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

Cynthia A. Challener

Analytical instruments are increasing in sensitivity and accuracy. Pharmaceutical methods applied today generate increasing quantities of data. These data are stored and manipulated using a variety of software platforms from different suppliers. Pharmaceutical scientists must be able to integrate and interpret these data in an efficient manner that ensures reliability, security, and regulatory compliance.

	Today’s modern laboratory is highly dependent on a range of instrumental technologies, all reliant on data output that has to be interpreted, managed, and maintained in a retrievable, secure, and non-corruptible manner, according to Mark Rogers, global technical director at SGS Life Sciences. The volume and complexity of these data make the move to electronic capture inescapable, he adds.

	For many of these techniques, however, the inevitable evolution from paper-based data collection procedures to electronic systems has not been without difficulties. “It may be argued, for example, that the relatively simple process of recovering and reviewing chart recordings from a well-maintained paper archive has advantages over the recovery of data from older software/operating platforms that may have become obsolete, making data difficult to retrieve,” Rogers explains.

	Regulatory considerations have also now become intrinsically linked to the traceability, security, and non-corruptibility of scientific data, again resulting in difficulties with older equipment, he notes. “The electronic modernization of older-but well-established and effective-equipment may be one of the most significant and ongoing challenges,” asserts Rogers.

	In addition, despite advances in the digitalization of analytical data, significant human intervention and manipulation is still required during any decision-making process based on data acquisition. For lot release, once a specification (identify, purity, physical form, etc.) has been established and test methods validated for a drug substance, there are many human intervention steps involved to get from a request for release to fulfilling that request, explains Andrew Anderson, vice-president of innovation and informatics strategy at ACD/Labs. Spectra must be collected and separation analyses performed. The data obtained must be generated as a table, chart, or other picture that describes the results, which must then be compared to reference standards to determine whether they conform or not.

	“Many of these steps cannot be digitized or even easily automated. Bringing data back into the decision-making mechanism is very difficult without specialized informatic tools that handle all different types of data. This challenge is the greatest latent pain for development organizations,” Anderson asserts.

	There will also always be challenges with getting the right data, according to Anderson. “There are trade-offs between project timelines and the data that can possibly be generated and ultimately handled by existing infrastructure,” he explains.

	One example relates to the move to a quality-by-design approach to process development. With this approach comes a geometric expansion in the quantity of data being acquired to characterize a process. Each possible parameter variant requires a data point for the modeling system used to determine the optimum operating conditions.

	In addition, the data itself is becoming more complex. A nuclear magnetic resonance (NMR) spectrum provides a significant amount of detailed information about a given molecule and is therefore attractive for small-molecule API proof-of-structure analysis. Interpretation of this type of spectrum, such as comparison with a reference standard to confirm identity, requires an expert, however. “A method for plant operators to use for determining that a lot spectrum conforms to a standard should be rugged and allow for simple acquisition and validation. Ultraviolet (UV) analysis is one example. Such a method leaves some doubt however; NMR provides more fidelity, so there is a tradeoff between absolute confirmation and practicality,” Anderson observes.

	The complexity of analytical experiments will, in fact, always outpace the ability to implement them in quality processes, he adds. “There are often challenges to implementing more complex analytical techniques in a quality paradigm. All of the aspects of quality assurance are increasing in complexity: software systems and how they handle data, quality practices, standard operating procedures, and test methods. Each of these factors must be considered to ensure that drug products introduced to the market are of the highest quality,” notes Anderson.

	It is not only the volume and complexity of raw data being generated that is the key issue for Marco Galesio, R&D team leader in the analytical chemistry development group at Hovione, but the lack of specific and user-friendly software to treat and interpret these data. “Most of the time there is a lot of relevant data being generated, but due to lack of suitable software and sufficient time, it is not possible to take the most out of it,” he says.

	Biologic drugs pose some additional challenges beyond those associated with chemical APIs. Small molecules have one structure and composition. Because biologic drug substances are produced in cells or microorganisms, their structures and compositions can vary slightly from batch to batch, leading to inherent variability, according to Tiffani A. Manolis, senior director of Agilent Technologies’ global pharma strategic program.

	Added to this variability is the complexity of large-molecule structures, which necessitates the use of a greater number of more complex analytical methodologies, according to Íñigo Rodríguez-Mendieta, technical client manager biopharmaceuticals, SGS Life Sciences. In most cases, specific expertise is required to interpret large-molecule data, notes Constança Cacela, associate director of R&D in the analytical chemistry development group at Hovione.

	The necessity to fully define the relatively complex and diverse structural features of large molecule entities has led to expansion in the variability and sophistication of the analytical tools in the biologics field, according to Rodríguez-Mendieta. “Many of these techniques have traditionally been employed in the academic sector where data interpretation relies heavily on subjective manual review, and this is often difficult to translate to machine-based understanding,” he says. Approaches to digitalization have included automated reference to library data as in the case of circular dichroism (CD) and/or the application of complex algorithms as in the case of mass spectrometry (MS)-based sequencing. “None of these approaches has yet been perfected, however, particularly for large-molecule applications where structural diversity can prove a significant impediment to accurate interpretation,” adds Rodríguez-Mendieta.

	The key challenge lies in the fact that with biologic molecules, identity has various meanings related to structure (primary, secondary, etc.), post-translational modifications (PTMs), etc. “Orthogonal analyses are required to ensure full characterization. Chromatography may be used to determine purity, while other methods must be used to determine the identity (sequence, location of PTMs, etc.). Structural assays are often augmented with behavior immunoassays. All of these data must be ‘assembled’ together to create the complete picture. That can be challenging to do digitally, because orthogonal data are often generated in a variety of vendor formats,” Anderson explains.

	The same issues exist for biosimilar comparability studies, Rodríguez-Mendieta notes. “Results have to be considered holistically, which remains a considerable challenge, as the data can be somewhat contradictory and often produced from a wide range of techniques with instrumentation from multiple manufacturers with different data platforms,” he says.

	Next-generation drug substances can complicate the situation even further. Anderson points to antibody-drug conjugates (ADCs) as an example. “ADCs comprise an antibody, a small-molecule cytotoxic payload, and a linker of some kind, which can be an oligomer or other small to medium-sized component. The dynamic range of MS, NMR, or other instruments must therefore be sufficiently wide to allow analysis of small and large molecules, and of course also validatable,” he explains.

	Separation techniques such as gas chromatography (GC), high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), and gel electrophoresis when coupled to UV, Raman, infrared, and fluorescence do not provide sufficient data per se, and particularly for large molecules, according to Cacela. “Data generated by these techniques must often be validated by more comprehensive techniques such as mass spectrometry,” she notes.

	In general, however, LC–MS methods, especially high-resolution MS (quadrupole time-of-flight [Q-TOF], triple quadrupole, etc.), generate overwhelmingly large data files, according to Manolis. “Data sets are becoming very large and pose challenges to any IT [information technology] infrastructure as they are transmitted across networks for storing and analysis,” she observes.

	An additional challenge is related to data interpretation. The acquisition of MS data occurs in much less time than it takes to interpret it, according to Anderson. “With TOF instruments it is possible to gather detailed spectra in just three minutes, so the technique can be useful for screening experiments or monitoring the progress of a synthetic reaction or cell culture. The data files that result can be a gigabyte in size, which is challenging not only from a hard disc perspective, but for interpretation, which can take much longer,” he comments. Furthermore, deep expertise is required to accurately evaluate and filter the meaningful data, Cacela adds.

