Change can be difficult. Whether an individual is trying to break an old habit, an organization is restructuring the way it does business, or society is adapting to technological and economic trends, the process is never easy. Discussions at two recent conferences illustrate emerging healthcare trends that could change the way pharmaceutical and biopharmaceutical companies do business. 

Elias Zerhouni, president, global R&D, Sanofi, outlined four areas—patient needs, regulations, payer-driven markets, and science—as key challenges for drug research and development during a keynote address at an innovation and funding summit hosted by BioNJ's Diagnostics & Personalized Medicine Initiative. 

Understanding patient needs and scientific approaches are closely tied. Early successes in animal models and genomics gave the drug research community a false picture and those findings did not translate to humans, Zerhouni said. He urged a shift in research strategy to one that looks first at the patient population and is based on a better understanding of disease biology.  

This new approach will require a change in the way drug companies conduct R&D business. Closed R&D campuses are a thing of the past in other industries, but pharma has resisted, Zerhouni said. The industry needs to evolve to an open R&D system.  

Traditional business, medical, and personal-health practices also face upheaval; event speakers identified examples in medical diagnostics. New diagnostic devices based on smartphone technology can monitor heart rates, blood pressure, blood sugar, and more. While many of these devices and applications are still unproven, the appeal for lower-cost diagnostic technologies is strong in emerging nations.  

US firms are developing technology that the US market does not want to adopt due to existing payer models, entrenched practices, and regulatory hurdles, said G. Steven Burrill, CEO of Burrill & Company at the BioNJ event. These technologies may allow emerging nations to "leap-frog" established countries and implement better healthcare systems, said Frank Prendergast, MD, PhD, professor of Biochemistry & Molecular Biology and Professor of Molecular Pharmacology & Experimental Therapeutics, The Mayo Clinic. 

While technology may allow a patient to turn to their smartphone for routine diagnostics, the high cost of medical care may force patients and doctors to use such technology. In 2010, the US spent 17.6% of its gross domestic product on healthcare. The average per-person-cost of $8,233 per year is more than 2.5 times more than most developed nations, and by far the most in the world, according to the Organization for Economic Co-operation and Development. For the medical establishment, including drug companies, the price people will pay for medical care is a deciding factor in how products are produced or if the products are produced at all.  

In mid-June, the International Society of Pharmaceutical Engineers (ISPE) released results of a survey on drug shortages, which examined manufacturing and quality issues that contributed to the recent spike in drug shortages. However, the survey did not address economic or business choices that may have had an impact on the shortages. Participants at the ISPE/FDA conference, 

Ensuring a Reliable Supply of Quality Medicines

, where the study was released, noted financial factors often drive corporate decisions about which products should be manufactured.  

New drugs are expensive to develop and produce. Some prove too expensive to be consumed. Others are too cheap to be manufactured for a profit. Change to achieve a patient-centered solution that still meets business goals will be difficult, but necessary. 

Articles

From the Editor

Pharma and biotech companies, with the rest of the healthcare industry, must face change.

The Pains of Change

To gain perspective on the implementation of quality by design (QbD) and process analytical technology (PAT) in biopharmaceutical processing, 

 spoke with Clinton Weber, associate director of bioprocess sciences, CMC Biologics Organization; Henrik Johanning, director QAtor; Nathan L. McKnight, PhD, principal engineer, late stage cell culture, BioProcess Development, Genentech; Anurag Rathore, professor, Indian Institute of Technology (IIT) Delhi; Frederic Girard, CEO, Spinnovation Biologics; Thomas J. Vanden Boom, PhD, vice-president, global biologics research, development and manufacturing operations, Hospira. 

PHOTO CREDIT: IMAGE SOURCE/GETTY IMAGES/DAN WARD			

 In implementing QbD, what would you identify as the critical quality attributes (CQAs) in a typical upstream bioprocess using cell-culture? 			

Generally, upstream critical quality attributes for a cell-culture manufacturing process are limited to the adventitious agent and bioburden testing of the cell-culture harvest material. This also holds for biosimilar products. 

CQAs are defined for the product, not identified as part of upstream or downstream portions of the manufacturing process. There are key performance indicators (KPIs) that are defined for upstream steps, including culture productivity (i.e., titer), cell growth, and viability. While KPIs may be correlated with CQA results, KPIs are not themselves product quality attributes. However, particular CQAs may be generated or modified during specific upstream or downstream steps. Protein glycosylation, for example, is generally determined during cell culture and minimally altered in downstream unit operations (at least for uncharged glycosylation species). Using this definition of CQAs, those CQAs observed to be potentially impacted during cell-culture steps include product attributes contained within the protein glycan distribution (e.g., afucosylated glycan), charge-variant distribution (e.g., glycated, deamidated forms), and to a lesser extent, molecular-size distribution (e.g., dimer or aggregate forms).    

It should be noted that knowledge of an association between cell-culture steps with certain product quality attributes is not a result of implementing a QbD approach but, rather, a result of knowledge gained through the basic scientific and engineering endeavors that should be elements of developing a bioprocess. 

 In the past, most CQAs could not be measured directly in the fermenter broth due to the interference from the numerous components present in the broth. As a result of major advancements in analytical science, direct measurements of CQAs are performed in bioprocessing today. These would be product-quality related parameters, including host-cell impurities (e.g., host-cell proteins, DNA), process-related (e.g., Protein A leachate), and product related (e.g., aggregate, basic variants, acidic variants, and glycoxylation pattern). Some of these CQAs, such as glycoxylation pattern for monoclonal antibody (mAb) products, are primarily impacted by the upstream process and are particularly important to monitor during process development.  

