Articles

Issue PDF

Celebrating 25 Years of BioPharma Innovation

BioPharm International, June 2012 Issue (PDF)

As Congress considers renewal of the Prescription Drug User Fee Act (PDUFA V), it must not lose sight of its most important beneficiary: patients. Patients deserve a clear, efficient, and predictable drug-review process that is science-based, judicious, timely, and appropriately balances benefits and risks. Patients and their families also must have the utmost confidence that the system will speed their access to new, safe, and effective cures and treatments. PDUFA, first passed in 1992, must be reauthorized every five years, and the Biotechnology Industry Organization (BIO) supports a "back-to-basics," patient-centric approach to PDUFA reauthorization. Over the past 20 years, the PDUFA program has contributed to the approval of more than 1200 new medicines and reduced review times for the newest, most innovative drugs by more than a year. In the past year alone (fiscal year 2011), biopharmaceutical companies have successfully brought to market new therapies to treat hepatitis C, melanoma, lung cancer, lupus, and rare genetic disorders.  

However, PDUFA review performance experienced considerable stress in the early years of PDUFA IV due to a number of factors, including the scientific complexities of new drug and biologic applications; implementation of the FDA Amendments Act of 2007, and of Risk Evaluation and Mitigation Strategies (REMS); more frequent Advisory Committee meetings; and the profound impact of globalization, including the occurrence of more foreign inspections. As a result, FDA's review performance diminished, review times lengthened, and more applications went into multiple review cycles, leaving patients waiting longer for new therapies. Although FDA review performance has improved in recent years, there is much more that FDA and industry can do to strengthen and reinforce the PDUFA program.   

After intensive technical discussions informed by an unprecedented level of public input, the biotechnology and pharmaceutical industries and FDA agreed on a set of PDUFA enhancements that seek to reinforce the agency's review performance.  Highlights include: creating a new molecular entity review program for novel drugs and biologics that strengthens scientific dialogue and transparency between FDA and sponsors so that potential review issues can be identified and resolved early in the process; ensuring timely and interactive communication with companies during drug development; making new resources available to modernize regulatory science; and strengthening FDA's postmarket surveillance and benefit-risk management capacity through earlier discussion of risk-management strategies, standardized approaches to REMS, and further validation of the Sentinel Network. 

In addition, there are several specific issues that BIO believes are crucial to modernizing the regulatory environment, promoting biomedical innovation, and encouraging investment. For example, user-fee legislation pending in both the House and Senate include provisions to modernize FDA's Accelerated Approval pathway. These provisions would expedite the development of modern, targeted, and personalized therapies for patients suffering from serious and life-threatening diseases, while preserving FDA's robust standards for safety and effectiveness. These reforms would expand the accelerated approval pathway to conditions beyond just HIV/AIDS and oncology, better utilize modern drug-development tools and new surrogate and intermediate clinical endpoints, and take into account the severity and rarity of a condition subject to approval under accelerated approval. In short, it will help make the drug-development process as efficient, effective, and streamlined as the biotech companies producing the next generation of scientific breakthroughs. We hope Congress will fully support FDA's human drug review program—both through user fees and the appropriated budget—and pass PDUFA V as expeditiously as possible.  

 executive vice-president for health, Biotechnology Industry Organization (BIO)

will return to the Boston Convention and Exhibition Center, June 18–21, 2012. Highlights include an FDA Town Hall, a Super Session on PDUFA V, a Breakout Session on the Analysis and Impact of PDUFA V, and a Meetup Event with key industry players hosted by 

on outsourcing, procurement, and partnerships. 

Guest Editorial

BIO is calling for a more patient-centric approach to user-fee reauthorization.

Back-to-Basics with PDUFA V

The bio/pharmaceutical industry is witnessing two important manufacturing trends. First is the increasing adoption of quality-by-design (QbD) approaches to enhance process understanding, which results in a long list of consumer, regulatory, and business benefits. The second trend is the increased use of contract manufacturing organizations (CMOs) to better manage plant capacity and control production volumes. 

According to the 2012 BioPlan Associates' 9th Annual Report and Survey of Biomanufacturing, "Relatively few companies have outsourced all of their manufacturing, but nearly one-half of surveyed manufacturers expect to increase their budgets for biopharmaceutical CMO outsourcing (in 2012)" (1). As relationships with CMO relationships increase and expand, and QbD becomes more essential to business strategy, it is important to examine best practices for determining quality metrics across CMO and sponsor networks. 

At the intersection of QbD and CMOs is the challenge for sponsor organizations, who have invested time, technology, and resources into QbD programs for their own manufacturing sites, to ensure that products manufactured by CMOs meet similar quality expectations for safety and efficacy. With QbD in mind, many biopharmaceutical manufacturing teams have integrated process intelligence technology tools and practices into their working approaches to collaborate across company-owned (or captive) global sites. Such tools can help teams access large amounts of process data stored in disparate systems (e.g., laboratory information management systems, enterprise resource planning systems, manufacturing execution systems, and records stored in paper formats) for proactive process monitoring and investigative analysis. 

As part of the QbD process, many sponsors have developed sets of critical process parameters (CPPs) and key performance indicators (KPIs) to routinely monitor processes and increase inhouse process understanding. When it comes to outsourcing, sponsor companies desire a similar level of monitoring and understanding from their CMO partners. 

The complexities of data sharing across sponsors and third party CMOs—many of which may be geographically dispersed—include the following challenges:  

Sponsors and CMOs have different operational models and, therefore, different interests when it comes to data. Sponsors are looking for quality assurance of the product, while CMOs most often use process data to compare one batch with another at a local level. The manufacturing processes of CMOs can also vary greatly between plants, which means that direct site-to-site data comparisons may not be appropriate.

Most existing sponsor–CMO contracts do not fully specify which data must be shared, or what mechanism should be used for sharing it. In addition, contracts often do not incorporate enough flexibility to take advantage of improvements in process or data sharing technologies that may become available during the life of the agreement. Data sharing is usually limited to release data for regulatory requirements, and does not include data that are comprehensive enough for the proactive monitoring and investigational analysis required for QbD and continuous process verification. In addition, CMOs tend to produce products for several customers and can be cautions when it comes to allowing sponsors to tap into existing IT systems to retrieve data.

CMO records are frequently stored and communicated to sponsors as paper-based documents, making access and analysis difficult.

Sponsors need to collaborate with CMOs to develop monitoring programs that assist in process understanding and verification at CMO sites, similar to the programs sponsors have developed for use across their own global manufacturing networks. 