	Similarly, the volume of data generated in NMR and surface plasmon resonance analyses can be challenging to manage.

	Another challenge given the volume and complexity of data generated today is the need for some sort of data abstraction in order to be able to efficiently leverage analytical data in the decision-making process. “Very large data sets need to be transformed in some way to make them manageable and interpretable in a practical and timely manner. The difficulty, however, is the potential for loss of information,” asserts Anderson.

	Reduction of data creates risk from a total analysis point of view, he adds. Centroided MS data vs. full-profile MS data is one example. The former involves a mathematical transformation of the data that provides simplification and easier interpretation, but the risk of missing important details must be weighed against that simplification.

	There is a big push, according to Anderson, to find ways to use data in a non-reduced way for more practical interpretations.  One example involves modifying the way signals are acquired. In NMR, for instance, Anderson points to nonuniform sampling, which involves pulsing the sample at nonuniform frequencies and allows the reconstruction of spectra close to what would be obtained with full-frequency pulsing but in a smaller data file.

	There is also a focus on the application of machine learning and artificial intelligence in this area, letting machines identify trends and make observations that humans could probably find but don’t have time to do, according to Anderson.

	A theme underlying all of the above areas of concern is the need for software platforms that enable viewing of data generated by different instruments from different suppliers. “The systems we have today generate huge amounts of data. But these same systems are not necessarily capable of integrating these large data sets and providing researchers with actionable information in a multi-modal view,” Manolis states. While data generation and usability of technologies are improving with better user interfaces and easier-to-use systems and applications, the integration of data sets and connectivity between data sets from different technologies and vendors remains a challenge.

	“Software analysis tools, rather than only gather data, should also be able to analyze and interpret that data and provide information as the output,” asserts Lucia Sousa, associate analytical chemist for R&D in the analytical chemistry development group at Hovione. “Vendors are creating software that interprets data, but even these advanced systems still require great effort from the user. Scientists in the laboratory should have knowledge in their fields of expertise and not need to be experts in software applications as well,” she adds. 

	Throughout pharma discovery, development, and commercial manufacturing, data are acquired and stored on separate and disparate systems that contain both structured and unstructured information, according to Manolis. The challenge is further complicated by collaboration with outsourcing partners, suppliers, distributors, and government agencies that have their own disparate systems. Overcoming these challenges will dramatically improve researchers’ abilities to make faster decisions and will ultimately accelerate drug development and approval, she adds. 

	Analytical manufacturers are working with pharma companies and others to build software solutions that ease these processes. The Agilent data system OpenLab CDS ChemStation Edition, according to Manolis, is the first to support the new Allotrope Data Format (ADF) (allotrope.org), an emerging standard developed by a consortium of pharmaceutical companies.

	“ADF standardizes the collection, exchange, and storage of analytical data captured in laboratory workflows and enables labs to transfer and share that data across platforms,” Manolis explains. “There needs to be continued focus on evolving customer requirements concerning analysis and integration of data sets, compliant solutions for analysis and storage, and the IT infrastructure challenges around large data sets, specifically those generated from high-resolution MS analyses,” she continues. 

	It is an exciting time with respect to advances in data analysis and interpretation, according to Anderson. “Instrument manufacturers and software vendors like ACD/Labs are facing a new paradigm. No longer are we dealing with the integration of monolithic systems through document exchange. Copying and pasting spectra into a word document isn’t good enough any longer. Integration of not only data, but applications is needed to provide a seamless user experience. Decision-making interfaces of the future will be interoperable and able to leverage a variety of heterogeneous and orthogonal data,” he explains.

	 The horizon for software solutions to address pharma customer needs is positive and a fast-moving and competitive space, agrees Manolis. “Broadly speaking, there are many organizations evaluating and using tools that were not designed specifically for pharma but perhaps for business or consumers, and these organizations have been adapting them to their needs. Moving forward, we see these boundaries continuing to blur as solutions are delivered from a variety of software vendors.”

	Pharmaceutical scientists will need to adapt as well. An understanding of data science is becoming essential. “This experience is key for analytical scientists to understand the data and challenge the data with the right questions and subsequent analyses,” Manolis says. “To avoid data silos and facilitate the sharing of data, the expertise gained by the data owner will be invaluable when developing ways to use existing information or to integrate additional data,” she adds.

	Furthermore, implementing end-to- end data integration requires capabilities that include trusted sources of data and documents, robust quality, and maintenance of data integrity. “The objective is to tackle the most important data first to achieve a rapid return on investment. Identifying the right infrastructure will therefore be of paramount importance,” states Manolis.

	Hovione also believes that data science will allow data-driven predictions from big data through modeling and statistical inference. “Data science will allow the extraction of meaningful information for decision making and consequently allow increased efficiency in pharma laboratories,” says Galesio. He does note, however, that many pharma researchers still lack expertise in this field. “Going forward it will be especially relevant to combine both data science and analytical expertise. We believe many companies are investing more and more in this area,” Galesio observes.

	Many pharma organizations are building structures or have built structures in the past 5–10 years specifically supporting data science and analysis, according to Manolis. “We would assume this investment will continue as modalities and data sets continue to increase in complexity,” she concludes. 

Vol. 43, No. 2
	February 2019
	Pages: 16–18, 47

	When referring to this article, please cite it as C. Challener, “Paradigm Shift for Data Analysis and Interpretation," 

Articles

Leveraging vast quantities of analytical data requires digitalization and platform integration. 

Paradigm Shift for Data Analysis and Interpretation

Editor's note: An abbreviated version of this article appeared in the January 2019 issue of 

FDA had a very active year in 2018. The agency investigated ways to improve the drug approval process, increase the efficiency of drug development and better incorporate patient voices in the process, increase access for the public to less expensive generics, and develop solutions for the prevention of drug shortages.

	In June 2018, FDA Commissioner Scott Gottlieb issued a statement about a proposal to modernize the agency’s drug review office (1). The proposed changes at the Office of New Drugs in the Center for Drug Evaluation and Research (CDER) were intended to provide its “clinicians and scientists more time, better tools, and greater support to advance the clinical and regulatory principles that the FDA uses to evaluate new drugs for safety and efficacy.”

	Also in June, FDA issued the first of four draft guidance documents intended to inform patients and product developers about rigorous approaches for obtaining and incorporating patient input in product development and how the agency will incorporate this information into its regulatory decision-making (2).

	To speed drug development, FDA announced in October 2018 that the agency is developing technology- and disease-specific regulatory frameworks for innovations that may not have previously had a clear development pathway, including modernization of the agency’s approach to clinical trial design (3). It also issued several guidance documents for newer trial designs and the development of next-generation therapies.

	These changes may have helped-or certainly not hindered-the ability of the agency to review new drug applications. In 2018, CDER had approved 59 novel drugs (4), 13 more than approved in 2017 (5). The following information was sourced from press releases issued by FDA and the drug license holders. A list of 2018 novel drug approvals can be found on the 

	Based on information in FDA and company press releases, approximately half of the new drugs were approved under an expedited review process-Fast Track, Breakthrough Therapy, Priority Review, Accelerated Review-or orphan drug status. These results suggest that both pharma companies and FDA remain committed to leveraging the shorter approval pathways made possible in the 2012 Food and Drug Administration Safety Innovations Act.

