Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	This month, the pharmaceutical industry has lost one of its most zealous advocates for modern quality and process improvement, with the death of chemist Pedro Hernandez Abad, an expert in the implementation of process analytical technology (PAT) and pharmaceutical quality by design (QbD).  Born in Puerto Rico, where he obtained his undergraduate degree in chemistry, Mr. Hernandez received his PhD in organic chemistry from the University of Pennsylvania and studied at Oxford University, where he did post-doctorate research in carbohydrate chemistry.  Early this year, he had set up his own independent consulting business, after working as director of QbD at Merck-Serono in Switzerland. 

	Prior to that, he had led quality and bioanalytical efforts for Frontage Labs in China, and oversaw PAT efforts at Wyeth, where he managed Wyeth’s “PAT Factory,” a model for many companies launching PAT programs.

	Mr. Hernandez established the company’s PAT team in Pearl River, whose many achievements include obtaining real-time release product approval from FDA.  Former colleagues have praised his dedication, with Jack Carroll calling him “One of the foremost effectors of PAT and QbD in the working pharmaceutical environment,” and Saly Romero-Torres noting that he always put the interests of his reports and the company above his own, and that he encouraged and promoted an environment conducive to new ways of thinking.

	As his LinkedIn profile notes,  Mr. Hernandez' career followed the path of a drug product, moving from discovery, at companies that include SmithKline Beecham and Johnson Matthey, to scaleup, and manufacturing.  He had worked on both the API and finished drug product sides of the industry. He had authored numerous peer-reviewed papers and held 13 global patents.  He had also taught at the University of Puerto Rico. 

	Mr. Hernandez was anything but one dimensional, with varied interests, a sharp, ironic wit and a pleasant way with people of all backgrounds. Never one to suffer fools gladly, he wasn’t above getting involved in “unorthodox” editorial projects from time to time, including this 

“letter to Santa Claus” on behalf of the industry.

	Informally, some of his colleagues within the PAT and QbD expert communities have been discussing programming a brief tribute to him at the next IFPAC conference in January, 2016.

	Many of the advances that we see within the industry and within FDA, and the dawning interest in robust quality standards in China and other developing nations, stem directly from the efforts of Mr. Hernandez and thinkers like him, who recognized the transformative power of PAT and QbD.  His example might serve as an inspiration for any scientist who struggles to get senior management support for a new, better way of doing things.

	Mr. Hernandez will be missed by many.  Below are some 

comments that he had on the progress of PAT, five years ago. 

 We do not have any more details, beyond confirmation of his death, at this time, but wanted to let the community know.  If anyone would like to share recollections of Mr. Hernandez, please leave a comment after this post. 

There is a fear of change and loss of control. When quality moves from lab to the manufacturing line, there’s a learning curve, and of course, there are issues of cost, and fear of the unknown, so there’s a big cultural component to implementing QbD that needs to be addressed in the transformation. 

There has been a lot of discussion about mandates and incentives.  The problem with those, which stems mainly from the industry’s global nature, is that the Agency can only provide a target or a goal, not a map.  There are too many specific processes and particular products, and there is so much variability in terms of unit processes and products, that efforts must be left to each organizations. 

One approach might be to do some benchmarking studies using “success stories” from pilot programs, but the secretive nature of the industry has made such data sharing difficult.  This approach could be dangerous too, because we could create silos for different groups within the same company, for different companies and the same group of inspectors and then end up with slightly different requirements for different companies, within the same company, or within the same regulatory agency, if we’re not all on the same page. 

There’s a need for champions.  QbD and PAT cannot be done part time.  You need to have champions who can drive the effort...  The big question is ‘How much is it going to cost?’

The roadmap issue is very specific to the process.  If I put $500,000 into equipment and training, I need the money back by the end of the year.  An exact number is not always possible to predict.  More and more companies are moving toward doing real financial viability studies for PAT. In the current environment that’s understandable.

Then there’s the lack of understanding, the question of “What’s in it for me?”  But if you don’t put product quality as the object of your organization, and think of good product quality and good patient outcomes as the target, there’s no financial argument that can be made. You have to first believe in these goals and then manage risk wisely, invest properly and innovate. 

Part of the problem is that we’ve stopped doing innovation.  We validate, and then the learning stops there. After that, we just put out fires.  There has to be a real change in the way we think….and an understanding that quality means continual improvement.

For some organizations, it’s a question of the support systems. It’s not just an instrument on the line, but the issues such as IT infrastructure and meaningful sampling strategies. Then there’s the question of which metrics will be most meaningful”

Articles

This month marks the death of a pragmatic, original thinker who helped make PAT and QbD a reality at more pharmaceutical facilities throughout the world.

Remembering Pedro Hernandez Abad’s Rich Legacy

Years ago, when excipients were called “fillers” or “inactive ingredients,” drug-product quality testing was simple. The traditional approach, however, often sets the stage for process variability and manufacturing and quality problems.

	Today, more is known about the potential interactions that can occur between excipients and active ingredients, as well as the impact of raw-material variability on the final drug-product quality. Quality assurance is evolving to a multidisciplinary approach that requires an understanding of materials properties on the molecular and physical level, and of critical quality attributes (CQAs) and potential product failure modes. 

