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

Cynthia A. Challener

Many of the drug substances under development today pose formulation challenges, from poor solubility and bioavailability to limited stability under physiological conditions. The application of nanotechnology in formulation development has the potential to address many of these issues, while also enabling targeted delivery to reduce off-target effects. Nanoparticles have the advantage of allowing chemical modifications, such as addition of ligands to target cell receptors and surface coatings (e.g., PEGylation) to prevent recognition by the body’s immune system, allowing them to carry drug compounds to the site of the disease without being captured and eliminated. The result: rapid development of the emerging field of nanomedicine.

	Indeed, the value of the global market for nanopharmaceutical drugs is estimated by market research firm BIS Research to be expanding at a compound annual growth rate of 8.1% and predicted to reach $79.3 billion by 2026 (1). Polymer and liposome drug carrier systems are the two sub-segments driving this growth.

	Pharmaceutical companies are always looking for opportunities to improve medicines for patients. Applying the use of nanoformulations to existing drugs based on previous learnings is one avenue for leveraging nanotechnology, but Pfizer is focused on developing nanoformulations and nanotechnology solutions that will ultimately enable the next generation of nanotherapeutics to be brought to cancer and other patients, according to Young-Ho Song, a research fellow at Pfizer Oncology. “We complete this work as early as the discovery phase in collaboration with our medicinal chemistry colleagues,” she notes.

	Nanomedicine research is focused in two main areas, agrees Stephan T. Stern, acting deputy director of the Nanotechnology Characterization Lab, which is part of the Frederick National Laboratory for Cancer Research. One area involves reformulation of existing drugs or drug combinations to decrease toxicity and/or increase efficacy, or to develop competing formulations of existing marketed products (e.g., nanosimilars). The second research area involves the formulation of novel drugs, such as difficult-to-formulate new chemical entities, oligonucleotides, and vaccines. “Most pharmaceutical companies have nanotechnology formulation research groups that are involved in resurrecting drugs that are failing due to toxicity/efficacy/formulation issues,” he adds.

	The most common dosage forms of nanomedicines on the market are intravenous liposomes (e.g., Doxil [Janssen], Onivyde [Ipsen Biopharm], Vyxeos [Jazz Pharmaceuticals]), intravenous polymerics (e.g., Genexol [Samyang Biopharm]), intravenous nanoemulsions (e.g., Diprivan, Intralipid), and oral nanocrystals (e.g., Rapamune [Pfizer], Tricor [AbbVie]), according to Stern. Generally, he observes that the formulation type is first chosen based on API liabilities. “The issue may be solubility, toxicity to off-target tissues, rapid metabolism, or poor distribution to target tissues. Once the liability is recognized, a series of formulations that could overcome the liability are identified and the optimum formulation and preparation method are chosen based on chemical compatibility of the API,” says Stern.

	Choice of appropriate formulation type is dictated by the properties of the API. “Certain APIs are better suited to certain formulation, due to loading efficiency and stability,” Stern explains. “Amphiphilic weakly basic/acidic drugs, for instance, are suitable for active loading of nanoliposomes, while highly hydrophobic drugs are better suited to nanoemulsions, polymeric nanoparticles, and micelles,” he says. High-temperature techniques, such as microfluidizer homogenizing, are not ideal for thermally labile APIs.

	The formulation type will then determine the formulation method. Liposomes and emulsions are produced by solvent evaporation or thin-film hydration followed by extrusion/homogenization (microfluidizer), according to Stern. Polymeric nanoparticles and micelle formulations are generated by solvent evaporation, single/double emulsion, or precipitation techniques. Nanocrystals are generated by top-down techniques, such as milling and homogenization. Stern notes that bottom-up techniques (i.e., precipitation) are not currently used in the manufacture of nanocrystalline APIs.

	Pfizer has been working with biodegradable polymeric nanoparticles for drug delivery. The most widely used processes for the production of these nanoparticles are nanoemulsion, in which the organic phase consists of water-immiscible solvents such as ethyl acetate or dichloromethane, and nanoprecipitation, in which the organic polymer-drug solution contains water-miscible solvents such as dimethyl sulfoxide, tetrahydrofuran, or acetonitrile, according to Song.

	The polymeric nanoparticles developed by Pfizer are based on a biodegradable polyester polymer commonly used in dissolving stitches. Loaded nanoparticles are prepared by dissolving the polyester polymer, API, solvents, and excipients in an oil to form an emulsion. Thousands of pounds of pressure are applied to the emulsion, leading to the formation of nanosized droplets. The solvents are removed, and the droplets are hardened into polymeric nanoparticles encasing up to 10,000 API molecules. The surfaces of the nanoparticles are modified with antibodies that will bind to a specific cell type, such as a specific tumor cell. Once bound, the drug will diffuse out from the nanoparticles, slowly releasing and accumulating the API at the desirable target sites.

	To date, the Pfizer researchers have investigated the application of their nanopolymeric technology for the development of drugs to treat various cancers and cardiovascular, inflammatory, and infectious diseases. “Our state-of-the-art nanoemulsion process and formulation approach have expanded the chemical space of compounds that can be formulated into our nanoformulations,” Song asserts.

	Despite their advantages, nanomedicines do face several challenges, including the lack of predictive preclinical models for safety/efficacy, problems with scale up, and an uncertain regulatory path, according to Stern. Song agrees that there are multiple hurdles that must be overcome before nanomedicines can become commercial products. “An individual’s perspective often determines what is the biggest challenge, and each medicine can present its own set of challenges. It takes a team effort, from discovery through approval, to address each challenge as it is presented,” she observes.

	Advances in technology are helping, too. “Recent advances in nanodelivery formulation around oligonucleotides (siRNA, mRNA, and genetic materials) using lipid nanoparticle (LNP) nanosystems are breakthrough technologies,” according to Song. “These new approaches can help to convert a very difficult drug formulation challenge ultimately into a drug product,” she states.

	Stern points to a gradual refinement in established platforms regarding improved stability, safety, and delivery as important evolutionary advances in nanomedicine. One example he highlights is the approval of Onpattro, a treatment of transthyretin-mediated amyloidosis and the first gene-delivery nanoliposome, which has been decades in the making. “With market approvals like this one, more venture funding will flow into nanotech, allowing for more research and advancement in the field,” Stern asserts.

	Another way these challenges are being overcome, says Stern, is through the participation of contract research, development, and manufacturing organizations that are developing and expanding specialized capabilities at the lab to commercial scale and can assist with the scaleup of complex drug formulations. He also notes that as more nanomedicines reach the clinic and eventually the marketplace, a better understanding of which preclinical studies are useful and important is being realized. In addition, FDA and the European Medicines Agency are in the process of streamlining the regulatory approval process for complex drugs, including their generic/follow-on versions, which should expedite future development.

