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

Cynthia A. Challener

Pharmaceutical laboratories are under pressure to increase productivity in order to speed up product development. The growing interest in process analytical technology has increased demand for more rapid analytical techniques that are appropriate for use in the manufacturing environment. More rapid analysis of production batches is needed to get material to market faster. Ultra high-pressure liquid chromatography (UHPLC), introduced in 2004, has become an important analytical tool for meeting these varied needs for higher throughput. Analytical instrument makers believe that further advances in the technology will enable UHPLC to have an even bigger impact on the pharmaceutical industry.


“The field of separation science was revolutionized with the introduction of the first commercially available UHPLC system,” asserts Eric Grumbach, senior product marketing manager for separations technologies with Waters Corporation.  “Today, there are tens of thousands of these systems in use, clearly indicating that the inherent business and scientific benefits of UHPLC technology are being realized,” he continues.Many factors are contributing to the demand for UHPLC. First, according to Grumbach, is the fact that the pharmaceutical and other industries, are under increasing pressure to improve overall profitability, from research and development through manufacturing and distribution, all the while facing the challenge of diversifying their product portfolio into new and unfamiliar territory. “One avenue towards improving profitability is to increase the throughput of their laboratory and manufacturing operations in an effort to decrease product development timelines and bring their products to market faster,” he notes.

The need for quicker results, but with moderate sample sizes, is another driving force behind the implementation of high throughput UHPLC, according to Michael Frank, marketing manager for HPLC at Agilent Technologies. “For the release of a production batch, not only the one sample has to be analyzed, but easily up to 20 if counting blanks, standards, repeated analyses, etc. The approval process using conventional HPLC, with typical run times of 20 minutes, can take nearly 7 hours. UHPLC, which is often 5 to 10 times faster, allows a significant reduction in the analysis time, and thus, production batches can be released in much less time. As a result, produced goods can be packaged and shipped sooner, streamlining the complete process and saving money.”

The online monitoring of products directly in the manufacturing facility is also much more feasible when using UHPLC compared to HPLC, according to Rainer Bauder, HPLC solutions manager for Thermo Fisher Scientific. “With UHPLC, the results are available within a few minutes rather than 30 or 45 minutes, which enables an immediate response to any undesired condition within the production cycle. Similar benefits can also be applied to process development and cleaning validation.”

	Multiresidue methods, including UHPLC, are also becoming the preferred way to monitor for drug residue contamination as the number of contaminants that are monitored increases, according to April DeAtley, LC product planner from PerkinElmer. “The combination of more complex analyses and a growing number of samples means that longer runs cannot be tolerated in high throughput labs, where the emphasis is put on achieving the maximum chromatographic resolution in dramatically reduced times.”


UHPLC is based on stationary phases using smaller particles. While conventional HPLC assays use 2.5–5 µm separation media, UHPLC assays use smaller 1.7–1.8 µm column chemistries that offer up to a three-fold higher separation efficiency. Thus, the same exact separation can be achieved in a column that is threefold shorter, which directly translates into higher throughput due to shorter analysis times. Alternatively, better chromatographic resolution can be achieved with UHPLC compared to conventional HPLC if the same method conditions are used. Bauder adds that in addition to faster results, the power of UHPLC as a technique lies in its extreme versatility, the opportunity to reduce operation costs and solvent consumption, and the ability to develop higher resolving methods for new products, which mitigates the risk of missing problematic impurities during drug development or production. Nearly all instrument suppliers offer online calculators for establishing equivalent conditions for UHPLC and HPLC. Thus, the analytical chemist now has the flexibility to decide between the same resolution and higher speed or the same speed and higher resolution, according to Frank.


While it may seem contradictory, one recent advance in UHPLC technology has been the introduction of the ability to run conventional HPLC methods on UHPLC systems. “Pharmaceutical customers need to be able to run legacy HPLC methods because these methods have been validated for approved drugs, and any change in the QC method requires revalidation, a halt in production, and an interruption of the revenue stream,” explains Grumbach.