	Taking a quality-by-design (QbD) approach can be difficult when dealing with semisolid dosage forms because of their complex flow behavior. Some semisolids can act like a liquid and a solid within the same formulation at different times and under different conditions.

	Another problem is the fact that every formulation is different, says Alyn McNaughton, director of analytical and product development, Encap Drug Delivery, a division of Capsugel Dosage Form Solutions. “Excipients are used functionally to achieve different objectives, including bioavailability enhancement, dose homogeneity for low-dose drugs, high-potency safety, and abuse resistance. As such, each product must be considered individually within the lens of its specific function and desired outcome.”

	A simple “cream” may contain several excipients, solubility enhancers, and partially dissolved API, and may distribute the drug in a potentially complex or dynamic way. Sameersingh (Sam) Raney, scientific lead for topical and transdermal drug products at FDA’s Office of Generic Drugs, and former professor of pharmaceutics at the North Dakota State University, reminded attendees of the challenges at a special session on October 2015, at the 2015 American Association of Pharmaceutical Scientists’ (AAPS) meeting in Orlando, FL (1). Given the complexity of creams, he said, several different attributes may be crucial to product quality, and several failure modes may be possible. Approaches will need to take multiple factors into account. Excipient selection can have a significant impact on performance attributes, as Norman Richardson, global development and technical marketing manager for BASF Pharma Ingredients Services, explained at the meeting. Research is under way to help clarify some of these issues. This article reviews some of the work going on in this area.

Traditional testing cannot address variability


	Traditional quality testing for semisolid dosage forms typically focuses on viscosity, the effects of changes in temperature, and flow. Although these test methods may be indispensible, when used alone, they are not sufficient in examining potential for variability, says Kuljit Bhatia, vice-president of research and development at DPT Labs and a North Dakota State alumnus. “These compounds contain emulsions, composed of an oil phase and a water phase, with surfactants and emulsifiers. We keep all these ingredients together on a shelf for two years during stability testing, but how can we ensure they are stable?” he asks.

	Test selection usually depends on the target product profile (TPP) of the dosage form and the formulation composition, explains McNaughton. For example, pH-stat digestion testing is typically used to quantify solubility improvement for lipidic bioavailability-enhancement projects, while x-ray powder diffraction and differential scanning calorimetry are usually applied to characterize amorphous dispersion and crystalline suspensions, he says.

	DPT scientists are focusing on microstructure, Bhatia says, which is directly related to factors and conditions on the manufacturing floor. Understanding microstructure allows processes to be optimized, according to Bhatia.

	Scientists use microscopy and laser diffraction to analyze microstructure, and then take mechanical measurements using a micelle counter (typically, a Clemex image analyzer or laser diffraction device attached to a computer).

	In addition, rheology, which observes how stress affects product flow, is being used to study the compounds. Plotting sheer stress vs. sheer rate results in a curve that can be used to help predict product behavior under different conditions, Bhatia says.

	“We are taking a step-by-step process to examine emulsification, chemical stress, mechanical stress, process development, and other factors including cooling and the impact of changes in temperature,” Bhatia says. One goal, he adds, is to ensure that laboratory materials are the same as scale-up materials and that such factors as globule and micelle size are uniform from batch to batch.

	Michael Lowenborg, DPT Labs’ senior manager of R&D formulation and process development, explained the “microstructure” approach to studying emulsions at the AAPS session (2), and gave an example of how this approach was used to optimize the formulation and process development for an emulsion, working back from results in the lab to process design and equipment selection. Part of the work involved optimizing the hydrophobic lipophobic balance (HLB) and mixing and temperature of emulsification.

	Applying design-of-experiments (DOE) and scale-up studies offers insights into the critical process parameters (CPPs) and CQAs at each process phase. Future work, he said, will focus on how variation in microstructure can affect nonphysical attributes such as 

	Capsugel is also applying QbD principles to semisolid dosage forms, from the very start of the design process through to clinical and commercial manufacture, says McNaughton. “The understanding and control of CQAs and CPPs, from the concept stages of dosage form design, helps minimize any impact of manufacturing later in the process,” he explains. “It is important to determine both the tolerances of formulation and excipient ratios and combinations and the processing parameters used during manufacture at a small scale, and how these factors can change during scale up. It is also critical to know the performance and limitations of the excipients and materials that are being used, particularly those that are functional,” he says.

	The fact that two companies that support contract development and manufacturing work are using more modern quality tools reflects a change in thinking within the industry. “The use of QbD has gone mainstream in the past five years, and led to a ‘debunking’ of the traditional process for semisolid dosage form development,” says Bhatia.