	Shift in focus to next-generation therapies

	The future for nanomedicines certainly appears to be exciting. “Complex drug formulation will always have a place in modern drug development for the simple reason that new drugs and drug classes are getting ever more difficult to deliver as a result of poor stability, solubility, and permeability,” Stern observes. There will still be reformulation and repurposing of existing drugs as nanoformulations, but Song agrees that research will move toward a focus on developing new drugs in nanoformulations starting from the early drug discovery phase.

	Research in nanomedicine has, according to Stern, already begun shifting toward the use of nanoformulation for immunomodulatory drugs and gene therapies. “Nanotech is well suited to overcoming the lack of selectivity and poor delivery, respectively, of immunotherapies and oligonucleotide-based drugs,” he says. One example is the use of gold nanoparticles rather than an inactivated virus to deliver clustered regularly interspaced short palindromic repeats (CRISPR) gene-editing tools to cells (2).

	1. BIS Research, “Global Nanopharmaceutical Drugs Market is Expected to Reach $79.29 Billion by 2026,” Press Release, Dec 11, 2018.
	2. Fred Hutchinson Cancer Research Center, “Could Gold Be the Key to Making Gene Therapy for HIV, Blood Disorders More Accessible?” News Release, May 27, 2019. 


	Vol. 43, No. 7
	July 2019
	Pages: 22–23

	When referring to this article, please cite it as C. Challener, “Facilitating API Delivery with Nanoscale Solutions,” 

Articles

Nanotechnology is enabling enhanced bioavailability, improved stability, and targeted delivery of challenging APIs.

Facilitating API Delivery with Nanoscale Solutions

Continuous bioprocessing provides numerous benefits, from high product quality and consistency to smaller physical footprints, increased flexibility, and potentially lower capital and operating expenses. It also provides the greatest benefits if real-time monitoring of process parameters and product quality, including detection and quantitation of residual impurities, is performed. While advances in analytical methods and automation are occurring, practical implementation of real-time monitoring of product- and process-related impurities has yet to be achieved.

	“In an ideal world,” asserts Byron Kneller, senior director for analytical and formulation development with AGC Biologics, “we would have simple, rapid, physicochemical tests for residual impurities.” 

	Unfortunately, there are different types of residual impurities. They can be classified as product- and process-related, and as chemical impurities (typically small-molecule process additives such as isopropyl β-D-1-thiogalactopyranoside, antifoams, antibiotics, etc.) or biological impurities from the host cell or processing steps (host-cell proteins [HCP], host-cell DNA, residual Protein-A, etc.).

	“Technologies that utilize mass spectrometry (MS) capabilities are, at this point, the seemingly best choice for residual impurity detection, characterization, and/or quantitation when coupled with liquid chromatography (LC) systems,” observes Amit Katiyar, director of analytical and formulation sciences for Thermo Fisher Scientific. Multi-attribute methods (MAM) capable of detecting, quantifying, and characterizing multiple product quality attributes are currently being developed. 

	A triple-quadrupole system would be best suited for quantitative analysis of small molecules/peptides, with quadrupole time-of-flight systems more appropriate for the characterization and semi-quantitative analysis of larger molecules, according to Charles Heise, senior staff scientist for bioprocess strategy and development at Fujifilm Diosynth Biotechnologies.

	An amalgamation of both technologies for a single quantitative measurement covering a wide mass range would be an ultimate solution, he adds. A series of standards could be used to generate standard curves for target impurities and the software needed for identification and quantification of peaks. Aspects of high-throughput proteomics analysis may also be applicable to the continuous manufacturing environment.

	Other analytical techniques Heise highlights include in-line spectroscopic measurements such as Raman, Fourier-transform infrared (FTIR), ultraviolet/visible (UV/Vis), and refractive index methods that can give quantitative as well as qualitative, real-time analysis. “The particular technology used will depend on the impurity, its expected concentration range, and whether monitoring is performed during steady-state conditions,” he observes. New methods or advances in current technologies may also become available that allow in-line measurements using nuclear magnetic resonance (NMR) imaging, sensor arrays, or LC systems.

	The final option, Heise says, is to do no process monitoring and rely solely on the quality-by-design data generated during process development to define the operating ranges and edges of failure.

	“In practice, the choice of method may be constrained by the availability of the instrumentation, turn-around time, analyst training, and potential interference from the complex matrices that may be involved in the downstream purification,” comments Ian Parsons, director of analytical development for biologics at Charles River Laboratories. His company has focused primarily on the use of high-performance LC (HPLC) and the enzyme-linked immunosorbent assay (ELISA), with MS and gas chromatography (GC) also used frequently. 

	“The pharmaceutical industry is still heavily utilizing traditional separation techniques such as size-exclusion, ion-exchange, and reversed-phase chromatography in addition to immunoassays such as ELISA and electrophoresis as the primary means for quantifying product- and process-related impurities,” notes Katiyar. 

	Often tests for process-related impurities require specialized reagents such as anti-HCP antibodies or natural products like limulus amebocyte lysate and can be more complex, adds Kneller. In addition, many impurities are heterogeneous (e.g., HCP) and thus not amenable to detection and quantitation using simple tests.

	In practice for continuous processes, in-line confounded (e.g., spectroscopy) or secondary parameter (e.g., off-gas, pH, basic physical property) measurements are most user friendly, but accuracy of residual impurity detection is sacrificed for real-time control, as a result of the heterogeneous nature of the signal, or to allow for detection of a secondary response, according to Heise. 

	He also notes that off-line LC–MS, where mass windows can be limited by buffer solution and scanning rates, or LC–evaporative light scattering detection (ELSD), is typically used for small molecules, but these are not sensitive enough and can take too long to run for large-molecule manufacture.

	These approaches could potentially be substituted for sensor technologies with equivalent modalities, according to Heise, such as the Octet system from Fortebio, which relies on biolayer interferometry. Similarly, he says that ELISAs for sensitive quantitation of biological impurities that have slow response times (material quarantining needed) could also be replaced with equivalent ‘dip-and-read’ methods.

	The new technologies (e.g., MAM, MS for HCP analysis, automation for DNA, HCP, and Protein A residuals) are just starting to be introduced in the process development space, according to Katiyar. “The transition from exploratory to fully validated methods will be slower for such methods in a cGMP environment where method performance, equipment validation, and data-integrity measures need to be at the highest level. There will also be a significant cost aspect of not only reconfiguring current laboratories to accommodate the equipment, but also for training and/or hiring new personnel with expertise in these new technologies,” he says. 