	Nearly one-third of the new drugs were granted orphan drug designation, clearly reflecting the shift taking place in the industry away from the development of blockbuster drugs to the development of therapies for rare diseases.

	Despite all of the hype about and investment in biologic drugs, only one quarter of medicines approved in 2018 by FDA were biologic-based drugs.

	In response to concerns about the growing prevalence of drug-resistant bacteria and the ongoing need for medications to treat a variety of infections, FDA has placed an emphasis on approving new antibiotics and antivirals.

	Paratek Pharmaceuticals received approval for its modernized tetracycline antibiotic Nuzyra (omadacycline) for the treatment of adults with community-acquired bacterial pneumonia and acute skin and skin structure infections (6). Nuzyra is specifically designed to overcome tetracycline resistance and exhibits broad-spectrum activity. It is also the first and only once-daily intravenous (IV) and oral antibiotic approved for the treatment of both types of infections. Its use enables physicians to transition patients from IV to oral treatment and potentially reduce hospitalizations. Xerava (eravacycline) from Tetraphase Pharmaceuticals is a novel, broad-spectrum antibiotic approved for the treatment of complicated intra-abdominal infections, the most common infection site in intensive care units (7).

	New antiviral medications approved in 2018 include Shionogi’s Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu), the first new antiviral flu treatment with a novel mechanism of action approved by FDA in nearly 20 years (8); and Tpoxx (tecovirimat), the first drug approved for the treatment of smallpox (9). Tpoxx was developed by SIGA Technologies in conjunction with the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA); SIGA received a Material Threat Medical Countermeasure Priority Review Voucher.

	Four new treatments for HIV patients were also approved by FDA in 2018. Biktarvy (bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg, BIC/FTC/TAF) from Gilead Sciences is a once-daily single tablet regimen for the treatment of HIV-1 infection (10); Trogarzo (ibalizumab-uiyk) from TaiMed Biologics is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options (11). Merck’s Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) is a once-daily fixed-dose combination tablet, and Pifeltro (doravirine) is a new non-nucleoside reverse transcriptase inhibitor; both were developed for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience (12).

	Treatments for rare genetic diseases, all with the orphan drug designation, received approval by FDA. Onpattro (patisiran) infusion from Alnylam Pharmaceuticals is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR and is the first in a new class of drugs referred to as small interfering ribonucleic acid treatments (13). Akcea Therapeutics’ Tegsedi (inotersen), also for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, is the first RNA-targeting therapeutic designed to reduce the production of human transthyretin protein (14).

	Takhzyro (lanadelumab) from Shire is a plasma kallikrein inhibitor and the first monocloncal antibody (mAb) approved in the United States to treat patients 12 years and older with types I and II hereditary angioedema, a rare and serious genetic disease that leads to unpredictable episodes of severe swelling in different areas of the body (15). Dompé farmaceutici’s Oxervate (cenegermin) is the first drug approved by FDA for the treatment of neurotrophic keratitis, a rare disease affecting the cornea, providing an alternative to surgical intervention (16).

	Galafold (migalastat) from Amicus Therapeutics is the first oral medication for the treatment of adults with Fabry disease and specifically for patients who have a genetic mutation determined to be responsive to treatment with Galafold based on laboratory data (17). Unlike enzyme replacement therapy, this drug increases the activity of the body’s deficient enzyme.

	Crysvita (burosumab-twza) is the first drug approved for the treatment of x-linked hypophosphatemia, a rare, inherited form of rickets that does not respond to vitamin D therapy (18); Ultragenyx Pharmaceutical received the 14th Rare Pediatric Disease Priority Review Voucher awarded by FDA. Palynziq (pegvaliase-pqpz) from BioMarin Pharmaceutical is a novel enzyme therapy approved for the treatment of adult patients with phenylketonuria, a rare genetic disease, who have uncontrolled concentrations of phenylalanine in their blood even on current treatment (19).

	Treatments for both common and rare cancers were approved by FDA in 2018, including Regeneron Pharmaceuticals’ PD-1 checkpoint inhibitor Libtayo (cemiplimab-rwlc) injection, the first approved treatment for metastatic or locally advanced cutaneous squamous cell carcinoma, the second most common skin cancer (20). Lumoxiti (moxetumomab pasudotox-tdfk) injection from AstraZeneca Pharmaceuticals is the first CD22-directed cytotoxin approved for the treatment of adult patients with relapsed or refractory hairy cell leukemia who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog (21). Kyowa Kirin’s Poteligeo (mogamulizumab-kpkc) injection is the first drug approved by FDA for the treatment of Sézary syndrome, a rare and hard-to-treat type of non-Hodgkin lymphoma (22).

	Erleada (apalutamide) from Janssen Pharmaceutical Companies is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer (23). The approval was the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment. It was the first participant in FDA’s Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals.

	Lutathera (lutetium Lu 177 dotatate) from Advanced Accelerator Applications (since acquired by Novartis) is the first radiotherapy approved for the treatment of gastroenteropancreatic neuroendocrine tumors, which affect the pancreas or gastrointestinal tract (24). The drug binds to the somatostatin receptors of tumor cells, enabling its entry and their ultimate destruction.

	In late November, FDA approved Vitrakvi (larotrectinib) from Loxo Oncology for the treatment of adult and pediatric cancer patients with a specific genetic feature, or biomarker, on their tumors. The approval marks the second time FDA has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated.

	Several other firsts were achieved by FDA in 2018. Approval of the first non-opioid treatment for the management of opioid withdrawal symptoms went to US WorldMeds’ Lucemyra (lofexidine hydrochloride), an oral, selective alpha 2-adrenergic receptor agonist that reduces the release of norepinephrine (25). Epidiolex (cannabidiol) from GW Research for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of epilepsy, is the first FDA-approved drug that contains a purified drug substance derived from marijuana and the first drug approved for the treatment of patients with Dravet syndrome (26).

	AbbVie’s Orilissa (elagolix) is the first FDA-approved oral treatment for the management of moderate to severe pain associated with endometriosis in over a decade and the only oral gonadotropin-releasing hormone antagonist specifically developed for women with moderate to severe endometriosis pain (27).

	FDA also approved new medications for the prevention of migraines. Aimovig (erenumab-aooe) from Amgen is a once-monthly self-injection and the first FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide (28). Teva Pharmaceutical Industries’ Ajovy (fremanezumab-vfrm) injection is the first and only anti-CGRP treatment for the prevention of migraine with quarterly and monthly dosing options (29). Eli Lilly’s Emgality (galcanezumab-gnlm) also received approval.

	Several drugs that received FDA approval in 2018 were targeted therapies, and some were even approved with specific diagnostic tests. Pfizer’s Talzenna (talazoparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, was approved for the treatment of for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2ânegative locally advanced or metastatic breast cancer (30). The BRACAnalysis CDx test from Myriad Genetic Laboratories, Inc. was also approved to identify patients who are eligible for the new drug.

	Agios Pharmaceuticals received approval for Tibsovo (ivosidenib), the first isocitrate dehydrogenase-1 inhibitor, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation (31). Patients must be identified using the FDA-approved RealTime IDH1 Assay from Abbott Laboratories.

	The combination of BRAFTOVI (encorafenib

 and MEKTOVI (binimetinib) from Array BioPharma was approved for the treatment of for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation (32). The mutation must be detected using the FDA-approved THxID BRAF Kit from bioMérieux.