	At the same time, more manufacturers are now using 

 release testing (IVRT) for semisolid dosage form manufacturing. A few years ago, the method was used only in some research projects, Bhatia says, but it, too, has gone mainstream, and more companies are even using it to submit new drug applications (NDAs). Two years ago, the United States Pharmacopeia (USP) published an entire chapter on the method (3), aligned with FDA guidance from 1997 (4). The goal was to standardize testing equipment and procedures.

 testing provides the only practical means of demonstrating shelf life and identifying potential changes in product attributes from unpredicted sources such as raw materials change or manufacturing impacts, explains McNaughton. “As we develop a greater understanding through the characterization of both materials and processes,

	it is likely that the QbD process will allow for a more relaxed approach to standard 

 stability testing,” he says. “However, the development of more sophisticated dosage forms could also result in an increase of more specialized testing until we develop an understanding of their performance characteristics.”

	Whatever directions this work may take in the future, the industry requires a new approach to semisolid dosage form development, and to staffing and training, Bhatia says.

	“FDA asks for specifics on rate of release to control processes and reduced variability batch to batch, requiring a clear understanding of rate of release, risk assessment, CQAs, and the design space,” he adds, noting that his company tends to hire mainly PhDs in formulation, but also more professionals with advanced semisolids experience using rheology and IVRT.

					Unlike homogeneous systems, where final product attributes depend solely on quantitative and qualitative attributes, creams, ointments, and gels are heterogeneous, and depend on additional factors such as temperature, the order in which ingredients are added, shear, packaging conditions, excipient source and grade, and storage time, explains Norman Richardson, global development and technical marketing manager at BASF Pharma Ingredients Services. Tests have been done on simple ointment systems containing two different polyethylene glycols and solvent to better understand issues (1). The best sensory properties were achieved by balancing fluid, gel, and solid states. When the molecular weight of one of the glycols was varied, and the ointment structure studied under cross-polar microscopy, bright regions showed less crystalline areas. Rheological studies then revealed the impact of viscosity and shear thinning. In studies of product stability, the amount of one of the glycols was varied and evaluated with cross-polar microscopy. At 5%, fluid weeping occurred immediately. At 20%, it took seven days. Formulations with 25–30% of the glycol were found to be the most stable.


					1. N. Richardson, Controlling the Physical Properties and Performance of Semisolid Formulations Through Excipient Selection, 

	“Multi-disciplinary teams are a key component of our formulation approach to customer projects, regardless of problem statement, TPP, or finished product presentation,” says McNaughton. Such teams are mainly comprised of fundamental scientists, including materials scientists. They often complement customers’ teams, which are generally applied science-focused, he says.

	While both companies recommend a QbD approach to clients as a matter of course, more pharmaceutical sponsors are proactively demanding that QbD methods be used for their projects. As a result, convergence is being seen between name-brand and generic-drug sponsors, Bhatia says. “NDA clients tend to ask for QbD explicitly, while generic-drug manufacturers may not ask for it at first,” he explains. “Given FDA’s mandate to use question-based review (QbR), however, more companies see they are going to need QbD-type data anyway, so they realize they will need to use newer methods to evaluate their products and processes.”

Modular PAT approaches likely in the future


	The future may see the application of process analytical technology (PAT) more routinely in semisolid formulations development labs. Typically, the approach is used for larger batches and continuous processing, but there may be a need for built-in endpoints (e.g., micelle size changes) that can ensure the best microstructure to ensure rate of release in the lab, says Bhatia. “PAT would allow R&D teams to build in that endpoint,” he says.

	R&D groups are already developing probes and taking samples and measurements at the plant. “Evaluated on a case-by-case basis, PAT would be the logical next step,” Bhatia says. PAT approaches can be used to characterize materials and processes during development and control materials and processes during manufacturing, and can result in a reduction in in-process testing while helping reduce finished product testing, says McNaughton, noting that PAT can be used at various stages in the manufacture of semisolid dosage forms, including raw material identification testing using near infrared (NIR); assay and homogeneity evaluation; and particle-size measurement or performance testing during milling of dry powders or in suspension.

	Currently, he says, these testing approaches are usually best-suited for dedicated product equipment, where they can target specific CQAs required for a particular product. As PAT system designs become more modular, he says, they will likely become standard for many areas within a manufacturing process. While not quite the same approach, similar

	techniques can also be applied to characterize performance attributes during formulation development, he says. Examples would be dissolution rates and concentrations, where solubility-dependent absorption is being improved through formulation development. This would allow more rapid product development, he says, and improve the potential for success through increased in-vitro screening.

	USP plans to launch a collaborative study that will involve equipment vendors, contract laboratories, and pharmaceutical companies that have expertise on the performance tests for semisolid dosage forms. The goal is to gain a better understanding of possible sources of variability when running these tests, and to better describe the test conditions in the USP General Chapter 1724, Semisolid Drug Products-Performance Tests (4), says Margareth R. C. Marques, principal scientific liaison, US Pharmacopeial Convention’s Science Division, Chemical Medicines General Chapters.

