Articles

BioPharm International, April 2012 Issue (PDF)

The strong boost to biotech stocks in the first two months of the year has energized the sector and allowed companies to make deals and raise funding. Of the 340 life sciences companies trading at or above $1 at the end of 2011, 253, or 74.4% of them, are trading higher after the first two months of the year, while 25% of those companies are up more than 25% so far this year.  

There has been a sharp improvement in the price of life-sciences stocks as economic news in the US has been generally positive this year, actions in Europe to address the debt crisis advance, and news within the sector is encouraging. All of the Burrill Life Sciences Indices have posted gains for the year with the flagship Burrill Select Index the strongest performer, climbing 15.5% through the end of February. The Dow Jones Industrial Average, up 6% for the same period, closed above the 13,000 mark in February, the first time since 2008.  

We are still in an environment where markets can turn quickly in response to negative news. Smart companies will take advantage of opportunities to secure financing and get deals done. Life-sciences companies through secondary offerings raised $1.4 billion in the first two months of 2012 through 29 financings, 23 of which were completed by therapeutics companies. 

Roche's hostile $5.7-billion bid for the tools and sequencing systems company Illumina reflected strong dealmaking activity for the life sciences at the start of the year. The wrangling between Roche and Illumina is likely to go on for months. The deal reflects Roche's efforts to build itself into a personalized medicine powerhouse and its belief that sequencing technology will eventually migrate from the laboratory to the doctor's office. 

Some of the year's biggest acquisitions have been traditionally structured takeovers. Bristol-Myers Squibb agreed to acquire hepatitis C drug developer Inhibitex for $2.5 billion. Amgen said it would buy Micromet, which is developing a new class of drugs that enlist the body's T-cells to battle cancer, for $1.2 billion. But a number of transactions of privately held companies included large milestone payments.  

Privately held companies that are being acquired today often find they will have to wait to reap the rewards of a transaction. In the absence of a vibrant initial public offering (IPO) market, buyers have the upper hand and often insist on sharing risk. Increasingly, the structure of these agreements may borrow from those of partnerships and may mean investors seeking exits will have to be patient to realize their full return. 

Celgene agreed to acquire privately held Avila Therapeutics for $350 million plus milestones that could push the total value of the deal up to $925 million. Dainippon Sumitomo said it would acquire privately held Boston Biomedical, a developer of oral therapies that target cancer stem cells with its lead candidate in late-stage clinical testing, for $200 million in upfront cash and milestones that could push the total deal value to $2.6 billion. Biogen Idec said it would acquire privately held Stromedix, a developer of therapies for fibrosis and organ failure with its lead candidate in mid-stage clinical testing, for $75 million upfront and milestones that could push the total deal value to $562.5 million.  

A total of six companies completed IPOs on US exchanges in the first two months of 2012, but investors still lack enthusiasm for new issues in the sector. Five of the six issues came below their target price range. Only Verastem, a preclinical therapeutics company developing drugs that target cancer stem cells, managed to price at the midpoint of its $9 to $11 target, raising a total of $55 million by selling shares at $10 each. Existing investors committed to purchasing nearly a third of the offering. The company is led by Christopher Westphal, the former CEO of Sirtris Pharmaceuticals, which he sold to GSK in 2008 for $720 million. 

Renewable Energy Group raised $72 million in the first life-sciences IPO of the year. The biodiesel producer sold 7.2 million shares at $10 each, well below its range of $13 to $15 a share. The therapeutics companies Cempra Pharmaceuticals and ChemoCentryx, the digital health company Greenway Medical Technologies, and the agbiotech Ceres all went public in February. Collectively, these companies that went public in the first two months of the year hoped to raise as much as $505.7 million, but raised $354.4 million, nearly 30% less than they sought. They also needed to sell 10% more shares than they set out to sell in order to raise what they did. 

Venture financings also got off to a strong start with companies raising $1.8 billion globally in January and February, a 22% increase compared with the same period a year ago. Among the largest financings so far was startup Warp Drive Bio's potential $125 million in funding, $75 million of which is equity financing tied to the achievement of milestones. The company, backed by Third Rock Ventures and the drug giant Sanofi, is using proprietary genomic tools to search inside microbes for potential new natural product drugs. The deal comes with a built-in exit for investors, by requiring Sanofi to buy Warp Drive should it meet its milestones. 

On the regulatory front, the Obama Administration's proposed budget for FDA in fiscal year 2013 calls for $4.5 billion, a 17% increase in funding. The increase is expected to come almost entirely from industry user fees. User fees overall are expected to fund about 45% of the agency's budget. The government's contribution to funding FDA will essentially remain flat under the proposal.  

It is critical that Congress move quickly to pass the renewal of the Prescription Drug User Fee Act (PDUFA) and not allow the legislation to get bogged down in extraneous issues. User fees provide nearly two-thirds of the funding for drug reviews today. They do not, however, address the chronic underfunding of the agency, which Congress will also need to address at this time when there is continued pressure to cut spending. 

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

Burrill on Biotech

Better news about the global economy buoys life-sciences funding.

A Strong Start to 2012

Increasing numbers of biological drugs are being developed, driving a strong demand for innovative injection technologies. This need extends far beyond the traditional syringe, and companies are now packaging their biological products into more advanced products, such as autoinjectors. Although these devices may be more expensive than basic syringes, they offer the potential for patients to self-administer a therapy outside of healthcare settings. 

The biopharmaceutical industry is under increasing pressure to justify the cost of therapies, particularly if they want them to be included in national healthcare programs. Self-administration is one way of significantly reducing costs and offers further benefits, such as being more convenient for the patient. Here, industry experts discuss the importance of self-administration and what technologies are best suited to this cause.  

 Why has patient self-administration of therapies become such an important driver in the healthcare and biopharmaceutical sectors? 

Self-administra-tion therapies have become an important driver in the healthcare and pharma sectors for a number of reasons. Empowering patients and giving them the freedom to take medications at home or while on the road is more than just a trend; it is vital to the economic viability of healthcare systems worldwide. Enabling patients to self-administer their medication means that healthcare practitioners can use their time more effectively. Most importantly, it has the potential to save money as fewer trips to the hospital can amount to millions in healthcare cost savings. 

This trend has had a significant impact on the evolution of injectable drug delivery technologies. Many people are familiar with self-administered medications, such as inhalers for treating asthma, but few individuals, other than diabetics, have experience of injecting themselves using a syringe. As a result, drug delivery companies have had to develop devices that are both intuitive and safe. With the increasing number of approvals for new biologics in recent years, demand will also be quite strong for autoinjectors and pen injectors. However, developing and producing an injection device that is safe, ergonomic, easy to use, and accurate enough for a patient to self-administer involves meticulous designs, innovative technologies and consistent manufacturing. For example, the spring mechanism inside an autoinjector controls the force and timing of the injection and is designed to accommodate the desired injection specifications, while the outer shell of the device may be affected in size and design by the primary container inside and human factor constraints. Once a proven mechanism is designed, ensuring consistent manufacturing then becomes vital because quality needs to be built into every device produced. At this time, there are only a few companies in the world that can design, develop, manufacture, and assemble these pen-like devices, and these companies will need to work closely with biopharmaceutical partners to ensure that patients get the best drug-delivery devices possible.  

 There is a growing prevalence of individuals living with chronic disease in the world. However, the good news is that pharmaceutical medicine is working in order to keep pace with this increase. Advancements in therapeutic agents and medicine have resulted in the availability of more sophisticated biologics for the treatment of many chronic diseases. In addition, there is a growing trend in self-administration medicines where patients can self-medicate. This trend has supported the need for further advancement in self-injection technology.  

These biologics often have complex technical requirements for injection. For example, they have higher volume or are more viscous, so the technical specifications of these biologics are more challenging and require complex delivery technology. This trend explains why self-administration has become so important. In this respective, device manufacturers must be proficient in patient-centric design and should consider the ergonomic and human factors.  

