In August 2012, FDA approved Zaltrap, a new therapeutic to treat colorectal cancer. What happened next says a lot about where the pharmaceutical industry was in 2012 and what's ahead in the new year. Zaltrap, developed by Regeneron Pharmaceuticals and Sanofi, essentially chokes off the blood supply to tumors. In the safety and efficacy nexus with FDA, it passed muster, but for others concerned about questions of value, Zaltrap reflected what's wrong in healthcare today.  

Critics of Zaltrap say the drug provides the same survival benefit as Genentech's Avastin when either drug is added to standard chemotherapy. Like Zaltrap, Avastin is also used to inhibit angiogenesis in patients with colorectal cancer, but Zaltrap did so at more than twice the price. At launch, Zaltrap was priced at an average of more than $11,000 per month for treatment compared with about $5000 per month for Avastin. Concerned about the question of Zaltrap's value, Memorial Sloan-Kettering Cancer Center decided not to give the drug to its patients.  

, three physicians at Sloan-Kettering (two of whom have served as paid consultants to Genentech) say the decision should have been a "no-brainer" (1). The exclusion of Zaltrap from Sloan-Kettering's formulary, though, didn't come easy, according to the doctors. That's because, they say, the culture of medicine equates new with better. "Our refusal to adopt this remarkably expensive therapy," they wrote, "risks being labeled 'rationing,' not 'rational'." Sanofi swiftly moved to cut the price of its drug in half, according to a report in 

Today's pressures on drugmakers reflect greater pressures throughout the entire healthcare ecosystem as payers, patients, and providers wrestle with the escalating cost of healthcare and push systems around the world away from cost-based to value-based. For pharmaceutical companies, this reflects not only a growing pressure on pricing, but pressure from all quadrants of the healthcare world to demonstrate the value their products provide to justify their costs. This new reality is altering the life-sciences landscape and changing business models, development strategies, and funding opportunities for companies.  

That pressure will only continue in the US, with the US Supreme Court leaving the Obama Administration's landmark healthcare reform legislation largely intact. The re-election of President Obama and the preservation of a Democratic majority in the Senate mean that efforts to repeal the legislation will be put to rest and the focus will shift to implementation of the law. 

As of this writing, a fight in Washington over the impending fiscal cliff was under way. If not resolved before year end, sequestration could trigger broad cuts to the federal budget that could have significant effects on the life-sciences industry. Most notable would be cuts to the National Institutes of Health and FDA, even cutting into the 2012 reauthorization of fees paid by industry to FDA under the Prescription Drug User Fee Act in exchange for timely reviews of products seeking marketing approval. 

The past year also saw passage of the Jumpstart Our Business Startups (JOBS) Act, which seeks to make it easier for emerging growth companies to access capital through the public markets. The Act provides exemption from compliance with costly regulations for smaller companies. It also allows companies to test investor interest before having to make sensitive information public in securities regulatory filings. 

Global life-sciences venture financings totaled more than $1.2 billion during the first 11 months of 2012, an increase of 23% over the same period a year ago. Venture investors, however, are moving away from early-stage financings. Companies are relying more on alternative sources of financing, including accelerators, angel capital, corporate venture sources, and private equity investment. In fact, of the top 10 private financings in 2012, four had significant backing from private equity firms.  

When venture investors do fund early-stage companies, increasingly they are providing large rounds to carry a company to proof-of-concept when investments can be exited or new financing at higher valuations can be raised. While therapeutics grabbed the largest portion of funding with a total of $3.1 billion through the first 11 months of 2012, digital health and life-sciences information technology deals showed the biggest jump in activity with a 63.2% increase to $690 million.  

It was a good year in the stock market for biotech stocks overall. The Burrill Select Index rose 41.8% through the end of November 2012. That compares to a 6.5% increase in the Dow Jones Industrial Average, a 12.4% gain for the S&P 500, and a 15.4% rise in the Nasdaq Composite Index. 

A total of 16 life-sciences companies completed initial public offerings (IPOs) in the US through the end of November, the same as last year. US life-sciences IPOs rose an average of 12% from their initial offering price through the end of November 2012. Of the 16 issues, 12 came below their target range. Overall, these companies sold their shares at an average of 22.7% below the median of their target price. The 12 therapeutics companies that debuted in public markets in 2012 outperformed life sciences IPOs as a whole. Those issues rose 17.8% by the end of November 2012.  

Through the end of November 2012, companies announced a total of $101.1 billion in mergers and acquisitions transactions, down 34.5% from the activity a year ago. Big Pharma and Big Biotech continue to be the most active acquirers. While generic drugs and consumer health were big areas of activity, the top deals involving innovative biopharmaceuticals in 2012 included Bristol-Myers' $7 billion acquisition of Amylin, GlaxoSmithKline's $3 billion purchase of Human Genome Sciences, and Dainippon Summitomo Pharma's $2.6 billion acquisition of Boston Biomedical, which is developing drugs to target cancer stem cells.  

Global partnering deals rose to $34.4 billion through the first 11 months of 2012, a 5.4% increase over the same period a year ago. Discovery deals led the way with a total of 66 transactions, followed by preclinical (42), phase 2 (36), and phase 1 (28) transactions. Most deals are back-end loaded with significant milestones tied to achievement of sales targets for drugs that are approved and marketed. Allergan's agreement with Swiss biotech Molecular Partners to develop and commercialize a class of biologics aimed at treating serious eye diseases was the largest deal of the year through the end of November, with $62.5 million in upfront payments and a potential total value of $1.4 billion. 

Through the first 11 months of 2012, FDA approved 31 new drugs and biologics, one more than approved for the same period a year ago. These approvals included Vertex Pharmaceuticals' Kalydeco, a targeted therapy for cystic fibrosis patients who have a specific gene mutation that drives their disease. Pfizer won approval for Xeljanz, the first oral disease-modifying drug for rheumatoid arthritis in more than a decade. The year also saw the European Medicines Agency issue the first approval in the western world for a gene therapy, UniQure's Glybera, a treatment for a rare, inherited disease where patients are unable to handle fat particles in their blood plasma. 

There were also some notable innovations in 2012 in the way approved drugs were made. Pfizer, along with its partner Protalix Biotherapeutics, won approval for the Gaucher disease drug Elelyso, the first drug to be manufactured using genetically engineered plant cells. Novartis, notably, won approval for Flucelvax, the first seasonal influenza vaccine licensed in the US and produced using cultured animal cells instead of fertilized chicken eggs.  

Despite ongoing financial concerns in Europe and the US, as well as tensions in the Middle East, the life-science industry is poised for positive results in 2013. The arrival of the $1000 genome is rapidly advancing the clinical applications of whole genome sequencing and the promise of personalized medicine to improve care and cut costs is starting to be realized.  

Emerging digital health technologies are pushing this trend further. As the demand to transition healthcare to a value-based system continues, the importance of digital health technologies will reverberate through virtually every aspect of healthcare. In 2013, these technologies will grow in importance as they empower patients to take greater control over their own health and wellness, provide real-time monitoring to improve efforts to prevent disease and improve outcomes, and help payers and providers harness vast amounts of new data, transforming them into actionable information that improves care and reduces costs.  

 is chief executive officer at Burrill & Company, San Francisco, CA, 415.591.5400, 

 1.  P.B. Bach, L.B. Saltz, and R.E. Wittes, 

www.nytimes.com/2012/10/15/opinion/a-hospital-says-no-to-an-11000-a-month-cancer-drug.html?_r=0

Articles

Burrill on Biotech

A handful of therapeutics have performed extremely well in 2012, but as a whole, life-sciences are still down from 2010.