	At the process level, identifying the residual impurities present and the appropriate analytical assays, with the required detection limits and sensitivity ranges, to monitor them across the process is critical, stresses Dan Pettit, senior staff scientist for analytical development at Fujifilm Diosynth Biotechnologies. At the operations level, he notes that identifying suitably equipped labs to develop and validate methods for GMP analysis is vital because of the heterogeneity of process impurities and the consequent analytical issues they pose. 

	Heterogeneous process-related impurities, specifically HCPs, are often quantified in early-phase projects using generic kits that may result in key impurities going undetected during purification process development. “These impurities have the potential to cause problems at production scale,” Kneller says. Current ELISA techniques lack the ability to identify specific immunogenic proteins, thereby making the process development aspect less strategic in design, agrees Michael Farris, scientific manager of analytical and formulation sciences with Thermo Fisher Scientific. “Building toxicology and immunogenicity databases for various HCPs and other process impurities would help fine-tune process development and, in itself, provide a deeper insight into process performance and robustness,” he asserts.

	Identifying/developing suitably sensitive methods is also challenging, according to Pettit. “Typically, ppm or ppb levels of analyte in a complex mixture must be detected, and therefore, isolation/derivatization of the analyte may be required. These activities tend to be prohibitively expensive to outsource,” he observes. 

	In addition, isolation of impurities prior to quantitation may introduce artifacts or cause the generation of various altered states during the isolation process. For example, physical manipulation of samples prior to the detection of multiple analytes may alter the HCP antigen profile and relative abundance of the analytes themselves, according to Farris. Additional studies to understand the stability of isolated product(s) may therefore also be needed. 

	Other process impurities such as Long R3 IGF-1, which is a component of some cell-culture processes, have a tendency to adhere to certain plastics, thereby making accurate quantitation more difficult, Farris adds. Sampling instructions must be clearly defined so as to not artificially deplete the analyte during sampling and/or storage prior to analysis. 

	Parsons agrees that the main challenges are focused around developing methods of sufficient sensitivity that also minimize product and matrix-related interference, and thereby accomplish sufficient recovery of the analytes. In numerous instances, Farris points out that the quantitation and/or characterization of impurities is hindered by the API and/or the matrix composition. 

	“Immunoassays, such as ELISA, used for quantitation of host-cell proteins and leachables like Protein A are sensitive to extreme pH, high salt concentrations, and certain detergents. The typical means for overcoming the signal suppression or interference associated with their presence is to dilute the sample, which acts to decrease the sensitivity of the method to maintain acceptable precision and accuracy,” Farris explains. As a consequence, sensitivity constraints imposed by matrix/API interference must be a point of consideration when demonstrating that a method is fit for use for process characterization and/or process validation activities.

	For products with small total batch volumes, the quantities of material required for analytical method development and sample analysis can also present a challenge, Parsons notes. “If method sensitivity is also an issue, an approach can be taken to spike an aliquot of upstream material with a higher known concentration of analyte and then demonstrate fold-removal of the analyte across the downstream purification step(s),” he comments.

	For continuous processes, the turnaround time of typical assays is a key issue, according to Kneller. “The challenge is to increase our testing throughput, decrease our reliance on heterogeneous reagents, and to find ways to either simplify the method types used or engineer robust, easy-to-use systems for more complicated analyses (e.g., mass spectrometry),” he says. 

	Real-time monitoring of representative material for modeling the residence time distribution in continuous processes is also required for process control, according to Pettit. “The range of appropriate analytical sensors for continuous monitoring of product specific critical quality attributes and impurities is limited. Additionally, sensor drift over the operating time, any on-going sensor calibration needs, and system suitability testing for quality critical attribute monitoring during continuous operation must be resolved,” he adds. “Here again, sensor technology could be the way to go (e.g., online Octet dip-and-read-type systems); however, the technology is not sufficiently developed yet. The final technology offerings need to be diverse, robust, accurate, reliable, and rapid,” he concludes.

	For off-line analysis of residuals from a continuous process, Parsons notes that methods for aliquot/sample withdrawal are needed. In addition, the sampling frequency should be sufficient to provide a statistical sampling of the material flowing through the process in order to account for any transient variation that may occur while avoiding significant depletion of the process flow.

	The analytical testing strategy associated with continuous processes can, however, be more demanding in terms of the number of sampling time points if in-line or on-line monitoring is not possible, according to Farris. “Process analytical technologies have generally been geared more toward product quality, cell-culture viability, and growth than active monitoring of process impurities. If a deeper understanding of any particular impurity is required, more complicated assays will likely be required,” he observes.

	Residuals analysis when moving from batch to continuous

	When moving from batch to continuous processing, it is likely that the same analytical methods for residual impurities can be used, but potentially in higher throughput versions. Offline analysis using LC, GC, ELISA, and MS should be possible as long as an appropriate sampling approach can be implemented, Parsons observes. 

	The throughput capability and time-to-result for the analytical method employed are also important aspects if at some point the impurity is deemed process critical, according to Darshini Shah, senior scientist and group lead for downstream process development at Thermo Fisher Scientific. Automation of methods (e.g., liquid-handling or use of systems such as the Octet for HCP analysis) can provide higher throughput both in terms of overall speed and analyst effort, according to Kneller.

	The analytical target profile must also be evaluated to ensure methods are capable of monitoring fluctuating analyte levels throughout continuous processing. “Retention rates or biomass removal may result in periods of correspondingly lower impurity levels, and the analytical method must be sensitive enough and support a large enough dynamic range to be able to actively monitor the process range without the need to constantly repeat analyses to better target the operating range of the assay,” Shah explains. 

	In addition, the typical approach in batch processing involves analysis of a small discrete sample number, with reference standards bracketing the samples and system suitability tests performed prior to analysis, according to Heise. Rotating through multiple identical analyzers would allow continuous monitoring, but the solution would be costly. “Validation of both system suitability tests and the analytical methods for continuous control/monitoring will need additional work to demonstrate that results do not require bracketing with reference standards and that the detection methods do not drift or get poisoned over time when operating for 90+ days,” he says. Failure mode mitigation strategies will also need to be developed, for example with respect to system suitability failure.

	In addition, Parsons points out that for in-line and on-line analysis, the inherent requirements of sensitivity and specificity for analysis of process residuals suggests that many of the current and potential online methods would have limitations and may perhaps be able to best provide supportive general information, rather than specific quantitation of residuals. “Offline analysis using traditional validateable techniques might still be required for specific and sensitive quantitation of the process residuals. Nevertheless, if a continuous process can be shown (perhaps by an online monitoring method) to be robust, then reduced sampling of the continuous process for quantitation of residuals may be justifiable,” he notes.