Integrating those biologics with the right delivery system has become critical, not only from a technical specification standpoint, but also from a competitive perspective. The competitive dynamics for new drugs in different fields will require different considerations in the selection of an injection device. Patient consideration is also a factor; for example, a patient with rheumatoid arthritis may have dexterity issues, requiring certain design specifications to make the device easy-to-use. In this respective, it's important for device manufacturers to be proficient in patient-centric design and to consider the ergonomic and human factors.  

Integrating the primary container with the secondary device successfully is also critical. Companies offering self-administration technology need to have that expertise in order to improve performance of a drug-device solution, reduce risk of failure, and accelerate speed to market.  

Rising healthcare costs mean that treating patients is becoming more and more expensive. If a patient can self-administer their medication then this reduces the time they need to spend with a healthcare professional and, thus, reduces cost. Most medications can be taken orally, but many peptides and proteins have to be injected to ensure they are not damaged by the acidic environment in the gastrointestinal tract. If a patient is to be trained to self-inject, however, then the technology needs to be simple to ensure that it is operated correctly. In addition, medication compliance is a serious issue with many patients; the easier and more convenient the product is to use, then the more likely the patient is to take their medication. These needs for lower cost of goods, ease of use, and convenience are also shaping the evolution in drug delivery technologies suitable for self-injection. 

 Self-administered products currently account for about half of the of therapeutic biologics market. The simple reason for this is that more biological agents requiring injection are being used in chronic conditions, such as rheumatoid arthritis, psoriasis, and multiple sclerosis. Since it is both costly and inconvenient for patients to go to their healthcare provider to administer these biologics daily or weekly on a chronic basis, the burden falls upon the patient. Fortunately, technologies exist that make the self-medication process as comfortable and easy as taking a pill.  

 Which technologies are most suited for self-administration and why? 

As patients are not medically trained, empowering them to feel comfortable enough to properly inject themselves requires a device that can make them feel safe both mentally and physically. To address this, devices with special features and technologies, such as the autoinjector, are often designed so the patient never sees the needle and may finish administering the drug within a relatively short period of time. While reactions to physical pain may vary for each patient, the mental pain connected to visually seeing a needle inject can be reduced, especially when the patient also has control over when to initiate the injection. As a result, autoinjectors are becoming a commonly accepted drug-delivery technology for self-administrated injectable therapies. 

Which injection technology is gaining the most ground in the market? ( POLL, BIOPHARM INTERNATIONAL ONLINE, 2012)			

However, it is important to note that each patient needs to be properly trained on how to use such devices and they must be provided with very clear instructions for use. The use of picture-oriented instructions and video has been a good step towards addressing this issue. Another potential drawback related to self-administration technology is the cost associated with developing a drug delivery device and the actual cost of each device. At this time, it is much easier for larger biopharmaceutical companies, which have the necessary financial resources, to initiate these programmes. Additionally, the market value of the drug must be able to justify the cost of the device. 

The most suitable technology depends on many factors: 					

Technical specifications: A high volume or highly viscous biologic, which may be infused in a hospital setting, may require a patch injector/patch pump to deliver the medicine in the home setting. It is also important that careful consideration is given to the delivery of drugs that have a unique viscosity or volume that needs to be delivered. 

Competitive dynamics: Pharma and biotech companies are increasingly looking to their device as a source of differentiation. 

Patient factors: Certain patients will have certain needs and preferences given their condition and how mature that market is with devices.  

Frequency of administration: Whether a drug is injected on a daily basis, versus a weekly or monthly basis, is also an important factor (along with the cost factor). 

All these considerations are crucial factors in selecting the right technology. For device manufacturers, it's important to have expertise across a range of delivery platforms and technologies in order to meet the above needs for customers. 

Autoinjectors and pen-injectors have been designed for self-administration. These technologies are widely used, work very well, and are far easier to use and more convenient for patients than a standard needle and syringe. However, they still use a needle, which brings about issues related to needle reuse, needle disposal and needle phobia. In addition, many drugs that have to be injected are not very stable in a liquid formulation. Some biologics are stored in a powdered form to provide better stability, but they need reconstituted prior to injection, which adds to costs and treatment complexity. Liquid jet injectors avoid the issues with needles, but still incorporate a liquid formulation. They are also very expensive and have not achieved significant market traction.  

None of the technologies mentioned really provide a simple way to inject a controlledrelease formulation. Typically, a controlledrelease formulation comprises polymer microspheres in a solution, but because of the issues of needle clogging these expensive products are normally injected by specially trained healthcare professionals. Other injection technologies, such as solid dose injectors and microneedle patches, are in development, but they are not yet ready for routine patient use. 

 The key to considering self-administration technologies is to focus on the patient. Our company, for example, is not committed to any particular injection technology type. Companies should design the technical solution that best fits the circumstances in a given therapeutic application. In particular, it's important to consider the patient's needs and limitations in the target disease condition, and then to look at how best to apply technology to make the patients' self-injection experience most acceptable and successful.  

 What extra steps do companies need to take to have a drug approved for use in a self-administrative form? 

 Generally, a biological drug will need to be first approved as an independent drug, regardless of whether or not it is to be used in a self-administrative form. For the device constituent of a combination product, the medical device manufacturer will generally support biopharmaceutical companies by filing a master access file and/or 510K to help with the customer's submission process. 

Self-administered biological drugs can generally be placed inside a primary container such as a prefilled syringe or cartridge, which will then reside in a device that possesses the mechanical system to perform the injection. The two together are a drug/device combination product that, although not yet official, has been identified by FDA as an area that requires regulatory guidance. Companies that wish to introduce a drug in a self-administrative form will need to start regulatory planning at a very early stage to ensure that approval times do not become a potential bottleneck to a successful global launch. 

The complexity of clinical development and the regulatory process is increasing, and companies must take every appropriate step to ensure that their products are in full compliance. In addition, companies have to bear in mind the lead times for regulatory processes. 

Any pharmaceutical product in development must undergo clinical trials. In addition, a product that is to be self-administered needs to undergo trials with volunteers and patients to ensure that the delivery system can be safely used by different patient groups in a non-clinical setting. Some of these trials may be userhandling trials, with no drug involved, just to demonstrate that the volunteer can safely use the delivery system. These trials are far simpler and cheaper to conduct than active drug trials. Once trials have been carried out for a first product, then further trials to investigate the handling and use of the delivery technology may only be required if the product is for a different patient group (e.g., elderly patients or patients with rheumatoid arthritis who may struggle to handle a delivery device). 

 How are designers and manufacturers of selfadministration devices approaching the challenges of ensuring sterility and accurate dosing outside of healthcare settings?  

 Accurate dosing is achieved through specially designed delivery mechanisms, rigorous testing, and precise manufacturing. For example, in a mechanical device, highly accurate dosing can be achieved using the appropriate spring technologies. Sterility is ensured again by designing a suitable device for the primary container selected by the biopharmaceutical partner; for example, a prefilled syringe that is assembled into an autoinjector under controlled procedures in line with related regulations and standards.  

 First, it is important to consider the fact that the product will be used without the direct supervision of healthcare professionals. Companies should conduct extensive background research and ethnographic studies to fully understand the patient and the likely environment of use. The design can be established based on the findings of the investigations and the pilot device can be tested with the patient in a variety of expected actual-use settings to confirm that the product will perform as intended. 

 The ability to offer adjustable doses, for example in diabetes, has great potential. What progress is being made in this area? 

We see progress in the development of unique and robust mechanical designs that can accommodate the need to offer adjustable doses. This allows for the device to remain cost effective, as some drugs do not have a market price that justifies complex drug delivery technology. However, we do see a renewed drive to incorporate electronics into some of the more expensive devices, which is perhaps inspired by the trend of cutting-edge designs related to smart phone and tablet innnovations. 

Technologies that provide dose adjustability have already been developed and commercialized. Cartridge-based, multidose pens, for example, have achieved excellent acceptance in the administration of insulin. Companies are now working on improving dose adjustability and confirmation of correct dose by applying advanced electronics that aid ease of use and add intelligent features. 