There have also been a number of developments with respect to separation column technologies, according to Bauder. “New sub-2 micron particle and core-enhanced column technologies boost separation efficiencies and are triggering the development of new generations of column chemistries that offer improved selectivity for previously problematic target molecules, such as small, highly charged ions and mixtures of acidic, neutral and basic analytes. Grumbach points to the development of alternatives to U(H)PLC  systems based on supercritical fluid chromatography (SFC), which he believes has enabled the development of a truly exceptional selectivity tool that is orthogonal to traditional reversed-phase methodologies. “This mode of chromatography has proven to be a clear replacement for normal-phase chromatography for most applications, and one that is ideally suited for chiral analysis. As an added benefit, the reduced solvent usage has significantly reduced assay cost and allows organizations to meet sustainability initiatives.”

The ability of the instrumentation to withstand increasingly higher pressures is also critical to the advancement of UHPLC technology. “Entire systems are now able to tolerate greater pressures, including pump backpressures and detector flowcells. As a result, UHPLC systems are increasing in their overall performance,” notes DeAtley. Bauder adds that the development of novel detection techniques fully supporting UHPLC-type separation deliver additional leverage for faster and more in-depth sample assaying. Thermo Fisher Scientific has also focused on improving workflows around and within UHPLC instruments, including the introduction of automation tools, such as its x2 dual gradient UHPLC pumps and autosamplers that perform sample injection and fraction collection.


 Workflow, in fact, is one of the factors limiting the ability of pharmaceutical companies to fully leverage UHPLC technology. “A consistent theme we have heard from many of our customers is that the bottleneck of their workflow has moved from analyzing their samples, to preparing those samples prior to analysis. There is a need to make sample preparation workflows more efficient such that they can keep pace with the higher throughput analysis that UHPLC technology inherently provides,” Grumbach observes. Frank believes, however, that automated liquid-handling systems and the ability to make automated changes with different ultra high-pressure valve solutions for rapid switching to different solvents and columns is increasing the flexibility of UHPLC systems.

	Other limitations of UHPLC are being addressed with column technology, according to DeAtley.  “Solid core column technology is allowing for very fast runs, incredible resolution, and lower pressures, which takes much of the stress off of the system,” he comments. Bauder believes that, in addition to needed advances in system control and sample management, there remains significant improvement potential with respect to data processing and detection technologies, and that new and exciting column technologies are also showing great promise.


 Clearly, much more can be expected from UHPLC in the future. DeAtley believes that column technology coupled with UHPLC capabilities will work together for lower pressure UHPLC applications with the benefit of fast run times and overall cost of ownership benefits. “We are definitely continuing to explore the boundaries of UHPLC technology. Further advances, however, may not come in the form of smaller particles (e.g. 1-µm particles) and higher pressures, but rather through the use of miniaturization, microfluidics, and different particle technologies,” says Grumbach. Concludes Bauder, “The ultimate goal for UHPLC is to reduce the variety of separation methods required by end users while optimizing run time and sample throughput. Near-universal separation methods, as well as near-universal or (alternatively), highly selective detection technologies, have the potential to transform the chromatography lab and make UHPLC the methodology of choice.”

Articles

Ultra high-pressure liquid chromatography (UHPLC) is enabling faster product development and production batch approvals with increased sensitivity.

Increasing Productivity with UHPLC

Increasing numbers of drug candidates suffer from poor solubility issues. Various amorphous dispersion techniques have been developed that increase solubility. Much work remains to be done, however, to improve the performance of such methods. Enhancement of amorphous dispersions prepared using spray-drying is the focus of an exclusive collaboration between excipient producer The Dow Chemical Company (Dow) and CDMO Bend Research. The two companies are developing fully characterized polymers supported by complete quality-by-design (QbD) principles that can be tailored to meet the performance needs of specific drugs.

David Lyon, senior vice-president of research with Bend Research and Karen Coppens, senior R&D manager, Bob Schmitt, R&D fellow, and Brian Koblinski, strategic marketing manager at Dow, shared details about the new partnership with 

Pharmaceutical Sciences, Manufacturing & Marketplace Report

Pharmaceutical Sciences, Manufacturing & Marketplace Report:

 What specific capabilities does each company bring to the partnership?

Dow brings over 50 years of experience as one of the leading polymeric excipient suppliers worldwide. This materials-science experience is supported by high-throughput synthesis capabilities with API/polymer screening, laboratory-scale product development and structure/property optimization, a fully cGMP market development plant capable of supporting the clinical development of optimized solutions, and world-scale manufacturing capabilities. 

 As one of the recognized leaders in spray-dried dispersions (SDDs), Bend Research brings proven feasibility screening, SDD formulation expertise, cGMP clinical manufacturing capabilities, and experience in successful technology transfer.