A global biopharmaceutical company needed to establish parameters to monitor processes at a CMO site to facilitate data analysis for science-based decision making and greater process understanding.  

The sponsor required data from the CMO to fuel the same automated observational software tools used at its own sites to monitor large amounts of disparate data. The sponsor had limited knowledge regarding the CMO's processes and restricted access to CMO process experts, since collaboration was not required by the sponsor-CMO contractual agreement, which only allowed for limited data sharing.  

Without a more informed starting point, preliminary parameters to monitor processes were based on educated guesses. The sponsor—with help from its analytical consultant team—set-up nearly 400 "suspect process and outcome parameters" to start the investigation. For example, the team monitored incoming material temperatures at a certain point in the process, under the suspicion that this variable would affect outcomes at the next process stage. It also predicted other parameters that had the potential to impact product quality, such as measuring the presence of synthesis-related impurities after ingredients were combined in one process step. 

If the sponsor had been working at its own manufacturing site, it might have used a typical riskassessment approach, as guided by ICH Q9

 (2). Authors from Pfizer have described this approach in detail: 

"Risk assessment is the process used to prioritize parameters and attributes most likely to impact the product quality... The focal point of a QbD risk assessment is to be able to link quality measures and process controls to the product quality of the drug delivery system, i.e., safety, efficacy, and performance. A Quality Target Product Profile (QTPP) is an effective tool to help identify the Critical Quality Attributes (CQA) of the manufacturing process that link to product quality" (2). 

Pfizer's approach requires access to experts and upfront risk assessment prior to setting up trending. Because the case study involved a CMO site, the team had to set up automated trend monitoring systems and then watch the data patterns to identify what was important.  

To do so, the sponsor team compiled electronic data supplied by the CMO for analysis at the sponsor's headquarter using the sponsor's process intelligence software system. Through automated trend monitoring of the suspect parameters, the team could eventually narrow down the 400 initial parameters to those that were critical to quality outcomes. The software was configured to send alerts when data was trending out of specified limits, and the team also had access to data required for investigation of potential cause-and-effect linkages. This approach was much more interactive and real-time compared with the up-front method used in Pfizer's risk assessment approach and involved continuous process improvement using the ongoing analysis of data to increase process understanding. 

The sponsor found this monitoring by exception method to be a helpful way of compensating for the limited access to process experts at the CMO site. It allowed the sponsor to see and learn from the data directly, and also facilitated collaboration by using data as a communication vehicle between CMO and sponsor. 

The above trend-monitoring approach was successful because the process monitoring systems were designed to monitor by exception (see sidebar), using an automated system to alert users when they should pay more attention to a specific parameter of concern and further analyze the data. However, the sponsor had to select suspect parameters for monitoring without knowing their criticality. Standard monitoring procedures were conducted, such as baselining data, removing special cause variation and estimating process capability, and control charts were developed to monitor process parameters by exception, which involved sending alerts when control and specification limits were violated. The true value of the control charts was not observed until a few months later when a deviation occurred at the CMO site. The sponsor had quick access to process monitoring information and could also use the charts to better communicate with the CMO site. 

Following the selection of suspect parameters, the next phase for the sponsor team was narrowing these to determine the true CPPs. The sponsor team received alerts automatically when exceptions occurred, but if one parameter revealed a deviation, then the team knew it needed to monitor three to five additional parameters closely related to the measurement area. As a result, these real-word deviations provided a mechanism for filtering the suspect parameters over time, helping to determine CPPs. 

When working with CMOs, sponsors often receive information regarding process indicator variables, but when the sponsor's analysts realize that a process is not functioning properly, they still have to pinpoint the root cause. Unless comprehensive contractual agreements exist with details of data access and analysis, it can be difficult for the sponsor to access the right data for root cause analysis and statistical modeling. This case study expanded the sponsor's process understanding and allowed for an open conversation with the CMO site regarding which additional indictors and process and outcome parameters would help both parties monitor processes in the future. In the end, the approach described above offered numerous benefits for both the sponsor and the CMO. Figure 1 shows the time saved through monitoring by exception. 

Figure 1: Potential time saved through monitoring by exception compared with manual monitoring using spreadsheets. 

BEST PRACTICES FOR CONTINUOUS IMPROVEMENT IN CMO PROCESS UNDERSTANDING

Stage 3 of FDA's new process validation guidance reiterates that the process of developing and monitoring CPPs and KPIs is continuous and dynamic. The document states, "In addition to being a fundamental tenet of following the scientific method, information transparency and accessibility are essential so that organizational units responsible and accountable for the process can make informed, science-based decisions that ultimately support the release of a product to commerce"(3). With sponsor–CMO relationships, this approach also requires ongoing analysis and refining, which can be performed by monitoring by exception. 

To carry out a QbD approach, Stage 3 of the FDA's validation guidance must be applied across the entire manufacturing network, including at CMO sites. Incorporating automation tools is important for achieving continuous and dynamic monitoring with CMOs because it allows complex processes to be monitored with minimal human error and resources. The following summarizes best practices and considerations for implementing a continuous improvement plan for process understanding based on the author's experience.  

Establish a baseline for how often the organizations should reevaluate parameters and processes.

 The sponsor in the case study described in this article reevaluated plans and parameters every six months. Process capability and quality monitoring tools should be used to help develop and revise baseline metrics. This approach is consistent with the notation that monitoring should be continuous and dynamic at CMO sites, as well as at owned manufacturing sites.

Use information from baselining exercises to increase process understanding at a CMO site. 

Develop, monitor and revise statistical plans and sampling plans for continuous quality improvement. Important elements include: Who are the key people to review monitoring charts and involve in deviation investigation? What are the parameters? How often should we evaluate these parameters?

Engage in proactive process monitoring that makes analytics easier to use, but with a system that ensures you are not simply validating what you want to hear. 

Check assumptions and insist on doing it "the right way" on an on-going basis in spite of human nature. Data-driven monitoring and decision making is an ongoing part of QbD. It is just not about simply clicking and seeing results that validate assumptions.

Conduct high-quality statistical analysis and use data-based decision making to interpret what has occurred in a process, and then revise appropriately. 

A trained statistician, for example, can determine if a credible sample size was used and make a solid recommendation for action. Outsource the analysis function if the skill set—or required time—is not available within your organization.

The sponsor and CMO must communicate, collaborate and be willing to adapt to new working approaches based on sound statistical analysis. 

Data exchange can be a vehicle to increase communication between sponsors and CMOs, which is valuable for both parties.