 What are the challenges of manufacturing devices suitable for self-administration?  

 Main challenges include anticipating numerous device usage scenarios against which to test the device, ensuring quality consistency, and providing robust production lines to respond to mass production needs. To address these challenges, device manufacturers should work closely with biopharmaceutical companies to better understand end-user feedback and use it to more accurately reflect and construct usage scenarios for device testing. In addition, device manufacturers need to continually invest in the latest in-house capabilities and processes. 

 In most cases, customers will want some level of customization; they rarely want off-the-shelf devices. The challenge for manufacturers is delivering these differentiated customized devices at an affordable cost—for both the customer and the manufacturer. Companies are utilizing modular platform technology to develop and customize devices. 

The market place is also uncertain and highly dynamic. Manufacturers are business-to-business organizations selling devices to pharma and biotech companies. If their business changes, suffers, or is impacted, so is that of the device manufacturer. This requires methodical portfolio management and operational planning to optimize the business. 

When customers choose a device partner, they make device-based decisions, but also company-based decisions. They will be looking for factors such as a global reach and full service support, including support with global registration, and the ability to offer a differentiated benefit. 

 The most important aspect of making devices for self-administration is ensuring that they perform as intended in the hands of the patient. That means we need to first understand the patient. There are well-established ethnographic research methodologies that can be used to learn about patients and the environment in which they will use medicine. However, even today, many companies delay addressing this aspect in clinical programs. As a consequence, products have been launched in a configuration that is clearly not well suited for self-administration. Only later, after the product fails to meet market expectations, does the company initiate programs to address the needs of self-administration. It can be argued that keeping the configuration as simple as possible (e.g., in a vial) reduces development risk and cost,but this must be balanced against the resulting market risk, particularly when competitors introduce a product that better addresses self-administration challenges. 

 Needle-free devices seem to have lost some traction in the market, why might this be the case?  

 At this time, innovations in drug delivery devices with needles continue to move forward in addressing the growing need to administer biologics. Autoinjectors and pen injectors have been proven to be effective, safe and reliable devices. With this established track record, needle-based devices will continue to strengthen their position in the self-administration market.  

There are two factors that may have contributed to this. First, needle-free technology can be more complex, and there are various safety and operational challenges. Secondly, needles are now available that are very fine, as well as being shorter and less painful than previous generations of needles. Self-injection devices also continue to become more advanced. 

 The needle-free devices that have been commercialized are all liquid jet injectors. These devices work by firing a tiny jet of liquid through the skin. The concept was first patented many decades ago and niche products have been on the market for years. The products are either disposable devices or reusable actuators with a singleuse drug component.  

The reusable devices have been used in the past in the developing world and in the military for vaccine studies, but lost favour when the potential for cross-contamination between patients was identified. Single–use jet injectors are expensive and have never been widely used. I believe this is because the benefit of needle-free technology does not outweigh the increase in costs over alternative technologies. Liquid jet injectors will continue to be used for a number of niche products, but they will struggle to increase their market share. However, other technologies in development, some of which are needle-free, are likely to get good market traction as they are commercialized. 

It's not a matter of needle-free having lost traction; it's a matter of the matching the technology to the needs of the patient population. I have no doubt that we will see greater applications of needle-free technology as additional biologic drugs are developed for populations best served by that approach, such as pediatric patients.  

 What recent groundbreaking innovations have you seen in the area of selfadministration devices? 

Ground-breaking is a powerful statement. I have seen a number of significant innovations in the area of autoinjectors over the past seven years, particularly when it comes to the look and the size of devices. Autoinjectors are more discreet and are now available in sizes that are not much bigger than a marker pen, which allows patients to travel and use the devices whenever and wherever they wish without feeling embarrassed. Industrial designers have also worked closely with human factors engineering groups to make several devices (launching soon) that are completely customized to suit the needs of a specific patient group. For example, if rheumatoid arthritis patients have difficulty removing a cap, industrial designers can overcome this by engineering a new solution for cap removal. These may not be groundbreaking, but to me they represent a significant shift in the way devices are being made—working more with patients at the earliest stages and making drug delivery devices that are simple and intuitive. 

 The innovations I am very impressed with are the patch injectors/patch pumps. This new technology is allowing companies to deliver therapies, which historically have been infused in a hospital setting, in the privacy and convenience of the patient's home. For example, technology is in development that can allow patients to have continuous infusion at home with a ready-to-use hands-free, device. 

Features

Industry experts discuss the benefits and challenges of self-administration of injectable therapies.

Pointed Debate

Adjuvants are becoming more common in vaccine and other drug formulations to increase therapeutic response. Some of these substances, however, are close enough in size to bacteria that they are unable to pass through sterilizing-grade filters. Others have low surface tension that can reduce a filter's bacterial retention. As a result, adjuvants can cause premature plugging of filter membranes and reduce filter capacity. BioPharm International spoke to several industry experts to gain insight on resolving these technical challenges. 

  Novel adjuvants are often based on emulsions or liposomes, which are suspensions of small particles made up of surfactant or lipid particles. Because these formulations have a relatively high viscosity and because the typical particle size of the micelles or liposomes is close to the size of the smallest bacteria to retain, they result in a difficult separation process. In addition, these fluid streams often contain high particle loads which can cause premature plugging of sterilizing-grade filters. How can pharmaceutical or filter manufacturers reduce such filter plugging or pore blockage?  

One possibility for filter manufactures to deal with these challenges is to develop sterilizing-grade filters that specifically address these needs. According to our experience at Sartorius Stedim, highly asymmetric membranes, such as polyethersulfone (PES) membranes provide higher flow rate and capacity for such type of formulations compared with symmetric membranes. According to practical experiences, the use of a heterogeneous double-layer membrane construction provides total throughput advantages compared with single layer membrane filters. The prefilter (i.e., upstream layer) protects the final membrane (i.e., downstream layer) from premature plugging. Of high importance is to find the optimal graduation between  two membranes. Studies with model solutions and test results with actual formulations in field tests have demonstrated that the combination of a finer prefilter membrane with the final 0.2 µm membrane achieves better results compared with combinations with a coarser prefilter membrane for adjuvants applications. 

Pharmaceutical manufacturers should carry out filtration studies to compare the performance of different membrane materials and construction principals of filters to find out the optimal solution for their specific formulation. Furthermore, the use of prefilters should be considered in such studies to protect final sterilizing-grade filters effectively and to reduce costs and filtration time. These studies can be used to determine the optimal parameters for the filtration process, such as differential pressure or temperature. Increasing the temperature can enhance filterability depending on the stability of the solution at higher temperatures. The same filter-selection process may be applied for other protein therapeutics or vaccines. 

 Pharmaceutical manufacturers can reduce filter plugging by optimizing formulation and process conditions for desired filter life, along with selection of appropriate filters with suitable capacity. Filter manufacturers can provide technical support for this process by conducting feasibility (filterability) trials, selecting appropriate filter-media grades, sizing of filter cartridges or capsules, as well as ultimately applying that knowledge to the development of new filters capable of providing greater capacity.  

Process parameters such as pressure, temperature, and flux (i.e., flow per unit area) can have a large impact on filter throughput and capacity. For example, with complex plugging biological fluids, performing the filtration in a constant flow mode, increasing pressure differential to maintain flux rather than operating under a constant pressure mode can often have a positive impact on filtration throughput (capacity). Process temperature can also have an impact but is product-dependent and needs feasibility (filterability) tests to determine whether an improvement can be achieved through modification.  Optimizing these performance variables is an acceptable (and recommended) technique to reduce the risk of premature blockage for vaccines or protein therapeutics.  