Accelerating Change Marks 2012 for Life Sciences

Regulatory science underpins innovation and practices in drug manufacturing. The most common definition of regulatory science is a discipline that creates new tools, standards, and approaches for use in assessing the safety, effectiveness, quality, and performance of products.  

In October 2010, FDA issued a framework for advancing regulatory science for public health, which focused on the following: accelerating delivery of new medical treatments; improving pediatric and children's health; protecting against emerging infectious diseases and terrorism; enhancing safety and health through informatics; protecting the food supply; modernizing safety testing; meeting challenges for regulating tobacco; and setting a collaborative implementation framework.  

Following that framework, in August 2011, the agency released a strategic plan for advancing regulatory science at FDA, largely focused on science-based decision-making to improve public health. Part of this initiative identifies specific standards, methods, and questions for drug reviewers to use in their review process. The overall effort builds upon the agency's Critical Path Initiative, launched in 2004, to drive innovation in scientific processes, which includes the 2011 report that prioritized eight areas, which included support for new approaches to improve product manufacturing and quality.  

FDA has launched several Centers for Excellence in Regulatory Science and Innovation (CERSI) to carry out these priorities (see 

 on academia's role on page 28). The agency's initiative in regulatory science also was enhanced with the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012. Section 1124 of FDASIA calls for improving medical product decisionmaking through guidance documents and the adoption of tools, methods, and processes. The US Health and Human Services (HHS) Secretary must issue performance reports on these goals for fiscal years (FY) 2014 and 2016. 

 spoke to FDA about these issues in a special interview on the future of bio/pharmaceutical regulation. 

Academia’s role in the future of biopharma manufacturing and regulation, by Angie Drakulich 			

 In August 2011, FDA released a strategic plan, Advancing Regulatory Science at FDA. Priority 3 of that plan focuses on product manufacturing and quality, including enabling the development and evaluation of novel and improved manufacturing methods to improve product quality, namely through continuous manufacturing, novel manufacturing technologies, excipients and complex dosage forms, and process analytical technology (PAT) and quality-by-design (QbD) approaches. What does FDA and the industry hope to gain by focusing on these areas? 

 FDA is responsible for protecting the consumer through the availability of quality products. These approaches focus on good, sound science in achieving a high quality product. By applying QbD and understanding the role of excipients and complex dosage forms, a higher level of product and process understanding will be obtained. The other approaches (PAT, continuous manufacturing, and novel manufacturing technologies) utilize that understanding to achieve a more robust and capable manufacturing processes, resulting in higher product quality. With this higher level of product quality, the product failure rate is expected to drop, which in turn, will increase product availability, and reduce product cost. Therefore, by focusing on these science-based approaches, FDA is confident that the overall quality of pharmaceutical products [will]  continue to increase.  

Modernizing manufacturing approaches for pharmaceuticals, such as through QbD, continuous manufacturing, and/or PAT, has the potential to benefit industry, regulators, and patients. Already, there have been multiple reports of quality and cost benefits to manufacturers through the use of QbD and/or PAT approaches. For patients, these approaches can lead to increased assurance of quality and product availability. For regulators, it potentially means less regulatory oversight postapproval due to regulatory flexibility (e.g., design space) filed with the application. FDA is currently pursuing additional pathways to ease postapproval changes for well-understood and controlled processes under a robust quality system.  

Continuous manufacturing, although new to most pharmaceutical manufacturing, is a commonly used technology in food and chemical processing. As more companies are gaining experience with continuous manufacturing, benefits are emerging, including cases of reduced manufacturing scale-up issues, reduced material usage in development, and flexible manufacturing capacities. Because of the changing dynamics of new drugs toward more specialized, lower-volume products, continuous manufacturing could become more commonplace in the years ahead. 

 Finally, it is becoming increasingly important to understand the interactions between drug(s), excipients, and device components as pharmaceutical dosage forms are becoming more complex, such as multiple active ingredients in a single drug product or drug–device combinations. The higher level of understanding should allow for more robust products that deliver their intended performance when either planned or unplanned changes are introduced. 

Priority 3 in the strategic plan also calls for developing new analytical methods, including those to determine similarity between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms. What gains are hoped for among agency scientists in these analytical areas? 

 Advances in analytical methods to determine 'similarity' between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms will allow for greater confidence that there are no structural differences between products or that any differences observed are minor. For biosimilars, this will reduce uncertainty and allow for a targeted development program. This can also facilitate the development and approval of generics with complex dosage forms as well as inform control strategies for quality of complex originator products. 

 Priority 3 of the August 2011 strategic plan calls for reducing microbial contamination of medical products. What specific goals does FDA have in this area? 

 FDA has attempted to identify and study specific gaps in pharmaceutical manufacturing. Studies are ongoing on sterilizing filtration, effects of terminal sterilization energies on classes of products, and methods for detection of elusive microorganisms in drug components and manufacturing environments.  

Filtration studies have included microbial penetration rates based on the cell's size and filter matrix composition as well as penetration due to time on various filters with two sizes of growing microorganisms. The goal of these studies is to improve filter-validation studies that previously were shown to have vulnerabilities. Future steps in the research will look into solution conditions that encourage miniaturization of the cells, neutralize cells, or filter surface charges that enhance cell entrapment on filter membranes.  

Many products are manufactured using aseptic processing, which may be less effective than terminal sterilization. Some other surgical products are not manufactured to be sterile at all, also posing risk. Each of these situations is the result of risk assessments that are based on the nature of the product and its vulnerability to sterilizing energy or other conditions. FDA and NIPTE [National Institute for Pharmaceutical Technology and Education] have initiated studies of products (the initial focus is surgical antiseptics) to assess the effects of sterilizing energy on selected products. The goal of these studies is to define conditions that may allow manufacturing to use processes intended to produce a sterile product, which is safer for use in surgical procedures.  

Nonsterile products often require a demonstration that microorganisms, normally expected to be in the product, will not grow or are killed. A similar demonstration is expected of sterile products that may be used several times (e.g., multidose vials). However, there exist microbial strains that can resist preservatives used to control contamination, and some of these strains even grow in the presence of the antimicrobial agents. If allowed to grow, large numbers of microorganisms may reach a potentially infectious dose upon exposure to patients. Among these species are common water bacteria that CDC [Centers for Disease Control and Prevention] have shown to be difficult to detect using compendial methods. In collaboration with CDC and with help from the University of Michigan, we are examining culture methods for recovering these organisms from pharmaceutical water and products. Alternative technologies for their detection are also being considered. The goal of these studies is the development of methods to reliably detect these potential contaminants. 

 One way to improve regulatory science (from a drug- review standpoint) is to work with the industry directly to identify and fill in scientific and technological gaps that exist across drug development and manufacturing. FDA has created a few grant-based CERSIs, specifically with Georgetown University (GU), the University of Maryland (UMD), and the State of Arkansas. Will the agency be opening any additional centers of excellence? 

 We hope in future to fund one to two additional CERSIs, outside the region, but if and when, depends on availability of funding. 