	In fact, because continuous processes are expected to operate under steady-state conditions, control through predictive modeling or by exception should be possible, Heise adds. “Multi-variant analysis during development may identify simple in-line monitoring techniques that can control the process to ensure residual impurities do not pass through the whole process. However, the dynamics of the process will be different at the outset until the steady state is reached. A testing strategy defining the frequency of measurement pre- and post-steady state will be required to identify when process equilibrium has been reached and when it begins to fail,” he observes.

	“Ideally,” Heise continues, “we don’t really want to be testing anything real-time and on-line. Instead, we want to have confidence that the process will deliver consistently over a defined time scale.” 

	Potential for on-line/in-line analysis of residual impurities

	Significant development is still needed before on-line/in-line analysis of residual impurities will be widely implemented. Shah is not aware of any on-line/in-line tools capable of monitoring residual impurities for either quantitation or characterization. “Offline analysis is the predominant means of analysis and the only on-line/in-line tools are related to product quality aspects,” he says. 

	Current solutions exist around automated sampling for at-line analytics, where process changes occur over a longer time span than the analysis time, such as in the case of mammalian bioreactor metabolite analysis, according to Pettit. 

	On-line process analytical techniques such as near-infrared spectroscopy (NIR) or mid-infrared spectroscopy (mid-IR) and UV may provide some general information on clearance of residuals but are unlikely to be specific or sensitive enough to enable detailed quantitation of analytes, according to Parsons. 

	Parsons does note that low-field NMR is a potentially promising technique for on-line analysis of process residuals. “The system is simple to operate, potentially applicable to both batch and continuous processes, and could be performed by stop-flow analysis with direct connection of the flow path to the downstream purification process,” he says. Attractive features of NMR in this regard are its inherently quantitative response factor and its relatively high resolving power, and hence higher specificity than a technique such as UV, while drawbacks include barriers to implementation of a conceptually complex analytical technique and limitations on sensitivity. 


	Vol. 32, No. 7
	July 2019
	Pages: 28–31

	When referring to this article, please cite it as C. Challener, “Analysis of Residual Impurities in Continuous Manufacturing," 

Continuous manufacturing poses its own unique challenges to real-time monitoring of product- and process-related impurities.

Continuous Manufacturing Poses Challenge to Analyzing Residual Impurities

New molecular entities have continued to increase in potency over the past decade as pharmaceutical and biotechnology companies seek to improve treatment options for oncology and other chronic and rare disease areas. Approximately 70–80% of drugs in the pharmaceutical pipeline exhibit low solubility and fall into the Biopharmaceutics Classification System (BCS) Class II or IV, according to a 2015 Market Study by Kline & Co., with the majority of these compounds being Class II (poor solubility, high permeability) (1).
	Lonza Pharma Biotech & Nutrition reported to 

 that 20% of the current drug development pipeline is highly potent and/or requires special handling and also has solubility or permeability challenges.

	While solubility and bioavailability challenges are not unique to highly potent APIs (HPAPIs) and in the small-molecule world are highly dependent upon their particular moieties and morphologies, poorly soluble HPAPIs can pose additional challenges with respect to formulation development and manufacturing. Several enabling technologies are helping drug makers and their outsourcing partners overcome these hurdles.

	Any handling of HPAPIs requires care, appropriate equipment, and good practice to ensure the operator is kept safe at all times, according to Alyn McNaughton, technical director with Lonza Pharma Biotech & Nutrition. “Biopharma companies and manufacturers must be dedicated to ensuring that operators are able to do their work safely and without concern for contamination. With the technical challenges of bioavailability enhancement, additional time and dedicated experimental areas can be needed, which can make it challenging to meet development timelines,” he observes.

	As one example, complex molecules designed to provide targeted activity, while minimizing side effects, also often have permeability that is limited due their larger sizes, according to McNaughton. As a consequence, the variability of absorbed dosage can be large if the product is not robustly formulated.

	Even for materials where bioavailability can be readily enabled, the dosage required in the product can be incredibly low, often only a few micrograms or less, McNaughton adds. “This situation presents the secondary challenge of achieving homogeneity within the product, where an individual particle of the HPAPI may be a large portion of, or sometimes even bigger than, the specified dosage,” he says.

	The particle size of APIs can strongly influence the rate of dissolution. With this approach, according to Jessica Mueller-Albers, strategic marketing director for oral drug delivery solutions at Evonik, the concentration gradient between the gut and blood vessels will be increased to facilitate drug transport and consequently absorption. However, micronized particles can be associated with increased health risks.

	“The high potency of these molecules can create potential exposure concerns for workers, even at extremely small amounts. There is a need for specialized processes and expertise in the handling and containment of the drug substance, as well as intermediates resulting from particle engineering and the manufacturing of the finished drug product,” she notes.

	In fact, challenges in containment can limit the technology that can be deployed for solubility enhancement, according to Adam Kujath, global senior director of manufacturing science and technology at Alcami. “Typical API approaches for solid dosage forms to improve solubility like micronization and spray drying are more difficult to outfit with appropriate containment systems. For instance, milling of solids, while not impossible to do in appropriate containment, poses a challenge since it tends to create dust in the breathing airspace for any worker. For parenteral formulations, lyophilization presents a similar challenge,” he says.

	The toxicity of highly potent compounds also drives low allowable carryovers in the manufacturing equipment at change over. “Low solubility means cleaning reactors is inherently more challenging, and analytically may provide poor surface recoveries or impact the achievable cleaning method sensitivity. Furthermore, if they happen to be organometallic compounds, you have to worry about not only the active compound, but related organometallic and inorganic metallic species (such as mercury, arsenic, and platinum) as typical byproducts,” Kujath explains.

	For contract drug-product manufacturers, the first hurdles can occur upon receipt of the HPAPI. Packaging systems can vary widely, and it is rare for the manufacturer of an HPAPI and the product manufacturer to use a common handling system, according to McNaughton. A suitable mechanism needs to be available for accessing the HPAPI in a safe and hygienic fashion.

	An effective containment strategy should include clear, standardized processes for equipment startup, as well as defined cleaning procedures and robust decontamination procedures, according to Mueller-Albers. “It is integral to have operators who are well-trained in the operation of relevant equipment and procedures for the types of substances being handled,” she adds.