	FDA is funding a number of research projects focused on semisolid dosage form measurement and assessment. DPT is working on some research that is funded by FDA under the Generic Drug User Fee Amendment of 2012 (GDUFA). FDA is also funding research by Michael Roberts and his team in Queensland, Australia, that aims to identify and define CQAs and potential failure modes for semisolid products. FDA wants to relate CQAs of drug products to 

	Research will examine the properties of APIs, excipients, and the interaction of product with the skin. The team will compare bioavailability, and use tools such as atomic force microscopy, confocal Raman, and multi-photon microscopy to study the effects of excipients and formulation 


	1. S. Raney, “Considerations Relating to Product Quality Characterization for Topical Semisolid Dosage Forms,” presentation at the AAPS Annual Meeting (Orlando, FL, October, 2015).
	2. M. Lowenborg, “Effect of Process Development on Emulsion Microstructure,” presentation at the AAPS Annual Meeting (Orlando, FL, October, 2015).
	3. V. Shah et al., 

Topical Drug Bioavailability, Bioequivalence and Penetration

, Second Edition, p. 65, (Springer, January 2015).
	4. FDA, 

Guidance for Industry SUPACSS: Nonsterile Semisolid Dosage Forms

:
	When referring to this article, please cite it as A.Shanley, " Optimizing Semisolid Dosage Forms," 

Quality by design, in-vitro release testing, and modern analytical methods are improving understanding and control of these complex formulations.

Optimizing Semisolid Dosage Forms

	For years, observers have criticized the pharmaceutical industry’s inefficiency in turning more of its discoveries into new drugs. To improve success, more companies are moving beyond high-throughput screening to “high content” screening and 3-D methods, bringing the spirit of high-throughput methods to biopharmaceuticals, and areas such as cell therapies. They are also rounding out target-based screening with more of the empirical aspects of old-fashioned phenotypic screening.

	At the same time, “open” partnerships with academic research labs and even with competitors, are pushing back the traditional boundaries of collaborative research.  The goal of these new deals, which, typically do not involve funding or financial arrangements, is sharing the risk and increasing the chances of success.

	In late November, AstraZeneca and Sanofi launched a precedent-setting partnership by agreeing to exchange 210,000 new compounds from their proprietary libraries, expanding each partner’s ability to find more diamonds in the rough.  The companies will share chemical structures and synthetic procedures, and sufficient quantities of compounds to allow them to carry out high-throughput screening for years. “The venture will accelerate our ability to identify unique starting points that could become new medicines for patients,” said Mene Pangalos, executive vice president of innovative medicines and early development at AstraZeneca.  Sanofi’s president of global R&D, Elias Zerhouni also commented, “We recognize that collaboration is the foundation of every medical breakthrough. We are happy to partner with other companies if it will speed the discovery of new life-saving or life-enhancing therapies for patients.”

	This openness represents a major change in mindset from the past, and a new approach to innovation that is slowly becoming part of pharma company cultures. However, a new survey by PA Consulting Group suggests that some companies are still struggling to develop a cohesive strategy and implementation for open innovation. 

	Collaborative partnerships can also extend to technology providers, at a time when pharma’s ability to develop trends and act on new leads has improved, and the assay has become far more powerful than it might have been in the past. As an article by Steve Rees, AstraZeneca’s VP of screening sciences and sample measurements, and his colleagues in the November 20, 2015 issue of 

 suggests, scientists can now start to talk about a world where there might be 

	In an environment where all leading pharmaceutical companies have focused R&D efforts in “hubs” in research-heavy regions of the world, whether Cambridge, U.K. or Cambridge, Mass., AstraZeneca recently launched new partnerships, focused on compound screening and management, that aim to improve the efficiency of its small-molecule-based research efforts. Its efforts will focus on work underway at its AstraZeneca MRC UK Center for Lead Discovery at the Cambridge Biomedical Campus.

	AstraZeneca’s Rees says his company is creating “cutting-edge capabilities for compound management and screening to deliver new ways of working, help reduce costs and transform our ability to identify new w molecules that could become medicines of the future."

	The company plans to screen roughly 2 million chemical structures per target, using advanced robotics and screening, and exploiting potential advantages of ultrasound.  Its new technology partners include 

s, a modular lab automation company that is developing new approaches to high-throughput genotyping, siRNA screening, next-generation sequencing, sample prep, and other functions based on its MicroDock system, which allows different robots or equipment to be connected much faster than possible with traditional systems.  The partnership’s goal is to develop robots that will interact more directly with researchers, to enhance flexibility and mobility.

	AstraZeneca has also launched partnerships with 

, which aim to improve liquid sample storage and handling. With Labcyte, AstraZeneca is working on an acoustic sampling method that would eliminate the need for pipetting and reduce compound volumes by a factor of ten.  The partners believe that the approach will vastly improve the quality of screening data generated from biological assays.

	The drug manufacturer is also working with 

, and has signed a five-year contract that would make it one of the leading users of the company’s data-analysis system for high throughput screening.  This agreement would also allow AstraZeneca's early-stage collaborative research partners to gain access to the platform. The overall impact would significantly reduce the cost of data analysis, the partners say.  Genedata also offers other software tools designed to improve the impact of translational research. 

	Other equipment vendors offering new technologies include 

 with its high content analysis systems such as Phenix, as well as its 

 and “sequencer-on-chip” products developed by companies such as ThermoFisher Scientific, which recently expanded its line of 

	For some pharmaceutical manufacturers today, the question is not whether open collaboration strategies are underway, but how well they are being implemented and managed. 