 Sponsors and CMOs may need to renegotiate contracts to specify how, when and which data will be shared, or to accommodate technological improvements that have become available since the contact was signed.

, Ph.D., is a senior analytics specialist at Aegis Analytical Corp., 1380 Forest Park Circle, Suite 200, Lafayette, CO 80026, 

. ditor's Note: Aegis Analytical produces monitoring by exception software. 

 1. E.S. Langer, BioPharm International 25 (2), 15–16 (2012). 

 2. V. McCurdy et al., Pharm. Eng. 30 (4), 12–32 (2010). 

and Practices (Rockville, MD, Jan. 2011).

Features

Implementing quality by design makes the determination of quality metrics across CMOs and sponsors essential.

Determining Process Quality Metrics for CMOs

Cumulatively, the years 2010 and 2011 witnessed the approval of 19 biopharmaceutical marketing applications by FDA in the United States and EMA in the European Union combined (see Table I). 2010 was the better of the two years, with 13 total approvals. While neither year compares favorably to 2009, during which 20 such products were approved, these approval numbers are in line with average approval rates reported during the past several years (1–4). Products approved within the 2-year period included 9 antibodies, 4 fusion proteins, and 3 enzymes, as well as an enzyme inhibitor, a hormone, and a colony stimulating factor.  Cancer and cancer-related conditions represented the principle indication (6 products), while the remaining products target a wide variety of conditions. 

In terms of expression systems used, 14 of the 19  newly approved products are produced using mammalian (mainly Chinese hamster ovary, CHO) cell lines, two are expressed in 

, an insect cell-based expression system and a transgenic system is used to produce one product in each case. In overall terms, these figures reflect the ongoing dominance of mammalian-based expression systems in biopharmaceutical manufacture.   

Digging a little deeper reveals that only 11 of the 19 therapeutic proteins were genuinely new biomolecular entities approved for the first time within the indicated timeframe. Three of the products (Actemra/RoActemra, Arzerra, and Victoza used to treat rheumatoid arthritis, chronic lymphocytic leukemia, and type 2 diabetes, respectively), although newly approved in one region over the past 2 years, had gained approval prior to 2010 in the other region (see Table I). Also approved, Nivestim is a biosimilar product used to treat neutropenia; while Prolia, used to treat osteoporisis, and Xgeva, used to treat bone loss associated with cancer, are effectively the same product with different indications. Lumizyme replaces the previously approved Myozyme, used to treat Pompe disease, while Scintimun, although gaining EU-wide centralized marketing authorization in 2010, had gained marketing authorizations in selected EU countries (the Czech Republic, Hungary, and Sweden) as far back as 1994.  

Of the nine antibodies that made it to market, one is chimaeric, one is humanized, and six are fully human. The period also witnessed the approval of a first generation murine antibody produced by traditional hybridoma technology (Scintimun). Such first generation monoclonal antibody (mAb) products are more characteristic of the 1980s and early 1990s than they are of this or indeed the past decade. Engineered antibodies (chimaeric/humanized/fully human) have predominated since that time due to the characteristic clinical disadvantages exhibited by fully murine products (e.g., immunogenicity, the inability to trigger effector functions in humans, and rapid removal from circulation). Given its 

diagnostic role (which does not rely upon triggering effector functions) and that it is radiolabeled, such characteristics are less significant in the context of the product in question. 

Adcetris is notable in that it is a (CD30-directed) antibody-drug conjugate (used to treat Hodgkin's lymphoma). The conjugated toxin is monomethyl auristatin E (MMAE), an anticancer agent. On average, four molecules of MMAE are attached to each antibody molecule. Binding of the antibody conjugate to CD30-expressing cells is followed by endocytotic internalization and subsequent release of MMAE 

 proteolytic cleavage. MMAE is a microtubule disrupting agent.  Binding to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and death by apoptosis. 

Of the four fusion products approved, two are Fc-fusion based (Eylea and Nulojix) with the antibody Fc portion of the products serving to extend the serum half life of the overall molecule. Nulojix, used to prevent organ rejection following kidney transplant, is interesting in that it evolved from Orneca, which was approved in 2005 for the treatment of rheumatoid arthritis. Orneca negatively regulates the activation of a range of T lymphocytes. Nulojix is a protein engineered version of Orneca, identified through mutagenesis and screening, which binds with greater avidity to a range of T lymphocytes. This engineering apparently underpins a more potent immunosuppresive effect. 

Eylea and Nulojix join several previously approved Fc fusion products. The additional two fusion products (Elonva and Provenge) are more novel in this context. Elonva, used to achieve controlled ovarian stimulation in some fertility treatments, is a modified recombinant human follicle stimulating hormone (FSH) in which the carboxy-terminal peptide of the β subunit of human chorionic gonadotropin (hCG) is fused to the FSH β chain. The resulting fusion product retains its ovarian stimulation activity, but displays an improved blood elimination half life. 

Provenge, used to treat hormone-refractory prostate cancer, is a more complex product in that it consists of twin active components: autologous antigen-presenting dendritic cells and the recombinant fusion protein, PAP-GM-CSF. The latter consists of human prostatic acid phosphatase (PAP), an antigen expressed in some 95% of prostate cancer tissue, linked to human granulocyte-macrophage colony-stimulating factor (GM–CSF) through a dipeptide (glycine-serine) linker sequence. The treatment approach consists of three phases: an initial collection of dendritic cells from the blood of the prostate cancer patient (dendritic cells are the only antigen-presenting cells that can prime native T lymphocytes to initiate an immune response); 

 exposure of the collected cells to the fusion product, which results in their activation (the GM–CSF portion of the protein helps to target the PAP protein to the dendritic cells and activate those cells; the PAP portion provides the tumor specificity that will eventually direct the immune system to target prostate cancer) and the final phase, that is, the re-infusion of the activated cells back into the original donor patient. 

In addition to Adcetris (described earlier), two additional products approved throughout 2010 and 2011 are engineered using an

conjugation process post protein synthesis. In both instances, the purpose of conjugation is to extend product serum half life. Krystexxal (a recombinant urate oxidase enzyme used to treat gout) is PEGylated with a 10kDa monomethoxy-polyethylene glycol (m-PEG) moiety whereas Victoza (used to treat type 2 diabetes) consists of glucagon like peptide 1 to which a C-14 fatty acid is conjugated. 