 The goal of a QbD approach is to develop additional knowledge of the impact of upstream process unit operation performance on the final purified product quality. The most likely or desired outcome is to develop a quantifiable correlation between upstream process outputs, such as cell viability or viable cell density (VCD), and product attributes, such as glycosylation. This approach can lead in the determination of CQAs for the cell production bioreactor unit operation. Upstream outputs classified as CQAs have proven to be controversial, because the bioreactor is so far upstream from the final product. However, if a strong correlation can be established between VCD/viability and other CQAs or final product specifications, this can be an appropriate approach. 

 The underlying concept for QbD of an upstream bioprocess is that the desired quality of the biological or biopharmaceutical product is assured every time. CQAs vary for each cell line depending on the nature of the bioprocess, with typical critical qualities such as metabolites and contaminants. CQAs usually include properties that affect product quality and eventually overall performance of the bioprocess. CQAs are typically also release tests, although they don't have to be as there are no real release tests as such in upstream processing.  

The variability and complexities associated with the upstream biological process make QbD a complex process, one that relies on defining operation specific critical process parameters (CPPs). CPPs are those likely to impact on the quality of a product or intermediate. For biological products, process control can be difficult to define and implement. O

 pressure, catalyst concentration, and pH are examples of critical parameters. It is important to note that mAbs are currently the leading area of biopharmaceutical research. One of the key parameters to monitor in the implementation of QbD in mAb production is the glycosylation process during formulation. Glycosylation is one of the overriding contributors to mAb heterogeneity and has significant implications for the function of the antibody 

 and immunogenicity. This means that glycosylation has been isolated as a critical parameter to follow during mAb manufacture. QbD for mAb development with specific glycosylation patterns enables researchers to optimize manufacturing and clinical efficiency. 

 The QbD concept works its way back so to speak from the patient to product to process and ultimately to the facility. A risk assessment will outline the risk profile in and between each area. 

The starting point for the risk assessment is R&D, which upstream has determined the CQAs on the product. CQAs are often product specifications, including eventual GMP requirements (if GMP is used as part of the biopharmaceutical process, which is often the case in multinational pharma companies in order to ensure a fast-track initiative from R&D to license to operate and market). The risk assessment includes a review and assessment of the products CQAs when manufactured on specific equipment. 

 In implementing QbD, what would you identify as the critical process parameters (CPPs) in a typical upstream bioprocess using cell culture?  

 Among cell-culture parameters, culture pH is typically the most difficult to control relative to its impact on cell-culture performance and product quality. This is generally the case for both mAbs and other products. 

Common CQAs in an upstream bioprocess (i.e., bio formulation process) using cell-culture include sterility and bioactivity. 

Typical CPPs for a fermentation step would be pH, sparge rate, agitation rate, and temperature. These are typically easy to control. Issues arise when one goes to volumes greater than 1000 L and when it increasingly becomes more difficult to strip off the CO

 generated by the cells and in ensuring uniform supply of O

 and other critical nutrients to the cells. Another set of challenges comes from raw materials that are complex and not well characterized (such as yeastolates) as these can result in significant variation in the CQAs from lot to lot. For mAbs, besides the afore-mentioned factors, concentration of critical nutrients has been known to affect the glycoxylation pattern of the product, thereby impacting product efficacy.  

 Parameters such as temperature, pH, osmolality, and dissolved oxygen have the potential to impact the CQAs of mAbs and other mammalian cell-culture derived products. However, with current bioreactor engineering controls, these parameters may be tightly and confidently controlled within the design space of the manufacturing process permitting these parameters to be downgraded from a CPP to a key process parameter (or other lower parameter designation used by different drug sponsors).   

For an upstream process, the process of expanding the cells is the primary purpose until the culture goes into the production bioreactor. Because the majority of product produced is in the production bioreactor, the expansion process is considered to have minimal impact on the final product. Additionally, most products have shown the ability to recover from suboptimal conditions during expansion without serious product quality impact. Therefore, for a typical upstream process, CPPs are identified at the production bioreactor stage. CPPs for the production bioreactor may include seed density, temperature, and process duration. Initial seed density can impact the overall growth profile and viability. Temperature is critical in maintaining viability and may impact the quality of product being produced by the cells. Process duration will impact the viability of the culture at harvest, which can be tied to product quality. 

Among the most difficult parameters to control in an upstream process is CO

 concentration. The difficulty of controlling this parameter depends on the complexity of the aeration control strategy and availability of dissolved CO

 probes. Though there can be typically broad ranges of acceptable CO

 concentrations can impact the product quality. A balance needs to be maintained between lowering CO

 and maintaining pH at a set point. Furthermore, these conclusions seem to be supportive of most cell-culture processes, not just mAb production. 

 What measurement tools are typically used to measure CPPs and the resultant process inputs and outputs, including PAT tools, in an upstream process? 

 CPPs are a subset of the environmental and batch-recipe settings (e.g., timing of feeds, culture duration) used to perform the process. Temperature and pH, which are commonly CPPs, are measured using on-line probes (a technology that is officially PAT, but far preceding the 'PAT initiative').  Timing of events and generation of basal and feed media are controlled with traditional process controls and standard operating procedures. Online cell-density measurement is an area of active development as is online nutrient measurement technology to enable advanced feeding or timing strategies. 

 Assuming this question is referring to the monitoring and control of CPPs and not the tools used to actually establish CPPs, the majority of upstream CPPs are monitored online and offline. Online instruments such as CO

 probes are verified against offline instruments to ensure that the conditions within the bioreactor have not caused the probes to 'drift.' Adjustments are made to the online instruments if drift is detected. Other outputs such as cell count and viability are measured strictly offline on a routine basis. PAT tools can be effective, though not necessary, to monitor parameters such as temperature and pH, but are not necessarily value-added for culture health outputs such as viable cell density, viability, or doubling time. 