 Why did choose to partner specifically with each other?

 We understand that successful solubility enhancement requires optimization of both the polymer and the formulation. In addition, it is imperative that QbD evaluations be incorporated early in the development cycle in order to facilitate robust formulations. Working jointly, we can seamlessly offer customers complete science-based support of their product development programs.

 How will the solid dosage industry benefit from the formation of this partnership?

The collaboration between Bend Research and Dow reduces drug-development risk by seamlessly combining materials development and optimization early in the formulation development process for spray-dried dispersions (SDDs) to achieve optimal clinical outcomes and robustness in drug-product manufacturability.

Our two companies use rigorous science that is grounded in fundamentals to develop new excipients and processes that improve the performance of solubilization technologies. This collaboration further extends that effort to use cutting-edge research to enhance existing technologies and ensures that our clients have access to a reliable supply of solubilization excipients that meet the critical-to-quality properties that are key to the performance of their compounds.

Pharmaceutical Sciences, Manufacturing & Marketplace Report: 

What does the collaboration enable you to do together that you could not each do on your own?

The collaboration allows Dow and Bend Research to offer a complete SDD solution to the market. Dow’s ability to design, synthesize, and characterize polymers is coupled with Bend’s ability to formulate and manufacture SDDs. These complementary skills distinctly position the collaboration to rapidly develop robust formulations that meet the clients’ clinical requirements.

 Can you explain further why you believe that incorporating QbD into the collaborative effort is so important?

 A properly designed and executed QbD study is the best way to develop a robust SDD product. QbD should be included in formulation development as well as in process development. Studies presented by Dow and Bend Research demonstrate that some SDD performance attributes show a high sensitivity to variations in polymer substitution while others can tolerate a wider variability. 

 Dow is able to produce and characterize QbD samples in a design space broader than the currently available commercial product, which helps Dow tailor the material to best meet the needs of the compound.

 Bend Research’s expertise in SDD technology addresses the variability in SDD process parameters that a formulation can tolerate. Coupling the polymer and process reduces variability in performance and leads to a robust drug product.

Specific polymer and formulation advances

 What types of polymers are you developing, and how are they differentiated from others on the market?

 Dow will provide hypromellose and hypromellose acetate succinate (HPMCAS), plus options to tailor these materials as well as next-generation cellulosic and noncellulosic polymers for enhanced performance. These new materials for SDDs will be developed and commercialized to address technology gaps in manufacturability and delivery, providing greater drug-product utility and therapeutic performance.

harmaceutical Sciences, Manufacturing & Marketplace Report:

 What new formulation processes are being investigated, and how do they advance SDD technology?

 Bend Research brings engineering solutions to SDD formation. For example, our patented hot-spray technology facilitates SDD production of API’s with low organic solubility at commercially relevant through-puts.

 What have you been able to achieve through this collaboration? Have you had initial successes?

Initial results were presented in 2012 at the annual meeting of the American Association of Pharmaceutical Scientists (AAPS) and the American Association of Chemical Engineers (AIChE). These presentations highlighted the solubilization optimization of several model drugs from SDDs using Dow’s fully characterized Affinisol HPMCAS and Bend Research’s science-based formulation approach. QbD principles were used in the studies to determine the performance sensitivity of the SDDs with respect to variations in the substitution levels of the HPMCAS. The results indicate that the sensitivity varies among drugs, and that a QbD study is one of the best ways to develop a robust formulation for each SDD drug formulation. The pharmaceutical industry has since embraced this concept, and we have several ongoing projects supported by our collaboration.

Dow Chemical and Bend Research are developing and commercializing new materials for spray-dried dispersions that address technology gaps in manufacturability and delivery.

Collaboration Targets Advances in Spray-Dried Dispersion Solutions for Poorly Soluble Drugs

As the demand for larger amounts of stem cells and other fragile cells grows, biopharmaceutical companies are struggling with how to effectively produce these specialized biological materials in larger quantities. ATMI LifeSciences has developed a new reactor to meet that need. Product Director Matthieu Egloff spoke with the 

 about the special conditions required for the larger-scale production of fragile cells and how its new Xpansion reactor was designed to provide them. 