Although the cumulative biopharmaceutical market value for 2011 is not readily available as yet, cumulative global sales of recombinant therapeutic proteins reached a notable milestone in 2010 (5). In that year, recombinant proteins surpassed the $100 billion mark, reaching an estimated $107 billion. Moreover, that same year 30 individual biopharmaceutical products recorded sales of more than $1 billion each, with Enbrel (etanercept) retaining  the top spot and boasting sales value of almost $7.3 billion (5). 

In terms of APIs, 2010 figures equate to approximately 21 metric tons (21,000 kg) of pure protein product. Almost two-thirds of that amount—approximately 13.5 tons—is produced in microbial systems (mainly insulin) with the remaining third being produced almost exclusively using animal cell culture (mainly mAbs) (6).   

it seems appropriate to conclude this article by briefly considering the new biologic drug approval profiles from the 1980s, and contextualizing them against the more recent approvals considered above.  

The first ever biopharmaceutical to gain approval for general medical use was that of Humulin (recombinant human insulin) in 1982. Throughout that decade, nine such products were approved in the US (see Table II). These products were expressed mainly in 

 or mammalian cell lines, with one product being produced in yeast. These expression systems remain dominant to this day. 

Table II: Biopharmaceuticals approved by FDA in the US during the 1980s. This era predates the EMA centralized approval system in the EU, although many of these products were also approved in several individual EU member states during this period. Note: EPO is erythropoietin, GH is growth hormone, IFN is interferon, rh is recombinant human, and tPA is tissue plasminogen activator. 

Products approved in the 1980s were mainly hormones and cytokines, with only one antibody based product among them. The intervening decades have witnessed a steady increase in biopharmaceutical approval rates, and certainly in their market value.  

One of the most striking changes is the current dominance of antibody-based products. During the past 5 years, for example, one-third of all approvals have been antibody-based, 6 of the top 10 selling biopharmaceuticals globally are antibodies and antibodies represent by far the single largest category of biopharmaceuticals currently in development.  Likewise, target indication profiles have changed. Today, cancer-targeted therapeutics dominate the market, while only two of the nine approvals throughout the 1980s targeted this condition.   

Another technical trend underlined by comparing products shown in Tables I and II is the evolution of engineered biopharmaceuticals. The vast majority of products approved throughout the 1980s were un-engineered first generation products, displaying an identical amino acid sequence to mainly native human regulatory proteins such as insulin and human growth hormone. The 1990s witnessed the approval of the first wave of engineered products (e.g., fast and slow acting insulin analogues chimaeric and humanized antibodies as well as PEGylated products). An ever-increasing proportion of product approvals are now engineered to tailor their therapeutic properties in a predefined way. Fourteen of the 19 products (almost 75%) approved in 2010 and 2011 are engineered. 

The biopharmaceutical sector has certainly matured rapidly since the 1980s. Depending on the specific year considered, anywhere between 20–25% of all genuinely new drug approvals in the EU and US are produced by modern biotechnological means. For example, Abbott's antibody product Humira (adalimumab), has a projected sales value of $9 billion for 2012 that will almost certainly displace Pfizers' Lipitor and Sanofi/BMS' Plavix as the world's most lucrative drug this year.  

The pace of discovery and innovation in the biotechnology research sphere continues to increase exponentially. The next 25 years will almost certainly witness the discovery, development, and approval of biopharmaceuticals that we cannot even envisage. In 25 years time, the authors of the 50th 

special edition will have much to discuss.  

 works in the Industrial Biochemistry Program of the Department. of Chemical and Environmental Sciences, Materials and Surface Science Inst.,  Univ. of Limerick, Limerick City, Ireland, and is a member of the BioPharm International editorial advisory board, 

 5. R&D Pipeline News, Special Edition (La Merie Business Intelligence, March 2010), 

 6.  T. Ransohoff, "Global Trends in Mammalian Cell Culture Capacity and Biomanufacturing" (2011), presentation available at 

A review of new biologic drug approvals over the years, featuring highlights from 2010 and 2011.

New Biopharmaceuticals

It is no understatement to say that the pharmaceutical industry is currently undergoing a sea change in attitude and approach to reducing errors caused by personnel, particularly in the operational areas. This area is broadly known as human error reduction (HER). Human errors can be expensive, lead to accidents, and risk product quality. Historically, there have been too many of them in the industry and the emerging approach for responding to them is promising to be fundamental and far reaching. 			

When something goes wrong in our bioprocess supply chains that could have an impact on product quality, the business is obliged to record and investigate the incident. This is required by industry regulators and accepted by the industry. Current practice is for a manufacturing deviation report to be issued and effective corrective and preventative measures to be implemented. Failure to see this process through (within a reasonable timeframe) can result in regulatory concerns and, in the worst cases, regulatory observations and Warning Letters.  

Analysis of the root causes of deviations is most commonly traced back to human error (more than 50% according to a recent survey of BioPhorum member companies). Where human error is the root cause, the most common corrective action set is to retrain the people involved. In most cases, training involves having staff read the relevant SOP and then having a supervisor or trainer validate that training by checking that the procedure is correctly understood by the staff. Unfortunately, evidence suggests that this approach does not eradicate the problem and the errors are repeated (47% of the time, in fact according to the same BioPhorum survey). 

Given the pressure to close corrective and preventive actions within a reasonable timeframe and the consequences of not doing so, it is tempting to think that the primary motivation is to get people working in compliance within quality policies and SOPs rather than to develop effective learning processes. These two motivations are not necessarily mutually exclusive, but there is a risk that our GMP compliance culture is preventing us from getting to true root causes. In other words, the corrective part is easier to do rather than the preventive part. 

When properly investigated, the incidence of human error is actually lower than normally cited. Is an ambiguous SOP that can easily be misinterpreted an operator error or a document error (written by another human)? One scenario might lead to the operator being retrained (expect a repeat) while another scenario might lead to the SOP being rewritten. 

Although this is the status quo today, there are two drivers changing the landscape. First, there is pressure to improve operational performance, which means it is no longer acceptable to bear the cost of repeated errors that can sometimes run into millions of dollars. Second, regulators are realizing that there is a better way to respond to human error. One only has to look to the aerospace and nuclear industries to learn that errors can be driven down to levels that the biopharmaceutical industry can only dream of. For examples closer to home, one can turn to the medical device and chemical manufacturing sectors. 

Dissatisfaction with current practice is clearly building. HER is relatively new to our industry despite the extent of manual intervention in the biomanufacturing process, but it is rapidly gaining boardroom attention. But if the current Retrain–Read SOP–Check cycle is not fit for purpose, what are the essential elements of this new landscape? And how should the transition be managed? 