 For upstream process, tools that researchers have used include:  					

Surface plasmon resonance (to assess product concentration and affinity)

High-performance liquid chromatography (HPLC) (to assess product concentration and structure)

Capillary electrophoresis (to assess product concentration and structure)

Dielectric spectroscopy (to determine biomass)

 microscopy (to characterize cell population)

Flow cytometry (to characterize cell population)

Metal oxide field effect transistor (to sense biological contaminants)

Infrared spectroscopy (to detect media components)

 2D fluorometry (to detect media components and metabolic end products)

Raman spectroscopy (to detect media components and metabolic end products)

UV spectroscopy (to measure homogenate components)

Mass spectroscopy (to detect metabolic end products)

HPLC (to detect media components and metabolic end products). 

Not all of these are amenable for online applications, but together they capture various attributes of upstream processing.  

Given the inherent variability in biologics manufacturing, how does QbD improve process understanding and control? What are the limitations of QbD in upstream bioprocessing? 

 The inherent variability in biologics manufacturing, and the general inability to define mechanistic equations (i.e., mechanistic process models versus empirical process models), limits the ability to precisely predict the outcome of specific runs at manufacturing scale. Application of multivariate, statistically designed experiments, however, is still valuable for identifying CPPs, defining parameter acceptable ranges, and understanding the variability that may be expected from the manufacturing-scale process. Biological variability likely limits the ability to control even the best understood process solely through control of process parameters—the need for some degree of product testing will be necessary to control for inherent variability. 

Implementation of QbD necessitates creation of information relating the process to the product and the product to the clinic. It is this understanding that lays the foundation for appropriate process control. A major limitation that I see with respect to implementation of QbD in upstream processing is the complexity of the sample medium due to the presence of the large variety of process related, host-cell related, and product-related impurities. Another limitation is the fact that the fermentation process is so complex. With the aforementioned, tools it is easy to monitor different process and product attributes. However, many different alterations in operating conditions and raw-material attributes can lead to similar changes in the process outputs and hence monitoring is merely the first and simpler step. The difficulty comes in diagnosing the root cause of variability and effectively dealing with it in real time.   

 Precisely because QbD is a scientific, risk-based, and proactive approach to biologics development, one can use it to define the ideal characteristics of a product to achieve CQAs relating directly to its clinical performance. On the basis of this information, product formulation and processes are designed within a specific framework to ensure the product meets these attributes. Variability within this framework can be monitored allowing scrutiny of the process to assure consistent product quality. However, it is important to consider the CQAs in a matrix since one knows that a biological system has the capability to compensate or adjust its metabolic pathway. 

 The enhanced design-space knowledge derived from the systematic risk assessments and design of experiment (DOE) work completed in association with a QbD approach offers the potential to significantly improve the level of process control for mammalian cell culture-derived products. A key factor to realize the full benefit of QbD is the establishment of robust small-scale model(s) of the upstream manufacturing process. This may be more challenging for certain products resulting in limitations to fully using QbD for upstream bioprocessing steps for these products. In the case of biosimilar products, the bioanalytical characterization of the originator product provides another useful input to determine the significance of product and process variability.    

 A QbD approach can lead to an early focus and understanding of what influences the CQAs. While scale-down models combined with screening and design space DOEs can be used to understand cell expansion and the cell-production bioreactor processes, full purification can be time consuming and costly for full characterization of the upstream process. In addition, as the downstream process is characterized, optimizations/changes in the downstream process can lead to the need to repeat upstream characterization efforts. Hence, the sooner a correlation between the main upstream outputs (such as viability) and primary product quality attributes (such as glycosylation) can be established, bench-scale work can be minimized. 

In implementing QbD, what would you identify as the CQAs in a typical downstream bioprocess in which the product was produced using cell culture? 			

 This is probably the most difficult question to answer. We have found the CQAs for downstream are very product dependent. Glycosylation and sialylation are definitely two outputs that require product and product quality understanding and are the most common across different cell-culture processes. After that, variation in the product profile begins to manifest itself too much, preventing universal CQAs to be established. 

 Some CQAs are generated in, or substantially changed by, certain downstream unit operations. Size variants or charge variants, for example, may be generated during hold times, and product quality attributes such as host-cell proteins and size variants are typically reduced through the purification process and controlled to an acceptable level by consistent purification process performance. 

 The downstream process attributes would be similar to those mentioned earlier for upstream processing. These include process-related impurities (e.g., antifoam, additives added during the processing, Protein A leachate), host-cell impurities (e.g., host-cell proteins), and product-related impurities (e.g., aggregate, basic variants, acidic variants, glycoxylation pattern). The big difference is that the ease of measurement of these attributes improves significantly in downstream processing as the samples are relatively cleaner. 

Features

Industry experts discuss the implementation of QbD and PAT tools in biopharmaceutical manufacturing.

QbD and PAT in Upstream and Downstream Processing

Healthcare professionals, NGOs and politicians have been stepping up the pressure for regulatory action on the worsening problem of medicine shortages across Europe. However, drawing up and implementing regulations at both national and EU levels appear to be far more convoluted than expected. Not only are there differences among the EU governments about what needs to be done, but such differences also exist within the industry and the pharmaceutical supply chain.  

Although it is generally acknowledged that drug shortages are causing problems to health services throughout Europe, some groups tend to be more outspoken about the issue than others. At a meeting at the European Parliament in Brussels in mid-May, three European pharmacists associations called for urgent action by governments and national regulators to tackle shortages. "With evidence strongly suggesting the problem is becoming worse, doing nothing is no longer an option," said Roberto Frontini, president of the European Association of Hospital Pharmacists (EAHP).  

A recent pan-European survey by the EAHP revealed that 99% of hospital pharmacists had experienced medicine shortages in the past year while 63% reported them to be a weekly, and sometimes daily, occurrence. Among the causes of shortages listed by the pharmacists were fewer manufacturing sites in Europe, globalization and extended supply lines due to outsourcing and low levels of contingency stocks because of financial pressures stemming from low generic-drug prices. The Pharmacy Group of the European Union (PGEU), representing more than 400,000 community pharmacists, has suggested that manufacturers and wholesalers be legally obliged to maintain minimum national stocks of certain medicines. 

