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

Cynthia A. Challener

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 

Pharmaceutical Sciences, Manufacturing & Marketplace Report

 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 

Articles

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.

Pharmaceutical Sciences, Manufacturing & Marketplace Report:

 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.

Pharmaceutical Sciences, Manufacturing & Marketplace Report: 

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.

Handheld Point and Shoot Instrumentation Changes the Game for Raw-Materials Identification and Verification

The Bio-Process Systems Alliance (BPSA) was formed in 2005 to encourage the adoption of single-use manufacturing technologies in biopharmaceutical and vaccine production. Kevin Ott, executive director of BPSA, shared his thoughts with the Pharmaceutical Sciences, Manufacturing & Marketplace Report, about the latest trends and issues surrounding single-use technologies and the role of his association.

Gains in adopting single-use technologies

What were major positive developments for single-use technologies in 2012? 

  There is increased and ongoing interest, as exhibited by the influx of pharmaceutical manufacturers into the BPSA, in adopting single-use systems in drug and vaccine manufacture, as well as in fill–finish operations. This interest is, in part, being driven by the move towards “ personalized medicines,” where it is important to fit the production facility to the production needs to fulfill drug demands for smaller patient populations versus a “ blockbuster” drug. 

The appeal of single-use in drug production is the reduced risk of contamination, reduced costs and scheduling, operational efficiency, and reduced capital expenditures, both from a fixed-facility investment standpoint and a consumables standpoint. The positive development here is that “ single-use” or “ disposables” are being seen less and less as “ just” tools for the biotech industry, but more and more as accepted, viable alternatives for pharmaceutical and vaccine production.

 What were major challenges/hurdles for single-use technologies in 2012?

 If you would have posed that question as recently as three years ago, the answer would have decidedly been concerns from the user base with extractables and leachables (E&Ls). But, it appears that there is a sense now that the “ problem” of E&Ls is morphing into one of how to best manage the risk. Through thorough vetting of this issue by the supplier side of the industry via, for example the BPSA Recommendations for Testing and Evaluation of Extractables from Single-Use Process Equipment (BPSA 2010), we have seen concerns allayed in the user arena as test methods can now be standardized to an extent that allows for comparative results vis-à-vis stainless steel. 

Some of the current concerns with end users in the universe of disposable bio-processing are now system robustness, particulates in solution (visible or invisible) and end-of-life disposal of the plastic. BPSA is addressing these issues through its End User Committee, which is actively engaged in technical document development and forums on these matters, and led by several larger biopharmaceutical manufacturers in tandem with the extensive component and system supplier base that comprises the broad BPSA corporate membership roster.

 What do you see as the general trends and issues for single-use technology for biopharmaceutical manufacturing and what will their impact be in 2013?

  We recognize both “ big-picture” and “ lower-level” aspects in the pharmaceutical business that will drive demand for single-use, such as demographics, healthcare reform, pandemic response, government’s role in healthcare delivery, military needs, even the ability of Medicare, for example, to pay for expensive therapies in an era of huge budget deficits. On the “ lower level,” concerns, such as supplier lead times and quality responsibilities, standardization of systems (plug and play), best practices, the aforementioned particulate and durability issues, and the ultimate comfort level with disposable plastic containers that might hold a million dollars worth of drug product in a 5-mL flexible container are all concerns to users, and should be. 

However, these general trends will be augmented by a clearer understanding of both the high utility of single-use as well as the concurrent (present day) technological limits of single-use in biopharmaceutical manufacture. Stainless-steel systems will never be fully replaced by single-use. But, business trends and economic demands will likely move more manufacturers into plastic. Competition demands it. 

Other trends in 2013 will be a continued focus on the “ factory of the future,” such as Shire’s in Lexington, Massachusetts, which pushes single-use in evolutionary ways and underscores the importance of operator training. Are we educating “ hands-on” technicians in plastics? Are we adequately training personnel? 

There are also many questions about the future. Will plastic components remain inexpensive enough to throw away? How can facilities be designed specifically to product and patient needs? Can we quantify the “ green benefits” of single-se? What will happen to raw material prices with the advent of cheap shale gas? Will advances in DNA profiling and stem-cell research drive demand for boutique drugs targeted at “ orphan” patient populations, demanding small-scale manufacture?