	One interesting trend is the development of new drugs by non-profit organizations, sometimes in collaboration with pharmaceutical companies. Two drugs approved to treat tropical diseases were developed using this approach. The not-for-profit company Medicines Development for Global Health (MDGH), in collaboration with the World Health Organization Special Program for Research and Training in Tropical Diseases, received FDA approval for moxidectin 8 mg oral for the treatment of river blindness, which is caused by the parasite 

(33). It is the first new drug approved for the treatment of river blindness in 20 years. MDGH received a priority review voucher (PRV), a saleable item that enables the owner to receive accelerated review of a new drug application (NDA)-the first not-for-profit company to do so under the tropical disease PRV program.

	Similarly, GlaxoSmithKline (GSK) received a tropical disease PRV for its part in the development of the first new treatment for 

) malaria in more than 60 years (34). Single-dose 

 (tafenoquine) was developed in collaboration with Medicines for Malaria Venture  and received FDA approval for the radical cure (prevention of relapse) of 

 malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute 

	Two other interesting examples are the first approval of a vaginal ring contraceptive: the Population Council’s Annovera (segesterone acetate and ethinyl estradiol vaginal system) (35); and Omegaven, a fat emulsion manufactured by Fresenius Kabi and demonstrated by researchers at Boston Children’s Hospital to be effective for preventing liver disease associated with parenteral nutrition in children (36).

	Most of the drugs on FDA’s approval docket through early 2019 include treatments for many common conditions, including heart disease, immune deficiency, diabetes, and influenza (37). There are also several treatments for neurological and psychology disorders, such as Parkinson’s disease and depression. Several drugs for pain management are under review, as are treatments for skin infections, glaucoma, breast cancer, and erectile dysfunction. Several new drugs for the treatment of rare cancers are also awaiting FDA decisions.

	Digital health became an increasingly important focus area for FDA in 2018. After launching the Digital Health Innovation Action Plan in 2017, which is seeking to modify the agency’s approach to digital health products (38), FDA formed the internal data science incubator the Information Exchange and Data Transformation (INFORMED) in 2018. The agency has also proposed to create a Center of Excellence for Digital Health in its Fiscal Year 2019 Budget.

	Also in 2018, FDA approved the first medical device that combined a special camera and artificial intelligence to detect greater than a mild level diabetic retinopathy in adults who have diabetes in a primary care setting (39) and permitted the marketing of an artificial intelligence algorithm for aiding providers in detecting wrist fractures (40). Most recently, FDA awarded 

 clearance to Apple’s Series 4 model of the Apple Watch (41).

	FDA Commissioner Scott Gottlieb has indicated that digital technology requires “a reimagination of healthcare delivery” (38). The agency is committed to fostering, not hindering, innovation in digital health technology. Gottlieb hopes the new Center of Excellence will “help establish more efficient regulatory paradigms, consider building new capacity to evaluate and recognize third-party certifiers, and support a cybersecurity unit to complement the advances in software-based devices.”

	From artificial intelligence technologies such as deep learning and natural language processing to smart devices and advances software and apps, digital technologies will clearly play an increasing role in drug and medical device development going forward.

Statement from FDA Commissioner Scott Gottlieb, M.D., on Proposed Modernization of FDA’s Drug Review Office

,” Statement, June 4, 2018.
	2. FDA, “

Statement from FDA Commissioner Scott Gottlieb, M.D., on New Agency Efforts to Advance the Patient Voice in Medical Product Development and FDA Regulatory Decision-Making

,” Statement, June 12, 2018.
	3. FDA, “

Statement by FDA Commissioner Scott Gottlieb, M.D., on FDA’s New Steps to Modernize Drug Development, Improve Efficiency and Promote Innovation of Targeted Therapies

,” Statement, Oct. 15, 2018.
	4. FDA, “

.
	6. Paratek Pharmaceuticals, “Paratek Announces FDA Approval of NUZYRA (Omadacycline),” Press Release, Oct. 2, 2018.
	7. Tetraphase Pharmaceuticals, “Tetraphase Pharmaceuticals Announces FDA Approval of XERAVA (Eravacycline) for Complicated Intra-Abdominal Infections (cIAI),” Press Release, Aug. 27, 2018.
	8. FDA, “FDA Approves New Drug to Treat Influenza,” Press Release, October 24, 2018.
	9. FDA, “FDA Approves the First Drug with an Indication for Treatment of Smallpox,” Press Release, July 13, 2018.
	10. Gilead Sciences, “US Food and Drug Administration Approves Gilead’s Biktarvy (Bictegravir, Emtricitabine, Tenofovir Alafenamide) for Treatment of HIV-1 Infection,” Press Release, Feb. 7, 2018.
	11. FDA, “FDA Approves New HIV Treatment for Patients Who Have Limited Treatment Options,” Press Release, March 6, 2018.
	12. Merck, “FDA Approves Merck’s Delstrigo and Pifeltro to Treat HIV,” Press Release, Aug. 30, 2018.
	13. FDA, “FDA Approves First-Of-Its Kind Targeted RNA-Based Therapy to Treat a Rare Disease,” Press Release, Aug.10, 2018.
	14. Akcea Therapeutics, Inc., “Akcea and Ionis Receive FDA Approval of TEGSEDI™ (inotersen) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults,” Press Release, 


	15. FDA, “FDA Approves New Treatment for Rare Hereditary Disease,” Statement, Aug. 23, 2018.
	16. FDA, “FDA Approves First Drug for Neurotrophic Keratitis, a Rare Eye Disease,” Press Release, August 22, 2018.
	17. FDA, “FDA Approves New Treatment for a Rare Genetic Disorder, Fabry Disease,” Press Release, August 10, 2018.
	18. FDA, “FDA Approves First Therapy for Rare Inherited Form of Rickets, X-Linked Hypophosphatemia,” Press Release, April 17, 2018.
	19. FDA, “FDA Approves a New Treatment For PKU, a Rare and Serious Genetic Disease,” Press Release, May 24, 2018.
	20. FDA, “FDA Approves First Treatment for Advanced Form of the Second Most Common Skin Cancer,” Press Release, September 28, 2018.
	21. FDA, “FDA Approves New Kind of Treatment for Hairy Cell Leukemia,” Sept. 13, 2018.
	22. FDA, “FDA Approves Treatment for Two Rare Types of Non-Hodgkin Lymphoma,” Press Release.
	23. FDA, “FDA Approves New Treatment For a Certain Type of Prostate Cancer Using Novel Clinical Trial Endpoint,” Press Release, Feb. 14, 2018.
	24. FDA, “FDA Approves New Treatment for Certain Digestive Tract Cancer,” Press Release, Jan. 26, 2018.
	25. FDA, “FDA Approves the First Non-Opioid Treatment for Management of Opioid Withdrawal Symptoms in Adults,” Press Release, May 16, 2018.
	26. FDA, “FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy,” Press Release, June 25, 2018.
	27. Abbvie, “AbbVie Receives US FDA Approval of ORILISSA (elagolix) for the Management of Moderate to Severe Pain Associated with Endometriosis,” Press Release, July 24, 2018.
	28. FDA, “FDA approves novel preventive treatment for migraine,” Press Release, May 17, 2018.
	29. Teva Pharmaceutical Industries Ltd., “Teva Announces US Approval of AJOVY (fremanezumab-vfrm) Injection, the First and Only Anti-CGRP Treatment with Both Quarterly and Monthly Dosing for the Preventive Treatment of Migraine in Adults,” Press Release, Sep. 14, 2018.
	30. FDA, “FDA Approves Talazoparib for gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer,” Statement, October 16, 2018.
	31. FDA, “FDA Approves First Targeted Treatment for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have a Certain Genetic Mutation,” Press Release, July 20, 2018.
	32. FDA, “FDA Approves Encorafenib and Binimetinib in Combination for Unresectable or Metastatic Melanoma with BRAF Mutations,” Statement, June 27, 2018.
	33. Medicines Development for Global Health, “US FDA Approves Moxidectin for the Treatment of River Blindness,” Press Release, June 13, 2018.
	34. GSK, “US FDA Approves Krintafel (tafenoquine) for the Radical Cure of 