		Demands for tougher regulatory measures are likely to intensify if July's implementation of tighter controls on GMP standards of imported APIs triggers more shortages, as is being predicted. The controls, targeting APIs produced mainly in Asia, are being introduced under the EU's new Falsified Medicines Directive (FMD), which stipulates that from July 2, all imported APIs must be accompanied by a written confirmation from the relevant regulatory authority of the exporting country that they comply with GMP standards equivalent to those in force in the EU. "The otherwise welcome FMD may unintentionally increase the experience of medicines shortages because of the new conditions placed on the import of APIs," said Luigi Martini, immediate past president of the European Industrial Pharmacists Group (EIPG) at the May European Parliament meeting. 			

Partly in response to worries about the possible impact of the stricter checks on API imports, the European Medicines Agency (EMA) set out late last year a series of proposed steps for dealing with shortages caused by manufacturing difficulties, including GMP compliance. Some of these initiatives have already been carried out or are close to being completed, including the drawing up of a catalogue of centrally approved products (CAPs) authorised by EMA, which have previously been subject to shortages. A similar exercise is being conducted at the EU state level with nationally authorized drugs (non-CAPs).  

On the issue of new controls on imported APIs, EMA is currently establishing a list of non-EU countries for which the requirement of written confirmation from the national regulatory authority on equivalent GMP standards can be waived. In the absence of a written confirmation from an API exporter, the EU may have to perform its own GMP inspections of the exporter's production site. 

"To avoid potential shortages of medicines, the agency has developed a risk-ranking methodology for centrally authorized medicines, which can be used to prioritize inspections of active-substance manufacturers in third countries," an EMA official told 

. "This methodology is applicable to centralized products and has been shared with member states that can use it or adapt it to their specific situations."  

On other specific measures for dealing with medicine shortages, EMA has been trying to thrash out a consensus among a broad range of stakeholders. On June 5, the agency held a meeting with representatives of healthcare professionals and patients on what should be the priorities. Sharp divisions on what needs to be done have been already evident within many of the EU's 28 member states on aspects like categorizing essential medicines and what should be the responsibilities of manufacturers and wholesalers in providing information on medicines availability. These differences are now beginning to appear at the EU level, particularly on issues such as what are essential medicines. 

In Germany, doctors' organizations have been urging the use of the category of "short-term indispensible" medicines for which there is no equivalent alternative. "We are not supporting the concepts of 'essential' or 'short-term indispensible' medicines being implemented on a national or on an EU level," says Dr Siegfried Throm, R&D and innovation director at the German Association of Research-based Pharmaceutical Companies (VfA). The concept cannot be applied to many patients with illnesses that cannot be treated "by a limited set of drugs," Throm stated to 

Germany is among the several EU countries that have national working groups of representatives of industry, wholesalers, pharmacists and other supply-chain players who share voluntary information on shortages. In some states, healthcare professionals are suggesting that the provision of information should be made mandatory. Under EU legislation, manufacturers have to provide information on plant closures and temporary shutdowns as part of their legal responsibility to ensure adequate supplies of certain pharmaceuticals. Some stakeholders, however, want a requirement for a broader range of information, which might be extended to information on difficulties with raw-material supplies. 

"There is an overall lack of information for supply-chain actors about the causes and possible duration of shortages," says John Chave, PGEU secretary general. "It is time for manufacturers, wholesalers and pharmacists to get together with the regulators in Europe and at the very least try to improve the flow of information," Chave told 

Some manufacturer groups are emphasizing that the main reasons for shortages are not so much because of manufacturing failures but due to inadequacies in the supply chain, especially at the wholesaling and retailing stages. They point to the variety of reimbursement systems among EU states that has led to big differences in medicine prices between countries. These disparities are heightened by fluctuations in exchange rates between the eurozone of 17 countries and other EU states with their own currencies, such as the pound in the UK, which is one of the few large EU pharmaceutical markets outside the euro area. 

These gaps between national prices has triggered a considerable amount of parallel trading in medicines with products manufactured to serve the needs of a country with low prices being diverted by wholesalers, many of them pharmacists with small short-line wholesaling businesses, to EU countries with higher prices. In the UK, an EU country with a high level of parallel trading, an estimated 10–15% of the country's 12,500 community pharmacists are using wholesale dealer licences (WDL) to export medicines to other EU states. 

"Parallel trading by pharmacists with wholesale dealer licences is the main cause of current shortages of branded medicines in the UK, not manufacturing problems," explains Sam Ogden, a supply-chain specialist at the Association of the British Pharmaceutical Industry (ABPI), London, to 

"UK medicine prices are, at the moment, among the lowest in Europe so there is a big incentive for pharmacist wholesalers to divert medicines supplied to them for dispensing purposes to other European countries with higher prices."			

Parallel trading is legal in the EU because the right to benefit from the free movement of goods underpins the Union's single internal market. As a result of it, the ABPI claims that manufacturers oversupply the UK market with their branded medicines by an average of 120–130%. Ironically, this excess supports the case put forward by the parallel traders that their activities are helping channel surplus supplies to countries with scarcities of medicines. Disagreement between different groups about issues like parallel trading merely highlights the complexities of sorting out the EU's problems with medicine shortages.

 is a freelance writer based in Essex, UK, 

European Beat

European governments are under pressure to take regulatory action, but solving the problem of medicine shortages is not as straightforward as it seems.

EU Battles Medicine Shortages

Outsourcing has become an important business strategy for biopharmaceutical companies looking to bring products to market at a reduced cost and lower need for capital investment. Many biopharmaceutical  companies gain a competitive edge from  outsourcing research, clinical trials, manufacturing, and packaging. Training is another area that can yield big returns when outsourced.  For managers who must show measurable  results from their training dollars while also meeting day-to-day business demands,  outsourcing can be especially appealing. However, there are some key attributes that a training partner must have. 

