and manufacturing organizations to provide scaling recommendations and new product sizing.

	For viral vectors that can withstand heat inactivation, these steps may also pose unique challenges with respect to scale up due to the need to adequately control both the temperature and duration of exposure in the liquid state, according Vitelli.

Vol. 32, No. 12
	December 2019
	Pages: 16–19

	When referring to this article, please cite it as C. Challener, “Prevent, Detect, and Remove: Viral Control for Viral Vectors,"

There is intense focus on the prevention and control of viral contaminants during viral vector manufacturing, which is driving the need for more accurate and powerful analytical methods for detection.

Ensuring Viral Control in Viral Vector Manufacturing

The FDA continues to approve drugs at a rapid pace, although fewer novel drugs (48) were approved by the Center for Drug Evaluation and Research in 2019 (1) compared with 59 in 2018 (2). Compared with other agencies around the world, however, FDA again lead other leading regulatory authorities in the number of approvals.

	According to the Kyoto Encyclopedia of Genes and Genomes Drug Database, 35 drugs with new active ingredients were approved in Japan by the Pharmaceutical and Medical Devices Agency (PMDA) as of Nov. 4, 2019 (3), while the total number of European public assessment reports (EPAR) authorized medicines as of Nov. 1, 2019 that were novel included 15 based on new molecular entities, approved under a biologic license application, and one cell therapy (4). In India, just 16 new drugs were approved by the Central Drugs Standard Control Organization as of mid-November (5).

	Looking at specific drugs, only one-Skyrizi (risankizumab-rzaa) from AbbVie for treatment of psoriasis-was approved in the United States, Europe, and Japan; the therapy was approved in Japan approximately one month in advance of approval in the US and Europe. Rozlytrek (entrectinib) and Evenity (romosozumab-aqqg) were approved in both the US and Japan, with the latter receiving approvals just days a part, and the former getting the okay in Japan two months before it received approval in the US (6).

	Interestingly, many more drugs in 2018 were approved in two or all three jurisdictions, and several of the drugs approved in the US and Europe in 2018 didn’t receive approval in Japan until 2019, including Erleada (apalutamide), more than one year later, Braftovi (encorafenib), three to six months later), Mektovi (binimetinib), three to six months later, and Onpattro (patisiran sodium), 10 months later.

	Many other drugs approved by FDA in 2018 did not receive approval by the European Medicines Agency (EMA) and/or PMDA until 2019, including Crysvita (burosumab), Trogarzo (ibalizumab), Palynziq (pegvaliase), Epidiolex (cannabidiol), Ajovy (fremanezumab), Lorbrena (lorlatinib), Vizimpro (dacomitinib), Libtayo (cemiplimab), Talzenna (talazoparib tosylate), Vitrakvi (larotrectinib sulfate), and Ultomiris (ravulizumab).

	A study of decisions by FDA and EMA for 107 new drug applications during the period 2014–2016 found that the two agencies were in agreement on the majority (more than 90%) of approval decisions (7). Differences were largely due to different conclusions regarding efficacy, sometimes based on the same data and sometimes on differing data.

	In a separate study, it was found that FDA approved 170 new therapeutic agents between 2011 and 2015, while EMA granted marketing authorization to 144 (8). In addition, the median total review time at FDA was much lower, on average 60 days shorter. FDA also approved more orphan drugs than EMA (43.5% vs. 25.0% of the total).

	Many of the new therapies approved by FDA in 2019 were developed to treat rare diseases, and most of these drugs are the first treatments ever approved for these diseases. Examples include Celgene’s Reblozyl (luspatercept–aamt), which reduces the need for blood transfusions in anemic patients with beta thalassemia (9); Ablynx’s Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura, a rare and life-threatening blood clotting disorder (10); and Pfizer subsidiary FoldRx’s oral therapies Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis), the first FDA-approved treatments for heart disease caused by transthyretin mediated amyloidosis (11).

	Other therapies for rare diseases for which the first new drugs were approved by FDA in 2019 include Givlaari (givosiran) from Alnylam Pharmaceuticals for acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules (12); Turalio (pexidartinib) from Daiichi Sankyo for symptomatic tenosynovial giant cell tumor, a non-malignant tumor that causes the synovium and tendon sheaths to thicken and overgrow (13); targeted therapy Adakveo (crizanlizumab-tmca) from Novartis for vaso-occlusive crisis, a common and painful complication of sickle cell disease (14); and Scenesse (afamelanotide) from Clinuvel for pain due to phototoxic reactions upon exposure to light (15).

	Several of the approved drugs are designed to treat cancer, including the first PIK3 inhibitor Piqray (alpelisib) from Novartis (16). The drug is used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor-positive, human epidermal growth factor receptor 2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. The disease must be detected with companion diagnostic test therascreen PIK3CA RGQ PCR Kit from QIAGEN Manchester, which also received FDA approval in 2019.

	Of note, Piqray was the first new drug application for a new molecular entity approved under the Real-Time Oncology (RTOR) pilot program, which permits FDA to begin analyzing key efficacy and safety datasets prior to the official submission of an application, allowing the review team to begin their review and communicate with the applicant earlier. Piqray also used the updated Assessment Aid, a multidisciplinary review template intended to focus FDA’s written review on critical thinking and consistency and reduce time spent on administrative tasks. With these two pilot programs, Piqray was approved approximately three months ahead of the PDUFA VI deadline.