The plugging of membrane filter systems by adjuvants is particularly undesirable when the process step has been validated to provide sterility assurance. The risk of filter plugging can be reduced by careful control of the filtration operating conditions, such as inlet pressure and optimum flux. The lifetime of the sterilizing-grade filter membrane will be greatly determined by the particle load in the process feedstream and the capacity may be extended with a prefiltration stage. A prefilter rated at 0.45 μm will remove larger emulsion micelles or liposomes which might ordinarily plug a sterilizing 0.2 μm membrane. Another option is to consider a 0.2 μm-rated bioburden reduction membrane as a prefilter. This can be of the same material as the final sterilizing membrane to simplify validation and may be effective for removing larger particle sizes from the process stream as a result of its pore size distribution. The prefiltration system selected should be sized appropriately to meet the demands of the process stream to minimize the expense associated with the final sterilizing membrane stage. When emulsions are used, the pharmaceutical manufacturer could investigate an adjuvant formulation with a sufficiently small particle size to make it filter-sterilizable. 

Some studies with oil-in-water emulsions have shown that increasing the pressure drop across the membrane can increase filter capacity. The coating of bacteria on the membrane with emulsion has been considered to contribute to bacterial penetration. In such instances, higher bacterial retention may be achieved by increasing the temperature if cold conditions are currently used. However, the reasons for adopting cold filtration (e.g., to maintain protein stability) may present an obstacle to implementing a change.  

This is rather hard to answer because the blocking can occur due to a wide range of issues related to product use and conditions such as pH, conductivity, protein concentration, viscosity, temperature, membrane incompatibility with what is in the adjuvant, and so forth. The best solution would be to better characterize the adjuvant, the product, and the combination to find the most stable and best filter condition possible, where material is not precipitating, too viscous, too high a concentration, and/or at the early stage or "edge" of aggregation and the filter type where the adjuvant's oil, if present, does not bind to or change/damage the membrane itself. 

There are really two choices: the brute force method, where one throws more membrane at the problem, or the better method, which would be to choose the right adjuvant for the job and choose conditions that fit into a high stability window of operation for the API.  Another more sophisticated solution to these kinds of clogging problems is to use a cascade of filters that end in the final desired porosity.  The upstream filter(s) can act as prefilters to increase final filter capacity.   

 Low surface tension of some adjuvant solutions can reduce the efficiency of filters' bacterial retention. How can this problem be mitigated? 

Protein Purification Using Single-Use Technology

It is advisable and required by regulators to carry out a comprehensive filter validation study, including bacteria-retention testing, simulating worst-case process parameters with actual product formulation using process related (i.e., pleated) scale-down filter devices. The design of the filtration system should consider reducing filtration time and differential pressure because these two parameters, among others, may increase the risk for bacterial breakthrough. During a filter evaluation study, the impact of different inlet pressure filtration conditions should be assessed, including constant flow or constant pressure conditions. Constant flow conditions may increase the risk of bacterial breakthrough, because of the increased differential pressure required to keep the flow constant during the filtration process and increased filter blocking. 

The use of filters specifically designed for adjuvant filtration as explained above is highly recommended because those filters will keep the process parameters at a moderate level. It is recommended to carry out a bacterial-retention study early in the filter-selection process to find the optimal solution based on retention efficiency and highest filtration capacity. 

Statistical and empirical studies at Pall Corporation have identified low surface tension of some adjuvant solutions as a risk factor for reduced bacterial retention efficiency of most sterilizing grade 0.2 μm rated membrane filters. The mechanism by which bacterial retention is reduced under lower surface tension in these fluids is not yet fully elucidated. Some mitigating factors appear to be membrane structure and layering of multilayer media, operating conditions, as well as reduction of bacterial bioburden or challenge levels and reducing challenge duration. Fluid surface tension affects the interactions between the bacteria and the membrane flow-path surfaces, but detailed mechanisms are not well known and specific surface tension thresholds cannot be determined.  

Membrane surface chemistry is also an element that may mitigate the negative impact of fluid surface tension. Determining how and to what extent membrane-surface chemistry can enhance retention requires extensive studies. Filters with positive zeta potential, which provide enhanced adsorptive removal properties for bacteria in aqueous ionic solutions, have been used in the past for such purposes. This was also one of the capability advantages of asbestos-containing filters, although these are no longer used because of asbestos safety concerns. 

Such reduced filter efficiency can be related to the mechanisms involved in bacterial retention, which can be based not only on sieving but also on entrapment and electrostatic attraction. The adsorption of bacteria to the membrane polymer surface can be caused by any combination of forces, including hydrogen bonding, charge-induced, and Van der Waals interactions. The presence of liposomes, oils, or surfactants in a process stream can disrupt these adsorptive interactions and consequently reduce retention of bacteria within the membrane structure.  

When there may be a high risk of bacterial penetration, it should be identified and considered in the planning of a filter validation study. The required minimum bacteria challenge (1 × 10

 effective filter area) must apply, although an upper challenge level can be considered and restricted to one log higher. In a full-scale production process, the bacterial challenge to the final filter membrane may be controlled by introducing a prefiltration stage that has been demonstrated to be effective for bioburden reduction. The careful management and control of the operating conditions during process filtration will also help mitigate the risk of bacterial penetration, with attention to flow rate and filter area sizing to avoid high pressure drop.  

This issue is typically not applicable to Asahi products, but with some filters, the lower surface tension can change the effective porosity rating of the membrane, allowing larger particles to slip through the membrane's holes. These low viscosity adjuvants effect the thickness of the boundary layer (where flow velocities at the membrane surface are at or close to zero) which, in turn, alters the effective pore size under those conditions. It can also affect how the API and contaminants build up around the membrane's pores hence altering the effective pore size. One can screen different membrane types, porosities, and brands of filters, and work closely with the membrane filter supplier to choose the best filter for the application.   

 Can certain types of adjuvants cause fewer problems with regard to filters' bacterial retention?  

A review of validation studies and field tests for a broader variety of fluid formulations indicates that low surface tension formulations, such as many adjuvants or adjuvanted vaccines, present a higher risk for bacterial penetration of sterilizing-grade membrane filters. Among such formulations, according to the data analyzed, liposome formulations present a higher risk than surfactant containing solutions. Therefore, the use of such formulations may be a suitable alternative to replace more critical formulations where applicable. 

 It is possible that certain adjuvants and related low surface tension fluids may be intrinsically less likely than others to cause reduced retention efficiency by membrane filters. However, there is insufficient data at this time to draw firm conclusions and make recommendations. In addition, awareness among vaccine producers that selection of surfactant-containing adjuvants and processing conditions can influence bacterial retention efficiency of sterilizing filters is not yet widespread. Until then, filter manufacturers must continue to work with vaccine developers to define appropriate membranes and optimize reasonable processing conditions to sterilize any vaccine formulation. Certainly, elaboration of an optimum adjuvant with such a goal would require an extensive amount of work and a very close partnership between filter manufacturers and vaccine producers.  

The choice of adjuvant is dependent on meeting the requirements of the process under consideration. The pros and cons of using a particular type of adjuvant must be considered and compared. When liposomes are selected as adjuvants their role as antigen carriers is utilized along with their immunological enhancement effect. 

These issues should be discussed with the membrane supplier's technical support teams and if they can't help, the filters must be screened to choose the best solution for the filter application. The answer depends on the membrane chemistry, but for large porosity filters, surfactant-containing solutions are typically not that large of a problem. Smaller porosity filters can be dramatically impacted in a negative way.   

 How can manufacturers maintain product flow g during adjuvant filtration?   

 For the manufacturer of the adjuvants, it is important to study and understand the process variables involved in making the adjuvant. The process variables identified to have a significant impact on the filterability of the formulation should be controlled carefully and kept within a narrow operating window. This will enable constant performance of the filtration process within established process parameters. 

 Filter plugging may or may not be an inherent part of a filtration process, depending on the particulate nature of the influent solution. An efficient filter is designed to retain bacteria and therefore tends to retain any particulate of a similar and larger size (e.g., micelles, liposomes). The ideal filter, with an extremely narrow pore-size distribution, a very high porosity, free of pinholes or other defects, and with sufficient area, will present the best compromise between bacterial retention and filtration capacity.  