Below is a top-10 list of best practices gleaned from a recent BioPhorum collaboration event in which 14 of the top biopharmaceutical manufacturing companies came together to benchmark their approaches and experience for handling human error.  

1. Change the perspective and the message. 

Advanced practitioners talk about increasing human performance and creating a high reliability workforce as opposed to reducing human error. But developing a positive, as opposed to removing a negative, is a subtle yet important difference. The development of these capabilities in a systematic and programmed way is underway in 75% of the top 20 biopharmaceutical companies. 

2. Educate people in the science of HER. 

The nature and causal factors of human error are largely behavioral and psychological. Only when these factors are understood can effective tools and techniques be developed and adopted. There is some great reference material available and specialists are now working in the industry. 

3. Encourage a climate of revealing errors as opposed to hiding them. 

This best practice means removing a blame culture if one exists in the company and replacing it with an open culture that focuses instead on transparency of exactly what happened. This means getting the operators, engineers, whoever was around to recall their observations as the error occurred. 

4. Track human errors in a way that underlying trends can be identified and analyzed. 

Record near misses as an additional source of useful information and to help prevention. 

5. Adopt effective investigation techniques, thereby establishing the true causalities.

 This practice may require the internal Quality organization to change the way it manages and measures some investigations. The 30-day rule-of-thumb target for closing investigations may not be sufficient if an issue is complex and difficult. However, an average closure time well below 30-days across all manufacturing deviations can be easily achieved. 

6. Use internal specialists and experts in root-cause analysis. 

These experts need to be viewed as independent and should be trusted so there is no fear of a comeback. The approach needs to have a light touch, recognizing that middle managers may be defensive about discussing mistakes made in their plants. 

7. Create effective lesson-learned processes and feed them across communities of practices. 

Companies are now leveraging their knowledge-management systems to capture single point lessons as well as broad lessons-learned case studies. In one case, "operations alerts" are formally written up and signed off by a vice-president. The implementation of the learning across the network of facilities is mandatory. 

8. Transform the role of trainers from tactical focus to business focus. 

Trainers need to think more about performance improvement overall than pure skills training. The emphasis must be to developing capabilities that make a real difference.  

9. Invert the pyramid, so that there is a "servant leadership" philosophy to support operators and the people at all levels. 

Senior managers need to ensure everything around operational staff is in place to enable them to get it right the first time. For example, procedures need to be fit for purpose, the work environment needs to be free from distractions, and the operating approach needs to be well thought through. 

10. Establish a vision and goals that help move the organization and culture away from reactive HER to active human error prevention. 

Many of the companies involved in the collaboration event boiled down the above top-10 list to three supporting pillars. They are: better training, open reporting, and rigorous root-cause investigation.  

The industry is at the beginning of its long journey to be able to claim it has human errors driven down to a level comparable with other safety critical industries. The early signs are encouraging. The BioPhorum members who gathered recently to share best practices are reporting greater than 50% reduction in human errors following implementation. Of course, statistics need to be used carefully. Tracking human errors through the lens of HER usually leads to more errors being counted because not all are picked up by the traditional means. Counter to this, many errors are recategorized when properly investigated because they are revealed to be system, equipment or organizational issues rather than human errors. 

From the HER practices being developed in the leading companies, the industry should be expecting and seeing a fundamental change in over the next two years. New best practices will change the landscape so completely that lagging companies will not be able to rely on Retrain–Read SOP–Check any longer. Time to fetch out the sea-sickness tablets. ? 

is director of the BioPhorum Operations Group, 

Manufacturing Best Practices

Leading industry collaborators outline top 10 best practices for human error reduction.

Reducing Human Error

The history of the US Food and Drug Administration is marked by significant revisions in its rules and policies in response to major crises in drug, food, and vaccine safety. Now, a surge in overseas production of FDA-regulated products is driving major changes in how the agency does business. Deaths due to adulterated heparin from China in 2008 jolted the regulators into action. FDA ramped up foreign inspections and opened its first foreign offices.  

That crisis, along with evidence of economically motivated drug adulteration, widespread drug counterfeiting, and extended supply chains that aggravated drug shortages at home, prompted FDA to recognize the need for further changes in agency operations. FDA Commissioner Margaret Hamburg responded by issuing a special report last year on the "Pathway to Global Product Safety and Quality" that outlines four main strategies for fundamentally revising FDA's approach to ensuring product safety and quality in a world of international outsourcing and soaring imports. The subsequent report on "Global Engagement" describes more specifically how FDA will seek to regulate food, drugs, and medical products through international collaboration and information sharing. 

These documents reflect the reality that FDA will never have the resources to inspect every foreign producer of food and medical products or to monitor the growing volume of products crossing US borders. Thus, FDA officials seek to work more closely with their regulatory counterparts to reduce redundant plant inspections and extend regulatory oversight.  

In addition, Hamburg restructured FDA's leadership last year by creating four overarching directorates to manage main program areas. These directorates include the new Office of Global Regulatory Operations and Policy, headed by Deputy Commissioner Deborah Autor. She is in charge of FDA's Office of International Programs (OIP), which manages the agency's foreign offices and deals with international trade, policy and regulatory issues, and the Office of Regulatory Affairs (ORA), which operates FDA's 4400-person field force that inspects manufacturers, clinical researchers, and food producers in the US and overseas.  

An attorney who has been a litigator in the Department of Justice and previously headed the Office of Compliance in FDA's Center for Drug Evaluation and Research, Autor is well positioned to take on the challenge of transforming FDA into a more data-driven, strategic, collaborative operation. She understands the pressures and incentives on biopharmaceutical manufacturers striving to adjust to the global economy, and told 

Washington Editor Jill Wechsler in a recent interview that industry must do more to ensure the quality and safety of its products.  

Why is it necessary to transform FDA to reflect global developments, and how will the agency accomplish this? 

I think the starting point is to recognize how much the world has really changed and how much globalization has fundamentally changed trade, the economy, and FDA's responsibilities. For example, imports of FDA regulated products have quadrupled over the course of a 10-year period, rising from 6 million to 24 million import lines. We now regulate products from hundreds of thousands of facilities in over 150 different countries. We import 10–15% of all food consumed in the US, 40% of finished drugs, 80% of active ingredients, and half of all medical devices.  

So that fundamentally alters the challenge that FDA faces. In 1938, when President Theodore Roosevelt established the modern FDA, we lived in a domestic economy. Our structure, our statutory paradigm, and our practices were all developed around domestic production of products. That production changed fundamentally over time, and the agency needs to adjust accordingly.  