 Can you comment on the staff training workshops held to date with these centers and their benefit to agency reviewers? 

Agency reviewers have had the opportunity to participate in training events sponsored by both UMD and GU CERSIs. These events have provided continuing medical education to staff and opportunities to network with leading researchers from around the country. Additionally, agency reviewers have also had the opportunity to maintain their scientific and medical skills by participating in clinical work, research, or teaching opportunities at UMD and GU CERSI. 

 Section 1124 of FDASIA states that the US HHS Secretary should have a strategy and implementation plan 'for advancing regulatory science for medical products in order to promote the public health and advance innovation in regulatory decision-making' by July 2013. What is FDA's role? 

 FDA is taking the lead in developing the Strategy and Implementation Plan for Medical Products as required in Section 1124 of FDASIA. 

 Are any additional major goals expected beyond FDA's current strategic plan surrounding regulatory science? 

: No, FDA expects to stay within the framework outlined in the Strategic Plan for Regulatory Science. The major areas of focus outlined in the Strategic Plan for Regulatory Science identify broad areas where advances in regulatory science are needed and are thus quite comprehensive. It is expected that the annual progress reports, which will follow in 2014 and 2016, will include more detailed information on specific accomplishments related to regulatory science. 

 Part of FDASIA helps to fund FDA foreign inspections through new user fees (i.e., the Generic Drug User Fee Amendments of 2012 [GDUFA]). Starting in 2014, inspections will use risk-based methodologies. What factors will the agency use to determine whether and when to inspect a foreign facility? 

 We have yet to finalize the revised risk-based approach although FDASIA Section 705 outlines the factors relevant to evaluating risk. All facilities will be inspected sooner or later. Firms new to FDA will be a priority as would be firms that are seeking approval for a type of manufacturing operation that is new to that site. FDA will consider establishing different frequencies for active ingredient and finished dosage form production facilities. Facilities that make sterile drugs will likely be a higher priority than other types of production. GDUFA expects the frequency and rigor of domestic and foreign facility inspections to be equitable, which makes good sense for all drugs, so the risk-based model will have to ensure this is achieved. 

 FDASIA calls for the agency to issue guidance by July 2013 that defines when an inspection may be denied or limited. What is the status ? 

 As required by Section 707 of FDASIA, FDA is currently working on a draft guidance that will address the scope of actions or inactions that constitute a delay, denial, refusal, or limitation of an inspection. Section 707 deems a drug misbranded if it is produced in a facility for which an inspection is delayed, denied, refused, or limited. This provision is important because it creates a strong incentive for all facilities, including foreign facilities, to allow FDA to conduct timely and complete inspections. If a domestic facility delays, denies, refuses, or limits an inspection, FDA has jurisdiction to obtain an inspectional warrant. Prior to FDASIA, however, FDA did not have an effective tool to facilitate the cooperation of foreign facilities with inspections. Now, if a foreign facility delays, denies, limits, or refuses an inspection, FDA may refuse entry for all drug products produced in that facility. This will save FDA time and resources and help ensure the safety of our drug supply. 

 FDASIA allows for FDA to use inspection information from other governments and agencies. Can you elaborate on this and other information-sharing? 

 FDA inspection reports are generally detailed accounts of each inspection that include the purpose, description of the breadth and depth of coverage, findings, and significant discussions with a firm's staff. FDA would be able to make use of comparably detailed reports from our counterparts and, under FDASIA Section 712, FDA would be able to recognize a foreign government's inspections once a review and audit of their system verifies their inspections to the satisfaction of FDA. FDA currently shares inspection reports, as well as data-systems access, with counterpart national regulatory agencies that often use these reports or inspection findings in lieu of their own inspection. Fortunately, there now exists an organization of pharmaceutical inspectorates that harmonizes drug regulatory practices: the Pharmaceutical Inspection Co-operation Scheme (PIC/S). FDA became a member of PIC/S approximately two years ago. Membership gives FDA an opportunity to work with fellow PIC/S member authorities to ensure that inspection standards are robust and followed. 

What’s ahead for biologics CMOs? A Q&A with DSM Biologics President Karen King, by Angie Drakulich 			

 Regarding imports, FDASIA notes that foreign manufacturers must demonstrate the regulatory status of their drug as well as cGMP compliance and prove facility registration within the US; otherwise, the agency has the right to destroy noncompliant imported drugs under a $2500 value. These rules are set to take place in July 2014 after further regulations are developed. How will the new standards differ from current import and foreign registration requirements? 

FDASIA provides FDA clear authority to require information about drugs offered for import and to refuse admission if it is not provided, which strengthens FDA's ability to monitor imported drugs for compliance with applicable laws. Similar to many other countries, FDASIA places the burden on the importer or product owner to prove its drug complies with applicable US requirements. These import authorities strengthen FDA's ability to evaluate imported drugs for compliance with US laws and regulations. The authorities also enable FDA to better target higher risk products and prevent violative products from entering the United States.  

FDASIA also grants FDA explicit authority to destroy violative drugs refused admission to the United States if they are valued at $2500 or less. Before FDASIA's enactment, FDA had no independent administrative destruction authority. Instead, FDA could only issue a 'notice of refusal of admission' for noncompliant drugs offered for import. Once FDA issued a 'notice of refusal of admission,' FDA had to rely on Customs and Border Protection (CBP) to either export or destroy the noncompliant import under the Tariff Act (19 U.S.C. 1595). By granting FDA administrative destruction authority after adequate notice and hearing, for violative drugs valued at $2500 or less, these new FDASIA authorities will not only create efficiencies and transparency in the import process, but also strengthen FDA's ability to protect public health. 

How will these new requirements affect the supply chain and drug shortages? 

 The new drug safety authorities FDASIA grants FDA reflect a more comprehensive and transparent view of the drug supply chain. For instance, FDASIA Section 714 requires that commercial importers register with FDA, and Section 703 requires that drug-product listings identify excipient information. By granting FDA new authorities that more accurately reflect the entire drug lifecycle, FDASIA better equips the agency to protect public health and minimize consumer exposure to unsafe, ineffective, and poor quality drugs in today's globalized supply chain. FDA will continue all efforts to address and prevent drug shortages while implementing these new requirements, which are anticipated to further strengthen efforts to assure the safety and quality of drugs for US patients. 

Be sure to see what the editorial board members think about the future of pharma manufacturing in this month's From the Editor column. 

Features

FDA talks about the changing scope of regulatory science.

A Look Ahead at BioPharma Manufacturing and Regulation

In the past two decades, epigenetics has grown from an obscure concept applicable mainly to X chromosomal inactivation to one of the dominant driving forces in pharmaceutical R&D (1). Briefly stated, the epigenetic model of regulatory control is based on the observation that half of the structural genes of higher organisms are preceded by CpG islands, clusters of cytosines alternating with guanadines that constitute signaling points that respond to epigenetic signals (2). Modification of these sites through a methylation reaction blocks the transcription of linked genes. Whereas numerous pathological conditions demonstrate an epigenetic connection, progress has been most notable in the field of cancer biology. 

Evidence linking epigenetic modi-fications to the activation of oncogenes or the inactivation of onco-suppressor genes is rapidly coalescing (3). Researchers currently propose a dynamically interactive model by which the genome and epigenome feed back on one another, driving the growth or the involution of tumors (4–6). 