If a specific flow rate is desired over the duration of a filtration operation where the  potential for plugging exists, the filtration operation should be performed under constant flow mode using an appropriately sized filtration area. Product flow can be maintained by increasing the inlet pressure as needed. Throughput of complex biological fluids often benefits from operation in his constant flow mode, as opposed to operating at high initial pressure and allowing flux to decay as the filter plugs.  

With adjuvanated vaccines, or similar products at risk for reduced bacterial retention efficiency, preliminary filterability trial performed at the initial stages of process developments can identify filters providing the highest level of sterility assurance for further formulation or process optimization, perhaps including limited microbial challenges to confirm initial suitability. Further filterability studies can then focus on optimizing process time and economy under operating parameters known to further increase bacterial retention likelihood with these highest assurance filters. This will maximize both retention and throughput to provide for successful sterilizing filtration, validation, and processing. 

 As mentioned, the careful management and control of the operating conditions during process filtration is usually advantageous for achieving consistency and robustness. In addition, the choice of filter membrane type can can contribute to maintaining a consistent flow. An asymmetric membrane structure, with a more open upstream zone, can provide a relatively higher initial flux, for example, which results in higher filter capacity for some process streams. 

A higher filter surface area can be obtained per cartridge cylinder by selecting products that use advanced pleat technologies, thus enabling higher throughput without increasing filter-system size. This approach may help with filtering highly viscous process streams, such as emulsions. 

Large areas of membrane is the brainless solution, but working with filter vendors and doing DOE-based filter screening under the desired, "high stability" API conditions is the better choice.   

Just like in horse racing, where some horses perform better than others on different courses, choosing the right filter type or perhaps a cascade of filters can solve the problem and provide a balanced solution to your filtration problem.  If your feed contaminant is primarily a slowly precipitating molecule of some sort, a relatively small coarse filter such as a 1 μm or 5 μm might be able to trap it and allow a medium-sized sterile grade filter handle the higher flow rate and process larger volumes.   

Depth filters often provide significantly higher capacity than membrane filters so placing them upstream of a sterile grade filter is often a good idea when possible.  As with any filter, but especially depth filters, a study of undesired reduction (by binding) in solution components should be considered. Find a balanced approach to this cascade of filters, with each filter sized appropriately to deal with and control the specific contaminant that causes the processing roadblock. 

Featured in the roundtable:  Holger Bromm,

 director of marketing and product management filtration technologies at Sartorius Stedim Biotech; 

senior vice-president of Global Scientific Affairs at Pall Life Sciences; 

 a technical filtration specialist at 3M Purification in the United Kingdom; and 

 business development manager of Asahi Kasei Bioprocess.

A technical rountable featuring Sartorius Stedim Biotech, Pall Life Sciences, 3M Purification, Asahi Kasei Bioprocess, and Bio-Rad Laboratories.

Optimizing Adjuvant Filtration

Foreign inspections have long been part of FDA's efforts in ensuring medical product safety and quality. In fact, FDA has been conducting foreign inspections for the past 50 years. It is through such foreign inspections that the agency monitors the manufacture of pharmaceutical products and ingredients that are imported into the United States. The primary goal of the inspections is to ensure that foreign establishments meet the same requirements as domestic establishments in regards to the quality, purity, potency, safety, and efficacy of pharmaceutical products marketed in the US. If a foreign pharmaceutical manufacturing establishment fails to meet FDA's cGMP standards—based on an inspection or otherwise—the agency has the legal authority to deny products manufactured at the violative facility entry into the US.  

FDA officials acknowledge that the agency is far from achieving foreign drug inspection rates comparable to domestic inspection rates. Each year, however, FDA investigators are appearing more frequently at the doors of foreign manufacturing facilities. For example, between 2007 and 2009, FDA inspections at foreign pharmaceutical manufacturing establishments increased by 27%. The agency seems to have no intention of slowing down—FDA has created a dedicated cadre of foreign drug investigators and established permanent offices in Europe, China, India, Central and South America, South Africa, and the Middle East. 

The US government's increasing focus on foreign inspections should come as no surprise. Pharmaceutical manufacturing has become more global, and the US market has, in turn, become more reliant on foreign medical products. Based on FDA's estimation: 					

40% of finished drugs, 80% of APIs, and 50% of all medical devices are currently imported.

There was a 13% increase in pharmaceutical products imported into the US between 2002 and 2009.

From 2000 to 2007, the importation of "high-risk" medical products, such as vaccines, quadrupled.

In 2002, there were just over 500 FDA registered foreign drug-manufacturing establishments. That number grew to more than 3000 in 2007, and registered foreign establishments now outnumber registered US establishments.

In 2000, the US imported roughly $1.7 billion more in biopharmaceutical and pharmaceutical products than it exported; by 2008, that gap grew to $18 billion. 

Because of the dramatic increase in the volume of imported drug products and the increasing complexity of the global supply chain, FDA is operating as an internationally-focused consumer safety agency. In doing so, the agency is pressing forward with increased foreign inspections, as well as partnering with foreign counterparts to create global coalitions of regulators focused on ensuring and improving global product safety. A clear result of which has been the significant increase in Warning Letters and Untitled Letters issued for international drug quality issues—in 2005, three such letters were issued; in 2010, FDA issued 23.  

As FDA's focus on foreign pharmaceutical manufacturing increases, it is critical that non-US facilities be prepared for an FDA inspection more than ever, particularly those establishments that have no—or limited—experience in dealing with FDA. Therefore, if your facility manufactures abroad for the US market, it is important to keep the following guiding principles in mind when preparing for an FDA inspection. 

The first step in preparing for an FDA inspection is implementing  an SOP that will govern employee activity during the inspection. This should be done whether or not an FDA inspection is anticipated. The SOP should provide guidance on a number of issues, including: greeting the FDA investigator, duties of key individuals, conducting tours of the facility, responding to FDA questions and requests for documents, employee documentation of the inspection, and inspection-closeout procedures. 

When FDA schedules the inspection, obtain as much information as possible. FDA's foreign inspections are announced in advance, and are generally scheduled for a predetermined period of time. So when FDA schedules the inspection, obtain as much information from the agency as possible. The more that is known about a planned FDA inspection, the better. Specifically, determine the reason for the inspection (e.g., cGMP, preapproval, followup, or for-cause), when the inspection will start, how long the inspection will last, whom from FDA will be attending, and whether there are any special requests or documents to have ready. As soon as notification of the FDA inspection is received, alert the company's regulatory affairs, quality, and legal departments. 

Once the dates of an FDA inspection have been established, make certain all crucial employees will be available during the inspection. Carefully select an inspection team that will be tasked with interacting with the FDA investigator. Part of this exercise is knowing who is crucial; knowing who is currently responsible and who was historically responsible; and ensuring that employees understand their responsibilities. One of the worst things that can happen during an FDA inspection is having an unqualified or unprepared employee answering vital questions posed by the investigator.  

REVIEW AGENCY GUIDANCE AND LEARN FROM OTHERS' MISTAKES

Prior to the inspection, review all the relevant and recent FDA Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) guidance documents and compliance policy guides, as well as the International Conference on Harmonization (ICH) Quality Guidelines. These documents are key to understanding FDA's often-evolving view of industry standards, which is as important to comply with as FDA's specific cGMP regulations. Additionally, it is helpful to analyze past Warning Letters and available Form FDA 483s; these documents offer valuable insight into what FDA investigators are keying on during inspections and what issues investigators deem to be worthy of a Form FDA 483 observation. 

Ensure that all required documents are available for FDA inspection, and make sure they are organized, complete, and current. Reviewing key documents will allow employees to refresh their memory and understand the organization of documents. It is also advisable to have an English translation of critical SOPs and documents, if possible. 

DISCUSS INTERNALLY ANY KNOWN DEFICIENCIES

Bring any known deficiencies to light; especially any that may relate to prior Form FDA 483 observations or recurring issues. The goal is to avoid any surprises during the inspection, as well as taking any preemptive steps to correct or mitigate the deficiency prior to the FDA inspection. 