	The PA Consultancy recently issued results of 

 in which their analysts interviewed 30 R&D directors from leading pharma and healthcare companies to get their perspectives on open innovation efforts in the industry. 

	At this point, for many companies, results suggest that the desire and commitment to open innovation may be there, but questions of risk and reward remain.  Some companies have created dedicated in-house teams focused on open innovation.

	However, a number of respondents noted a lack of company-wide strategy, and an 

 approach to open innovation partnerships, which as caused efforts to stall.  IT and cultural issues also remain an obstacle for some companies, the research suggests. 

	“Gaining access to a range of insights, ideas, capabilities and partners for different sectors is seen as essential….but also a complex, time-consumng task regarding significant resources,” writes Paul Barrett, author of the report.

	For now, for many companies, open innovation is a work in progress, but the factors driving this trend are not going away.  All indicators suggest that this risk-sharing model will continue to take root, and drive, discovery, research and development in the future.

As 3-D screening and lab automation improve lead optimization, open collaborative models are breaking down long-established walls. Will the industry redefine the way it handles R&D?

“A Hit for Every Target” and Changing the Model for Pharma Innovation

	The past five years have been extremely challenging for parenteral pharmaceutical manufacturers. For commodity workhorse products, the aftershocks of manufacturing and quality issues and pricing pressures continue to be felt in operating rooms, neonatal facilities, ambulances, hospitals, and healthcare facilities, particularly in the United States.

	On the large-volume (i.e., 100 mL or higher volume) side, intravenous fluids and compounds used for dialysis, nutritional supplementation, and irrigation have been in short supply due to contamination, manufacturing problems, or product discontinuation. On the small-volume side, supplies of chemotherapy agents and anaesthetics may have emerged from the crisis they faced in 2013, but continue to be tight.

	In 2015, Baxter had to recall some basic large-volume parenterals such as intravenous saline and dextrose, which were found to contain particulates. The same problem had prompted the company and other suppliers, including Hospira and B. Braun, to recall large-volume parenterals in 2013 and 2014 (1). For large-volume products, most of which are heat-sterilized, the major problem continues to be particulates. Small-volume products are vulnerable to both microbial and particulate contamination, which has been traced to glass and packaging materials, and problems such as leaching and sorption (

: Product recalls for parenteral drugs.			

	As experts from the Parenteral Drug Association (PDA) have pointed out (2), particulates are either extrinsic or intrinsic, based on whether they originate from outside or within the project. Recalls called out both types of particulate contamination. Between January 2013 and June 2014, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom found that 11 out of 42 drugs listed on its Drug Alert website were listed because of particulate contamination. Between 2008 and 2012, particulate contamination issues led to 22% of all injectable drug recalls (3).

	Microbial contamination can have several sources. In an interview with 

, consultant Barry Friedman traces many recent cases to inadequate sampling plans and media fill studies. Ideally, media fill studies should be designed to account for worst-case conditions (4), and they should be repeated periodically and adjusted for batch size.

	“With both small-and large-volume parenterals, people often come up with sampling plans based on small lots. They do media fills and get acceptable results, but then lot sizes increase,” Friedman says, “and some of them don’t increase the size of media fills to a comparable degree.”

) <71> guidance in the number of samples taken as the drug moves from Phases I to commercial production, says Friedman. The number of samples required is based on the size, volume, and number of containers to be filled (5). In addition, Friedman notes the need to reduce the potential impact of operators on the process and product. Investing in isolators can often be the best way to go, he notes, as long as the equipment is properly maintained and operators are adequately trained to recognize potential sources of problems. “It’s important to check seals and to examine sample ports and gloves for cracks,” Friedman says.

	Solutions to parenteral manufacturing challenges focus on technology, new materials, and components. A number of companies are using automated systems to reduce the potential for operators to contaminate product. Vetter AG, a contract development and manufacturing organization (CDMO) in Germany, has invested EUR 300 million to more than double its sterile fill and finish and other capacity (6). The expanded sites are expected to become fully operational in 2017. Central to Vetter’s efforts is its “Improved RABS Concept,” developed inhouse, that combines the features of an isolator with those of a restricted access barrier system (RABS). The Improved RABS Concept creates a design with two barriers, including a walk-in isolator to reduce risk. Cleanroom staff work in a Class 10,000 area that can be entered only after proper gowning and passage through air locks. The RABS contains the filling line in an ISO-5 area, providing redundancy so that problems can be detected, contained, and fixed before they affect product (7).

	Vetter’s equipment includes an automated hydrogen peroxide decontamination module, and can reportedly complete a sterilization cycle in three hours. After successful pilots, the company plans to implement this module in all its cleanrooms within the next few years.

	In September 2015, Italian equipment manufacturer Fedegari opened a technology innovation center in Philadelphia that features advanced equipment and aims to facilitate collaboration on development of new processes (8). It also launched a new website, 

, where specialists can share data and collaborate.

	Other companies are developing prefilled technologies to improve ease of use and protect product safety. On November 3rd and 4th, PDA will focus exclusively on this topic with a specialized event, The Universe of Prefilled Syringes and Injection Devices.