This complex model of regulatory control offers many opportunities for a more nuanced understanding of the cancer cell and how it spans the transformation from normal to various stages of malignancy. The new knowledge base opens up possibilities for early diagnosis, because subclinical tumors may release DNA molecules into the circulation that bear highly specific epigenetic modifications defining the type and stage of malignancy of a particular tumor type. These markers can be methylated sites in target genes, and as such, provide a specific and sensitive target. Currently, numerous diagnostic tests for these markers are under development (7).  

By the same token, an epigenetic-based therapeutic attack on cancer has been launched. There are a number of basic science teams working with industry to define new epitherapeutics for a range of different cancers.  

These changes, affecting both the diagnostic and the therapeutic aspects of oncology, demand a restructuring of our strategies for attacking this disease. There is much interest in other diseases that may have an epigenetic basis, but cancer-based investigation is far advanced over other diseases, so for the next few years this will no doubt be the prime focus of epi-drug development.  

New targets call for new strategies for synthesis and production. This may influence the relative balance between small molecules and biological drugs, decisions that will affect the allocation of resources for large-scale production in the coming years. Companies have made decisions in the past reflecting their projected bioprocessing needs, with serious implications for cash flow, so it is crucial that these allocations be assigned on the basis of the best information available. 

In addition to the four drugs that have already been approved by FDA (see 

), a number of new compounds are in clinical trials. Although they are a miniscule component of the current anticancer drug market, their usage is expanding. Cai et al. (2012) have summarized those compounds under scrutiny for use in the treatment of breast cancer (8). 

Table I: FDA-approved epigenetic anticancer agents.			

Until recently, epigenetic changes had not been recognized as playing a significant role in the origin and progression of cancers. This lack of attention is changing rapidly, as a wealth of research findings are appearing, documenting epigenetic variation and its role in many disease processes. The dominant paradigm, however, has been based on the concept that alterations in DNA base pair sequences are responsible for practically all the variability observed in normal and pathological expression in humans and other living forms. 

But the new concept of the origins of cancer is more complete, and proposes an interplay between epigenetic and genetic changes. Baylin and Jones have summarized the history of this movement over the last decade, and they note that there is an emerging view of what has come to be called "the cancer epigenome" (9). The cancer epigenome is essentially a wide collection of abnormalities based on somatically heritable alterations that are not due to primary DNA sequence changes. In fact, the genesis and progression of tumors appears to be a complex process in which DNA-based alterations can favor the development of epigenetic changes, which increase the malignant status of a particular cancer.  

The additional layers of complexity introduced by findings in epigenetics are highlighted by Tessema et al., who state that in the past, the main focus was on the damage to the DNA caused by cigarette smoking, but now there is a major concern that epigenetic control molecules may be as important a cause of cancer (10). This more complex mechanism means that an interactive picture will need to be developed which takes into account the feedback between carcinogenic changes in the genome reflecting back to the epigenome, and 

The extent of epigenetic damage in cancerous tissue is startling. For example, epigenetic molecules are affected in 60% of patients with pancreatic neuroendocrine tumors. Other molecules are abnormal in 41% of cases of kidney cancer. The aim with epigenetic drugs is to revert those bar codes back to normal, according to Jonathan M. Yingling, vice-president for cancer research at Eli Lilly (11).  

EPIGENETICS AND THE   BIOPROCESSING INDUSTRY

The epigenetics revolution has arrived at an opportune moment, in which old business models are under siege, and there is an aggressive reassessment taking place within the pharmaceutial industry (12). For years, Big Pharma R&D pursued blockbuster drugs that targeted chronic, widespread conditions requiring pharmaceutical agents to be taken over an extended and indefinite period. Lipitor was the all-time poster child of this strategy, and brought in $70 billion in sales for Pfizer over the course of its patent lifetime. Numerous other drugs developed for the treatment of allergies, high blood pressure, and sexual dysfunction were extremely successful in the marketplace. This model has received a drubbing as year after year R&D costs rose and productivity dropped. 

But the rise of epigenetics has introduced a new variable into the equation. All the major pharma companies have epigenetics divisions in place, and some latecomers may not be able to catch up with competitors such as Merck and Novartis. And while the focus is currently on oncology-based drugs, evidence is emerging that many psychiatric disorders have a strong epigenetic contribution (13).  

Currently, epigenetics-based drugs are small slice of the large pharma pie. However there are a number of epigenetically targeted compounds in clinical trials, all oncology-based. It is noteworthy that they are all small molecules that will not call for bioprocessing facilities. The global market for one biologic product, monoclonal antibodies, was $44.6 billion in 2011, predicted to grow to $58 billion by 2016. In 2011, epigenetic drug sales were only around $1 billion, but some analysts predict that their growth rate in sales will be much higher, 80 to 100% annualized growth (14).  

Of course such predictions come with many caveats, and many factors can intervene in the coming years. The most crucial unknowable is how successful advances in epigenetics research will be in the near future. However, making reasoned assumptions concerning the transformations of the industry driven by the epigenetics revolution, the bioprocessing industry should be prepared to participate in a smaller percentage of the overall oncology drug market.  

 is head of Newport Biotechnology Consultants and a member of BioPharm International's editorial advisory board , 

 onlline, DOI :10.1155/2012/738274 738274, February, 2012. 

  M. Esteller, N. Eng. J. Med. 358, 1148–1159 (2008).  

  J.M Yingling JM, "The Changing Field of  Drug Development," online Jul. 16, 2012. 

  T. Kubota, K. Miyake, and T. Hirasawa, 

 K.J. Morrow, Kalorama Reports, Pub ID: KLI3860511, pg. 160 (2012).   

Therapeutics targeting epigenetic mechanisms of disease will change the pharmaceutical marketplace.

Epigenetics Drives Pharma Innovation

From time to time, it's important to take stock of the industry from both a retrospective and prospective point of view. Throughout 2012, we celebrated 25 years of 

, looking back at major advancements in technology, biologics development and processing approaches, and regulatory science. As we enter 2013, we are eager to envision what the future of biopharmaceutical manufacturing will bring. We've asked our editorial advisory board members to provide their perspective on what's ahead. Below are a few highlights. 

"As biopharm molecules continue to grow relative to small molecules, classical pharma companies will invest and acquire more biopharm companies. The number of new drug targets is growing slowly, so firms are focusing on specific clinical areas. Monoclonal antibodies (mAbs) and mAb-similars will continue to be the biggest molecule segment because it offers a flexible drug platform. We will see improvements in ease-of-use and cost, such as smaller volume dosage and less frequent administration. Biosimilars will emerge over the next 10 years, driven by customer cost pressures and the reduced development risk for manufacturers. Improvements in disposables (e.g., integrity, extractables) will drive further adoption to reduce classified air and water utilities and speed process turnaround." 

"As technologies continue to improve, 'fit-for-purpose' manufacturing will become even more prevalent. Large, single-product manufacturing factories will be replaced by smaller, more modular, multiproduct facilities using disposable equipment. Companies will use an ever-growing network of CMOs. Moreover, these facilities will increasingly be located within the country/region whose population is served by life-changing medicines."