A FORMAL TRAINING ORGANIZATION  AND SUBJECT MATTER EXPERT

While in-house training programs may  capitalize on how well a company knows itself, in-house development and execution of  training programs can drain resources from revenue generating activities, divert attention from necessary day-to-day operations, reinforce institutional bad habits, and remain behind the curve of industry-wide best  practices. The right training partner—a formal  training organization and subject matter expert—is exclusively focused on industry-specific training. Such organizations carry experience  and knowledge from across the industry. These trainers can quickly hone in on a company's needs and they require much less time to ramp-up. 			

If an outside training organization or consultant is needed, it is important to properly vet the organization and make sure that their qualifications meet the desired needs. Perform the basic checks and common practices such as: 					

Determine and apply a set of criteria for selecting the best consultant (e.g., industry  knowledge, experience with similar  projects, subject matter expertise, etc.).

Provide clear program needs and guidelines—based on needs analysis and initial design specification—when requesting a proposal.

Solicit proposals from more than one  consultant for comparison sake.

Check references—especially if this is the first time working with a consultant.

TRAINING PROFESSIONALS THAT TAKE  STOCK OF, AND BUILD UPON, CURRENT TALENT

			In today's business environment, talent quality  matters more than ever to pharmaceutical,  biotech, and medical-device companies. Competitors can always match technologies, processes, and tools, but the creative power of a company's human resources is what will set it apart. An effective training strategy  recognizes this fact and starts by taking stock of current talent and then performing a  strategic assessment from both an organizational and individual standpoint. It is important to always know where a company's capabilities stand and how they need to grow to successfully meet future demands (see 

Figure 1: Successful training organizations look to develop effective and comprehensive training programs by way of key building blocks. One such block, an analysis of current capabilities, is an important foundation for optimizing a company’s success. (FIGURE 1 IS COURTESY OF THE AUTHOR)							

AN ORGANIZATION CERTIFIED AND FOCUSED UPON RECOGNIZED PROJECT MANAGEMENT PRINCIPLES

Developing effective project  management skills is crucial for globally competitive pharmaceutical, biotech, and medical-device companies where every advantage counts and project lifecycles are long. Managing a project-based business is fundamentally different from managing a traditional functional organization. It requires careful rethinking of roles, skills, organizational systems, tools, and metrics to support project performance. Many of today's successful organizations require the type of training that is deeply rooted in project management methodology. Training organizations that engage life-sciences industry experts and certified project management professionals (e.g., PMP or PRINCE2) to develop solutions based on acknowledged standards (such as PMI's PMBOK) and proven industry practices can ignite focused performance improvements with significant bottom-line impact. 			

The benefits of a standardized project management methodology and certification include: 					

An increased attention towards developing the right project management competencies at both organizational and  individual levels.

Formation of global project work environments that are populated with people who speak a common language in project management.

Improved return on investment from projects that are based on more predictable, consistent delivery. 

AN ORGANIZATION THAT  POSSESSES STATE-OF-THE-ART TRAINING RESOURCES AND DEDICATED SERVICES

	Solid training organizations offer extensive tools of the trade that effectively address a company's complex and varied training needs. From virtual training and self-study modules to custom curriculum and consultative services, a qualified  training partner has right-fitted  offerings for pharmaceutical,  biotech, and medical-device  companies. What's more, training organizations bring with them tried an tested educational materials,  broad industry knowledge, the  latest training technologies, and dedicated staff and services.  			

Consider whether the proposed training organization has:  					

Resources to provide the same training material in a variety of media and delivery methods, such as online or classroom-based.

Expertise and willingness to customize training materials to suit an organization's specific needs.

In-depth understanding of adult learning principles and how to address them in the training delivery.

Instructors who are also skilled facilitators—able to manage small to large groups as well as conflict situations.

A PARTNER FOCUSED ON LONG-TERM, CONTINUOUS IMPROVEMENT

Having an agile organization that responds quickly to the ever-changing healthcare market to produce innovative products to meet customer needs is the result of high organizational effectiveness. A highly effective and efficient organization achieves the outcomes it intends to produce,  specifically focusing on structure  and human dynamics as two  factors strongly affecting outcome.  A long-term, productive relationship with the right training partner—one that focuses on  regular assessment and continuous  improvement—can assure that a company will achieve and  maintain high organizational effectiveness. 			

Some of the ways an effective training organization will ensure continuous improvement include: 					

Being up-to-date on industry practices, standards, and regulations.

Using actual client projects in class exercises to effectively illustrate concepts and allow students to hit the ground running after training.

Providing follow-up support to students to ensure that the tools, techniques, and principles of the training are being implemented correctly.

Holding briefings with management to share evaluations, provide post-workshop analysis, and discuss next steps.

Scheduling regular capability assessments to ensure that organizational skill and knowledge levels continue to increase.

Outsourced training can yield major results for biopharmaceutical companies and help them remain competitive in an increasingly challenging marketplace. The right training partner can help an organization get unstuck, move to the next level, and enhance their entire value chain. The challenge is finding a training partner with the experience and qualifications to address your specific needs. If you take the proper approach, and look for and assess key attributes, you are much more likely to find and forge a successful, long-term relationship with the right training partner. 

 CAPM,  Customer Relationship Manager,  Action for Results (AfR), Inc. 

Boot Camp Business Guide

Five key attributes to look for in a biopharm training partner.

Outsourced Training: A Primer

Pharmaceutical demand in Brazil continues to grow steadily with sales figures expected to reach $87 billion in 2017 according to IMS Health. It is anticipated that the country will become the fourth largest global market for pharmaceuticals by 2016, leading the Latin American region. 