 Malaria,” Press Release, July 20, 2018.
	35. FDA, “FDA Approves New Vaginal Ring for One Year of Birth Control,” Press Release, Aug. 10, 2018.
	36. Nancy Fliesl, “A Life-Saving Adjustment in IV Nutrition Cleared by the FDA,” Aug.13, 2018.
	37. RTT News, “

tatement from FDA Commissioner Scott Gottlieb, MD, and Center for Devices and Radiological Health Director Jeff Shuren, MD, JD, on Agency Efforts to Work with Tech Industry to Spur Innovation in Digital Health

,” FDA Statement, Sept. 12, 2018.
	39. FDA, “

FDA Permits Marketing of Artificial Intelligence-Based Device to Detect Certain Diabetes-Related Eye Problems

,” Press Release, April 11, 2018. .
	40. FDA, “

FDA Permits Marketing of Artificial Intelligence Algorithm for Aiding Providers in Detecting Wrist Fractures

,” Press Release, May 24, 2018. .
	41. Conor Hale, “New Apple Watch Receives FDA Clearance for Built-in ECG,” FierceBiotech, September 12, 2018.


	Vol. 43, No. 1
	January 2019
	Pages: 30–33

	When referring to this article, please cite it as C. Challener, “FDA Marks Record Year for New Drug Approvals," 

Orphan and cancer drugs continue to lead, but treatments for many common diseases were also approved in 2018. 

FDA Marks Record Year for New Drug Approvals

In bio/pharmaceutical manufacturing, monitoring the bioburden of raw materials, intermediates, drug substances, formulated drug products, and processing environments is essential for ensuring patient safety. Successful bioburden monitoring requires knowledge of both the quantity and identity of detected microbes. The level of information and extent of microbe characterization, and thus the testing protocols, required depend on the specific sample and situation. In cases of potential contamination, knowledge of the identity of a contaminant can help determine its source and thus an appropriate course of action. It is essential, therefore, to implement a microbial identification strategy as part of an effective microbial control program.

	Microbial identification is an important and often overlooked component of bioburden monitoring programs, according to Phil Tuckett, study director at Nelson Laboratories. The intent is to characterize microbes to differentiate one type from another. Identification allows placement of the microbe, depending on the required level of identification and the type of testing employed, into a specific family (genus), species, and/or strain.

	Microbial identifications can be used to provide a platform for thorough investigations, such as for determining the nature of specific contamination events, according to Poonam Bhende, assistant manager at SGS Life Sciences. Microbial identity determination can also be used in a broader manner to provide a rough estimate of the bioburden in a dose of product as an indication of its sterility.

	“It is important to understand not only the numbers of microorganisms present in a product, but also the types of microorganisms they are. Particularly with regard to bioburden reduction strategies, the identity of a microorganism can dictate the best practice for eliminating it,” says Tuckett. Indeed, Bhende notes that through detailed and accurate microbial identification, it is possible to narrow down the source of contamination and take appropriate measures to mitigate the risk for future contamination.

	There are several methods available for microbial identification. They are generally classified as phenotypic or genotypic techniques.

	Phenotypic testing provides data on the physical properties (i.e., morphology, reaction to different chemicals, behavior under certain conditions) that are indicative of a microbe’s genus and in some cases species. “Phenotypic methods, which focus on outward characteristics of an organism-appearance, staining characteristics, biochemical utilization, metabolic requirements, protein analysis-are important components of the microbial characterization level. Given enough of these tests, along with a high level of expertise, a genus/species ID may be obtained,” observes Tuckett. Currently, these methods are most widely used because they tend to be lower in cost and easier to implement. They are, however, generally culture-based and growth dependent, and results can vary with the media and growth conditions that are used. In addition, because many phenotypic tests involve studying the response to treatment with biochemical reagents, repeatability can be an issue.

	Automated systems have been developed to overcome some of these limitations, including Fourier-transform infrared spectroscopy, matrix-assisted laser desorption ionization–time of flight (MALDI–TOF) mass spectrometry, and flow cytometry.

	The industry is, however, moving toward genotypic identification methods due to the growing number of species that are being described every year, according to Tuckett. Genotypic methods involve analysis of the genetic makeup and provide information on the genus, species, and in some cases, the strain of the microbe.

	Analysis of the genome is achieved either through hybridization or sequencing. In hybridization, the extent to which the microbe’s DNA binds with known DNA strands provides information on its structure. Sequencing, generally of the 16S rRNA region, a highly conserved, sufficiently large region present in most bacteria (or the large subunit ribosomal gene in yeasts and molds) is achieved using automated blot technology or polymerase chain reaction (PCR) approaches. Importantly, genotypic testing is not affected by culture or media conditions. “As technology becomes cheaper and more available, whole genome sequencing may provide accurate species and strain identifications,” Tuckett states.

	Separately, the detection and identification of endotoxins indicates the presence of gram-negative bacteria. “Contamination with high levels of endotoxin can be fatal, so accurate results are vital,” asserts Bhende.

	Microbial identification, according to Pia Darker, global senior product manager for the pharmaceutical analytics division of Thermo Fisher Scientific, is most often the end point of different microbiological tests, such as out-of-specification bioburden, failed sterility tests, excursions from environmental monitoring, etc.

	The strategy for identification will depend on the origin of the test samples, as well as the microbial identification method, both of which depend on the overall microbial test strategy. “The first thing to consider is what level of identification is appropriate, and that depends on what the data will be used for,” adds Tuckett.

	There are three basic levels of identification: microbial characterization, genus/species identification, and bacterial strain typing. “For tracking and trending of bioburden levels only, microbial characterization may be sufficient, such as descriptions of the colonies and cells as well as gram staining and other descriptive microbiological assays,” he notes. Such characterization requires a certain level of expertise because appearances can be variable and many characteristics of microorganisms change over time. Given the inherent subjectivity of some of these tests, Tuckett strongly recommends that genus/species identification be performed for at least the overall three to five most common organisms.

	In situations where action/alert levels are exceeded or when contamination events are encountered, genus/species level identification is more appropriate. “Since microbial identification is used to understand the source of contamination, it is important for the identification method to give an accurate species identification in order to implement appropriate corrective actions and preventative actions (CAPA). Implementation of the appropriate CAPA will prevent the re-occurrence of microbial contamination and reduce the risk of quality issues in the manufacturing process,” Darker comments.

	Species identification is also an essential part of testing for objectionable organisms (

 62 testing), according to Tuckett, because mere characterization can sometimes be insufficient to rule out specific species.

	At SGS, most clients ask for species-level identification. “Species-level identification helps us to eliminate the risk of an antibiotic-resistant pathogen becoming prevalent if a new strain is observed that cannot be eliminated through cleaning by disinfectant. Additionally, seasonal change can see a change in bioburden levels which need to be identified,” says Bhende.