PLAN FOR ANSWERING  INVESTIGATOR'S QUESTIONS 

First and foremost, all employees need to be directed to be honest and to avoid any speculation. Of equal importance, be prepared to speak with one voice and avoid internal disagreements while in front of the FDA investigator at all costs. Also, employees should be instructed to ask for clarification if FDA's questions are not completely understood (e.g., be clear on what timeframe FDA's request for documents covers). This is important so that all questions and requests are fully addressed, while at the same time refraining from saying more than what is necessary. Employees should also understand that it is acceptable to take a reasonable amount of time in responding to the investigator's questions and requests; responses do not always have to be instantaneous.  

Generally, the best way to prepare for an FDA inspection is to actually practice one. This can help pinpoint any weaknesses in procedures or inadequacies in records, and it prepares employees for the types of questions that will be asked by the FDA investigator. Another benefit of practicing an inspection is—by providing a dry run for employees—they will be more comfortable when the actual FDA inspection occurs. The mock inspection should be scheduled far enough in advance to afford time to implement any corrective actions which become needed as a result of the mock inspection.  

HAVE A ROOM RESERVED FOR THE INVESTIGATOR

While a simple matter, always set aside a quiet and securable conference room or office for the FDA investigator to review documents and to conduct his or her business. Ideally, this room should be away from any high-traffic employee areas, as well as the manufacturing areas. 

An FDA inspection is an important event and should not be taken lightly. This is particularly true for non-US facilities that manufacture biopharmaceuticals, pharmaceuticals, and APIs for US importation. In these cases, the legal standard for FDA to refuse the entry of drug products into the US is significantly lower than what is required for FDA to initiate a domestic enforcement action (i.e., a seizure or injunction). FDA can refuse admission of an imported drug product if the product merely appears to be violative. 

One way a drug product can appear to be violative—and therefore be denied entry into the US—is if it was manufactured at a foreign establishment that had a poor FDA cGMP inspection. Therefore, taking the time to carefully prepare the items discussed above, in advance, can greatly reduce any tension and increase the likelihood of a positive FDA inspection. 

is an associate at Hogan Lovells US LLP, Washington, DC, tel: 202.637.5600, 

Compliance Notes

FDA has created a dedicated cadre of foreign drug investigators and established permanent offices worldwide.

Preparing for an FDA Inspection in a Global Pharmaceutical Environment

Historically, orphan drug development has existed on the margins of R&D spend, but increasingly, this product class is attracting attention and value. With the blockbuster model wearing thin, the pressure for lower cost drugs with better outcomes is growing. It's time  for the industry therefore to diversify its strategic approach. 

The benefits of shifting focus to orphan drugs are many, including a streamlined approval process, patent extension and exclusivity, tax credits, and smaller clinical trials based on narrow indications. But as competition moves into these niche spaces, everyone will be looking for an opportunity to get an orphan-drug designation (ODD). This strategy may lead to additional scrutiny and intensify the need to demonstrate the economic and clinical value of a product as it applies to a particular population before approval.  

The pursuit of orphan drugs has implications for change across the entire business. It will require a new R&D approach that addresses economic and clinical value data, and goes beyond randomized clinical trials for regulatory approval to alternative types of data (e.g., observational or "real-world" studies that demonstrate product value over time in real-life scenarios). Companion diagnostics used to identify the patient population most likely to benefit from orphan drugs represent another key area that biotech and pharmaceutical developers will need to explore. This area may present licensing and acquisition opportunities on both sides.  

The growing emphasis on orphan drugs and more targeted diagnostics represent an increasingly personalized approach to medicine in general. An inevitable impact will be shrinking target patient populations, where the majority of blockbuster drugs will be suitable for a significantly smaller group of patients, the number of whom may well fall within the definition of rare diseases (6–8% of world population) (1). As genomics define specific subpopulations within larger disease conditions (e.g., hypertension), bio/pharmaceutical manufacturers of all sizes will increasingly need to shift to thinking about drug development within the context of the orphan model. 

In this context, companies will have to seek indications for their products within narrower patient populations and build a large population of patients incrementally, rather than as one single, huge population used in the rolling blockbuster model. To develop a successful model based on orphan drugs, manufacturers will need to adopt a new approach to both product development and commercialization.  

Rising product development costs, stingier public and private reimbursement, and increasing regulatory hurdles mean that companies are struggling more than ever to bring new products to market at prices that sustain ongoing investments in innovation. Ongoing waves of blockbuster-drug patent expirations are offering insurers cheap and effective generic drugs. Concurrently, rare but significant side effects (as in the case of Vioxx) have eroded regulators' willingness to approve drugs for primary care indications without prohibitively large and expensive clinical trials (2). Additionally, the situation is complicated by a shift in the balance of power among industry stakeholders, each of which may require different evidence to be convinced of a product's value.  

Instead of thinking big, innovators need to think small. If a company shrinks the denominator to just the segment of the market that genuinely benefits, then the value element starts to look a lot better. This shift can mitigate business risk, as well. Rather than seeking a single indication for one, large group of patients, the rolling blockbuster approach for orphan drugs segments the market for a drug more minutely, creating a large number of target populations in which the drug's value can be assessed. Such an approach reduces the risk inherent in clinical trials because the binary outcome (reimbursed/not-reimbursed) applies only to the small segment under consideration. The population becomes the sum of those small segments, eventually comprising a much bigger population.  

Compared with the bleak landscape of aging blockbusters, the orphan-drug market is appealing, especially when considering drugs that successfully made the leap from orphan to rolling blockbuster. Take, for example, Botox—a drug approved with orphan status in 1984 to treat uncontrolled blinking, neck pain, and muscle spasms. Since then, FDA has approved numerous additional indications, including the treatment of frown lines (2002) and migraines (2008). Today, there are 5 million doses of Botox administered annually in North America, which translates into approximately $1.5 billion in sales. 

PRODUCT-DEVELOPMENT IMPLICATIONS OF ORPHAN DRUGS 

Orphan drugs have historically focused on a small, defined market need. Because the population of individuals likely to optimally benefit from any individual drug may be small, drugs produced will be higher cost because drugmakers will have to recoup their investment from a smaller population of patients. Proving the economic and clinical value of treatment is therefore more crucial for orphan drug. This value case can include elements such as high quality outcomes, better patient experience, sufficiently improved health to allow the patient to more effectively manage other conditions, or product characteristics that improve overall patient adherence. Each of these elements should be explored and planned for early in product development.  

Because the target population will be smaller, clinical-trial participants may include some people suffering from comorbidities that would otherwise be excluded from the sample. In this regard, the trial participants begin to look more like people in the real world. As a result, careful tracking of all patient outcomes will be crucial. Preparing to track these outcomes will need to start early in product development and continue postmarket to develop the kind of longitudinal data required to make the case for premium reimbursement rates to payers.  

Finally, developing more targeted drugs alongside similarly targeted diagnostics will be key. As medicine becomes increasingly personalized and diagnostics become more targeted, it will become easier for orphan-drug makers to identify the population most likely to benefit from their drug. Developing drugs and diagnostics together will not only improve the likelihood that the drug will be successfully used, but can also improve the likelihood that the drug will be approved. In 2011, two personalized drugs were approved for use in conjunction with a specific diagnostic test— Xalkori (crizotinib) for lung cancer and Zelboraf (vemurafenib) for melanoma (3, 4).  

The advantages and benefits of adopting an orphan-drug centric approach reach beyond product development because the smaller population doesn't require large marketing or promotional campaigns. As a result, companies pursuing orphan drugs have adopted different kinds of promotional campaigns, often partnering with patient advocacy groups to get in front of their target populations.  