Brazil has come a long way since its era of high inflation, achieving low national debt, with a rapidly growing middle class hungry for almost anything money can buy, including top-notch electronics, imported automobiles, international vacations, and MBA courses. In addition, access to private healthcare, an expansion of the generic drug market through government policies, as well as the increased national healthcare services along with better business regulations have attracted the eyes of international pharmaceutical companies. 

PHOTO CREDIT: JEREMY WOODHOUSE/GETTY IMAGES			

"Brazil, compared with its emerging counterparts, presents an important advantage [for international companies] because we are a democratic country with knowledge in the law field, have institutions that work properly as well as [the benefits of] free press and judicial resources," says Antônio Britto, executive president of São Paulo-based Interfarma (a pharmaceutical research industry association). Britto adds that this environment presents Brazil's main differential, followed by the fact that emerging markets have been expanding mainly on common or popular pharmaceutical products amid the rising purchase powers in these regions. 

Pharmaceutical companies around the world are aware that the industry is currently facing a strategic crisis. According to Roland Berger Strategy Consultants, this crisis means that business models must be adjusted given the shrinking margins of pharmaceutical companies as a result of increasing pricing pressure, regulatory changes, and expiring patents.  			

Emerging markets show strong growth despite the lower margins, driven heavily by non-patent-protected products. According to data from Roland Berger Strategy Consultants, the biggest growth opportunities for the pharmaceutical industry would be in such markets because these regions are set to rise to nearly 40% by 2016. The firm believes that greater efficiency in research and more collaboration with third-party providers will become increasingly important given that R&D costs have risen by more than 80% worldwide over the past 10 years, while the number of new product launches has dropped by 43%.  

Interfarma's Antônio Britto notes that there has been a rise of global pharma dynamics in the past five years, moving from the US, Europe, and Japan towards emerging markets such as Brazil, Mexico, Russia, and Turkey. Brazil, China, India, and Russia have been experiencing above-average growth rates with emerging markets expected to account for nearly 40% of the global market for pharmaceuticals by 2016. Focusing on high-growth markets could, therefore, be a solution to the crisis for the pharmaceutical industry. Figures from Roland Berger Strategy Consultants show that the market for pharmaceutical products will grow by 4.5% annually on average through 2016, while growth in emerging markets will increase by approximately 12%.  

As the country's economy becomes more stable, Brazilians now face "wealth-related" health issues including obesity, diabetes, and cancer. Consequently, the best opportunities found within the local industry will be from common illnesses as well as complex diseases, says Antônio Britto. 			

Another opportunity cited by most pharma analysts is related to the local generic-drug market, which currently accounts for more than 20.5% of generic-drug sales. Analysts agree that the expansion of the generic-drug market in Brazil and the expiry of various blockbuster drugs have attracted international manufacturers overseas. Moreover, the government of Brazil supports local generic-drug manufacturers, and production figures have growing quickly as a result.  

Of the 540 pharmaceutical companies in the country, 90 produce generic drugs. International manufacturers including Roche, Pfizer, and Sanofi-Aventis for example, have developed facilities in Brazil to compete with local companies despite the strong government support towards the domestic players. Nevertheless, the need for research and innovation continues as the region presents many growth opportunities for access and consumption of pharmaceutical drugs and products, according to Interfarma.  

"Brazil shows important advantages [compared with other countries]; however, there are also issues to be faced," says Britto. For example, the local taxes are an issue to be dealt with when entering the market as well as well-recognized infrastructure problems, which have always been a concern to companies because the transportation infrastructure has not been able to keep up with demands.  			

While the local government has in the past invested in this area and is set to invest further to cater for upcoming international sports events that will be staged in Brazil, goods, including pharmaceutical products, still continue to pile up at airports and ports. According to Britto, new players must be prepared to bear the high costs of regulatory delays and taxes, of which Brazil is among the highest in the world, as well as put up with infrastructure challenges that pose difficulties in ports and airports. He also mentions challenges in recruiting highly technical employees for specific jobs due to the country's education deficiencies, mainly in the areas of science, chemistry, and engineering.  

International press reports have stated that the regulations in Brazil tend to be confusing; hence, partnering with a knowledgeable supply-chain provider would be best for new companies entering the local market. In fact, the government has suggested that new companies partner with a local firm to enter the Brazilian market. However, Britto does not believe in a formula that applies to all companies. "It all depends on the type of company and product to be developed in Brazil and it depends on the market it will be competing in," he says.  

Britto considers Brazil to be well regulated and states that the system is rigorous. "Brazilian regulation is as good as the best global regulations on average. The problem is not the lack of regulation, but the lack of professionals capable of putting the existing regulation in practice."  

It is clear that to succeed in this complex market, pharmaceutical companies will need to rethink their strategies carefully. Roland Berger Strategy Consultants agree that there is no such thing as a generally valid strategy but a multi-dimensional plan to thrive in such an unknown environment. 

Hellen Berger is a business writer based in São Paulo, Brazil.

Global News

Brazil offers opportunities and challenges for global pharmaceutical companies.

Report from Brazil

Over the past few years, China and India have been the up-and-coming destinations for international outsourcing of biopharmaceutical manufacturing. Last year, industry research pointed to China and India as the industry's top potential destinations for offshoring over the next five years, which put them ahead of traditional biomanufacturing hubs in the US and Western Europe. China was seen as a favorite likely destination for both US and European respondents to prior studies, with India close behind. 

10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

, however, that initial enthusiasm appears to have diminished (1). Of the more than 25 countries identified as potential destinations for international outsourcing, India fell to the fourth spot among all respondents, with only 14% of respondents indicating there was a likelihood or strong likelihood that they would consider outsourcing production there in the next five years. Surprisingly, that was a more positive result than for China, which was cited by just 10.6% of respondents, putting it in the ninth spot, behind countries such as Austria and Australia. 