All of these “ externalities” may impact Single-Use in 2013 and beyond, but it is evident that the “ raging incrementalism” that has brought Single-Use to the business forefront will continue in this decade.

What were BPSA’s key activities in 2012?

 All of the “ big-picture” and “ lower-level” aspects have been addressed, or are being addressed, either in working committees of BPSA or at its annual eetings. Context here is key; technology always lives within the scope of market demands, pricing, efficacy of use, and in some cases, government regulation. 

	From Day One, BPSA has served as the focal point for accelerating the adoption of single-use in both the clinical pipeline and at commercial scale, including upstream and downstream. To that end, BPSA has been actively filling the gap with technical deliverables in the form of GMP guides and by educating a variety of audiences on the critical business aspects of single-use adoption. The bottom line is that BPSA’s core activities are targeted at safeguarding the quality of drugs and therapies produced with plastics-based technologies and platforms. 

:  There are several significant projects on the BPSA agenda for 2013, all driven by member participation:

The issuance of a BPSA Quality Template Agreement to help suppliers and customers build a contractual relationship based on common terms and responsibilities

The revision and re-issue of our BPSA Component Quality Test Matrices Technical Guide from 2007 to identify consensus quality tests for film and containers, sensors, connectors, fittings, and tubing

An in-process deliverable by 2014 that will identify, qualify, and address particulates in final drug products

A continuing education series for FDA about single-use systems;

A continuing dialogue with industry, both user and supplier, on system and component standardization and harmonization; and

The 2013 (3rd Annual) International Single-Use Summit (ISUS) to be held in Washington, DC July 15-17, 2013.

Kevin Ott, executive director of the Bio-Process Systems Alliance, discusses the latest trends and issues surrounding single-use technologies and the role of his association.

Growth of Bio-Process Systems Alliance Reflects Rising Interest in Single-Use Technologies

It is well-known that increasing numbers of new drug candidates suffer from poor solubility and, consequently, poor bioavailability. Several methods have been developed to overcome poor solubility, including various solid-dispersion technologies, such as spray drying and hot-melt extrusion (HME) with specially designed polymers. Although the technique is not currently suited for all APIs, excipient producers, extruder manufacturers, and formulators are extending the applicability of HME to a broader range of drug compounds.


The goal of dispersion is to bring the API into solution before administration of the drug and reduce its particle or crystallite size in order to increase its wettability after administration, explains Andreas Gryczke, global marketing, new products, Pharma Ingredients and Services at BASF. “The solid glassy solutions formed using HME hold the drug molecularly dispersed in a matrix that can contain additional solubilizing functionality and can produce the solid dispersion using gentle shear conditions and high mixing but without the use of solvents,” he explains.

HME is attractive for many different reasons. One of its most desirable features is its minimal environmental footprint with no use of organic solvents, according to Vivian Bi, technical director for pharmaceutical solubilization and contract services at Ashland Specialty Ingredients. “HME is also a continuous processing method that can impart sufficient mixing, heat, and time to result in homogeneous amorphous solid dispersions for APIs with appropriate chemical properties on a scale ranging from batch sizes of approximately 10 grams to 100’s of kilograms per-hour throughput. HME also has a small footprint and minimal special facility requirements and infrastructure needs, allowing for more flexibility in process siting,” adds Ron Beyerinck, senior research fellow with Bend Research.

There are further benefits of HME that go beyond enhancement of solubility, according to Steven Hamlen, group product manager, MRT with Catalent Pharma Solutions. He cites the elimination of hydrolysis associated with wet agglomeration; the suitability for sustained-/controlled-release or enteric coating; flexibility to develop alternative final dose forms (i.e., tablets, capsules, etc.); high drug loading (up to 90%) for certain molecules to allow for decreased tablet size and/or dosing schedules; potentially more stable final compounds, and in some cases, avoiding the need for cold-chain storage; and taste-masking.


To be effective, the API must be thermally stable and have a sufficiently low melting point and/or high solubility in the dispersion polymer of choice.  The most important properties of the polymer matrix are its glass-transition temperature (Tg) and melt viscosity, solubilization capacity, stability, and toxicity/regulatory status. Excipients play a critical role in HME, according to Bi. “In addition to their contribution to stability and dissolution performance, excipients affect the processability. An excipient with suitable processability in HME not only can improve product quality, but also reduces time and cost related to manufacturing,” she notes. Gryczke adds that polymers can also play a role in drug release by keeping the drug dissolved in a supersaturated solution, thus avoiding precipitation. Low hygroscopic excipients also alleviate moisture uptake, which can lead to nucleation and crystallization of the API during storage. 