This kind of commercial model could become the model pharmaceutical manufacturers adopt increasingly across their portfolios. Orphan-drug manufacturers have historically had to develop a deeper understanding of that population's characteristics than drug companies seeking blockbusters. As diagnostics become more targeted and the use of personalized medicine grows, companies pursuing all types of drugs will need to understand their target populations better and partner with advocacy groups like orphan drug companies have done. Ultimately, the growth of orphan drugs is one element of a larger paradigm shift in the pharmaceutical industry—one that manufacturers will need to adjust to. 

is managing partner, both with Numerof and Associates, 

1. European Organization for Rare Diseases, "Rare Diseases: Understanding this Public Health Priority" (Nov. 2005). 

2. FDA, "Risk of Acute Myocardial Infarction and Sudden Cardiac Death in Patients Treated with COX-2 Selective and Non-Selective NSAIDs" (Sept. 2004). 

3. FDA, "FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer" (Aug. 2011). 

4. FDA, "FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer" (Aug.  2011). 

Final Word

Rather than seeking a single indication for one large group, the orphan-drug approach segments the market for a drug more minutely.

The Growing Orphan-Drug Paradigm

The United States is caught in an epidemic of prescription-drug overuse and abuse, and federal enforcers are revving up forces to counter illegal diversion of approved drugs. Nearly 7 million Americans abuse psychotherapeutic drugs, according to a survey by the Department of Health and Human Services (HHS), and prescription drug abuse now exceeds that of cocaine and heroin. Consequently, manufacturers of opioids and other painkillers, along with prescribers and drug distributors, face increased scrutiny from the Drug Enforcement Administration (DEA) and other regulators seeking to monitor drug distribution and prescribing more aggressively. A House Energy and Commerce subcommittee held hearings in April 2011 and again in March 2012 to examine how DEA is tracking and preventing inappropriate prescription-drug use, the effectiveness of state prescription drug-monitoring programs, and how well manufacturers, distributors and pharmacists prevent illegal diversion. Subcommittee Chair Rep. Mary Bono Mack (R–CA), has pressed for policies to aggressively curb access to painkillers and anxiety drugs more severely since the suicide of her son related to oxycontin abuse.  			

Of the thousands of pharmaceuticals approved by FDA for US marketing, about 250 are regulated by the the Controlled Substances Act of 1970 (CSA). Some 80 drugs with high abuse potential but important medical uses fall under schedule II, including sleep aides, diet pills, antidepressants, psychiatric drugs and antihyperactive therapies, as well as painkillers. Another 150 drugs have relatively low abuse potential and are in schedules III–V with minimal restrictions, while more than 130 schedule I drugs are dangerous and not approved for any uses.  

DEA and other federal and state agencies have responded to the sharp rise in abuse of opioids and other legal drugs as part of the 2011 Prescription Drug Abuse Action Plan released last year by the White House Office of National Drug Control Policy. DEA agents have been closing down illegal online pharmacy sites and rogue pain clinics, particularly in Florida, that dispense thousands of prescriptions for pain medicines. A main DEA thrust is to target drug wholesalers and distributors that fail to detect and halt diversion; DEA recently moved to shut down a Cardinal Health distribution facility and four pharmacies in Florida allegedly for overlooking highly excessive oxycodone orders.  

Recent legislation also authorizes more aggressive efforts to remove leftover prescription drugs from family medicine cabinets, and DEA is holding another national "take-back" initiative this month, aiming to collect tons of expired or unwanted medicines for proper incineration. Brand and generic-drug manufacturers support these efforts, but are wary of proposals from the state of Washington and a California county that call for manufacturers to foot the bill for more extensive collection of leftover prescriptions.  

		  Another concern for industry is that added requirements for bringing schedule II therapies to market can delay patient access to new drugs by six months or more. DEA also sets annual quotas on production of controlled drug substances, a factor that may aggravate shortages of certain widely used drugs.  			

FDA assesses about one-third of new drug applications (NDAs) to see whether they warrant additional scheduling review by the DEA, noted Douglas Throckmorton, deputy director of the Center for Drug Evaluation and Research (CDER), at a February 2012 seminar on controlled substance regulation sponsored by the Food and Drug Law Institute (FDLI). CDER's Controlled Substance Staff (CSS) determines whether DEA should evaluate the product further, which can lead to a complex scheduling process after FDA approves the NDA.  

This DEA review, for example, delayed marketing 11 months after FDA approval in 2008 of Esai's sedation medication Lusedra (fospropofol). GlaxoSmithKline had to wait nearly six months to market its new epilepsy drug Potiga (ezogabine), despite early communication with DEA on the product's unique features. DEA scheduling "is a big black box for industry," observed Esai regulatory policy executive Ginny Beakes-Read, with no timelines for its actions and recommendations.  

FDA officials advise manufacturers to address scheduling issues early in drug development to facilitate the review process. Sponsors need to characterize whether a drug produces positive psychoactive effects, such as sedation, euphoria and cognitive distortion, explained CSS pharmacology team leader Silvia Calderon-Gutkind. NDAs should clearly identify abuse liability— or its absence—through evaluation of chemical properties, pharmacological and pharmacokinetic characteristics and clinical data relevant to abuse.  

CDER is working to improve its internal assessment process for controlled substances and to negotiate a memorandum of understanding with DEA to facilitate exchange of confidential information on new drugs earlier in the review process. FDA issued draft guidance last year on how manufacturers should assess the abuse potential of new drugs, and advice on developing abuse-deterrent formulations is expected this year.  

Although there's great interest in abuse-resistant patches or capsules, so far none have emerged that are "truly effective," said Gary Boggs, executive assistant in DEA's Office of Diversion Control, at the FDLI meeting. Manufacturers look to add antagonists or change formulations to improve resistance, but DEA wants data to show that it works and warrants "down-scheduling" to a DEA category that carries less regulation of production quantities, physical security, prescribing, and distribution.  

Ultimately, better science may establish a clearer roadmap for assessing drug pharmacology and clinical studies related to abuse issues, particularly for new drugs with novel mechanisms of action. Criteria for identifying and reporting adverse events related to prescription-drug abuse also could provide safety data that supports changes in controls, as would efforts to increase prescriber and patient education on the appropriate use of opioids and abused drugs.		  

					  DEA quotas on active ingredient supplies and production volume for schedule II drugs also have drawn scrutiny as factors contributing to shortages in critical drugs. Manufacturers claim that such controls have reduced supplies for treatments for attention-deficit/hyperactivity disorder (ADHD), which often contain amphetamines. DEA can amend aggregate drug production quotas during the year when there is a "legitimate need," explained Boggs. But he noted that it's hard to quantify such need, and the amendment process involves a lengthy comment-and-rulemaking procedure. FDA has been able to work with DEA to prevent shortages in several cases, notes Valerie Jensen, associate director of CDER's drug-shortage program, and Congress may modify the DEA quota-setting policy as part of legislation to address drug shortages in development on Capitol Hill.  			

FDA is moving aggressively to deal with shortages of critical drugs on all sides, as witnessed in recent actions to ensure access to two key cancer medicines. Commissioner Margaret Hamburg announced at a February 2012 briefing that FDA remedied a serious shortage in a version of cancer drug Doxil (doxorubicin hydrochloride liposomal injection) by authorizing Caraco Pharmaceutical Laboratories to temporarily import a replacement drug, Lipodox, produced overseas by India's Sun Pharma Global FZE. Serious manufacturing problems at contract supplier Ben Venue Laboratories, a division of Boehringer Ingelheim, dried up Doxil production for Johnson & Johnson's Janssen Products, leaving physicians desperate for supplies of this important cancer and AIDS treatment. FDA officials emphasized that import of this unapproved foreign drug will be a temporary, limited arrangement and was authorized only after the agency evaluated Sun to ensure the quality and safety of the product.  

FDA also resolved a critical shortage of methotrexate, also related to Ben Venue production problems, by expediting approval of a manufacturing supplement from APP Pharmaceuticals and release of thousands of vials produced by Hospira. Preservative-free methotrexate is needed to treat children diagnosed with acute lymphoblastic leukemia as well as other serious conditions. FDA also is working with Mylan and Novartis' Sandoz Pharmaceuticals to increase their methotrexate production.  