	Any handling, introduction, and transfer of powder between processing steps must be conducted in a closed or isolated system, which requires more complex and specialized equipment, according to McNaughton. “Highly diligent processes are required to prevent operators and the surrounding environment from being exposed to dangerous airborne powders,” Mueller-Albers adds. She notes that in addition to closed systems for milling, containment systems for spray drying have also improved considerably over the past decade, which has created opportunities for the spraying of HPAPIs to form amorphous solid dispersions.

	For some technologies, equipment may be specific to the individual process and require specialized handling protocols. “HPAPI product manufacturing is most straightforward for processes that have minimal steps, can be serially conducted, and do not require the material to be transferred to a completely different area,” adds McNaughton. “The resulting process commonly needs to be qualified to ensure the containment is sufficient for the product being manufactured so that any resulting operator contamination is significantly below the level at which the HPAPI could have a therapeutic effect,” he continues.

	Cleaning of processes involving HPAPIs must also be conducted in a closed system and is often the time where there is the greatest risk of exposure for the operator, according to McNaughton. A key challenge for HPAPIs is the fact that cleaning must be conducted to a level at which there is no risk of contamination of subsequent products-a level at which residual HPAPIs are often difficult to detect. When detection cannot be achieved, dedicated equipment or even facilities are often required for a single product to ensure no cross-contamination with other products is possible.

	Even though risks are believed to be controlled or removed, McNaughton stresses that it is important to ensure plans, systems, and training are established so that in a worst-case scenario, such as an accidental release, there is no risk of contaminating the environment and a mechanism is in place to clean the area back to a safe standard without any risk to the operators.

	Excipients that are helpful in any low solubility drug are generally applicable to an HPAPI with low solubility. Solubilizers and disintegrants are two examples, according to Kujath. Excipient selection should be based on a combination of the chemical and physical properties of the HPAPI and the target product profile, according to McNaughton. “Meeting a target product profile for a poorly soluble API requires both the correct technology selection and the appropriate science-led formulation development,” he comments.

	While there are no specific excipients that are suited to highly potent materials, there are certain aspects of some technologies that offer advantages if they are also the correct technology for the product, McNaughton adds. “Under certain permeability-limited situations or biological obstacles, there are specific lipidic excipients that can provide some permeability enhancement, others that inhibit efflux, and others that could avoid first pass metabolism through utilization of the lymphatic system,” he says.

	The use of polymer-based excipients is widely appreciated in the formulation of poorly soluble HPAPIs, according to Mueller-Albers. They play a key role in the formation of solid solutions, stabilizing the amorphous HPAPI in the solid state to prevent recrystallization, and also helping to maintain HPAPI supersaturation in physiological media, she explains. Polymeric excipients are also used in formulations prepared via granulation using high-shear mixing or fluid-bed spraying, which can under certain conditions be applicable for poorly soluble HPAPIs.

	The first HPAPIs were often formulated as liquids and then filled into capsules to reduce safety risks such as dust formation. Liquids, however, present challenges when solubility is an issue, according to Kujath. “While micronization and spray drying of the HPAPI can be helpful for oral solid formulations, these techniques to drive initial dissolution for liquid formulations can present stability challenges, such as crystallization of an initially dissolved amorphous HPAPI from the vehicle or ripening in a micronized dispersion,” he explains. Thermocycling during terminal sterilization can also cause ripening or recrystallization or break complexes formed by solubilizers such as (2-hydroxypropyl) beta-cyclodextrin.

	As the number of HPAPIs in development has increased, however, manufacturers have aggressively examined new processing techniques suitable for oral solid-dosage forms, according to Mueller-Albers. Particle-size reduction, or particle-size design, amorphous dispersions, and lipid-based formulations are all suitable techniques for improving the bioavailability for solubility-limited HPAPI, according to McNaughton

	“Particle size reduction is likely to lead to an increase in the rate of solubility for an API and may provide some supersaturation effects, but is unlikely to result in the same level of potential increase that can be achieved by amorphous dispersions or lipid-based formulations,” he says. Lipids also offer a further advantage for low-dose HPAPIs where these can be fully solubilized because the potential for poor homogeneity is eliminated and accurate dosing can be provided, even for the lowest possible dose. “Achieving such formulations may be impossible in the solid state, so a lipid/liquid approach can be enabling for the molecule to be advanced,” McNaughton states.

	Kujath notes, though, that while lipid-based solubilizers and the formation of nanoemulsions can be an effective way to deliver an HPAPI of low solubility, these techniques should generally be combined with the use of a low-energy means of sterilization.

	If the API is not “greasy” (logP < 3), lipids are unlikely to provide the same improvements that amorphous dispersions can, according to McNaughton. In addition, processing to achieve particle-size reduction can be simpler than developing an amorphous or lipid formulation.

	“Every day the industry is improving containment solutions, making it easier to leverage HPAPI handling technologies that previously may have been less accessible,” says Kujath. He also notes that more and more focus has been placed on not just patient safety, but on worker safety. There are always new and improved excipients being developed, new approaches, and better understanding of how to use them, agrees McNaughton. He adds that improved technologies to remove the vulnerable operator from harm include more hygienic valves, in-line testing to minimize operator interaction with potent molecules, and increased automation that completely removes the operator from the vicinity of these process.

	However, it is important, according to Kujath, to remember that the issue of low solubility is not unique to HPAPIs and can be vastly improved in the active molecule design process. For instance, he points to technologies such as antibody-drug conjugates, which are useful for targeted delivery of small-molecule HPAPIs, but also offer a means to chemically modify a pharmacologically active compound so it can be more effectively delivered if poorly soluble.

	“In the small-molecule world, time spent during molecular selection for not only potency but solubility and bioavailability should be a focus in good drug design. That would reduce the need for exotic formulations to compensate. Understanding the active sites of drugs and what can be potentially modified allows for better structural designs or the creation of pro-drug analogs to increase solubility and bioavailability,” he concludes.

	1. Kline & Co., “Solubility Enhancement in Pharmaceutical Oral Solid Dosage Forms: Global Market Analysis and Opportunities,” Report, March 2015.

Vol. 43, No. 6
	June 2019
	Pages: 20–22

	When referring to this article, please cite it as C. Challener, “Enabling Technologies Advance Poorly Soluble Highly Potent APIs,” 

Excipients and new processing techniques can make a real difference in the development of highly potent therapies.

Enabling Technologies Advance Poorly Soluble Highly Potent APIs

Before syringes are used on patients, they must go through rigorous quality control testing. Empty syringes must be tested at the site where filling will be completed as part of an incoming quality control protocol. Filled syringes are subjected to release testing.

	Prefilled syringes can help reduce medication errors; however, the devices pose challenges in manufacturing and require extensive testing.