This year, the US took the top position for biopharmaceutical outsourcing, with 26.3% of global, non-US respondents, ranking it as the top destination. This ranking likely reflects European companies' plans, as respondents were asked to indicate potential international destinations (see 

). Next on the list were Germany and Singapore, each indicated to be a "likelihood" destination by 15.8% of all respondents. Beyond those top three countries stood a group of countries (India, UK, Austria, and Ireland), each receiving the nod from approximately 14% of respondents. 

Figure 1: Destinations for international outsourcing of biomanufacturing (all respondents). (FIGURE IS COURTESY OF AUTHOR)			

As noted previously, the US' position atop the rankings this year is reflective of the substantial European presence in this industry. When the respondent sample is narrowed to Western Europeans only, the US is easily the favored destination for outsourcing in the next five years cited by 35.3% of respondents, up slightly from last year's 31.8%. After the US, Europeans are most likely to look in their own backyard, with strong consideration shown for Germany (29.4% of respondents cited in 2013, from 22.7% in 2012) and Belgium (23.5% in 2013, from 22.7% in 2012). 			

European responses were evaluated indicating more positive consideration for country destinations as either a "strong likelihood" or "likelihood." The US was again the top response (23.5%), with European countries following: Germany and Ireland (each at 17.7%), followed by Belgium, France, and Sweden.  

This year India was a consideration for outsourcing by just 11.8% of European respondents, down from last year's 22.7%. China's fall has been more precipitous: it was indicated to be a country in consideration by only 5.9% of respondents, down from last year's leading 36.4%.  

US-based respondents are more favorable to Singapore, handing it the top position, with 32.3% of respondents considering it a "potential" destination. After Singapore came Germany (29%), followed by the UK, China, and India.  

This list suggests that US companies appear to be seeking traditional biomanufacturing hubs rather than emerging ones at this time. Compared to last year, respondents in the US demonstrated a heightened potential for outsourcing to some destinations in Western Europe, such as Germany (29% vs. 25%), the UK (26% vs. 22%), Scotland (16% vs. 6%), and Italy (13% vs. 6%). Respondents, however, cooled on China (26% vs. 34%) and India (23% vs. 28%).  

After several years of study data showing China and India becoming more heavily favored outsourcing destinations, this year's results are striking and merit some attention. There are some signs that respondents' increased attention to traditional hubs, at the expense of China and India, is likely related to a renewed focus on regulatory issues. This may be drawing industry attention away from emerging manufacturing clusters, where there may be less confidence in the regulatory expertise.  			

As with years past, geographic location continues to be one of the least important factors: only 7% of respondents this year indicated "be local to me" to be a "very important" consideration, squarely in the less than 2-10% range found in the past 4-5 years. 

As geography plays a lesser role, regulatory expertise is becoming a crucial factor in decision-making.  This year, 45.6% of respondents said that it was "very important" that CMOs have regulatory compliance expertise, a significant rise from 38.1% who attached that level of importance last year. This comes amidst separate data suggesting that biomanufacturers are focusing more on regulatory issues to improve operational performance and avoid capacity constraints. It could also be a result of clients outsourcing more core activities than in earlier years, with regulatory compliance more rigid for these activities than for the lower value-added services that have typified outsourcing in the past.  

Finally, although much investment has been made in facilities in China and India for biogenerics production, some companies have been using their existing facilities, looking to leverage well-understood facilities that might otherwise be under utilized, and which are able to quickly and cheaply produce clinical material. Much of this CMO-sourced material has been produced in the US, which may be slanting future expectations for outsourcing. 

Although there has been a noticeable shift in attention away from China and India as outsourcing destinations, there is reason to believe this situation will reverse. Those countries are accounting for an ever-greater share of global biomanufacturing capacity—together, they represent approximately one-sixth of capacity, according to BioPlan's WIKI resource on global biopharmaceutical facilities (2), which pegs China's share of biopharmaceutical manufacturing concentration at 8.6% and India's at 8.1%. Although that's significantly behind North America (35.9%) and Western Europe (26.1%), it's a growing trend that the industry is not ignoring.  			

It's important to remember that China is a relatively new player, which continues to suffer from legal and regulatory aspects that hinder commercial-scale contract manufacturing. It may take years for Chinese CMOs to come up to full cGMP standards and to be permitted to operate at commercial scale. These study results may simply be a reflection of the industry thinking that such progress may not come as quickly as expected. Nevertheless, it's short-sighted to believe that this situation will not change. China and India represent a majority of the world's population, and with its growing middle class, biologics production will likely continue to play an important role in their healthcare policy. While some emerging destinations may not find substantial growth in the short term, India and China will need to produce biologics for their huge local populations, and some of this experience will have Western markets taking a close look at their capabilities. 

is president of BioPlan Associates, tel. 301.921.5979, 

 10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production 

Top 1000 Global Biopharmaceutical Facilities Index

Perspectives on Outsourcing

The industry may not be ready for India and China as regulatory issues emerge.

What Happened to Outsourcing in Asia?

Stability assessment is a crucial aspect of all drug-development activities.  Stability of the drug product and drug substance may impact both drug efficacy and drug safety and is generally regarded as a critical quality attribute (CQA) of every drug and vaccine. Both small-molecule and large-molecule drug substance and drug products are impacted by stability concerns. Primary consideration is given to those factors that impact drug potency and the formation of impurities over time. 

Specifically ICH Q1A(R2) 1.3. General Principles states (1), "The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions." 

The primary factors for any stability study are time, batch, and environmental factors. The primary environmental conditions are moisture/humidity and temperature. A risk assessment should be completed to evaluate any additional environmental factors the drug may be sensitive to (2). In addition, there are factors associated with the drug product and drug substance that may impact stability such as pH, excipients, API concentration, and hold times that should be included in the overall stability evaluation and during drug development.  