A written version of the interview also may be found 

Matthieu Egloff, product director with ATMI LifeSciences, discusses the need for larger, special reactors that can provide the necessary conditions for the production of fragile cells on a larger scale.

New Reactor Technology Enables Larger Scale Manufacture of Fragile Cells

With biologics accounting for a greater percentage of the drugs on the market today, manufacturers, healthcare professionals and home-care patients are looking for safer, easier, and more cost-efficient means of delivering these therapies as well as vaccines.

Leaders in the prefilled syringe market shared their thoughts with the 

 about prefilled syringes (PFSs), including specific drivers for growth, their advantages, current issues, and recent technology advances. Participants in the roundtable discussion included: Brian Lynch, program lead for health science and technology, immunization, and Justin Wright, director of pharmaceutical development, both with BD (Becton, Dickinson and Company); Jo Anne Jacobs, manager, technical sciences and services of drug products with Cook Pharmica; William J. Lambert, PhD., fellow, drug-delivery and device development at MedImmune; Peter Soelkner, managing director with Vetter Pharma International; and Graham Reynolds, vice-president of marketing and innovation for West Pharmaceutical Services.

 What are the drivers for the growth in the use of prefilled syringes?

One of the primary drivers is the growth in biotechnology-derived therapeutic agents, particularly those that are organ or tumor-specific. These drugs are generally lower dose, but are rarely oral dosage forms.

 Another primary driver for the growth in the use of PFSs is the need for convenient self-administration of protein and peptide drugs by patients, and, of course, the number of these drugs has been increasing dramatically over the past two decades.

We are seeing a significant trend in the use of injection devices to deliver drug products effectively in the home environment, especially where there may be repeated treatments necessary for chronic conditions.

Because they require minimal overfill (enough to manage the dead space of the needle and hub), PFSs offer an opportunity to extend supply in both the biologics segment for chronic care and the vaccines segment. Supply extension can be important for public health in times of shortages. A vial, on the other hand, must have sufficient excess to allow a dose to be drawn out —20% overfill or more is typical.

What advantages do prefilled syringes provide?

PFSs offer advantages to both pharma/biotech companies and healthcare professionals and patients. For manufacturers, prefilled syringes are a safer form of packaging that offer a means for higher quality manufacturing. In addition, it is possible to achieve real cost savings because of the increased efficiency of the delivery system. Furthermore, PFSs are often seen as an added value and can help differentiate products from others on the market. For healthcare professionals, there is reduced risk of needle sticks, and, in general, the risk of contamination of the drug is lower when using prefilled syringes.

 As patients take an even greater role in decisions regarding their treatment, prefillable syringe systems offer a convenient solution that can be used in the home environment by a patient or caregiver. PFSs also can be combined with auto-injectors and other safety systems to create an integrated drug-delivery system that may help manufacturers offer patients a variety of choices for delivery from one standard container system.

 PFSs offer a unit-dose, ready-to-administer format that simplifies the preparation and administration of injectables by a patient or caregiver (versus, for example, a vial, which requires many more steps and ultimately the transfer of the injectable from the vial to a syringe). The time savings can mean more time on higher value activities involving patient care or shorter patient wait times. A recent study by the Johns Hopkins Bloomberg School of Public Health found that the time savings in preparing a vaccine for injection using a PFS vs. a vial was 37 seconds, which translates to over 15 minutes for every 25 doses given. This time can be significant in a busy pediatric office or during the flu immunization season.

Greater safety is another important advantage. There is a heightened focus in the United States (FDA Safe Use Initiative, for example) for greater safety in injectable medications due to a number of preparation mistakes that have led to problems ranging from the wrong drug being administered to re-use of syringes that can lead to infection transmission. Because they are filled, labeled, and packaged by the pharmaceutical company, and because they are unit doses and ready-to-administer, there are fewer steps involved in the preparation and fewer opportunities for human error.

There are cost advantages for the manufacturer, the practitioner, and the patient. There is also a gain in patient compliance. A regimen involving a premeasured dose that can be delivered at home is much more likely to be followed than if the patient has to go somewhere to be dosed. For medical practitioners, prefilled syringes offer ease of administration, require less storage space, and can decrease the overall inventory space required. Also, dosing precision is increased with the single-dose syringe versus having to draw up the dose from a vial.

What major hurdles do prefilled syringes still face?