 —Denny Kraichely, Johnson & Johnson Pharmaceutical R&D

"Despite the continued growth of biopharmaceutical products worldwide, their high cost and foreign manufacture make them expensive and difficult to obtain in many emerging markets. These countries want to provide top-tier medical care to citizens but struggle to pay for expensive therapies. To meet these challenges, the manufacture of biopharmaceutical products will require local stateoftheart facilities designed on standard platform processes, built using advanced modular design and construction, and incorporating single-use technologies wherever possible." 

—Howard L. Levine, BioProcess Technology Consultants

"Uniform product quality is a key issue as manufacturing expands globally. Regulatory oversight should prevent entry of low quality material into distribution chains. The solution will be a global regulatory force to match the global industry. Early forms may be found among the International Conference on Harmonization, the Global Harmonization Task Force, and the Pharmaceutical Inspection Co-operation Scheme. The problem will be to create a system where quality standards have the legal status to prevent distribution of substandard products within cooperating countries." 

—Steven S. Kuwahara, GXP BioTechnology 

"Pharmaceuticals, biologicals, biosimilars, and vaccines will increasingly be produced in Asia by low-cost suppliers, provided they can follow globally harmonized GMP standards. Much of this work will use single-use technologies where scale is appropriate, based on capital cost savings, enhanced containment, elimination of cleaning concerns, and reduced water requirements. Vaccines will be produced locally in emerging markets, also using single-use technologies. Concerns over counterfeiting and other supply-chain risks may generate the return of jobs to the US pharmaceutical industry, provided that wages can be competitive." 

"The limit between large and small molecules will become blurred. Small molecules will become more functionally complex, while large molecules will be trimmed to their essential functions for easier application. Fragment antibodies, conjugates, targeted glycoforms and oligosaccharides, 3D matrices, large-scale stem-cell production, and others will need new and affordable production approaches, which one day may include cell-free production or plant-based biofactories. All this is likely, while one old challenge remains: the downstream bottleneck." 

From the Editor

Our editorial advisory board members provide their perspective on what's ahead in the biopharmaceutical industry.

A Look Ahead in Biomanufacturing

A decade-long effort to modernize biopharmaceutical production and regulatory policies has fallen short of its goals and is prompting a re-evaluation of FDA regulatory efforts and industry's response. The shift in drug sourcing and production to foreign sites heightens demand for more efficient oversight, as do provisions in the FDA Safety and Innovation Act (FDASIA) that support accelerated development and approval of breakthrough therapies to enhance patient care.  

Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), consequently is taking a fresh look at FDA programs designed to ensure that manufacturing quality requirements promote biomedical innovation that leads to safe and effective products. The CDER "Pharmaceutical Quality for the 21st Century" initiative was launched in 2002 to encourage manufacturer adoption of modern quality management systems, process analytical technology, and automated production methods. This program has yielded many accomplishments, "but we're not there yet," Woodcock stated at the December symposium sponsored by the International Consortium for Innovation & Quality in Pharmaceutical Development (IQ).  

Woodcock made similar observations about lagging manufacturer investment in quality-by-design (QbD) approaches in June 2012 at the FDA/ISPE conference in Baltimore. Despite years of discussion about QbD and modern manufacturing systems, FDA still sees high reject rates and widespread product defects, Woodcock notes. Ongoing drug shortages, the recent drug compounding crisis, and frequent product recalls have intensified FDA's focus on strategies for improving quality drug production. These failures add to the cost of drug production, which depletes a company's R&D resources and often leads to higher drug prices.  

Instead, biopharmaceutical executives should regard quality drug production as a means to achieve a clear competitive advantage over competitors and as a "core competency" for management—an attitude that Woodcock finds rare. This approach could involve developing quantifiable metrics of quality, something that is done in other industries such as with automobile or television repair rates or airline on time percentage.  

For pharmaceutical companies, metrics could be public, such as product recalls or inspection citations. More internal measures may include production cycle delays, rates in meeting specifications, or theoretical versus actual cycle times. Such assessments can document how more efficient production reduces waste and saves money, while also avoiding the recalls and safety problems that can damage corporate reputations. And savings in the manufacturing arena that support lower prices for new therapies will be particularly important as more personalized treatments emerge. Pharmaceutical management may be more willing to invest in modern production technology if it can decrease the cost of production, support faster approvals, avoid burning up patent coverage time, and facilitate reimbursement by payers.  

Ensuring quality drug production has become more urgent as FDA faces added pressure to facilitate patient access to new "breakthrough" drugs, a goal that could be undermined by delays in manufacturing scale-up. The new Breakthrough Therapy Designation, which FDA can apply early in clinical development as authorized by FDASIA, "looks like a game changer" for cancer, genetic diseases, and other serious conditions, Woodcock observes. If FDA is prepared, however, to approve a priority drug while the sponsor is still at clinical production scale, final approval could be delayed if reviewers find that the product does not meet "ready for manufacture" criteria.  

 "This has happened," Woodcock asserts, "and it's going to get worse" as FDA encounters more highly targeted cancer therapies that demonstrate complete response in phase I or II, but manufacturers that lack the capability to supply the product quickly. At a November 2012 conference on cancer research sponsored by Friends of Cancer Research and the Brookings Institution, Woodcock highlighted the potential benefits of the new policy for breakthrough therapies, while warning that drug manufacturing could be a "rate-limiting step" in development. To avoid such roadblocks, she recommended early, separate FDA meetings with sponsors on manufacturing issues to discuss the scale-up plan for a potentially critical drug. 

Such discussions could highlight the benefits of adopting continuous manufacturing processes and QbD approaches to facilitate efficient transfer from development to commercial production. Manufacturers that adopt QbD early in the development process also may experience "fewer nasty surprises" in production, less waste, and more positive plant inspections down the road, Woodcock notes.  

The potential impact of quality manufacturing systems on innovation and drug access provides a strong platform for change in quality regulation, says Woodcock. CDER's pharmaceutical quality initiatives have yielded many successes, as seen in expanded online monitoring of production lines; development of software and other technology to monitor manufacturing processes and detect errors; harmonization of quality risk-management concepts through the International Conference on Harmonization; and implementation of QbD approaches at many companies.  

FDA has been less productive with efforts to provide industry with relief on manufacturing supplements and to build a pharmaceutical inspectorate with greater expertise for evaluating innovative quality production systems. Woodcock is hopeful that added resources provided by the Generic Drug User Fee Act (GDUFA) will revive the inspectorate program and provide more parity between foreign and domestic site visits.  

CDER also is responding to these developments by establishing an Office of Pharmaceutical Quality (OPQ), another "super office" that will coordinate the review of chemistry, manufacture, and controls (CMC) data in applications with compliance efforts to ensure adherence to good GMPs at plant sites. OPQ will replace the Office of Pharmaceutical Science (OPS), whose long-time director, Helen Winkle, is retiring from the agency.  

This change will bring together all CMC reviewers for generic drugs, conventional drugs, and biologics. In addition, the Office of Manufacturing and Product Quality (OMPQ) in CDER's  Office of Compliance will join the new entity. Meanwhile, the Office of Generic Drugs (OGD) is becoming a separate CDER super office and will operate more like CDER's Office of New Drugs, with responsibility for reviewing bioequivalence, microbiology, and clinical data and clearing product labels. More details about the reorganization and OPQ should emerge over the next six months.  