	Knowledge and understanding of the various tests involved is essential for ensuring patient safety. A holistic approach to syringe manufacturing that includes formulation, process, packaging, device integration, quality control, and an understanding of the user needs is essential.

Biologics and Sterile Drug Manufacturing 2019

	When referring to this article, please cite it as C. Challener, "Test Methods and Quality Control for Prefilled Syringes," 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing 

Empty and prefilled syringes must pass a range of quality control tests.

Test Methods and Quality Control for Prefilled Syringes

Excipients are essential components in drug products. Although sometimes defined as “functional” or “inert,” each has a specific role within the formulation that is necessary for the overall function of the medicine. Variability in the properties and performance of excipients may, depending on the nature of the variability and the role and quantity of the excipient, have a significant impact on the safety and/or efficacy of the final drug product. Managing-minimizing-excipient variability is, therefore, an essential part of drug product development and manufacture.

	Excipient variability depends on many factors. One important determiner relates to whether the excipients are prepared from natural materials or via chemical synthesis, according to Liam Cullen, an engineering specialist with Servier. For example, he points to cellulose-based materials, which are derived from wood pulp that is then chemically treated. “Natural materials, particularly those that are grown, can be subject to environmental conditions such as soil type, weather, and the use of fertilizers. Secondary processing steps can also provide further material variability,” he explains.

	Materials that are manufactured by chemical synthesis alone tend to have less variability, but changes in the manufacturing environment, including the raw materials used, processes, and manufacturing locations can occur. For instance, Cullen notes that suppliers may elect to move the manufacturing of an excipient from one plant to another for cost reasons, and then replace some or all of the raw materials with locally sourced alternatives. “While the overall material specification ranges do not change, the once-typical values may be impacted,” he says.

	Variability is most commonly encountered at ACD/Labs in the impurity profiles of excipients, according to Andrew Anderson, the company’s vice-president of innovation and informatics strategy. Generally, excipient attributes such as rheology, granulometry, viscosity, and impurity profiles have been better indicators of change compared to more specific material characteristics such as purity, appearance, or loss on drying, according to Cullen.

	Because both changes in the raw materials and processes used to manufacture excipients can impact final drug product performance, Mike Tobyn, research fellow in the materials science and engineering group at Bristol-Myers Squibb (BMS) stresses that it is important to understand the sources of variability for any excipients used in drug formulations.

	In addition, he observes that the analytical methods used to generate results for certificates of analyses (CoAs) and by pharmaceutical companies upon receipt of excipients are often an unappreciated source of variability. “When debating whether a material is ‘different’ based on these results, it is necessary to consider whether the variability is in fact due to the different capabilities of the methods being used. In some cases, a change in the analytical results may be due to analytical ‘noise’ and not because the attributes of the material have changed,” states Tobyn.

	Impacts from development to commercial production

	Understanding the impact of variability in excipient properties or specifications on the critical quality attributes (CQAs) and performance of the final drug product is key to developing a robust strategy for selecting the right formulation and process that will result in a robust drug product, according to Anil Kane, executive director and global head of technical and scientific affairs at Thermo Fisher Scientific. “Challenges (and failures) start in development. Hence it is key to evaluate variability in the excipients, the API, and the process parameters during the development and pilot stages before pivotal clinical trials,” he states.

	Excipient variability can impact product consistency, stability, and dissolution profiles, among other properties. Most often these impacts occur with excipients that have functional roles, such as in drug release. Variability in inert excipients (diluents, fillers, etc.) can have an impact on product performance, but the impacts may be more difficult to detect at the development stage, according to Cullen.

	At both the development and commercial stage, excipient variability can result in a batch failing to meet specifications, which equates to a loss of time and money, according to Tobyn. “Failure could be obvious, such as sticking or tablet breakage for oral solid dosage products. Or it could be more subtle, such as interference with an established analytical method. In the latter case, the process understanding and control provided by the method may no longer be in place, which slow down release or threaten the batch,” Tobyn says.

	While all levels of development and commercial production can be affected by changes in the performance of excipients, some stages may not display any negative effects. “It is important to take a holistic approach that considers all of the information gathered from various sources and includes comparison with historical data as well as computer modeling of the data gathered,” Cullen asserts.

	He notes as an example issues that can develop with particle segregation that typically aren’t detected at development scale but become noticeable in the plant. In development, the distance from the feed intermediate bulk container to the tablet press feeder is approximately one meter; in commercial production, the feed IBC can be on the floor above the tablet press, and the acceleration involved when the material is released from the IBC to the press can result in a de-mixing phenomenon called segregation that affects smaller particle sizes in the feed mixture. “This issue is not immediately obvious in production but is normally identified during validation or standard product testing,” Cullen adds. As a result, he suggests that design-of-experiment (DoE) and quality-by-design (QbD) models currently used in smaller-scale development should be expanded to commercial-scale activities.

	Lack of variability at the development stage can also be a problem when processes are scaled up, according to Tobyn. “It is important during development to establish potential excipient variability issues that might occur and how they might affect product quality and performance. Tales abound of products developed using unusual or atypical batches throughout the development stage with no issues observed that fail in the plant due to an unexpected change. The formulator must work to avoid this situation,” he comments.

	Special considerations for continuous processes

	In continuous manufacturing, material characterization of each and every excipient is extremely crucial because continuous processes rely completely on uniform continuous blending and feeding to tableting or encapsulation machines, according to Kane. Physicochemical properties such as particle size distribution, densities, flow properties, surface morphology, and other characteristics play a critical role in developing an efficient continuous process.

	Unlike for conventional processes where the first step is usually blending, Tobyn adds that in a continuous process there is a period where the excipient is not blended but is transported via a feeder to the blender. “The flow of this powder is a consideration that does not exist for batch processes. Although loss-in-weight feeders can cope with changes in flow and feed rates, it is still beneficial to keep these changes to a minimum,” he notes.

	Here again, employing QbD for continuous manufacturing is an effective approach to risk mitigation, according to Anderson. He also notes that the use of process analytical technology is imperative for QbD implementation.

	Drug makers face many challenges when approaching the management of excipient variability. One basic issue is the locations of excipient production, according to Cullen. Excipients are often not manufactured nearby or even in the same country or on the same continent, particularly for specialized materials. “Issues of distance, language, and time zones make it challenging to maintain concurrent or even regular contact,” he notes. Online help desks often provide limited support due to insufficient staffing or unwillingness of suppliers to share process or material sensitive information, even where dedicated secure client accounts have been created, adds Cullen.