	Two of the new drugs approved by FDA in 2019 address medical conditions suffered by women. Zulresso (brexanolone) injection from Sage Therapeutics is the first drug approved by FDA specifically to treat postpartum depression (17). Vyleesi (bremelanotide) from AMAG Pharmaceuticals treats acquired, generalized hypoactive sexual desire disorder in premenopausal women (18). FDA identified female sexual dysfunction as one of 20 disease areas of high priority and focused attention in 2012.

	Some of the drugs approved by FDA are interesting due to their route of delivery. Novo Nordisk’s Rybelsus (semaglutide), oral tablets, is the first glucagon-like peptide receptor protein approved by the agency to improve control of blood sugar in adult patients with type 2 diabetes that does not need to be injected (19). Baqsimi nasal powder, from Eli Lilly and Company, meanwhile, is the first glucagon therapy approved by FDA for the emergency treatment of severe hypoglycemia that can be administered without an injection (20).

	Also of note was the agency’s approval of Janssen Pharmaceuticals’ Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (21). Esketamine is the s-enantiomer of ketamine, which was approved under the brand name Ketalar in 1970.

	New antibacterial, antiviral and antifungal meds

	Developing new antibiotics and antiviral agents is a priority of FDA as concerns over drug resistance continue to rise; three 2019 approvals fall under this category. The Global Alliance for TB Drug Development received approval for Pretomanid tablets in combination with bedaquiline and linezolid for the treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs (22). This drug was approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs pathway and also received FDA’s Qualified Infectious Disease Product (QIDP) designation and a Tropical Disease Priority Review Voucher.

	Nabriva Therapeutics’ Xenleta (lefamulin) was approved for the treatment of with community-acquired bacterial pneumonia and also received QIDP designation (23). Fetroja (cefiderocol), an antibacterial drug from Shionogi & Co. for treatment of complicated urinary tract infections also received the QIDP designation (24).

	FDA also approved Sentosa SQ HIV Genotyping Assay (Vela Diagnostics USA), the first HIV drug resistance assay that uses next-generation sequencing (NGS) technology (25).

	One of FDA’s 2019 approvals making significant news for its price and questions about data integrity was for Zolgensma (onasemnogene abeparvovec-xioi), the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), the most severe form of SMA and a leading genetic cause of infant mortality (26). AveXis, which is a division of Novartis, also received a rare pediatric disease priority review voucher.

	The oral drug Ruzurgi (amifampridine) from Jacobus Pharmaceutical Company was granted the first FDA approval of a treatment specifically for pediatric patients with Lambert-Eaton myasthenic syndrome (27). Pfizer’s Fragmin (dalteparin sodium) injection, initially approved for adults in 1994, received approval for reducing the recurrence of symptomatic venous thromboembolism in pediatric patients (28).

	AbbVie’s oral drug Mavyret (glecaprevir and pibrentasvir), approved to treat hepatitis C virus (HCV) in adults in 2017, received approval for the treatment of children in 2019 (29). Glaxo-
	SmithKline also won approval for Benlysta (belimumab) intravenous (IV) infusion (initially approved for adults in 2011) for treatment of children with systemic lupus erythematosus (SLE) (30).

	Two new vaccines received approval from FDA in 2019: Jynneos Smallpox and Monkeypox Vaccine, Live, Non-Replicating from Bavarian Nordic, the only current FDA-approved vaccine for the prevention of monkeypox disease (31), and Dengvaxia from Sanofi Pasteur, the first vaccine approved by FDA for the prevention of dengue disease caused by all dengue virus serotypes in people ages 9 through 16 (32).

, accessed Dec. 18, 2019.
	3. Kyoto Encyclopedia of Genes and Genomes Drug Database, “

New Drug Approvals in Japan: Drugs with New Active Ingredients

,” www.genome.jp.com, accessed Dec. 18, 2019.
	4. Kyoto Encyclopedia of Genes and Genomes Drug Database, “

European Public Assessment Reports (EPAR) Authorised Medicine

, accessed Dec. 18. 2019.
	6. Kyoto Encyclopedia of Genes and Genomes Drug Database, “

New Drug Approvals in the USA, Europe and Japan

, accessed Dec. 18, 2019.
	7. M. Kashoki, et. al., 

 (July 15, 2019).
	8. N. S. Downing, A. D. Zhang, J. S. Ross, 

FDA Approves First Therapy to Treat Patients with Rare Blood Disorder

,” Press Release, Nov. 8, 2019.
	10. FDA, “

FDA Approves First Therapy for the Treatment of Adult Patients with a Rare Blood Clotting Disorder

,” Press Release, Feb. 6, 2019.
	11. FDA, “

FDA Approves New Treatments for Heart Disease Caused by a Serious Rare Disease, Transthyretin Mediated Amyloidosis

,” Press Release, May 6, 2019.
	12. FDA, “

FDA Approves First Treatment for Inherited Rare Disease

,” Press Release, Nov. 20, 2019.
	13. FDA, “

FDA Approves First Therapy for Rare Joint Tumor

,” Press Release, Aug. 2, 2019.
	14. FDA, “

FDA Approves First Targeted Therapy to Treat Patients with Painful Complication of Sickle Cell Disease

,” Press Release, Nov. 15, 2019.
	15.       FDA, “

FDA Approves First Treatment to Increase Pain-Free Light Exposure in Patients with a Rare Disorder

,” Press Release, Oct. 8, 2019.
	16. FDA, “

FDA Approves First PI3K Inhibitor for Breast Cancer

FDA’s approval rate slowed, but the US agency is still ahead of its international counterparts in green-lighting new drugs for market.