Hamburg said that FDA is dealing with these problems by expanding its drug-shortage team, providing guidance to industry on drug shortage notification procedures, and backing legislation to expand required reporting. By working closely with generic- and brand-drug makers, FDA has prevented 114 shortages since October 2011, Hamburg pointed out.  

Yet, the commissioner also noted in a speech to the annual meeting of the Generic Pharmaceutical Association in February that the majority of drug shortage problems are related to compliance issues affecting product safety and quality. On almost the same day that APP announced expanded methotrexate production, FDA issued a scathing Warning Letter citing the company for significant manufacturing violations at its Grand Island, NY. facility, primarily related to heparin production. Hospira was able to ship some 65,000 vials of methotrexate in February because it obtained additional supplies of active ingredient and invested hundreds of millions of dollars in extensive plant remediation efforts to resolve serious quality manufacturing issues cited multiple times by FDA.  

Manufacturers of medically necessary drugs "must invest in their manufacturing facilities," Hamburg advised the generic-drug manufacturers, noting that "quality is crucial for all products," and that visible shortages involving generic drugs could lead to public "to equate generics with quality concerns."

In addition to relying on ever-greater user fees to finance FDA operations ($2 billion in fees on a $4.5-billion budget), the Obama administration's spending plan for fiscal year 2013 takes some heavy swipes at biopharmaceutical companies. The president proposes to lower the exclusivity period for innovator biologics to seven years from 12 and to ban brand-generic "pay-for-delay" settlements. There's also the Democratic favorite to extend Medicaid rebates to all low-income beneficiaries in Medicare Part D plans, which is calculated to cut spending by $156 billion over 10 years. John Castellani, president of the Pharmaceutical Research and Manufacturers of America (PhRMA), blasted these proposals in a statement as a counter to "Obama's many pronouncements to support innovation, advance biomedical research, promote job creation and control healthcare costs for seniors." Congressional Republicans rejected the Obama budget immediately, taking particular aim at the administration's request for another billion dollars to fund healthcare reform, along with the antipharmaceutical provisions.  

US regulators have expanded the so-called "import alert" list to include 14 more Chinese producers of heparin and related products, for a total of 22 Chinese firms linked to the heparin contamination crisis of 2008 and still unable to meet FDA standards for manufacturing and quality control. The move additionally aims to assure Congressional Republicans that FDA is serious about ensuring the safety of heparin products in the US.  

FDA also aims to bolster its presence in China by seeking an additional $10 million in its FY 2013 budget to expand the scope of in-country inspections and staff. A new FDA report to Congress on its foreign offices and operations, as required by recent food-safety legislation, summarizes FDA overseas activities and interactions with regulatory authorities in China, India, Latin America, Europe, Africa and the Middle East, designed to build rapport and obtain important information on local production and regulatory operations. 

Manufacturers are supporting a new mandatory code of conduct for dealing with doctors and other providers around the world, largely to offset charges of violating the US Foreign Corrupt Practices Act (FCPA) and similar laws set by other countries. Spurred by a rise in investigations and charges levied against pharma companies by US and foreign enforcement agencies, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) has updated its ethical practice code to cover broader industry interactions with health professionals. Astra Zeneca CEO David Brennan, IFPMA president, said in a Mar. 1, 2012 statement, that the new policy can help industry "act with integrity and build trust." The code bans gifts and curtails entertainment to docs—and may save manufacturers in legal fees and fines:  Johnson & Johnson paid some $70 million last year to settle charges of illegal payments overseas, and Serbia is investigating several bio/pharmaceutical companies for bribery and corruption.  

Counterfeiters continue to become more sophisticated, as demonstrated in the recent discovery of fake Avastin sold to doctors in California, Texas, and Illinois. Unfortunately for patients, this "lower-priced European alternative" of Avastin has no active ingredient (bevacizumab). FDA sent letters to 19 doctors instructing them to stop using this unapproved product and pointing out the dangers of purchasing critical medicines from unknown sources, in this case from Quality Specialty Products (also known as Montana Healthcare Solutions). The doctors evidently were attracted by a $1900 price tag on a drug that usually costs about $2400 from Roche's Genentech. The Avastin incident prompted the Senate to approve a bill stiffening penalties on drug counterfeiters, and further legislation may authorize a better drug tracking system to distinguish genuine medicines from fakes. In addition, the Institute of Medicine is preparing a report for FDA on ways to detect and prevent drug counterfeiting and adulteration, hoping for delivery by year-end. 

Biotech manufacturers are cheering new legislation to strengthen the nation's response to public health emergencies, which provides added support for developing new medical countermeasures critical to such efforts. The US House or Representatives approved the Pandemic and All-Hazards Preparedness Act (PAHPA) in late 2011, and the Senate followed suit last month. The bill authorizes about $8 billion over five years to bolster detection and response to threats by the Centers for Disease Control and Prevention (CDC) and increases funding for countermeasure development and procurement. FDA also gets support for expert teams to provide technical assistance to manufacturers of vaccines, treatments and diagnostic tests important for responding to threats.  

Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During an Influenza Pandemic (FDA Final Guidance)

Size of Beads in Drug Products Labeled for Sprinkle (FDA Final Guidance)

Q3C Impurities:  Residual Solvents (FDA final recommendation based on ICH guideline)

Drug Interaction Studies–Study Design, Data Analysis, Implications for Dozing, and Labeling Recommendations (FDA Draft Guidance)

H.R. 4056, Science and Technology Regulatory Relief Act of 2012, proposed by Rep. Brian Bilbray (R-CA), would prevent states from duplicating FDA inspections of drug or medical device manufacturers. 

S. 2113, the Transforming the Regulatory Environment to Accelerate Access to Treatments Act, or Treat Act, proposed by Sen. Kay Hagen (D-NC), would speed new therapies for critical diseases through the FDA regulatory process.

Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

Soaring opioid use creates challenges for new drug development and supply-chain control.

Manufacturers Wrestle with Drug Abuse and Critical Shortages

The butterfly effect is a much cited phenomena where a small change in a system can have a significant effect on the overall state of the system. In a similar way, relatively inexpensive elastomers can contribute disproportionately to the cost of running a biopharmaceutical manufacturing operation.  

Elastomers and plastics play a vital role in the operation of a bioprocessing plant, forming gaskets, "o"-rings, and diaphragms deep within the structure of the processing equipment. Their function is to prevent leaks and to separate fluids that should never come into contact. These rubber-like materials are useful because they are flexible, elastic, and can ensure tight seals between hard metal surfaces. 

Over time, and with the harsh temperature, chemical, and pressure cycles that they are subjected to, these materials can become brittle and deformed, and can fail. They need to be exchanged well before there is a risk of failure, the consequence of which could be a contaminated product or a dangerous breach of a system. Many biopharmaceutical plants have a large installed base of valves for example, maybe 5000 or more. Each one needs to be maintained correctly to avoid problems.  

Although the cost of failure is high, the cost of exchange is also high. It is estimated that up to 50% of maintenance activity is consumed by soft parts changeout. Add this to the plant downtime and there is a clear target for cost-saving scrutiny. So, what scope is there for improvement? Can current practice be challenged? 

A closer look at elastomer changeout times provides one example of using industry knowledge to improve operations and cost.

BioPharm International-04-01-2012

BioPharm International, April 2012 Issue (PDF)

A Strong Start to 2012

Pointed Debate

Optimizing Adjuvant Filtration

Preparing for an FDA Inspection in a Global Pharmaceutical Environment

The Growing Orphan-Drug Paradigm

Manufacturers Wrestle with Drug Abuse and Critical Shortages

Small Changes, System-Wide Impact

Knowledge Management Implementation

Ways to Recover Lost Margins

Single-Use Redundant Filtration

Growing Your Biopharmaceutical Product Pipeline

A 25-Year Retrospective on GMP Training

A Look at INTERPHEX 2012

PDA Tackles Changing Industry Times