	There are also different types of suppliers, according to Cullen. Some are dedicated to the pharmaceutical industry and understand the extensive requirements of the industry. Others serve multiple sectors with the pharmaceutical industry comprising a significant part of their businesses. These suppliers generally recognize the special requirements of their pharma customers, but may need some additional support. There are also suppliers for whom the pharmaceutical industry is a small percentage of their business. These suppliers may not fully understand the specific needs of pharma companies and communication may be difficult.

	As one specific example, Cullen notes that some suppliers will indicate on CoAs that a specific attribute “complies” with the specification rather than providing an actual value, which makes it difficult to identify variations and to use data for trending analyses to determine patterns of variability that can assist in understanding the subtle changes in the CQAs of an excipient.

	A deeper understanding of how variability in excipients can affect drug product performance and proposed control strategies is essential for improving drug product development, according to Kane. Gaining that understanding can be difficult, however, because pharma companies don’t have the internal capability to manipulate excipients and their manufacturing processes. “Variability in excipients is a function of the control strategy used by the suppliers of these materials, and it can be challenging for drug makers to obtain ideal sets of samples for adequate investigations,” he observes.

	Furthermore, the number of excipient material properties combined with the number of excipients in a drug product formulation present cost and logistics challenges for executing manageable experimental designs. “Risk-based approaches may be helpful for identifying the excipient material properties (typically functional) that have the greatest impact on product performance,” says Kane.

	In addition to finding sufficient time to run a systematic DoE to evaluate the influence of excipients, Thermo Fisher is often also challenged by the need to work with minimal quantities of API at the clinical and pilot scale, according to Kane. For ACD/Labs’ customers, data analysis and reviews are a challenge, and the company is working with a variety of customers to address this issue, according to Anderson.

	Tobyn agrees that there are business and quality barriers to completing the processes necessary to ensure that excipient variability is minimized from the start. “The technical processes to establish which materials have low variability exist. We currently need the business processes to exploit that,” he adds.

	One of the most common tactics for pharma companies is to, where possible, choose excipients that have worked well in the past and to purchase them from reliable suppliers with a track record of providing excipients with minimal variability.

	For instance, BMS uses platform formulations that allow the company to work closely with and gain a greater understanding of a limited number of materials. “Because the platform is known, and how those materials interact has been demonstrated, the only material ‘variable’ is the API,” Tobyn remarks. He adds that the platform utilizes high-volume, widely available excipients that are expected to demonstrate lower variability.

	BMS has also used a range of techniques to identify vendors with proven track records in producing low-variability materials. “Use of these vendors, along with ongoing monitoring of the variability of their products, provides a stable base for the platform,” Tobyn explains. Other vendors can be introduced, along with more variability, at key stages if the business requires.

	Beyond the use of well-known excipients, the most basic step at Servier is to monitor and analyze the data from both CoAs and on-site testing results, according to Cullen. Functional excipients are monitored more closely than less functional materials, but all can have an impact. The data are trended along with the performance data of the finished product, and over time it is possible to identify which materials have the greatest effect on finished product. Servier also conducts regular supplier audits.

	Once the most impactful excipient material properties are identified, this understanding can be combined with knowledge of the API properties and the process parameters used to manufacture the drug product to develop an appropriate control strategy that ensures consistent supply of safe and efficacious drug product, according to Kane. He also stresses that the experience of formulation scientists is essential for developing robust optimized formulations.

	In addition, employing a QbD approach, and specifically accounting for each material’s CQAs, can help with developing appropriate procedures and mitigating the risk of commercial production failures when any excipient has attribute variability, according to Anderson.

	Of course, suppliers play a crucial role in reducing excipient variability. In general, BMS has found that the more experience a vendor has with a material the less variable it is likely to be, according to Tobyn. “A major excipient that has been produced for 50 years on a tonne-per-day basis and is in thousands of products is less likely (although not totally free from risk) to have variability that will influence final drug products,” he says. On the other hand, suppliers of niche, specialist, novel materials may need some time to develop process and product consistency.

	Cullen would like excipient suppliers to openly discuss planned and unplanned process changes with their suppliers, provide specific values of CoAs, not just “Complies”, and prepare annual summaries of CQAs for their processes and finished materials that also include timelines for any changes. He would also like to see more direct communication and opportunities for site visits to suppliers, such as workshops and plant tours, so pharma companies can gain a greater understanding of excipient manufacturing processes.

	Excipient suppliers should, in fact, be open to sharing their data, with appropriate controls, on the variability of their products, according to Tobyn. He notes that some vendors, mainly the ones who are aware that their products are low variability, do so, but others are reluctant. “Data sharing would allow customers to make informed decisions about which materials are low and high variability and potentially provide pressure for vendors with high variability to improve that variability,” he observes.

	BMS would also like to monitor excipient properties in real time with vendors in order to be able to select batches during the purchasing process, either in a regular process or opportunistically when suitable batches became available. “This type of purchasing, however, will require new processes for our company and the vendors,” Tobyn notes. In addition, he would like to see more focus on analytical methods and reduction of analytical “noise” so that “real” variability can be readily probed, identified, and minimized.

	Both Kane and Anderson would like to see more excipient suppliers adopt and apply QbD principles in the manufacture of their excipients.

	Essential to minimization of excipient variability is the building of relationships with suppliers, according to Cullen. “Waiting to commence a dialogue with suppliers until an issue arises or until it is time for an audit does not provide good results. It is important to establish and maintain contacts within supplier organizations so that issues can be discussed freely and directly as they occur or ideally in advance of their occurrence where issues during the manufacture of an excipient have arisen. It is an area for constant development. Drug manufacturers must work closely with their excipient suppliers at all times,” he asserts.


	Vol. 43, No. 5
	May 2019
	Pages: 24–26

	When referring to this article, please cite it as C. Challener, “Avoiding Excipient Variability,”

Knowing the source and understanding the impact on CQAs is crucial to optimum drug formulation and processing.

Avoiding Excipient Variability

The presence of the probable carcinogens N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) found in APIs used for the production of a number of generic versions of angiotensin II receptor blocker (ARB) medicines has raised concerns about how manufacturers and regulatory bodies address the potential for production of undesirable impurities (1). The products in question complied with regulations yet contained genotoxic compounds. FDA has taken several steps to address this particular issue (2,3). Drug makers also clearly need to consider what approaches they should be taking to ensure their API suppliers are supplying high-quality material that is safe for use in final drug formulations.

	“Despite the fact that manufacturers have the process knowledge and experience that regulatory bodies do not have, we are still dealing with massive recalls of very important medications, the scope of which just keeps increasing,” observes Macniell Esua, chief compliance officer at CordenPharma International.