 The viscosity of concentrated antibody formulations is probably one of the most significant challenges we face today for PFSs. Formulators attempt to balance the desire to minimize the subcutaneous injection volume while avoiding the dramatic increase in viscosity that is seen as concentration increases. Injection time in a PFS is primarily dictated by the flow rate through the needle, and the flow rate is inversely related to the viscosity. Furthermore, patients prefer narrow gauge needles. A flow rate, however, is related to the needle’s inside diameter to the fourth power. Thus, using a slighter smaller needle can lead to a large decrease in flow rate (and long injection times).

 Many biologic products exhibit increased sensitivity to materials found in traditional glass-syringe systems, such as silicone oil, tungsten and adhesives, and may also need to be delivered in higher dose volumes due to increased concentration or molecular weight. Tighter requirements/standards for visible and subvisible particles, cosmetic defects, interaction with devices, and concerns about glass breakage are leading companies to consider very carefully the selection of an appropriate container for their newer molecules.

 Prefilled syringes are more sophisticated and thus require more sophisticated manufacturing processes, particularly given the increased number of transfers that take place. On the patient side, the needs of different homecare patients who are self-injecting must be considered. Many patients that are using PFSs have arthritis and problems with their joints, and need delivery systems with broader finger flanges for self-administration. Manufacturers must have knowledge about both production issues and patient needs, which requires extensive experience in biologics manufacturing and packaging.

What advances in technology and other approaches are being developed to address these issues?

 Methodologies now exist to evaluate the sensitivity of a molecule/formulation to discrete surfaces and materials in the syringe. These shorter and less expensive tests help minimize time risk by demonstrating any potential interactions in advance of longer and much more expensive stability studies.

In addition, continuous improvement programs have reduced the occurrence of residual tungsten species to near undetectable levels, and advances have led to significantly better control of silicone deposition amounts and uniformity. Innovations in glass handling and processing have also yielded glass PFSs with significantly enhanced strength and durability profiles and reduced defects.

The introduction of “thin wall” needles and formulation-based approaches to minimize viscosity has led to some improvement, but viscosity is still a significant problem. Dozens of companies are currently working on novel designs for subcutaneous large volume injectors (LVIs). These devices typically are attached to the skin with an adhesive, hide the needle from view, and are able to deliver larger volumes of the formulation (up to 10 mL or so) over a longer period of time than is practical for a PFS. LVIs should significantly increase the number of drugs that can be self-administered by the patient.

 When developing sophisticated devices, plastic PFSs may offer advantages such as consistent functionality, increased dimensional precision, break resistance, and reduced extractables and leachables, particularly when combined with fluoropolymer-coated plungers. Plastic systems offer the ability to contain larger volumes more effectively, and can be customized to offer the ability to develop novel, patient-focused delivery systems that are optimized for size and functionality.

Automation in the clean rooms at Vetter is helping to minimize risk and human error, and the use of robots is becoming more commonplace as the benefits become apparent. Separately, with increasing numbers of smaller volume, niche drugs being developed, the ability to allow for dedicated production of specific products while still  maintaining efficient and flexible manufacturing facilities has been necessary. Adoption of quality by design and process analytical technology for the manufacture of PDSs is also becoming more formalized and having a positive impact on quality.

The growth in biologics drugs and vaccines is leading to greater demand for prefilled syringes, which provide greater safety and convenience for healthcare workers and patients.

Technology and Adoption of Prefilled Syringes Advance

Growing numbers of new drug substances, particularly oncology therapies, have very high potency and thus can be toxic upon exposure even at low levels. Specialized manufacturing equipment, procedures, and systems are required to ensure worker safety and protection. Recently, custom manufacturers with expertise in the production and handling of highly potent APIs (HPAPIs) joined in a roundtable discussion with the 

 to examine the latest issues and technology developments in the field. Participants included: John Michnick, associate director of sales and business development for Cambrex; Jean-François Marcoux, technical business manager with Novasep; Waldo Mossi, senior director of business development at Helsinn Advanced Synthesis; Stefan Stoffel, head of chemical manufacturing for Lonza; and Trevor Calkins, director of process development and manufacturing for SAFC.

Pharmaceutical Sciences, Manufacturing, & Marketplace Report:

 What are the key attributes for HPAPI production services?