The regulations for CMC submissions and GMPs cover much of the same territory, so it makes sense to bring together the staff members that evaluate them, commented Jon Clark, OPS associate director for regulatory policy, at the IQ symposium. One advantage of the new structure is that it will encourage discussion of GMPs much earlier in the development process and hopefully avoid the kinds of production delays that could stymie market approval. The appointment of Howard Sklamberg, deputy associate commissioner for regulatory affairs, to head CDER's compliance office also brings in someone highly familiar with FDA's field force operations to help shape new inspection models. 

Woodcock is hopeful that this reorganization and other initiatives will promote better ways to ensure drug quality, while also encouraging innovation. The current system for monitoring manufacturing activities is highly resource intensive, yet it fails to direct oversight to higher risk situations. "We're not just moving boxes," she insists, but looking to focus more on data surveillance and metrics, instead of site inspections, to provide faster review of applications plus improved procedures for ensuring quality manufacturing around the world. 

Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

Shortages spur efforts to overhaul manufacturing oversight.

Drug Quality at Center Stage for FDA and Manufacturers

The European Union (EU) approved the Falsified Medicines Directive (FMD) last year in an attempt to tackle the growing problem of counterfeit medicines. In addition to combating the trade in fake pharmaceuticals, another prime objective of the legislation is to deal with the increasing amounts of substandard pharmaceutical ingredients entering the EU under the guise of unverified compliance with cGMP standards. Currently, 70% of the EU's APIs are imported according to the European Fine Chemicals Group (EFCG). 

There has been a lengthy debate about the contents of the directive in the European Parliament and the Council of Ministers, and it has become apparent that the implementation of the directive could be as difficult as its approval. Differences over some of the final details of the legislation could mean that it will not come into full operation for at least a few years because there are still disagreements over how the GMP standards on APIs should be embodied in the directive.  

FMD is scheduled to come into effect this month, Jan. 2013; however, the European Commission (EC), the Brussels-based EU executive, is still in the early stages of deciding on the legal status of GMP guidelines in relation to the legislation. Some EU member states are also being slow in incorporating the directive into national legislation. For example, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) was scheduled to complete, only by Nov. 19, 2012, a consultation exercise with stakeholders on how to transpose the FMD into national law. "We are working hard to make sure deadlines are met," says an MRHA official. Furthermore, groups like European producers of APIs, whose grievances about low-quality imports have helped trigger the drafting of the directive, are still complaining that the FMD is not tough enough on GMP standards for non-EU APIs. 

The primary intention behind the directive is to establish a secure pharmaceutical supply chain with rules stipulating quality requirements extending from starting materials to the distribution and packaging of medicines. European manufacturers of generic medicines have, however, warned that the legislation's aim to cover both counterfeit and substandard products could push up the cost of low-priced, off-patent pharmaceuticals at a time when European governments with austerity budgets are trying to reduce healthcare costs. Because of the range of the FMD, the EC has been given the power to draw up "delegated acts" or additions to the legislation that do not have to be approved by EU legislature, but have to be adopted by member countries without any changes. These extra details cover areas such as Internet marketing and security features on medicines packaging, on which the EC has been issuing drafts in the form of concept papers for consultation.  

A key area to be covered by a delegated act is GMP rules on active ingredients. A concept paper on proposals on principles and guidelines on GMP for active substances has completed its consultation process. At the moment, the drawing up of a delegated act on the guidelines is being handled by an expert group, in which all member states are represented. "The delegated act will be adopted and published by the Commission in 2013," an EC spokesperson said. 

The paper's main suggestion is that a 2003 directive that gave legal backing to GMP guidelines on finished medicinal products should be extended to cover the EU GMP guidelines on active substances. "This approach would bring coherence in terms of the regulatory setting for both medicinal products and active substances," the EC said. "The principles and guidelines for GMP would (as a result) be the same during the manufacturing of active substances as well as medicinal products."  

There are, nonetheless, parts of the 2003 legislation that would not apply to the GMP guidelines on active substances; for example, marketing authorization for the manufacturing of pharmaceuticals and responsibility for ensuring adherence to GMP standards being allocated to a specific "qualified person" within a drug company.  

The EC has proposed that the active substance guidelines would not only apply to APIs, but also to starting materials with an obligation placed on API manufacturers to ascertain that these materials are sourced from premises claimed by the supplier. In addition, the EC suggested that the delegated act on the guidelines would have to be transposed into national legislation within six months of publication so that it can be enforced within nine months. 

Several groups within the pharmaceutical industry have criticized the EC proposals. Some are particularly concerned that by bringing together the two sets of guidelines, the Q7 standards for API GMP drawn up by the International Conference on Harmonization (ICH) will be undermined. ICH Q7 provides a basis for international agreement on GMP standards on active ingredients. 

The European Federation of Pharmaceutical Industries and Associations (EFPIA), which represents Europe's research-based drug companies, said that bringing the two guidelines together would make interpretation of GMP both ambiguous and complicated. Instead, EFPIA suggested placing the active substances guidelines in a separate section in the 2003 directive or putting these guidelines into a new directive. EFPIA stated that the obligation on API manufacturers to verify the source of starting materials was unenforceable, while the European Generic Manufacturers Association (EGA) thought that it was beyond the scope of the existing EU guidelines for active substance GMP. 

Several groups involved in the consultation warned that adapting to the new framework would require a period of more than nine months after publication, particularly for API producers outside the EU. Some suggested that this period between publication and enforcement should be as long as two years, which could result in the FMD not being fully implemented until 2015. 

Another controversial aspect of the legislation is the need for imports of active substances into the EU to be accompanied by written confirmation from a national regulatory authority that the plant manufacturing the API complies with GMP standards equivalent to those in the EU. Proposals on this subject were brought forth by the EC in a public consultation. According to the EC, "equivalence" to EU standards is defined as adherence to ICH Q7 and the active substances GMP standards of the World Health Organization (WHO). Under the FMD, written confirmation will have to be provided with API shipments from July next year. 

However, the EC is also planning to operate a two-tier system under which some countries will be exempted from having to provide written confirmation on the grounds that their GMP regulatory and monitoring standards are equivalent to those in the EU. To date, Switzerland, Israel, Singapore, Brazil, and Australia have requested to be assessed for exemption. Earlier this year, it was widely reported in the media that India and China, which together account for approximately 80% of API imports into the EU, considered lodging a complaint with the World Trade Organization (WTO) that the written confirmation requirement was an unfair barrier to trade. India seemed to be backtracking in September when the country's Pharmaceutical Export Promotion Council (Pharmexcil) announced that the Indian government would be shortly setting up a competent authority to certify the quality of API exports to Europe.  

In a comment on the EC's concept paper on GMP guidelines for active substance, the China State Food and Drug Administration (SFDA) said that APIs should be given the same manufacturing authorization as the production of medicines. Furthermore, the SFDA said that the EU should launch its own compulsory GMP inspections for active substances so that it can issue its own GMP compliance documents. 

SFDA's line on GMP is similar to that being pursued by the EFCG. EFCG has been recently reiterating its stance that the only sustainable solution to the EU's problems with substandard imports of active substances is the mandatory inspection by EU regulatory authorities of non-EU active substance plants or by those whose competence is acknowledged through mutual recognition agreements (MRAs). "The implementation of mandatory inspections, via an MRA approach, is a relatively small price to pay to guarantee that the quality of APIs meets the EU standard," said Gian Mario Baccalini, chairman of the EFCG pharmaceutical business committee, in a recent group press conference in Madrid.  