	In this particular case, Esua points out that it appears that a trace impurity in a solvent reacted with a process reagent used, resulting in a genotoxic impurity. “Surprising levels of the impurity are being found in the drug that exceed the levels one might have predicted and that are allowed. One guess is that recycled solvents may be a contributing factor,” he notes. Esua adds that it is critical that the full investigation findings be shared with the industry in an open fashion, so everyone can learn from this potentially tragic situation.

	Looking specifically at the issues concerning valsartan, it is also important to note that after the initial recall of drug product containing an API manufactured by Zhejiang Huahai China, additional API manufacturers in China and India had their approvals recalled for the same reason. “The presence of nitrosamines is not only a ‘variation’ problem but has also been shown to be a GMP cross-contamination problem at some of the manufacturing sites involved,” says Rolf Arndt, senior quality assurance and regulatory affairs specialist with Cambrex.

	He adds that the fact that different nitrosamines were identified for both APIs and drug products makes the problem more challenging, because the required maximum specification limits of nitrosamines are substantially lower than for normal impurities.

	“The issue is not a simple question of ‘approval systems,’ but more a combination of better evaluation of the risks of formation of nitrosamines as well as better analytical techniques; but most importantly, that API manufacturers have sufficient controls within their GMP procedures to avoid cross contamination,” Rolf asserts. “Furthermore,” he states, “Because this field is so fast moving, it is not enough to merely comply with the regulations; it is important to be ahead of them.”

	During a process validation exercise related to an investigational new drug, a full fate and purge study should normally be conducted, according to Esua. In the current situation with valsartan and related products, Esua suggests a fate and purge study would have correctly identified NDMA as a potential impurity in the process. “As a result, work would have been conducted to identify the potential risk of introduction of NDMA in the final product and to develop mitigation strategies. Through the change control process, full consideration should have been given to the change in solvent, the potential impurities that the change was introducing, and the downstream implications,” he says. He also points out that this issue is again related to the scientific competence aspect-and whether the study was conducted with sufficient rigor or paid “mere lip-service.”

	Any process change must involve a risk assessment that includes a judgement of whether the proposed changes have the potential to result in the production of new or additional impurities, according to Arndt. The assessment should also identify whether there is a risk of formation of impurities that may fall under International Council for Harmonisation  M7 guidelines.

	“If there is a risk of formation of so-called ‘M7 impurities,’ further investigation must be performed, and the basis to exclude any process change must rest fully on supportive analytical data,” Arndt states. “These types of impurities cannot normally be detected by simple chromatographic methods that are used for ‘related substances’-substances similar to the API, so more advanced techniques must be used, for example, [tandem mass spectrometry] MS/MS,” he adds.

	When considering drug process changes, the burden resides rightfully with the manufacturer, according to Esua. It is also the manufacturers’ responsibility to complete a comprehensive scientific review of the proposed changes, with thorough consideration of all possible implications, and a detailed impact assessment as part of the change control process.

	“In the case of the NDMA contamination of valsartan, is it known that dimethylamine could be an impurity in the solvent [drug master file] DMF? Yes. Is it known that dimethylamine would react under the reaction conditions to give NDMA? Yes. Where, then, did the manufacturer go wrong? Were dimethylamine levels higher than anticipated in the DMF (since it’s not a typical impurity that would be screened during a DMF solvent release), or was the combination of these two factors (the presence of dimethyl amine and reactivity in the reaction) simply not considered?” Esua asks.

	What is important to remember, according to Esua, is that although a regulatory inspection is a tool to measure compliance against current manufacturing regulations, it does not, nor can it, dictate a certain level of scientific competence on the part of the manufacturers, or unfortunately, the regulatory agencies themselves.

	So how can drug makers be sure they are selecting API suppliers with the appropriate level of scientific competency? “It is imperative that pharma/biotech companies understand the partners they choose to do business with,” asserts Stephen Houldsworth, director of global small molecules and antibiotics platforms at CordenPharma International. “They must have confidence in the company’s quality systems and its manufacturing team, as well as the team’s scientific competence and ability to make the correct decisions,” he explains.

	Houldsworth points out that there are suppliers in the marketplace today that perhaps make decisions based on incorrect assumptions or poor science, the consequences of which are often not discovered until much later, as in the case of valsartan and similar drugs. “Unfortunately, price drives a lot of purchasing decisions-especially in the generic API business-but this cannot be the only priority. Considerations such as quality controls, process development, project management, and scientific expertise must also be factored into these decisions,” he stresses.

	The first and most important step is to evaluate and audit the API manufacturer to ensure that it has a sufficient standard of GMP protocols and procedures in place to minimize the risk for cross contamination, according to Jonathan Knight, director of marketing intelligence for Cambrex. The second step is to ensure further evaluation where necessary, such as for potential toxic elemental impurities originating from the environment, the raw materials used for manufacturing, and/or corrosion of manufacturing equipment. “Confirmation is needed that these types of impurities are not present in the API and thus do not impact the product quality,” Knight observes.

	In addition, Cambrex suggests reviewing the company’s regulatory history and its corrective actions around observations and GMP compliance and training. Additionally, Knight notes, it is important to assess the company’s experience in developing new chemical entities, and the proficiency and experience of its chemical-development, analytical-development, and quality-assurance departments. That includes checking the investment history of a manufacturer, especially with respect to the acquisition of the most up-to-date analytical equipment.

	“Having a good understanding of what the potential risks are can be determined by the development of good design of experiments. In addition, ensuring openness between parties and clear documentation can avoid problems,” Knight adds.

	The success of a company’s outsourcing efforts is driven by the quality of their vendor qualification and management systems, according to Houldsworth. “They need to be robust, structured, and detailed to provide a high level of confidence that the API suppliers in question are reliable and competent,” he concludes.

	Esua cautions that regulatory agencies should not respond to the valsartan contamination issue with a simple knee-jerk reaction and demand that all process changes must be approved by regulatory agencies before implementation. “Apart from crippling both the manufacturers (via delays in change approvals) and the regulatory agencies (by drastically increased burden of work), this approach would lead to rising costs in an industry that is already under intense pressure from a costing point of view, without any guarantee that problems will be avoided in the future,” he states.

After Valsartan Recalls, Regulators Grapple with Nitrosamine Contamination in APIs

Statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research on the FDA’s Ongoing Investigation into Valsartan and ARB Class Impurities and the Agency’s Steps to Address the Root Causes of the Safety Issues,

Vol. 43, No. 4
	April 2019
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, “Select Suppliers with Demonstrated Expertise to Avoid Sourcing ‘Bad’ APIs," 

Confidence in the quality systems and scientific competence of the API manufacturing team is essential.