	When investigations are being conducted to determine if multiple contaminants are of the same source, bacterial strain typing is necessary. “This testing reveals if different isolates come from the same strain or source, which cannot be determined from species level identification methods,” Tuckett explains.

	An effective microbial identification strategy, according to Darker, results in an appropriate CAPA to reduce any risk of microbial contamination and in the event of microbial contamination enables the determination of the root cause of the contamination. “In essence, if CAPA has been put in place and it mitigates any further risk to product quality and patient safety, then the microbial identification strategy was effective,” she states.

	For Tuckett, an effective microbial identification strategy is one that provides meaningful data pertinent to the given situation and draws upon sufficient resources to ensure the identification is as accurate as possible. “The basic principle behind microbial identification is comparison of the characteristics of an unknown organism to those of a known organism. The more that is known about the known organism, the better the comparisons can be. When genotypic data [are] analyzed, [they are] generally compared to a library or database of known DNA sequences and [are] therefore only as accurate as the database [they draw] upon. An extremely limited database may provide inaccurate identifications,” he explains. In addition, methods based on automated identification software may be inadequate for the intended use if a high number of “unidentified” results are obtained.

	An ineffective strategy is also one for which a CAPA cannot be implemented to stop the reoccurrence of contamination by an identified microbe, according to Bhende. Therefore, as with bioburden and environmental monitoring programs, continuous evaluation and assessment of microbial identification strategies are essential. “As compendial requirements change, and as new technologies become available, identification procedures should be revaluated to ensure they are sufficient for their intended purpose. If a specific identification method doesn’t yield adequate results, alternate methods should be considered,” asserts Tuckett.

	For clients of SGS, Bhende also recommends for critical microbial identification applications the establishment and maintenance of a database logging the trending data for locations and accurate identifications. “This information can be used to identify early on any potential patterns of contamination that need to be addressed,” she says.

Vol. 42, No. 12
	December 2018
	Pages: 44–45

	When referring to this article, please cite it as C. Challener, “Microbial Identification Strategies for Bioburden Control," 

Microbial identity data can be critical for determining contamination sources.

Microbial Identification Strategies for Bioburden Control

The rise of antibiotic-resistant bacteria is recognized as a significant threat to the future practice of medicine. Continually rising resistance rates have resulted in infections with bacteria resistant to all existing antibiotic treatment options. There is concern that if the current treatment system remains unchanged, the resistance epidemic could push the world into a post-antibiotic era.

	Alternatives are therefore needed to replace current small-molecule antibiotics. Given that the development of resistance is a natural form of evolution for bacteria, the challenge is to find new drugs that kill bacteria in a way that dramatically slows down their ability to counteract them. Biologic drug substances-monoclonal antibodies (mAbs) in particular-may be a key component of the solution.

	Regardless of the antibiotic, resistance will develop, according to MedImmune’s director of microbial sciences Bret Sellman. “Most available antibiotics are related to natural products for which resistance already exists in nature,” he explains. Bacteria also divide rapidly, which increases the likelihood for antibiotic-resistant mutants to evolve.

	In addition, over the past four decades there have been few truly novel antibiotics, according to James Levin, director of preclinical development at Cidara Therapeutics. “We have been targeting the same limited subset of essential proteins, and therefore, bacteria have ample opportunity to evolve and become resistant to entire antibiotic classes over time,” he observes.

	Sellman argues that development of antibiotic resistance has less to do with the structure or chemistry of antibiotics than it does their method of attacking a pathogen and their widespread use in modern medicine and farming. “By killing bacteria directly, antibiotics select for the outgrowth of resistant mutants. In addition, the misuse of antibiotics to treat viral diseases (e.g., the common cold) unnecessarily exposes patients and their bacteria to antibiotics and fails to treat the actual disease being experienced. This ease of access only increases exposure and subsequently the risk of resistance,” he asserts.

	Resistance can arise from chemical modification of the antibiotic by bacterial enzymes or mutations to the antibiotic target, adds Levin. He also notes that bacteria are able to swap genes that impart antibiotic resistance with other bacteria, allowing resistance to spread rapidly.

	Adding to these escape mechanism issues, Levin points out that gram-negative bacteria are intrinsically resistant to many antibiotics because they possess an outer membrane that is impermeable to most drugs-and they can mutate to reduce permeability further when under selective pressure.

	The problem with broad-spectrum antibiotics

	There is an additional problem associated with the use of broad-spectrum antibiotics: they kill not only harmful pathogens, but “good” bacteria that make up the microbiome within humans. Doing so results in the development of resistance in the target pathogen as well as the members of healthy microbiome, which can then transfer resistance to pathogens they encounter, further spreading the problem, according to Sellman.

	Damage to the healthy microbiome can have significant consequences as well. “Killing of the healthy microbiome has been linked not only to the development of 

 diarrhea but also diabetes, obesity, immune defects, and antibiotic resistance spread through gene transfer,” he says.

	While antibiotics will always play an important role in saving and preserving life, the growing antibiotic resistance epidemic and increasing understanding of the adverse effects of broad-spectrum antibiotics on the healthy microbiome necessitate the development of alternatives such as pathogen-specific strategies to prevent or treat bacterial infections, according to Sellman. “We firmly believe that moving away from traditional small molecules is the path forward in anti-infectives research,” Levin agrees.

	Most efforts are focused on new drugs based on mAbs because of their specificity. “Such targeted antibacterials should have reduced toxicity, cause less harm to patients’ beneficial microbiomes, and not promote resistance in bacteria not targeted,” Sellman comments.

	Antibacterial mAbs also directly neutralize bacterial virulence mechanisms and engage the patient’s immune system, according to Sellman. “By boosting the immune system to kill the pathogen rather than killing the bacteria directly, the emergence of resistance might be reduced,” he explains.

	Cidara Therapeutics is developing antimicrobial antibody-drug conjugates (ADCs). “These bispecific molecules capitalize on the potency of antibiotics coupled with the beneficial aspects of an effective and robust immune response and can be designed with a prolonged half-life,” says Levin. He believes that any antimicrobial, including small molecules, that binds to a surface or cell-wall component of the bacterium is a viable candidate for conjugation to an antibody fragment crystallizable (Fc) region.

	In addition to antibody-based drug candidates, Sellman notes that researchers across industry and academia are also exploring phage lysins and viral phage approaches as alternatives to small-molecule antimicrobials.

	Antibacterial biologics require new thinking

	Development of mAb antimicrobial drugs does not come without challenges, but those difficulties are not solely in the scientific arena. “In order to realize the promise of biologics in infectious disease, we need to evolve the way we plan to manufacture and diagnose for these medicines,” Sellman states. Because antibacterial mAbs would likely be most effective in the earlier stages of infections, a move to integrate mAbs into the mainstream infectious disease protocol would require a commitment to more rapid diagnostic methods.

	In addition, he notes that because pathogen-specific mAb treatments must account for bacterial strain diversity and the expression of multiple virulence determinants by the infecting pathogen, mAb combinations may be required for optimal efficacy.

	The higher cost of biologic antibiotic drug substances compared to their small-molecule counterparts could also be an issue, according to Levin. His hope is, though, that the significantly longer half-life that should be achievable for biologic antibiotics, including ADCs, will enable less frequent dosing and thus offset the higher cost.