EGA estimates the extra costs of a strict regime for vetting GMP standards for imported APIs to be as much as €1 billion (US$1.27 billion). Coupled with possible shortages of active substances if Asian producers cease their exports to Europe, this factor could decide the outcome of the current discussion about the final implementation of the FMD. 

is a freelance writer based in Essex, UK, 

European Beat

The EU fine-tunes the Falsified Medicines Directive.

Falsified Medicines Directive Takes Shape in Europe

The biopharmaceutical industry continues to evolve with expectations of a positive future. Much of this anticipation is driven by pressure for the next new thing, demand for better bioprocessing technologies, and by concerns about weak development pipelines. In response, most large pharmaceutical companies are now devoting increasing development efforts on biopharmaceuticals rather than small molecule drugs. Some are now spending 40% or more of their R&D budget on biopharmaceuticals.  

Innovation resulting in improved productivity continues unabated and is a primary driver for many of the current biopharmaceutical trends. Innovation speeds discovery, drives down costs, and improves productivity. The current situation in the biopharmaceutical industry is exciting enough, with biosimilars, new technologies, personalized medicines, and opportunities in emerging markets. The industry, however, believes more opportunities for advancement are coming in the near future. Innovations are driving a number of major industry trends; and many ongoing trends, themselves, are driving innovation. 

PHOTO CREDIT: DAN WARD/MARIA TOUTOUDAKI/BUENA VISTA IMAGES/GETTY IMAGES 

Biosimilars (and biobetters) are driving trends as well. With more than 700 biosimilars/biobetters in the development pipeline, there will be many more biopharmaceutical manufacturers and products, perhaps as many as a dozen or more for each emulated reference product. This pipeline will mean a lot more new biopharmaceutical industry players, ranging from virtual and foreign to the largest Big Pharma companies, with many new manufacturers and facilities. These competitors are expected to compete on the basis of price; therefore, low manufacturing costs will be required. This low-cost requirement is driving many companies to seek out and adopt bioprocessing innovations that achieve the most cost-effective manufacturing. 

Some of the biopharmaceutical trends coming in 2013 support a future vision that includes:   

increasing number of global biopharma facilities 

more biological products, many with smaller niches

adoption of single-use systems at clinical and commercial scale

continuous processing, including perfusion

high-tech expression systems and other genetic engineering advances

automation, monitoring, and process control

modular facilities adaptable to new enabling technologies, with the ability to repurpose spaces. 

To gain perspectives on these and other trends, BioPlan Associates asked the 425 global subject matter experts and senior participants on its Biotechnology Industry Council to evaluate the current trends in bioprocessing and biopharmaceuticals. The more than 100 trends identified were categorized as follows:  

22% single-use implementation and improvements

30% others: product platforms, cost reductions, materials sourcing, supply chain regulatory compliance, biosimilars, etc.

This relatively evenly distributed breakout suggests that the industry expects advancements in virtually all areas (see 

DEMAND FOR A BETTER TECHNOLOGY EVALUATION PROCESS

Rapid and cost-effective evaluation of new technologies is crucial to the industry achieving this expected progress. Evaluating new technologies in the regulated pharmaceutical environment can be slow and costly to both innovators and to the end-users doing the beta or evaluation testing. To reduce these challenges, BioPlan Associates has implemented a New Technology Evaluation Program (NTEP) to help kick-start innovation in bio/pharmaceutical manufacturing. The program helps ensure that the best technologies are eventually adopted by industry, even when their originators are small or resource constrained.  

The program benefits suppliers by providing high-value evaluations, rapidly getting new products into the right hands for testing, and coordinating multi-site testing with integrated, compiled data and reporting. The program benefits those testing new products by giving them access to the most promising and cutting edge technologies while eliminating the need to deal with multiple contacts from multiple suppliers. This process can provide available data from other commercial evaluations as an unbiased resource, and can rapidly integrate, publish, and disseminate these findings to industry. 

The key trends in this industry are being driven by the need for new efficiencies, greater quality, and cost reductions in manufacturing processes. To remain competitive, especially as biosimilars and biobetters evolve, better ways of evaluating new technologies are needed that cut down on time to market and streamline the overall testing process. There is an increasing demand in the industry today for improved productivity, cost reductions, and higher quality, as companies continue to struggle to do more with fewer resources. Many are relying on suppliers' innovations to advance production processes for current biologics, emerging biosimilars products, and for the production of biologics in emerging markets using flexible processes. The industry's suppliers/innovators continue to demonstrate their commitment by investing in development of new technologies. Concurrently, end-users' demand for improved productivity continues to fund these improvements. More streamlined new product and technology evaluation programs, coordinating trial users throughout the industry, promise to facilitate innovation and its dissemination. 

 is president and managing partner at BioPlan Associates, Inc., 

What the industry's future holds and what needs to be done to get there.

The Future of Biopharma

The health ministry of Brazil recently signed an agreement with US-based Bristol-Myers Squibb to obtain its patented production technology to locally develop the antiretroviral drug atazanavir sulfate. The drug is used, together with others, to treat HIV-infected patients in Brazil.  

The process of transferring the drug's production technology will take place until the end of 2016, while domestic production is planned to begin by 2017, according to the country's health ministry. Before the patent for atazanavir (held by Bristol-Myers Squibb) expires by the end of 2017, Brazilians will be trained by experts at the company's USA-based facility on how to produce the drug. The drug will be produced at a Rio de Janeiro-based pharmaceutical plant named Farmanguinhos, operated by Oswaldo Cruz Foundation (Fiocruz). 

Atazanavir is distributed to approximately 45,000 patients by the public health system, which corresponds to approximately 20% of all the HIV-infected patients cared for under this system. According to data from the health ministry, the government of Brazil spends approximately R$86 million (US$41.4 million) annually to purchase the drug abroad. When atazanavir, which is taken daily by patients, starts being produced domestically, the country is expected to save a total of R$385 million (US$185.3 million) in five years, the ministry added. 

Starting in 2013, the drug will be distributed nationwide inside locally-produced packaging. Output from the new domestic plant will add one more drug to the locally-produced drug list for HIV-infected patients, totaling up to 11 drugs produced in Brazil from the 20 medications offered at no cost to HIV-infected men and women in Brazil. According to government figures, some 127 million capsules will be produced annually in Brazil by 2017.  

Atazanavir is a protease inhibitor. This class of drugs is used to treat or prevent infection by viruses. Atazanavir is administered in combination with two other antiretroviral agents to prevent the risk of developing drug-resistant mutated viruses.  

According to the Oswaldo Cruz Foundation (Fiocruz), the plan is to meet at least 50% of the demand for atazanavir sulfate by 2015. Fiocruz says this deal guarantees that Farmanguinhos will set a final price for the drug that is 5% lower than the current price.  

The Brazilian government will not pay for the technology but guarantees purchasing the drug from Bristol-Myers Squibb until the end of the deal in 2017. According to the health ministry's AIDS department, this is the first deal of its kind for developing domestic production of a drug whose patent has not yet expired.  

The Brazilian Interdisciplinary Aids Association (ABIA) disagrees with the details of the deal, and has questioned the need for the government to pay such a high price for a drug that will only be produced in 2017. The health ministry, on the other hand, says that prices will drop gradually. Minister Alexandre Padilha has publicly defended new deals with private laboratories in order to maintain the local HIV/Aids treatment program, which cares for approximately 217,000 Brazilians.  