One of the major steps is the Global Pathway report, with its four pillars: forming global coalitions of regulators to strengthen the product safety net around the world; developing global data systems for sharing information across markets; using advanced risk analytics and modernizing IT capabilities; and leveraging the combined efforts of public and private third parties.  

It recognizes that we can't do it all, and that we have to be smarter and more information-driven and more technology-driven. We have to learn to rely on others because it will never be possible for FDA to have enough resources to be everywhere, to see everything, to do everything.  

When we talk about global coalitions and global data, I think that we would like to get to a point where we really are able to have inspectional reports from inspectorates around the globe, and we're able to share our inspection reports so that we can work with our counterparts to leverage resources.  

How does this affect biopharmaceutical manufacturers?   

Industry needs to ensure that it has done everything it can to assume responsibility for its supply chains, for its component suppliers, for its own production around the world. It comes down to companies really understanding what they're making and what they're buying and how they can best ensure product safety and quality.  

At around the same time that we issued the Pathway report, the Commissioner reorganized FDA. She established four directorates—the Directorate of Foods and Veterinary Medicine, the Directorate of Medical Products and Tobacco, the Operations Directorate run by our Chief Operating Officer, and my Directorate, called Global Regulatory Operations and Policy. My mandate is to implement the Pathway report, to ensure that FDA fully integrates its domestic and international programs to best promote and protect public health, and to make import safety and globalization a top priority in the years to come.  

My directorate includes OIP, which leads, manages, and coordinates FDA's global engagement work, including our 13 foreign posts. In addition, the Directorate includes ORA, which provides FDA leadership on imports, inspections, and enforcement. My job is to take all of those resources and align them against our global challenges.  

I think, for example, that we ought to be treating like risks in equivalent ways regardless of where they're located. So a sterile drug facility in China should not be getting a different level of regulatory oversight than a sterile drug facility in Chicago. If you look at reports from the Government Accountability Office (GAO), you'll see that our inspection coverage on the foreign side is not nearly as frequent as our inspection coverage on the domestic side. Now, I don't think that means that in the future we inspect everybody equally all the time. But we should have equal assurance of safety and quality regardless of where the product comes from. And that can involve using our own inspections or data from our counterparts, or third-party coverage, or any other means that we can come up with. 

It's an interesting challenge because, as I said, we are a domestic organization. My directorate includes 4400 people in ORA, pretty much all domestic; and less than 100 people in OIP dedicated to international work.  

Does this mean that ORA will be shifting more inspectors overseas? 

We're not necessarily spreading all our people around the globe, but we need to figure out how to use our resources to make sure that we have the best coverage of all of our global risks. It's about strategic and risk-based global industry oversight. We need to be gathering data and information, analyzing it, identifying risks, and devising targeted, tailored, strategic approaches that are flexible, that address those specific risks.  

Those approaches can be anything from inspections, to enforcement, to incentives, to education and training. We need to implement those strategies, to see what works, and continue to learn and improve. Inspections are a significant part of it, but certainly not all of it. 

There also is a lot of work to be done in gathering information about emerging risks, whether it's product quality defects or problematic environmental trends. It could be almost anything that helps us understand more fully the breadth of the risks and how to intervene. Right now we, and a lot of regulators, have very operational models of doing business. We go out on the ground and see what we find, and then we figure out what to do about it. That's important, but information can help us know, in advance, what the challenges are, what the risks are, and what the opportunities are.  

When you think about a world with hundreds of thousands of producers in 150 countries, that's such a monumental challenge. The only way to really address it is to be as strategic and risk-based and leveraged as possible. 

During the heparin crisis, for example, would more timely information on the pig virus have alerted FDA and industry to be on the lookout for adulterated product?  

Yes, both industry and FDA need to be more aware of red flags for emerging risks. In the heparin situation, there was a virus killing pigs in China that caused a shortage of heparin and rising prices. We know from history that when there's strong demand, diminished supply, and high prices, that is an opportunity for criminals to step in. So we need to be smarter about looking for those kinds of things. That applies to regulators, but it also means that industry should be paying attention to what's going on in their markets; looking at procurement of components is a very important aspect of business.  

Do manufacturers do enough to ensure product quality? 

What I hear from the pharmaceutical industry is that the quality side and the supply side aren't always connected. So you have someone who is out buying components, and they're just looking for a slightly less expensive supplier. But they may not take into account the full range of costs associated with a less expensive component.  

Often a component may be cheaper to buy, but it may be made at a facility far away, which is harder to really have a handle on from a quality perspective. It may be that, in fact, that component could cause a serious product quality problem, which ultimately could cost the company much, much, much more money than it ever saved by knocking a penny or two off the price of the component.  

Do you think industry is getting this message?  

I think there have been a lot of good efforts underway recently. For example, I think Rx–360 [the international pharmaceutical supply chain consortium] is a great way for industry to work together to share information, both about specific suppliers and about emerging risks and issues.  

My view is that there is a range of companies. There are some that, frankly, I think are still not as proactive about quality as they could be. There are some companies that really do constantly aspire to best practices, there are others that don't, and then there are some in between. What I often hear in those situations is that there may be people in the quality units who are very vocal proponents of this, but they may not always get the attention and the resources they need from high levels of the companies. 

Other industries—aerospace, automotive—have really grappled with the challenges of globalization and outsourcing and put in systems that aren't necessarily replicated in the pharmaceutical industry. There is a lot of information in the literature about how investing in quality pays dividends, and some companies have embraced that. It really starts at the very beginning in understanding your process and your product, and goes on to understanding your suppliers and your supply chain.  

Ultimately, some of the risks [from producing low quality drugs] are just devastating, as with the incidence of glass particles in vials of injectable drugs. That cost industry at least $250 million. As I understand it, glass production processes can make the glass vulnerable to this damage, and a lot of very expensive injectable products had to be recalled. And the heparin crisis cost Baxter at least $30 million in sales and $4.7 billion in market capitalization. So these can be really devastating. 

: Will regulatory collaborations address some of these issues?  

I would like to make sure that we are being strategic and cohesive globally in addressing criminal threats to the drug supply. Whether it's counterfeiting or cargo theft or economically motivated adulteration, I think there's a real opportunity to make sure that we take a holistic look. We need to make sure that the civil side out there monitoring facilities and the criminal side catching criminals are talking so that we're able to both punish crime—and also prevent and detect crime by building stronger regulatory safeguards and by telling industry what the risk might be and how to be proactive in protecting itself from potential risks.  