	Cidara Therapeutics set out to develop ADC antibiotics that exert a direct killing effect on the pathogen; engage the immune system, bringing a second mechanism of killing into play; potentiate standard-of-care antibiotics by attacking the bacterial cell wall and allowing them to penetrate the cell more effectively; and have superior (antibody-like) pharmacokinetic and distribution properties.

	The company conjugates surface-acting antimicrobials (targeting moieties [TMs]) to Fc regions of human antibodies using non-cleavable linkers. The bispecific Cloudbreak ADCs exert direct killing activity on bacteria while targeting the cell for destruction by the immune system, according to Levin. “We believe that by developing drugs with a dual killing mechanism we will reduce the opportunity for the target pathogen to develop resistance. In addition, since our TMs do not have to reach the inside of the cell to kill the bacterium, we avoid the daunting problem of having to breach the bacterial membrane in gram-negative bacteria,” he says. In addition, because antibodies can remain at effective concentrations in plasma for a month or longer, Cidara believes its ADCs can ultimately be engineered to achieve a similar half-life.

	The company recently demonstrated proof of concept with an ADC comprising a peptidic antimicrobial conjugated to a human Fc. “Although not our final drug candidate, this ADC was efficacious in murine 

 pneumonia models. It also demonstrated a much longer half-life than the polypeptide alone,” Levin notes. In-house characterization by Cidara’s immunology team further demonstrated the ability of this conjugate to successfully engage the immune system to enhance bacterial killing. Some of this work was performed in collaboration with Professor Ashraf Ibrahim at UCLA and has yielded important insights into the mechanism of action of ADCs.

	The Cloudbreak ADCs are in preclinical development, but Levin expects a clinical candidate to be nominated in 2019. Current efforts are focused on evaluation of lead candidates in preclinical toxicology studies and exploration of Fc modifications to further extend 

 half-life. The company received a National Institutes of Health grant in 2018 in conjunction with Professor David Perlin at Rutgers that should accelerate the pace of its ADC program, according to Levin. Cidara is also applying its Cloudbreak technology to the development of antivirals.

	Within MedImmune, the global biologics research and development arm of AstraZeneca, two Phase II mAb assets are in clinical testing. MEDI4893 (suvratoxumab) is under investigation for the prevention of Staphylococcus aureus pneumonia in intensive care unit patients, while MEDI3902 is being developed for the prevention of 

 pneumonia in intensive care unit patients.

	“As we continue to explore this field, we are constantly learning about the critical role of the commensal microbiome in maintaining overall health, and even the role it can play in possibly treating certain diseases. With this understanding comes a commitment to exploring new therapeutic options that avoid damaging these beneficial bacteria. The targeting specificity of biologics offers tremendous promise in making this goal a reality,” Sellman concludes. 

Vol. 42, No. 12
	December 2018
	Pages: 36–37

	When referring to this article, please cite it as C. Challener, " Fighting Bacterial Resistance with Biologics," 

Antibody-based drugs offer new mechanisms of action and greater specificity.

Fighting Bacterial Resistance with Biologics

Highly potent APIs (HPAPIs) are an increasingly important segment of the API market. While there are many contract development and manufacturing organizations (CDMOs) that claim to have potent compound production capabilities, few have the facilities, equipment, and trained personnel needed for the production of highly potent compounds with occupational exposure levels (OELs) of 10 µg/m

/8h. CDMOs with established expertise are investing in expanded capabilities to meet the growing need for HPAPI production capacity.

	Global demand for HPAPIs is estimated by various market research firms to be approximately $17 billion in 2018 and expanding to about $26 billion by 2023, according to Claudio Salvagnini, director of CDMO API and HPAPI activities at Minakem. The rapid growth is driven largely by the global oncology market, as many highly potent compounds are used for the treatment of cancer. This market has already surpassed $100 billion in global sales and is expanding at double-digit rates, according to intelligence reports reviewed by Minakem.

	Maurits Janssen, head of commercial development, API development, and manufacturing with Lonza Pharma & Biotech, adds that the percentage of HPAPIs that are cancer treatments has grown from more than 50% in 2015 to approximately 60% in 2018, with the rest found in hormonal treatments, central nervous system treatments, and all other therapeutic areas. There are also many rare diseases under focus, and many of these conditions are being treated with highly active compounds according to Marko Salo, vice-president of marketing and sales with Fermion.

	Three-quarters of HPAPIs are novel compounds. In particular, the growing focus on precision and personalized medicines such as antibody-drug conjugates (ADCs) that treat specific patient subgroups or conditions is driving development of novel APIs. Innovation is therefore another important factor in the growth of the HPAPI market, according to Salvagnini. He adds that despite the increasing number of biologic drugs in the pharmaceutical pipeline, the HPAPI market remains dominated and is foreseen to continue to be dominated within the next five years by small-molecule, chemical APIs.

	Lonza also expects the generic HPAPI market to see strong growth over the next few years due to patent expirations of some branded HPAPI products, according to Janssen. Another driver for the growth of HPAPI capacity demand is the additional knowledge being obtained for existing compounds that previously were not considered to be HPAPIs. As new toxicity data are generated, some of these compounds are being reclassified as HPAPIs, according to Salo.

	Outsourcing of HPAPI production is also expected to expand faster than the overall HPAPI market, according to Janssen. “This growth is due to the fact that the majority of innovation is taking place in smaller emerging biotech companies with no in-house manufacturing capabilities and therefore the need to outsource,” he explains.

	Limited options for highly potent production

	The number of companies advertising highly potent manufacturing capabilities is quite high, according to a recent survey conducted by Minakem. “In a market analysis, approximately 100 [contract manufacturing organizations (CMOs)]/CDMOs were identified as claiming to focus on high potency and making numerous investments in the past 10 years, so what was once a niche segment appears to be more crowded,” Salvagnini notes.

	Upon closer look, however, Minakem found that classification of highly po.tent manufacturing capability comes down to how each company defines potent vs. highly potent. Many of these companies are capable of processing compounds with OELs down to 10 µg/m

/8h, but only a handful of active CDMOs have the capability of handling highly potent intermediates and APIs with OELs of 0.10–0.01 µg/m

/8h and lower, Salvagnini says. This HPAPI business is highly concentrated in West.ern countries, according to Janssen.

	Salo adds that many of these recent investments have involved smaller capacities. Janssen notes that the majority of HPAPI equipment for commercial manufacturing is mid-scale (4–6m

), where there is the highest de.mand. “Only a few companies, including Lonza, can cover the full range of reactor scales along the drug lifecycle from 2–10m

, allowing customers to access phase-appropriate equipment for their individual needs,” he says.

	“Entry into this segment of the market is limited by the high initial investment required to install containment systems, glove boxes, proper air flow and conditioning systems; develop effective processes; and train operators,” observes Salvagnini. He adds that having a solid reputation for success in HPAPI manufacturing is probably more important than in other segments of the pharma industry, given that the safety of operators, the environment, and patients is a key concern. “We have seen that clients looking for HPAPI services conduct more thorough audits and risk assessments when evaluating potential outsourcing partners,” Salvagnini says.

	There are currently no indications of overcapacity in the market, according to Janssen, but increasing competition may lead to a lower perceived market growth of the segment in the future. Continued investment will still be needed, however; as manufacturing and handling technologies for HPAPIs continue to improve, older facilities will require upgrading from time to time to prevent becoming sub-standard.