	Driving innovations include high heat-resistant and non-leaching plastics, new processes such as blow-fill-seal (BFS), and new configurations for bottles, closures and caps. The CDMO, Catalent, used quality-by-design (QbD) principles to develop its glass-free Advasept vial design to improve BFS systems. The process aims to reduce particulates, the number of process steps, and the need for operator intervention, thereby, reducing contamination risk. By using medical-grade polypropylene, the risk of glass delamination and breakage is eliminated (9).

	West Pharmaceutical Services has developed closure and capping technologies to reduce risk (see 

Addressing Parenteral Manufacturing Challenges

). The company established a center of excellence in Ireland in 2014, devoted to improving new generations of this technology.

	Companies are also investing in new capacity and buying CDMOs that have special expertise wotking with parenterals. Pfizer, for instance, bought Hospira in September 2015 (10), while a number of Indian pharmaceutical companies have acquired contract manufacturing organizations (CMOs) in the US (Table 2). Piramal Enterprises’ Pharma Solutions CMO division bought Kentucky-based Coldstream Labs earlier in 2015 (11).  Coldstream has special expertise in advanced aseptic manufacturing equipment and highly potent API (HPAPI) handling and processing.

	The large-volume parenterals market is fairly staid, with competitive pressures and low profitability. In 2014, some manufacturers withdrew long-established products for financial reasons. Small parenterals, however, are seeing healthy innovation and growth, according to Vivek Sharma, CEO of Piramal Enterprises’ Pharma Solutions, who summarized market developments in CPhI’s 2015 Annual Industry Survey (12).

	Over the past 15 years, Sharma says, 900 new injectable drugs have been approved, and another 2400 are currently in the pipeline. Innovation is being seen in oncology, particularly in the use of targeted delivery systems using liposomes, PEGylation, and depot injections. Prefilled syringes, which reduce safety risks, will experience major growth, Sharma predicts, with biologics accounting for half of the injectables R&D budgets for the top 15 pharmaceutical and biopharma companies.

	Generic injectables, which were a $37-billion market in 2013, should grow to $70 billion in 2020, he says, while the need to reduce risk will drive more pharma companies to outsource parenterals development and manufacturing to CDMOs and CMOs. Currently, injectables outsourcing is a $6-billion business, and Sharma expects it to show 10% annual growth for the next five years.

Industry Perspective on the Medical Risk of Visible Particulates in Injectable Drug Products

, Jan. 5 2015.
	4. M. Akers, “Parenteral Preparation,” Chapter 26 in 

, Ed. Felton, L, Pharmaceutical Press, 2013.
	5. E. Kastango, 

Understanding USP 71 Sterlity Tests and Extending Beyond Use Data

, accessed Oct. 20, 2015.
	6. Vetter, “Vetter Embarks on a 300 Million Euro Investment Strategy for Further Development To its Manufacturing Sites,” Press Release, Sept. 30, 2015, accessed Oct. 22, 2015.
	7. Vetter, “Improved RABS concept combines two proven aseptic processes,” accessed Oct. 22, 2015.
	8. Fedegari, “Official Opening of Fedegari $2.9M State-of-the-Art Technology Centre,” Press Release, 15 Sept. 2015.
	9.  Catalent, Advanced Aseptic Processing, www.catalent.com/index.php/offerings/A-Z-Offerings/advanced-aseptic-processing/.
	10. Pfizer, “Pfizer Completes Acquisition of Hospira,” Press Release, Sept. 3, 2015.
	11. 

Piramal Invests $30.6 Million in Coldstream Acquisition

” Jan. 26, 2015, accessed Oct. 22, 2015.
	12. 

Injectables to Show Double-Digit Growth Through 2020

,” Oct. 14, 2015, accessed Oct. 22, 2015.

: 
	When referring to this article, please cite it as A. Shanley, “Better Days for Parenterals?,” 

Although shortages, quality, and regulatory challenges remain, improved technologies and new investments suggest that the worst may be over.

Better Days for Parenterals?

 spoke with Miriam Beyer, European marketing manager, West Pharmaceutical Services, Inc, Germany about the company’s parenteral business.

: The past few years have seen manufacturing issues as well as severe shortages of both small- and large-volume parenterals, including basic electrolytes and glucose. What are the reasons behind these problems? 
	Beyer: The US Food and Drug Administration has recognized that drug shortages are a critical issue for the healthcare industry. Approximately 37% of shortages are due to manufacturing issues. Other major factors causing drug shortages are issues associated with raw materials (27%) as well as delays and capacity difficulties (27%). Drug shortages can result in problems ranging from the wrong expiration date on the package to particulates in the drug product or sterility issues with injectable drugs (see Table I). 

			Table I: Trends in injectables shortages. Source: FDA			

: What are some best practices for maintaining sterility and avoiding non-compliance for each type of parenteral? 

: Maintaining sterility is vital to avoiding the main causes of drug shortages. Primary packaging plays a pivotal role in ensuring sterility, since it is in direct contact with the drug and poses risk of interaction if the packaging is not compatible with the drug product.