Another proposal is to do more to leverage third parties for conducting inspections. This has not been a big success at FDA so far, so is it still promising?   

It is true that the agency hasn't always had perfect results in relying on private third parties for inspections, but I think that there is real potential there. We are further ahead in our exploration with respect to devices and foods, but I think we've got what we need to get there on the drug side as well. This approach creates some real challenges, and we need to be frank about those and to figure out how to overcome them.   

For regulators, it's hard to let go and to let someone else help us. But given the realities of globalization, we just can't do it alone. If we can work with others, if we can let go of control to some extent, we will have many more resources at our disposal. We shouldn't walk into this blind to the downsides, but it is possible, and I believe we can get there. 

Another recent report from the Institute of Medicine (IOM) recommended that FDA pursue "mutual recognition" agreements of inspection findings. Is that a realistic approach? 

 I believe that we need to look for "mutual reliance." That means sufficient comfort with each other's standards to be willing to rely on work done by a counterpart. We don't necessarily need to go the whole way to mutual recognition agreements. I hope, over time, that regulatory standards globally will converge, something that is already happening. As we work together, we all learn from each other.  

That IOM report also mentioned the Secure Supply Chain pilot program and greater use of low-cost technologies to oversee imports. What role can those play? 

The Secure Supply Chain is a pilot project that aims to facilitate imports from companies and facilities where we have a certain level of assurance. It is in the process of moving forward and presents a risk-based concept: If you can know that certain imports are low risk, then you don't have to devote much time to them. 

We also see opportunities to utilize more low-cost technologies in dealing with imports and supply chain security. One example is employing hand-held laboratory devices at the border. And in Africa there's use of a scratch-off number on a drug package that you can text in and find out if the drug is authentic. Manufacturers also are using barcode technology on brand name clothing or handbags and a call-in system to learn if the product is legitimate or not. I understand that certain large chain stores have RFID tags on underwear, so it seems that there's potential for pharmaceuticals.  

There's another IOM report coming on counterfeit drugs; what is its focus? 

We asked IOM to address the gaps globally in dealing with SSFFC drugs—substandard, spurious, falsely-labeled, falsified, and counterfeit products. How can countries and other stakeholders come together to really ensure that we are doing the best job we can in dealing with those products? Often that discussion gets mired in intellectual property issues.  

 Should we be looking for more reports on globalization from your office and more FDA foreign offices?  

I think our job now is to bring the current program to life. I don't think we know, at this point, exactly what our global presence will be over time. Our foreign offices have been key to enhancing our effectiveness overseas, helping us to know our counterparts, to understand them, to gather information about emerging issues, and to be there when we need to jump in and do an inspection quickly.  

We may get additional money in the 2013 budget for more inspectors in China for food and drugs. And if the Generic Drug User Fee Act is enacted, we will have a lot of responsibilities to expand foreign inspections and will need to take a hard look at how we can meet those. At the moment, we don't have any concrete plans to open new offices, but over time, we'll have to see what we need to do. 

 How will FDA be different in 5 to 10 years?  

 I believe that we will be more data driven, more risk-based, more strategic, more leveraged. We will be collaborating with our counterparts in global coalitions, we will be using data and advanced risk analytics, and we will be working closely with public and private third parties.  

In a special anniversary interview, Washington Editor Jill Wechsler speaks with with FDA Deputy Commissioner Deborah Autor about where the agency is headed.

Interview with FDA: Adopting New Strategies to Oversee Global Economy

Auditing a firm's complaint and out-of-specification systems have always been favorite areas for regulators to assess to determine the compliance, effectiveness, and adherence of a company's quality system to the regulations. In today's regulatory environment, it is important for organizations to know the regulations with the same depth of knowledge and understanding as regulators. If an organization happens to be a contract manufacturer, it might also find itself in the position of providing that in-depth regulatory expertise to customers. The contract manufacturer and its customers must be able to work with each other and within the regulatory requirements to assure that the product manufactured and released for patients is of the highest quality. The partnership between the contract provider and contract giver must reflect the requirements and time commitments as defined in the regulations.  

In situations where more than one organization is involved in the complaint and out-of-specification (OOS) processes for the product, all participating organizations must be harmonized in their approach for handling customer complaints and OOS results. In this author's opinion, it is the responsibility of the license holder (i.e., the NDA holder) to make sure its contract providers have the necessary processes and timelines in place to meet the necessary regulatory expectations. Likewise, it is up to the contract providers to make sure their internal systems meet regulatory expectations for all their clients. 		  

These systems should have established, agreed-to turnaround times regardless of whether the organization manufactures its own products or contracts the manufacturing and testing to external organizations. Complications can arise when more than one organization is involved in the processes and timelines for handling complaints and OOS results.  

The parties involved therefore must establish internal requirements that are consistent with the regulatory guidelines and give both parties sufficient time to conduct the needed activities required for the investigation into the complaint or OOS. The processes and timelines for handling complaints should be defined in a Quality Agreement and the related SOPs of the respective organizations and should include a clear delineation of which organization is responsible for various aspects related to the investigation.  

Contract organizations should establish timeframes for completing certain investigation activities, which may vary from client to client, but are usually completed within 30 days. The internal SOPs for handling complaints should be robust enough to be able to handle various clients' needs without creating multiple SOPs on the same topic. The process for investigating and handling OOS results should be similarly defined.  

The complaint SOP and the Quality Agreement also should address the turnaround requirements needed to investigate complaints associated with adverse or serious unexpected adverse events. For these complaints, the turnaround time must be able to accommodate tighter regulatory requirements. The license holder (i.e., the client) is required to submit a Field Alert within 3 working days after becoming aware of a reported problem either through a complaint or internal testing.  

In these cases, the complaint must be investigated quickly by the contract manufacturer. The turnaround time for these types of investigations should be defined in the Quality Agreement and subsequent SOPs and must be more expeditious than the timelines for handling routine investigations. OOS reports also require an expedited timeline for communicating confirmed results to the client because of the potential impact to product already distributed for use.  

In some cases, there may be more than two organizations involved in product manufacturing. These relationships can be complicated and communication lines blurred. The license holder must make sure through its various Quality Agreements that compliance to the regulations is met and responsibilities are clearly defined and adhered to.  

Below are few scenarios that demonstrate how complaints and OOS reporting can be handled.  