 Perhaps the most important attribute a customer is going to be looking for is the assurance of the ability to manufacture HPAPIs safely and the documentation to prove it. SafeBridge certification is really the ultimate proof that a facility’s handling capabilities are up to par. The certification covers four broad areas: program management, hazard identification and evaluation, hazard control, and communication, education and training. Achieving SafeBridge certification is demanding, and only a few sites around the world have been shown to meet these standards.

 Many clients have expressed a preference to work with experienced US or European CMOs with stellar audit and regulatory records. Proper facility engineering, effective containment safeguards, and proven quality systems help to reduce potential risk related to facility audits and supply-chain continuity.

 Specifically, clients are seeking HPAPI handling knowledge and expertise. Instruments, equipment, and facilities must have appropriate heating, ventilation, and air conditioning (HVAC), barrier isolation, and separate gowning and degowning areas based on the toxicological and chemical/physical properties of the molecules.

 Having SafeBridge certification showing our ability to handle very toxic compounds with occupational exposure limits (OEL) of 0.03 µg/m

/h and lower (SafeBridge 4) is also a key point. It requires specific expertise and equipment that few manufacturers master. Currently, the demand for low OEL compounds is increasing due to the development of immuno-conjugate drugs, among other factors. Purification capabilities are also critical.

 Customers are looking for seamless execution of their complex HPAPI projects. Due to their limited volume requirements, often only single sourcing strategies are applied, even at maturity. Therefore, the establishment of a reliable source that can provide security of supply is key. If the CMO does not need to be changed between first clinical supplies, product launch, and regular market supplies, customers save effort, time, and cost for technology transfer, and they can leverage potential optimization based on process knowledge.

 What are the main challenges that you face as an HPAPI manufacturer, and what advances have been made to help overcome these challenges?

 Some of the main challenges we have seen revolve around the complexity of the HPAPI chemistry and the assessed risks associated with exposure limits and occupational safety. To help resolve the challenges, we focus on constant communication with our clients. Our HPAPI chemists, production teams, and project managers work alongside and educate clients on HPAPI procedures, SOPs [standard operating procedures], and training associated with the exposure limits of their compounds.

Getting to mutual recognition that a compound is classified as an HPAPI and has to be handled adequately can represent a challenge. It is key to synchronize the toxicity and safety aspects at the beginning of a project stage and ensure we’re not compromising on safety. Lonza has established a six-band safety categorization system that can easily be referenced to a client’s in-house categorization system or the widely utilized SafeBridge four- band system. This transparent determination of the appropriate containment and safety measures helps to maintain quality products. If during drug development, additional toxicologica data is generated that allows reclassification of an intermediate or API, we are happy to re-assess the production concepts.

 One of the biggest challenges involves materials handling, particularly when manufacturing HPAPIs on a larger scale. Bottles with alpha–beta connectors are too large and heavy to manipulate. We have addressed this issue by creating a system that allows hazardous reagents to be dispensed directly from drums. The drum and reactor are attached to a portable isolator, and a powder-transfer system is used to move the reagents from one to the other. The system is also used if the reagent is not hazardous, but the contents of the reactor are. The reactor is on load cells, enabling all components of the reaction to be added while minimizing manual handling requirements. We also use this system to transfer the completed reaction mix to a Nutsch filter. 

 There are two main challenges. First is defining the categorization class and OEL with limited information available from the client. Helsinn's solution is the use of internal assessment coupled with outsourcing hazards analysis and definition of appropriate OELs by an external expert group experienced in the field. Second is containment and protection in high-risk areas, such as product charging, isolation, milling, and transfer. Helsinn's solution has been to engineer its facilities to further mitigate that risk. A new, state-of-the-art, fully closed and comprehensive containment system was installed [at our facilities] that is capable of managing the entire process from raw material to finished HPAPI, including cytotoxic molecules.

 On an industry level, what are some recent technology developments that have advanced HPAPI capabilities?

 The challenge in HPAPI manufacture is to bring together very high containment capabilities with advanced purification technologies within the same facility. Industrial preparative chromatography is now generally well-established as a state-of-the-art purification technique for the production of APIs and is also becoming key for HPAPI production. 

 Biotech and pharma development has evolved in recent years to leverage the value of cytotoxic compounds while minimizing drawbacks. Much of this evolution can be attributed to antibody-drug conjugates (ADCs) and cytotoxic analogs. Several CMOs are contemplating collaborative opportunities to support diverse manufacturing technologies for ADCs (i.e., cyto, linker, antibody). 