PHASE APPROPRIATE  STABILITY DETERMINATION

Stability testing should start at the beginning of early drug development with early formulation and process/method development (3). Generally, accelerated stability testing, followed by confirmatory long-term stability testing, is considered a best practice (see 

). Care needs to be exercised that accelerated stability testing is representative of long-term testing and does not cause degradation pathways that are not present in the nominal storage environment. Once long-term stability data are available, calibration and correction of the accelerated stability estimates are possible.  

Figure 1: Phase appropriate stability testing. (ALL FIGURES COURTESY OF AUTHORS)						

At each phase of development, formulation modifications, process changes, and refinement in analytical methods are made, causing the stability evaluation to be challenged, updated, and modified. Care should be exercised that representative material batches are selected for testing and the associated stability data, analysis, and reports are submitted to the regulatory agencies. 

If the parameters are stability indicating (i.e., change over time), regression analysis is a primary method for determination of stability, as the factor is time and the response(s) are the release drug attributes and any additional attributes for drug characterization. The two methods are based on a rate of degradation and the confidence interval associated with the rate of degradation. Rate of degradation is best for early development when sample sizes are small, confidence interval based expiry is best for long-term studies when the sample sizes, and time intervals have more data. Simple linear regression provides a rate of degradation (slope), starting value at time 0 (intercept), a confidence interval of the mean estimate at each time point, and residual error around the regression line (see 

). Nonlinear and other types of special linear models (e.g., sqrt,1/x, log, exponential, polynomials) are generally avoided unless specifically indicated from the data, historical experience, and/or a careful analysis of the residuals. The extrapolation of the nonlinear or special fits may produce nonsensical and/or irreproducible estimates of shelf life when extrapolated, so they must be used carefully.  

Figure 2: CI-based and slope based expiry.						

ICH Q1E, 2.3 regarding extrapolation states, "An extrapolation of stability data assumes that the same change pattern will continue to apply beyond the period covered by long-term data. The correctness of the assumed change pattern is critical when extrapolation is considered. When estimating a regression line or curve to fit the long-term data, the data themselves provide a check on the correctness of the assumed change pattern, and statistical methods can be applied to test the goodness of fit of the data to the assumed line or curve. No such internal check is possible beyond the period covered by long-term data. Thus, a retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data as soon as these data become available" (4). 

The 95% confidence interval is used in determining expiry and takes into account the sample size, variation in the batch data, and number of time points. In early development, when the sample size is small, it is best to focus on degradation rate. In Phase III stability, when the number of batches are higher and the sample sizes are greater, it is best of focus on the confidence interval and the predicted expiry at 95% CI. 

STATISTICAL MODELS  FOR STABILITY ANALYSIS

The general multivariate analysis for stability and expiry is an analysis of covariance (ANCOVA) or mixed model. Alpha for all model terms are set at 0.05 except for all batch related terms (main effects and interactions) and they are set per guidance at alpha=0.25. Setting the batch-related terms to 0.25 will cause the expiry to shorten and favor the consumer/patient with shortened shelf life.  Stability analysis is typically analyzed for each storage condition, and rates of degradation and expiries are determined. The simplest model where every term is significant per the alpha criteria aforementioned is selected for computing the expiry. The model type is ANCOVA. The statistical test is an ANOVA (see 

) and should be included in submission reports to make sure the model used is appropriate for the analysis and tests for lot pooling have been correctly conducted. The ANOVA summarizes the significant model terms and indicates the correct model has been selected for the data being analyzed. ICH QE discusses the analysis of stability data and the general guidance on analysis, pooling lots, and submission. There are four models that are most often used in stability analysis (see 

Figure 3: ANCOVA full model-individual slopes and intercepts.						

Design of experiments (DOE) is often used to include additional factors in the analysis and evaluation of stability. This is particularly true of formulation studies, influence of excipients, and pH. ICH Q1D provides guidance on designing and analysis of stability studies using DOE (5). In general, when designing stability, DOE time is not included in the matrix generation, it is typically included as part of the response as there are multiple measurements per time point for each condition in the matrix. The matrix is stacked, time is crossed with each model term, and then the appropriate analysis is performed with time as a factor and all other model terms.  

Table I: Most often used models in stability analysis.										

Stability is a key consideration when setting product specification acceptance limits. Specification limits should first and foremost take into account the impact of variation of the drug product on efficacy and safety, and then secondarily, it should take into account three sources of variation: product/process variation, assay or method variation, and stability variation (see 

).  Failure to understand or account for stability when setting limits will assure a problematic stability program and may prevent the product from being commercially viable or create excessive unnecessary product and supply-chain costs in many cases.  

Figure 4: Tolerances and stability.						

Specifically ICH Q6B 1.2 Back-ground states, "Specifications are one part of a total control strategy designed to ensure product quality and consistency. Other parts of this strategy include thorough product characterization during development, upon which many of the specifications are based, adherence to Good Manufacturing Practices, a validated manufacturing process, raw materials testing, in-process testing, stability testing, etc." (6).  

Stability and rates of degradation should be compared to the upper specification limit (USL) and lower specification limit (LSL) during early development and throughout the product lifecycle. Stability effect size (see 

				(Slope/(USL-LSL))*100= percent of change in tolerance per time period  

			USL only: (Slope/(USL-batch average))*100=percent of design margin 

The author discusses the need for stability analysis.

BioPharm International-07-01-2013

The Pains of Change

QbD and PAT in Upstream and Downstream Processing

EU Battles Medicine Shortages

Outsourced Training: A Primer

Report from Brazil

What Happened to Outsourcing in Asia?

Essentials in Stability Analysis and Expiry Determination

Kinetic Analysis of Antibodies from Different Cultured Media

FDA Urges Greater Focus on Contractor Quality

IPO Market Heats Up for Life-Sciences Companies

Quality by Design: A CMO's Perspective on Gaining Knowledge Faster and Better

BioPharm International, July 2013 Issue (PDF)