	Manufacturing quality can be affected by several issues, including bacterial endotoxin, particulate matter, and bioburden. One example of the impact is well reflected in an FDA guidance recommending ‘the time between washing, drying (where appropriate), and sterilizing should be minimized because residual moisture on the stoppers can support microbial growth and the generation of endotoxins’ (1). This can cause a challenge if primary packaging components are not available already sterilized. 

	Achieving lowest visible and subvisible particulate levels is currently a hot topic. While associated with cleanliness, it is a key factor today to meet product target profiles and ensure compliance.

	Close collaboration between a pharmaceutical manufacturer and its drug packaging partner is key to ensuring that high quality standards are maintained throughout the manufacturing process. In terms of packaging, it is important that both parties agree upon the validation processes that will be used during manufacturing in order to establish--and adhere to--quality specifications for primary packaging components.

	Validation processes can have significant benefits for drug manufacturing. For instance, a state-of-the-art validated washing process must reduce endotoxin content by at least 99.9% (a 3-log reduction).

	Sterilization processes are generally also validated to meet sterility assurance levels. Furthermore, a sterilization process validation is maintained through appropriate change control and revalidation/periodic review programs, all of which comply with applicable cGMP requirements.

	There are, however, additional variables that play a role in meeting best practices. Product configuration and formulation, for instance, may have an impact on quality, as do bioburden resistance and weight, along with bag material. It is also important to note that the packaging of the actual components in question should also be evaluated to determine whether a component/packaging format meets the necessary regulatory specifications.

: What role can packaging play in preventing these problems?

: Packaging plays a significant role in maintaining the quality of a drug product and preventing impurities. To minimize interaction with the drug, it is essential that the packaging components’ design and formulation meet the containment requirements mandated by the physical and chemical attributes of the drug. Different drug products have different packaging needs, and what works for one product might not necessarily be the best choice for another. Selecting the right closure for a particular drug product is crucial to ensuring that the drug reaches the patient safely and with the intended therapeutic effect.

	To ensure the perfect match between a drug and its packaging, it is important for pharmaceutical manufacturers to work closely with experienced packaging partners from the early stages of drug development through production. Having a reliable packaging partner allows pharmaceutical companies to focus on their core competencies: bringing valuable drug products to the marketplace. 

: Can you please describe your company’s technology, its history, how it was developed, and how it is being applied?

: West was founded in 1923. Its early efforts pioneered the safe distribution of penicillin, insulin, and other life-saving drugs. Today, approximately 110 million West components and devices are used around the world every day. 

	West has a long-standing partnership with Japan’s Daikyo Seiko, a manufacturer of high-quality pharmaceutical delivery system components. Daikyo has built a strong reputation for materials and manufacturing innovation. Our partnership with Daikyo has enabled us to develop products that help customers mitigate drug product development risks and enhance patient safety. These products include: FluroTec coated serum and lyophilization stoppers, syringe plungers, and tip caps, Daikyo Crystal Zenith vials and syringe barrels, and ready-to-sterilize (RSV) components. 

	We recently launched Daikyo ready-to-use/validated (RUV) components. We believe these components meet the highest sterilization and quality standards, helping pharmaceutical manufacturers comply with rigorous aseptic processing requirements while reducing operational and capital resources.

: Can you please elaborate on any innovative science/methods used and results achieved so far?

: Daikyo RSV and RUV components are manufactured using clean, high-quality elastomer formulations, and then washed and sterilized as needed to help reduce the manufacturing footprint, streamline processes, outsource risks around component preparation, and eliminate bioburden.

	Both Daikyo RSV and RUV components are prepared to a tight particulate specification and fully visually-inspected. The new Daikyo RUV offering, which takes RSV components and steam-sterilizes them in a validated process, offers pharmaceutical manufacturers the opportunity to focus on the fill-finish with a high-quality, ready-to-use component.

 Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practice 


	When referring to this article, please cite it as A. Shanley, “Addressing Parenteral Manufacturing Challenges,” 

Miriam Beyer, European marketing manager, West Pharmaceutical Services, describes causes of recent parenteral drug shortages.

Addressing Parenteral Manufacturing Challenges

	For the past few years, pharmaceutical outsourcing has been moving from a tactical, transactional business to a strategic partnership model. Discussions at the 2015 ChemOutsourcing Conference in September drove home this point. 

	Breaking the staid pharma event mold, the conference is held from September 17 - 20, the last days of summer, at Oceanside Resort, a hotel in Long Branch, N.J., complete with potted palm trees. Locals report that film studios often use it as a Caribbean standin for movies and TV shows, including The Sopranos.

	The program aims to encourage networking and interactions “in the moment,” by featuring interactive panel discussions, rather than individual powerpoint presentations.  

	For several years, the conference has included the equivalent of speed-dating, three-minute supplier “speed meetings” between prospective business partners.  Services and technology vendors not only exhibit but give presentations on their product lines and new focus. This year, it featured a beach bonfire, karaoke night, and simulated rodeo with a mechanical bull.