Separate plasticizers also can be used to improve processability by lowering the polymer’s Tg and melt viscosity while solubilization agents can prevent the API from crystallizing within the polymer or in the digestive tract, according to Hamlen.


Recent advances in various aspects of the HME process are increasing its suitability for a greater number of APIs. Beyerinck points to the definition of continuous process trains from the unit operations for dispensing and blending upstream of the extruder to the milling, blending, and manufacture of the final dosage form downstream as key. He also notes that process analytical technology tools are enabling the real-time monitoring necessary for scale-up and manufacturing. For Bi, important innovations include the use of supercritical CO

 improvements in extruder screw designs to achieve better dispersive and/or distributive mixing. Hamlen adds that accelerated screening technologies have been developed for salt screening of the base molecule itself to optimize bioavailability.

The development of excipients that are specifically designed for use with HME technology to enhance solubility, combined with high-throughput screening of these excipients for use with specific APIs, is also noted as important by Hamlen and Beyerinck. In particular, BASF has developed special HME excipient grades, along with easy-to-follow approaches for process characterization, including a special process parameter chart that enables formulators to easily understand and optimize the extrusion process, according to Gryczke.

Limitations remain, however. “In comparison with spray drying, the mixing efficiency of HME is lower, which could impact the content uniformity and quality of the extruded SD [solid dispersion] although by selecting suitable excipient(s) and process parameters, the mixing efficiency can be improved,” says Bi. Drug loading in the matrix can also be a challenge, and HME poses constraints related to the thermal properties of the API, according to Beyerinck, with thermal instability or high melting-point molecules leading to narrow processing and formulation spaces for a compound. 

“Excipient choice is a balance across the Tg difference between the API, the excipient itself, and the resulting viscosity limits for processing within the hot melt extruders,”  agrees Hamlen. “To address this issue, Catalent has partnered with BASF, academia, and key opinion leaders to integrate polymer selection with hot-melt extrusion design and operating parameters into a comprehensive solution that will represent a significant step forward for the technology application overall.”

Gryczke points to the exploitation of near infrared, terahertz, and other sophisticated tools in downstream processing, which is enabling the monitoring of the homogeneous mixing of drugs in polymers and thus production of robust formulations that meet quality-by-design (QbD) requirements. “The advent and implementation of such new techniques will lead to greater adoption of melt-extrusion technology for future drug development in the pharmaceutical industry,” he asserts.

The key to successful HME, according to Hamlen, however, is to remember that solubility, and thus bioavailability, can be enhanced in four main ways: optimizing the API form itself; optimizing the formulation; optimizing HME processing; and optimizing the dose-delivery form. “Optimization of solubility can require iterations across all four factors, and they are not mutually exclusive in most cases, nor predictable without integrated screening, feasibility, and scale-up trials.”


Several companies have made investments in HME. For example, Ashland Specialty Ingredients added both non-GMP and GMP extruders and a laboratory extruder for formulation screening at a gram scale, and various rheometers, which are instrumental for understanding the thermal rheology of excipients and formulations. BASF formed a strategic partnership with Catalent in 2012 to merge formulation and excipient expertise to deliver the right solutions. BASF also has a partnership with the extruder manufacturer Thermo Fisher Scientific to ensure that processes and excipients are aligned for optimal results. Catalent expanded its OptiMelt HME GMP capabilities at its sites in Somerset, New Jersey, and Schorndorf, Germany for laboratory, pilot, and commercial scales. Bend Research added an 18-mm Leistritz corotating, twin-screw extruder for both development and cGMP manufacture. Processes are routinely scaled up from the 18-mm extruder to two 27-mm extruders (one non-GMP and the other GMP) to support its customers’ clinical-supply needs from Phase I through Phase III.

Specially designed excipients, improvements in processing capabilities, and a growing understanding of the hot-melt extrusion (HME) process is increasing the use of HME as an approach for enhancing the bioavailability of poorly soluble drugs.