	Minakem recently expanded HPAPI capabilities at its Louvain-la-Neuve plant in Belgium, which it acquired in 2015 from Ajinomoto OmniChem. “We acquired high-containment technology with this site and set as a goal to become a leader in high potency development and manufacturing,” notes Salvagnini. With available space for expansion within the building and on the site, it was possible for Minakem to revamp existing facilities and add new equipment and production trains. In addition, the company has access to talent due to its location near universities and pharmaceutical companies.

	“The HPAPI segment is a high-technology market that requires continuous investment to ensure state-of-the art capabilities,” Salvagnini asserts. Not only is the HPAPI market expanding, highly potent compounds are becoming increasingly complex and more potent. “We need to be certain that we have the broadest range of synthetic and containment capabilities to meet the evolving needs of the marketplace,” he adds.

	The new closed-controlled, high containment laboratory facility was opened in August 2018 and extends Minakem’s capacity to develop and manufacture HPAPI compounds from small-scale development to full GMP batch releases. In addition to nine fume hoods, a double-barrier of protection in the form of new-generation glove boxes in a room dedicated to dry powder handling and weighing, air locks, HEPA air filters, and cascading flow, the facility includes a preparative chromatography system for the isolation and purification of target molecules from milligrams to hundreds of grams for analysis and production applications.

	The current production suite enables production of gram, 1–10 Kg, 20–50 Kg, and 100–150 Kg batches of compounds with OELs down to 0.1 µg/m

/8h. Minakem has also installed 5-, 50-, and 300-mm preparative high-performance liquid chromatography (HPLC) columns, according to Salvagnini. The company is also looking to invest in additional hydrogenation equipment under containment.

	Fermion’s three-year project to expand HPAPI production capability at is Hanko, Finland plant reached its conclusion in the summer of 2018, with first batches and regulatory inspection completed. Unit 4 consists of a fully automated, completely closed HPAPI unit of more than 50 m

 capacity for the production of highly potent compounds with occupational exposure bands (OEBs) 4 and 5, according to Salo.

	The facility can be run by just three operators due to a high level of automation. As a result, Fermion is able to produce HPAPIs cost-competitively, Salo adds. A bar-code system is fully integrated into the automation system, preventing charging of the wrong materials and avoidance of paperwork.

	The project was commissioned in response not only to the growing demand for HPAPIs, but also because Fermion was finding that some older generic APIs that were previously categorized as OEB3 are today considered to be category OEB4 or OEB5 compounds. “We want to protect our operators to the highest possible degree and would rather overprotect our employees than take any risks even for lower OEB class products,” asserts Salo. He adds that it is Fermion’s point of view that operator working conditions with modern containment protection systems such as isolators are better than those that rely on old-fashioned personal protective gear.

	One factor contributing to Lonza’s continued investment in HPAPI capacity and capabilities is the growth of oncology as a focus of biopharmaceutical research and development, according to Janssen. “Since these products use increasingly complex and toxic molecules, the companies that develop them more frequently seek external partners like Lonza Pharma & Biotech with the facilities and track record and expertise to properly handle HPAPI formulations,” he says. As an example, he points to ADCs and their use of highly toxic molecules to specifically target and kill cancer cells as representing a step up in oncology treatment that would neither be possible nor effective without extremely potent payload molecules and the capabilities required to handle them.

	The company’s HPAPI investments have focused on providing agile manufacturing solutions for the wide range of product volumes required by biopharma companies’ increasingly specialized and pharmaceutically potent products, according to Janssen. Lonza Pharma & Biotech’s Visp, Switzerland Center of Excellence in HPAPI Development and Manufacturing has multi-purpose facilities designed to efficiently and safely manufacture multiple products simultaneously at various scales. Lonza currently has active HPAPI projects with OELs ranging from 5 to 0.04 µg/m

	In February 2018, the company announced expansion of its HPAPI capabilities in North America, including the addition of two commercial-scale processing suites for the handling and encapsulation of HPAPIs using drum-dosing technology for powder-in-capsule filling at its Tampa, FL site.

	In late 2017, Cambrex announced a $24-million investment in a new facility to manufacture HPAPIs at its Charles City, IA plant in the United States. The 4500-sq.-ft. production area will operate to an OEL of 0.1 µg/m

 and have a total reactor capacity of 2200 gallons and be able to manufacture batches from 50 to 300 kg. The small-scale manufacturing area at the site is also being reconfigured to provide a single high-containment building to support early stage development and manufacturing. Construction and installation of all new equipment is expected to be completed by Q1 2019.

	The investment is in response to the growing number of highly potent, small-molecule APIs in the pharma pipeline, according to Shawn Cavanagh, COO of Cambrex. It is also part of an ongoing strategic campaign to invest in small-molecule API development and manufacturing across Cambrex’s global network of facilities.

	Implementing new HPAPI development and manufacturing capabilities presents multiple challenges that must be addressed within a limited timeline, according to Salvagnini. “Multiple departments are involved, so cross-functional teams with representatives from environmental health and safety, program management, R&D, production, etc., must collaborate with external consultants and project design and construction companies. Having solid internal experience in containment technology and working efficiently together in close collaboration on a daily basis is essential for keeping such types of investment projects on track,” he says.

	Previous experience with the addition of HPAPI units is also highly beneficial for successfully completing new projects on time and without major issues, according to Salo. Janssen agrees: “Considering Lonza’s 20 years of experience in handling HPAPIs and in maintaining the required facilities, the construction of new capacity was supported heavily from past experience, and progress was demonstrated by the short realization timeline and absence of critical challenges,” he observes. He also notes that Lonza has found it extremely valuable to build on a stable team of specialists and to keep everyone pointed in the same direction.

	In addition to the expected healthy growth of the HPAPI market that is expected to continue in the coming years, significant changes in manufacturing and logistics are anticipated in response to changing market dynamics. “The move into personalized and specialized medicines means that large numbers of molecules will be produced at small scale, which is quite a massive change from the way the supply chain operates today,” asserts Salvagnini.

	There is also a movement toward higher containment protection levels, according to Salo. Molecular complexity will increase further as well and present ongoing manufacturing challenges, according to Salvagnini. In addition, many HPAPIs in the pharma pipeline face bioavailability challenges and/or require modified-release technologies, according to Janssen. “As a result, HPAPI production and manufacturing today requires more specialized capabilities than ever before,” he says.

	In addition, many drug formulating companies are closing their in-house production facilities and shifting toward contract outsourcing as a more cost-effective approach to HPAPI manufacturing. “These companies are looking for external CDMOs that offer integrated services and can tailor their enhanced technology platforms and supply-chain solutions to specific companies’ needs to facilitate development and reduce time to market,” Janssen comments. Outsourcing, he adds, is strongly driven by emerging and mid-sized pharmaceutical companies, which account for most of the innovations in the pharma industry today.

	“CDMOs will need both flexibility and agility to accommodate the broader range of chemistries, toxicities, delivery technologies, and product volumes for highly potent intermediates and products that will exist in the near future,” asserts Salvagnini. Responsiveness will also be important, as increasing numbers of projects are designated as accelerated approval programs. “Minakem is preparing by adapting both its facility and internal organization, building dedicated supply-chain and building project teams in order to rapidly proceed through increasingly complex processes and stay on the critical path for shortened timelines,” Salvagnini says. He adds that its ongoing investments are made with this new future in mind, including investments in analytical capabilities and skilled and talented workforce.


	Vol. 42, No. 11
	November 2018
	Pages: 24–26

Demand for highly potent APIs continues to rise.