Pharmaceutical Sciences, Manufacturing, & Marketplace Report

: What do you anticipate in terms of market and technology developments in the HPAPI space in the near term? Longer term?

 At present, there are a very large number of compounds in clinical trials for oncology indications. As established pharmaceutical and emerging biotech companies increasingly devote development resources into oncology products, a continued expansion in the demand for HPAPIs and cytotoxics can be expected. At the same time, the target compounds become more potent while the related synthesis processes become increasingly complex. A broad technical set-up and the ability to cover a great variety of unit operations, scales, and reaction conditions in a contained fashion is required, along with the ability to safely and efficiently handle the product and waste-related process streams, at any scale.

From a technology point of view, the advent of single-use production technologies could probably strongly benefit HPAPI production. Most of the current single-use devices, however, are not compatible with the use of organic solvents yet. When ready, it could definitely become a major tool for overcoming containment, cleaning, and cross-contamination issues.

ADC products are starting to be approved for use in cancer, and many more are under development. The ability to take an HPAPI and conjugate it to an antibody via linker technologies is going to become more important in the future as the number of these products rises.

There is a chance for additional regulatory guidance related to product classification (i.e., cyto vs. HPAPI). It is not clear, however, if this guidance will allow global agencies to align perspectives. CMOs that properly assess OEL categorization and compound classification will have the best chance to serve future market needs. HPAPI benchmarking, fully closed systems, and standardization for cleaning procedures and cleaning validation are areas that could further advance the technology in this space.

Pharmaceutical Sciences, Manufacturing, & Marketplace Report: 

What recent investments have you made or are planning in your HPAPI production capabilities? 

Helsinn expanded existing HPAPI containment facilities in 2012 with a new state-of-the-art, fully closed and comprehensive containment system that will be fully validated and operational in March 2013. GMP manufacturing will begin before the second quarter of 2013.

Novasep recently announced a $4-million investment to expand its HPAPI manufacturing capabilities at its Le Mans, France site for the synthesis, purification, and isolation of very highly potent compounds with an OEL lower than 0.03 µg/m

/8 h at kg scale. Cryogenic chemistry at -60 °C in Hastelloy reactors and large-scale high-performance liquid chromatography and drying in confined areas will be available for the manufacture of ADC toxins at commercial scale.

In the US, Cambrex Charles City recently added preparative chromatography and milling and micronization equipment and is currently undergoing an expansion to increase large-scale capacity for HPAPIs. In Europe, the Cambrex Karlskoga site is being upgraded to increase capacity and capabilities for developing and manufacturing HPAPIs.

In 2012, Lonza upgraded its Visp, Switzerland HPAPI center of excellence with a small-scale train for clinical and niche commercial HPAPI quantities (10–100 kg/campaign) and integrated its proprietary microreactor technology into the mid-scale cGMP setup there. HPAPI processes benefiting from continuous flow technologies can now be well-contained within one single cGMP-facility with outputs per campaign ranging from 10s to 1000s of kg. Lonza also established a dedicated manufacturing train for cytotoxic compounds under cGMP that combines fermentation and chemical capabilities with the handling of highly potent compounds that can be used for the production of either microbially derived secondary metabolites (toxins) or chemical compounds. In addition, our ADC capacity in Visp is being doubled and will be on stream in 2014.

Custom manufacturers with expertise in highly potent API production discuss the latest issues and technology developments in the field.

Setting the Bar in Highly Potent API Manufacturing

Requirements for 100% identification of raw materials coming into a pharmaceutical manufacturing plant can overwhelm the quality-control (QC) department. At the other end of the supply chain, halting the flow of counterfeit drugs can be quite challenging without the ability to conduct on-the-spot analyses. Handheld Raman instrumentation (TruScan, Thermo Fisher Scientific) is an example of how those problems may be addressed. 

“With the need to sample and analyze every drum, container, and package of raw materials that comes into a pharmaceutical plant, QC departments are inundated with these requests, which while routine, can take hours to days to complete due to their sheer numbers,”  notes Maggie Pax, senior director for pharma-chem, Thermo Fisher Scientific. In addition, opening all of those containers poses a contamination concern, and storage of sampled raw materials that are awaiting approval is yet another issue.