The license holder receives a complaint from a hospital indicating that a lyophilized product will not completely dissolve. The license holder manufactures and tests the product. It completes its investigation and closes it within 30 days as defined in the SOP. In this scenario, there is little risk of regulatory audit action should the complaint be reviewed during an inspection. 

 The license holder receives a complaint from a hospital indicating that a lyophilized product will not completely dissolve. The Quality Agreement indicates the contract manufacturer has 30 days to complete a complaint investigation but restricts them from closing the investigation until the license holder gives approval. The complaint is passed on to the contract manufacturer for investigation within 5 days of receipt. The contract manufacture investigates the complaint and the results of the investigation are provided to the license holder within 20 days from receipt. The license holder reviews the investigation and closes the investigation in its system and notifies the contract manufacturer to close its investigation. The timelines for handling complaints and completing the investigation as defined in the Quality Agreement and SOP have been met. In this scenario, there is little risk of regulatory audit action should this complaint be reviewed during an inspection. 

The license holder receives a complaint from a customer indicating that a lyophilized product will not completely dissolve. The Quality Agreement indicates that the contract manufacturer has 30 days to complete a complaint investigation but restricts the contract manufacturer from closing the investigation until the license holder gives approval. The complaint is passed on to the contract manufacturer for investigation within 5 days of receipt. The contract manufacture provider investigates the complaint and the results of the investigation are provided to the license holder within 20 days from receipt. The license holder reviews the investigation and closes the investigation in its system but does not notify the contract manufacturer to close its investigation. In this scenario, the typical timelines for handling complaints and completing the investigation as defined in the Quality Agreement and SOP have been met.  

In this scenario, there is a slight risk of regulatory audit action at the contract-manufacturing site because its complaint displays as "open." The contract manufacturer needs to show due diligence that it has requested a statement from the license holder to close the complaint should this complaint be reviewed during an inspection. 

The license holder receives a complaint from a hospital indicating a patient experienced a serious adverse event (SAE). The Quality Agreement indicates that the contract manufacturer has 30 days to complete a complaint investigation but restricts the contract manufacturer from closing the investigation until the license holder gives approval. The contract manufacturer has an SOP in place that defines the process for handling complaint investigation for SAEs. The complaint is passed on to the contract manufacturer for investigation within 24 hours. The contract manufacturer investigates the complaint and the results of the investigation are provided to the license holder within 24 hours. The license holder accepts the investigation of the contract manufacturer and completes its own investigation within 24 hours. The result of the investigation is satisfactory and no field action is needed.  

In this scenario, the typical timelines are not appropriate. There is a risk that the contract manufacturer could be cited for a regulatory violation because its complaint remains "open." In this case, it is fortunate that the contract manufacturing organization has an SOP that defines its heightened reporting requirements for handling complaints associated with SAEs.  The contract manufacturer needs to show due diligence that it has requested a statement from the license holder to close the complaint should this complaint be reviewed during an inspection. Both parties need to revise the Quality Agreement to define responsibility and timelines associated with investigations associated with SAEs. 

The license holder is informed of an OOS result from the contract-testing laboratory responsible for final product testing. The OOS was for a moisture failure on stability. The license holder has independent Quality Agreements with the contract testing organization and the contract manufacturing organization. The OOS is confirmed by the contract-testing laboratory. The separate Quality Agreements, in this case, may not have been reviewed to ensure consistency regarding timelines, notifications to regulatory agencies and partners, and authorizations to close. These inconsistencies may lead to increased regulatory scrutiny and possible actions if deemed sufficiently serious. 

The above scenarios illustrate how important it is for all parties involved in product manufacturing to understand the regulatory requirements and build requirements into SOPs and agreements so that unnecessary regulatory actions during inspections can be averted. In today's environment, all parties must take responsibility for product quality and regulatory compliance through clear delineation and communication of responsibilities. 

is  vice-president of quality at  OSO Biopharmaceuticals, 

Compliance Notes

The contract provider needs to know as much as the NDA holder.

Know the Regulations

Flexion Therapeutics was founded in late 2007 with the idea of rapidly progressing compounds in the clinic to meaningful proof of concept. Today, the company, based in Woburn, Massachusetts, has a full range of therapies for osteoarthritis and, in particular, therapies that are injected within the joint (i.e., intra-articular treatments). Here, CEO Mike Clayman talks about Flexion's business model and how focusing on one therapeutic class is making the biotech company a leader in its class. 

 Mike Clayman is CEO of Flexion Therapeutics, Woburn, MA.			

How did Flexion decide on osteoarthritis as a therapeutic target? 

 Osteoarthritis affects over 100 million people worldwide in terms of symptomatic disease, 27 million of which are in the US. Flexion's goal is to treat patients with osteoarthritis of the knee, which is the most commonly injected joint (over 10 million patients have knee osteoarthritis in the US). The prevalence of knee osteoarthritis is actually growing in light of an aging population and an increasingly obese population; it is also driven by sports injuries. If you tear your anterior cruciate ligament as a young athlete, you have a 60% chance of developing osteoarthritis within 10 to 15 years. 

What drew us to this field was the recognition that the current osteoarthritis treatments are inadequate. Oral therapies provide limited pain relief and are associated with serious organ toxicities. Current intra-articular therapies (e.g., steroids and hyaluronic acids), either provide pain relief of inadequate duration or inadequate magnitude. Yet, intra-articular therapies generate well over $1.5 billion per year worldwide in sales. And in the US, successful commercialization of these therapies entail sales forces of fewer than 100.  When we put this scenario together, we said to ourselves, 'This is a space that is ripe for innovation with a substantial and growing unmet medical need. Flexion could make a real difference by advancing to launch and commercialization—at least in the US—important new medicines.' We came to believe that our sustained-release intra-articular approach had the potential to provide real and meaningful benefits for patients with limited options. 

Mike Clayman, CEO of Flexion Therapeutics, talks about his company's strategy to focus on a single therapeutic area.

BioPharm International-06-01-2012

BioPharm International, June 2012 Issue (PDF)

Back-to-Basics with PDUFA V

Determining Process Quality Metrics for CMOs

New Biopharmaceuticals

Reducing Human Error

Interview with FDA: Adopting New Strategies to Oversee Global Economy

Know the Regulations

Creating a Product Portfolio from the Ground Up

25 Years of Nanoparticles: A Look Forward

25 Years of BioPharma Industry Growth

Developing Alternatives to ELISA-Based Biomarker Assays

25 Years of Protein Expression

Developing Discoveries into New Therapeutics

25 Years of Biopharmaceutical Innovation: An Expert Roundtable

BioPharm Celebrates 25 Years