	Attendees say the event’s unusual program and proximity to their business have made it an annual ritual. This year's conference featured a wide range of discussions on topics ranging from scouting new API synthesis routes, to Quality by Design, to contract partner oversight and global industry developments.

	One highlight was “Both Sides of the Fence,” a panel discussion offering insights from experts who have worked at both pharmaceutical company sponsors and contract research, development and manufacturing organizations (CROs, CDMOs and CMOs. 

	Panelists agreed that today, 80% of pharma's CRO, CDMO and CMO business is now built around strategic partnerships.  Transactional approaches currently account for about 20% of business, but the move to partnerships continues.  

	The partnership approach tends to get better results for both sponsor and partner, panelists said. “Those companies that do not engage often don’t get the full value of what a contract partner can bring to the table.  Those projects can run into difficulties when customers don’t communicate or engage sufficiently,” said Ray Forslund, senior director of project management at Laurus Synthesis, Inc.

	One key issue the panelists brought up was the need to improve project management and handoffs from sponsor to contract partner.   “Project managers can muddy the waters if they are the single point of contact,” he noted. “We get out of chemists’ way.”  The goal, he said, is to keep them in the lab so that they don’t have to respond to every small issue.  “Let chemists focus on chemistry,” he said, noting that this is what he asked for when he was working for a pharmaceutical company. Laurus uses teleconferences and video conferencing to ensure communication with sponsors.

	Project management is also focus a key focus for Kalexsyn, a CRO based in Michigan, which bought Pharmacia facilities in Kalamazoo.  As Stuart Garmon, director of business development, explained, there are no project managers, per se, and the chief science officer works as overall project manager overseeing all projects.  “We focus on direct, scientist-to-scientist interaction,” he said, with a focus on speed and two-way communication.  Weekly teleconferences and reports keep both sides connected, he noted.

	Any discussion of outsourcing would have to address offshoring, and attendees asked panelists about geographical strategies.  “We see that companies are now more open to doing early R&D work in China now,” said Mark Herbert, senior director of business development at WuXi AppTec.  Regional focus is becoming less critical, he said, as local companies build up quality reputations.  “They are paving the way to an idea that geography doesn’t matter, but, rather, the quality of work.”  Generally, he says, as company size increases, so does its comfort with outsourcing overseas.

	Tech transfer is a challenge, for sponsors and contract partners alike.  “Every client is unique and invidual,” said Laurus’ Forslund.  “You want to walk in their footprints and understand what they want.  Often, you’re not transferring with them but with one of their business partners, so three-way communication is crucial, as well as understanding and ensuring responsiveness.”

	Responding to a question on whether customers demand a quality by design (QbD) approach, panelists suggested that the idea is gaining adherents but isn’t a pre-requisite yet. “It’s not yet fully adopted by industry, and there have been hurdles in getting regulatory authorities to agree on design space issues, so clients may not all be interested in investing in the time and resources required. However, we focus on the essential requirements:  critical quality attributes and the formal design space,” said Kalexsyn’s Garmon. 

	The idea of QbD has been brought earlier into the value chain, to a point where “people are doing it but may not know it,” said Simon Tyler, commercial director of UK-based CatSci Ltd.  “Within the past five to ten years it has become a mindset for more people in the industry, and just the way people think.”  

	Design of Experiments (DOE) is  clearly becoming much more important, the panelists said.“It is never too early or late to use DOE,” said CatSci’s Tyler.  “Any time you come to manufacturing positions you want to have the best process you can have at the time.  Good chemistry and good design are vitally important.”

	One audience member asked what panelists had learned now that they wished they might have applied when they were on “the other side.”  Each of them stressed the value that working for a pharmaceutical company has for anyone in contract services. “You understand the decisionmaking process in pharma, what key stakeholders are responsible for, how key purchases are authorized, and you oversee large numbers of CMOs and CROs and know what they did well and didn’t do well.  It brings insight and knowledge to the table,” said Laurus’ Forslund.

	They agreed that communication and dialogue are vital to ensuring that the right questions are asked, and getting the best information.  Sponsor companies should make their contract partners feel more like part of their team, said Kalexsyn’s Garmon.  “Let them know the importance of the work they are doing for you and your company,” he said, but then, later, he suggested, “Loop back and let them see the impact of their work.”

 asked conference director Mark Alexay about the Chemoutsourcing event.  Alexay, who has graduate degrees in business and international affairs, worked for Pfizer for five years in the early 1990s.  After living and working in Colombia for two years, he worked on conference development for SRI for about 10 years,  before coming up with the idea of a new conference model. 

	He saw the need to develop agendas based on broader business issues.  Although most attendees are older, senior managers, Alexay says that younger entrepreneurs have a growing presence. Pharma’s biggest challenge today is innovation, Alexay says.  “It’s not 1985 anymore, and a lot of the low-hanging fruit has been picked.  The question now is how do you discover the next wave of blockbusters?”

	In general, this year’s event featured interesting discussions in a different atmosphere.  It will be interesting to see what topics are addressed, and how, next year. 

Closing the summer of 2015, the ChemOutsourcing conference examined contract services from both a sponsor’s and a CMO or CRO’s perspective