“Through our close relationships with customers in the pharma industry, it became apparent that another solution to raw-material analysis was needed, and preferably one that would enable direct analysis. We previously developed handheld instruments for the military and recognized that a similar approach would be effective in this application,”  Pax says.

With miniaturization of the laser accomplished and robust, proprietary algorithms validated, the challenge in developing a handheld instrument specifically for the pharmaceutical industry lay in meeting all of GMP requirements for electronic devices, particularly electronic signatures, and creation of the extensive supporting documentation demanded by highly regulated pharmaceutical customers.


Once the Thermo Scientific TruScan was available, the next hurdle was to develop an effective program designed to help pharmaceutical companies implement changes to their raw-materials identification and verification procedures, which included numerous document templates as well as training and validation-assistance programs. “While the adoption process is not complicated, it is cumbersome to meet all of the regulatory requirements involved in switching to a new raw-material verification technology. Providing support and helping to simplify the process has been critical to our successful implementation of this handheld analysis approach,”  Pax observes.

The ease of use of the TruScan has made it attractive. No scientific training is required, and the analysis result is presented as a basic “pass/fail”  reading. In addition, the instrument weighs only two pounds, has no moving parts, and was designed to withstand fairly harsh conditions. Furthermore, materials stored in clear packaging can be analyzed without opening the package. Therefore, not only do samples no longer need to be sent to QC, in many cases the potential for contamination can also be avoided.

The technology behind the TruScan instrument is Raman spectroscopy. The vibrational energy of atoms is unique to their specific bonding environment. When interrogated with light, the energy signatures emitted due to those vibrations create a spectrum that serves as a “ fingerprint”  for each different molecule. The TruScan compares the obtained spectrum with that of the expected raw material and indicates whether the substance is the right compound. “The matching program is based on well-established algorithms that are very robust,”  says Pax. She adds that the instrument comes with a basic spectral library, and users then build a customized version for their specific set of raw materials.

Raw-materials testing and anticounterfeiting uses


Pax believes that the instrument has real potential for use in raw-material analysis throughout the supply chain. “With outsourcing on the increase, there are growing numbers of places in the supply chain where the evaluation of raw materials/ingredients would be valuable,”  she notes. There is also particular interest in emerging markets, where the pharmaceutical industry has been growing significantly and many companies are hoping to expand beyond their domestic markets. Before they can begin to export to more highly regulated regions, however, they have to make significant advances in their processes and procedures to meet international standards, according to Pax. Thermo Fisher Scientific was recently invited to work with the US Pharmacopeial Convention on the development of spectral libraries for GMP pharmaceutical use in the US and in emerging markets.

The handheld instrument also has been used successfully by regulators for authenticating drug products in the marketplace. Dangerous counterfeit drugs have been identified and seized based on TruScan analyses. In one notable example, the Nigerian National Agency for Food and Drug Administration and Control credits the instrument with a significant reduction in substandard and counterfeit antimalarial tablets in Nigeria. Counterfeit drugs are a serious problem in developing countries, where the World Health Organization estimates that, in some less developed regions, counterfeits are higher than 39% of the drug supply. Nigeria has been aggressive in addressing the problem, and has reduced levels from 42% to 16% of the drug supply, partly aided by the ability to carry out on-the-spot analyses. “The advantage of using the TruScan is that the results are immediate. The counterfeit product can be immediately confiscated, and the perpetrators have no time to hide the evidence, as would be the case if a sample had to be sent somewhere for analysis,”  Pax remarks. Agencies in developed countries use the instrument as well because counterfeiting is a problem worldwide. Pharmaceutical manufacturers send people out in the field with TruScan instruments to look for counterfeit products. Doing so is a way to not only ensure the safety of the products, but also to protect their intellectual property and prevent adverse events, according to Pax.

She also notes that on-the-spot analyses would be useful at many different points in the pharmaceutical supply chain, whether during the manufacturing process or for raw-material identification and drug authentication. “We are collaborating with our pharma customers to understand where other problems exist that might be addressed with such rapid analysis systems. Just as cell phones have become ubiquitous, we imagine that someday handheld analytical instruments will become commonplace out in the field and in the process environment, helping to improve manufacturing quality, productivity, and efficiency,”  Pax concludes. Thermo Fisher also offers a near-infrared handheld instrument that complements the TruScan Raman device.

New handheld Raman technology is helping improve raw-material analysis and counterfeit-drug detection.