Zidovudine (AZT), one of the first drugs to treat HIV, was made free for all Brazilian patients in 1991. In 1996, when antiretroviral treatments were developed, the drugs were offered for free to local patients, causing national AIDS mortality rates to decline, as observed by the 1992 International Conference of AIDS. By 2002, figures from the Brazilian health ministry showed that the drugs had helped to save more than 1.1 billion people by preventing deaths and hospitalizations.  

According to the World Health Organization (WHO) guidelines of 2010, the levels of treatment coverage in Brazil were more typical of a developed country than a middle-income nation such as Brazil. Specialists, as well as WHO, say that Brazil's program success is based on the fact that the country has produced various AIDS drugs locally. Currently 50% of the drugs offered by the public health program are produced domestically.  

Brazil has complied with the international Agreement on Trade Related Aspects of Intellectual Property (TRIPS) since 1996, which limits the production of generic drugs that have been patented abroad. However, various generic drugs produced in Brazil were patented before the agreement and can be legally copied (1).  

In other cases, such as for atazanavir, Brazil has obtained the drugs internationally, and was forced to put pressure on the pharmaceutical companies to lower their prices. In order to force price drops, the country has used a clause found in the TRIPS agreement, whereby "compulsory licenses" are given to developing countries, allowing them to produce generic versions of drugs when the government considers it to be a public health emergency.  

The government had never actually issued a "license" despite obtaining price reductions. However, in 2007, Brazilian President Luiz Inacio Lula da Silva announced that the country would issue a compulsory license for a drug named efavirenz, patented by Merck. The decision received mixed reaction. AIDS activists supported the decision, while Merck, as well as other pharmaceutical firms, said the move was unfair and could impact new investments in drug research and production in Brazil.  

On the other hand, there is no doubt that the move has saved lives, while analysts say that the tactics have influenced the market globally by increasing competition and driving costs down. A publicity poster released earlier by the health ministry said, "Local manufacturing of many of the drugs used in the anti-AIDS cocktail permits Brazil to continue to control the spread of AIDS. The drugs industry sees this as an act of war. We see it as an act of life."  

is a business writer based in São Paulo, Brazil. 

Global Reports

Brazil to locally produce HIV/AIDS antiretroviral drug atazanavir.

Report from Brazil

In this fifth part of a series of primers with training experts from the National Institute for Bioprocessing Research and Training (NIBRT), Operations Consultant Ray O'Connor discusses the basics of biopharmaceutical facility design and operation. NIBRT provides training, educational, and research solutions for the international bioprocessing industry in state-of-the-art facilities. Located in South Dublin, it is based on an innovative collaboration between University College Dublin, Trinity College Dublin, Dublin City University, and the Institute of Technology Sligo.  

 Why is aseptic processing crucial for injectables, such as vaccines and other biologic-based products? 

 Certain pharmaceutical products must be sterile as they're introduced to the patient by injection because this mode of drug delivery bypasses the body's natural defenses. Therefore, with biologics, there is an increased risk of infection being introduced to the patient. Sterile drug products can be manufactured using two techniques: terminal sterilization or true aseptic processing. Terminal sterilization usually involves heat or irradiation; however, quite a large proportion of vaccines and biological-based drugs can be destroyed by exposure to heat or irradiation, hence, the requirement to manufacture in an aseptic manner. 

According to the FDA guidance for industry on sterilized drug products produced by aseptic processing issued in September 2004, in an aseptic process, the drug product and container/closure are subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is crucial the containers be filled and sealed in an extremely high-quality environment. Therefore, aseptic processing involves more variables than just terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product must be subjected to various sterilization processes. 

Similarly, in the European Union, GMP guidelines state that the manufacture of sterile products is subject to special requirements in order to minimize the risk of microbial contamination and of particulate and pyrogen contaminant. So, as a result, much of the aseptic process depends on the scale of training and attitudes of the people involved. 

It's particularly important that this type of manufacture strictly follow established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects would not be placed on any terminal process or finished product testing. To summarize, aseptic processing is minimizing the risk of introducing any microbial contaminant into your product as you move it through the manufacturing process. 

 Aseptic processing and the term "fill/finish" are often used interchangeably throughout the industry. Are these two terms truly the same or are there unique steps for each? 

 Fill/finish is a discrete part of the manufacturing process. If you have an upstream or downstream process, that will be where you manufacture your active ingredient. Fill/finish is the filling and packaging part of this process. It comes after the product has been manufactured and is ready to be put into its final package container that the patient will see. 

Aseptic processing refers to the various techniques that go into ensuring that the product is free of contaminants, thereby reducing the risk of infection to the patient. Aseptic processing, is the processing of drug components, drug product containers, and excipients in a manner that precludes microbial contamination of the final sealed product. 

 What types of product contamination can occur during bioprocessing? 

 Contamination in the biopharmaceutical industry can have serious health effects on the patient, so it is crucial to monitor and avoid. The different types of contamination one might find include bacteria, which could cause an infection in someone who is already ill, thus making the actual condition worse; chemicals, which could cause poisoning or other effects on the patient; and physical contamination, which could be particulates that can cause serious problems, such as cuts, blockage, or even death in the patient. If work is being done in a multiproduct facility, cross-contamination from one product to another can occur as well.  

With regard to bacteria, viable particles are of particular concern in the biopharmaceutical industry. If they enter a product, they will multiply rapidly (e.g., they can double in under 20 minutes in the right conditions). If bacteria get into the system, they can actually overpower the product being made, and you may end up losing the product. 

Most bacterial contamination comes from human beings.  Hence, it's vitally important that, when staff walk into a cleanroom or work in a cleanroom, they be appropriately garbed to ensure minimal exposure of skin to the environment. 

Overall, there are five main routes of entry into the product of any type of contaminant. First is raw materials. All the raw materials used in the manufacturing of the product are potential sources of contamination. Quality systems associated with the supply and release of raw materials into the manufacturing processes are critical. A second source is the plant. Poorly sanitized equipment can lead to contamination. A third source is the environment. The cleanroom design, as described below, must be executed properly. Fourth is movement of personnel. It's important that people move in a controlled and deliberate fashion in a cleanroom. Erratic behavior can generate particles. A fifth source is gowning. People represent 80 to 90% of common contamination sources. Proper gowning behavior and training in aseptic technique and aseptic processing is vital. 

 What type of equipment is typically used for aseptic processing? 

NIBRT's Ray O'Connor provides an overview of aseptic processing.

BioPharm International-01-01-2013

Accelerating Change Marks 2012 for Life Sciences

A Look Ahead at BioPharma Manufacturing and Regulation

Epigenetics Drives Pharma Innovation

A Look Ahead in Biomanufacturing

Drug Quality at Center Stage for FDA and Manufacturers

Falsified Medicines Directive Takes Shape in Europe

The Future of Biopharma

Report from Brazil

Aseptic Processing: A Primer

Biologics: What Does the Future Hold?

Polishing Complex Therapeutic Proteins

The Future Quality Laboratory

Bioconjugates: The Adaptable Challenge

Offshoring Biomanufacturing

BioPharm International, January 2013 Issue (PDF)