Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Tastemasking of solid dosage forms and liquid drugs is a challenge for pharmaceutical manufacturers. Most APIs are unpleasant or harsh tasting, which can lead to patient noncompliance. This challenge affects all age groups, but is specifically problematic for pediatric patients. Implementing tastemasking programs into the drug-manufacturing process is crucial to avoid losses due to noncompliance. Pharmaceutical manufacturers are faced with challenges in life-cycle management, cost control, global regulations, and patent protection. In a Q&A, 

 examines excipient selection and functionality in tastemasking applications. 

 examined formulation development in product life-cycle management, including specialized formulations such as pediatric formulations, and related technical issues in excipient selection and functionality, including tastemasking and moisture protection, to develop an orally palatable product (1). Participating in the webcast were: Avinash Thombre, PhD, research fellow, pharmaceutical sciences with Pfizer Global Research and Development, who discussed life-cycle management and new dosage-form options; Karen C. Thompson, PhD, distinguished senior investigator, pharmaceutical sciences at Merck & Co., who discussed insight into pediatric formulations and related dosage forms; and Nigel Langley, PhD, MBA, head of North American technical sales, Pharma Ingredients & Services, BASF, who discussed novel tastemasking excipient solutions. For a perspective on excipient selection and functionality in tastemasking applications, Patricia Van Arnum, executive editor of 

and moderator of the webcast further discussed these issues with BASF's Langley.  

The dialogue was initiated following the launch by BASF of an excipient, Kollicoat Smartseal 30 D, an aqueous dispersion of a film-forming polymer with tastemasking and moisture-barrier applications for solid dosage forms. The product is a new coating polymer and is supplied as a 30% dispersion in water. From a product-characteristic perspective, the excipient is highly impermeable to water vapor, which helps preserve the potency of sensitive active ingredients. The polymer is stable in saliva and specifically soluble in gastric juice. These properties allow for effective protection from unpleasant taste in the patient's mouth and rapid release and onset of active-ingredient action in the stomach. 

In October 2011, BASF and Colorcon formed a collaboration for developing future film-coating systems using BASF's Kollicoat Smartseal 30 D and a new Colorcon preformulated additive. Colorcon developed the preformulated additive system for use with Kollicoat Smartseal 30 D to enable efficient preparation and application of this polymer in tastemasking applications. The preformulated additive lowers the number of materials to be dispensed by 50% and reduces the preparation time by almost 40%, according to an Oct. 21, 2011, Colorcon press release. 

 What characteristics does an excipient need to have to provide tastemasking? 

The material has to be stable at pH 6.8 to 7.2, so you do not get any of the bitter drug released in the saliva. In addition, the drug has to, upon entering the stomach, be rapidly released at a low pH. We are basically looking for a reversed enteric polymer to provide that functionality. With respect to Kollicoat Smartseal 30 D, specifically, the polymer is insoluble at basic and neutral pH value and has very low vapor permeability, which is characterized by the structure—primarily, the two ethyl groups that are attached to the nitrogen moiety and the polymer itself is the methyl methacrylate diethylaminoethyl methacrylate copolymer. It is very insoluble at pH neutral values as well as basic pH. It forms a salt at pH values below 5.5, so the polymer dissolves quickly in the stomach releasing the drug. 

What are the applications for this excipient, how is it used to provide tastemasking, and what are some examples? 

 It has wide applicability, not only in tablet coatings, but also in pellet, particle, and crystal coatings. It is useful for orally disintegrating tablets, for tastemasking oral dispersibles, and also in granulation processes.  

The recommendation of tablet-coating levels to provide tastemasking is between 2–5 mg/cm

, a little bit more is needed for moisture protection at 5–20 mg/cm

. Kollicoat Smartseal 30 D has very low water-vapor permeability. As a result, it is not plasticized by water. So, in coating, it is necessary to add a plasticizer in order to reduce the minimum film-forming temperature (~57 °C) to an acceptable level. Triethyl citrate and tributyl citrate are recommended for this purpose. In addition, an antioxidant, preferably butylated hydroxy toluene (BHT, 1–2.5 % based on polymer weight) is also required in the coating formulation.  

A good tastemasking polymer would show no drug release at pH 6.8 to 7.2. And this is what Kollicoat Smartseal 30 D has been designed for. Let's compare different coating levels and the amount of drug release relative to the uncoated cores for the bitter drug, quinine hydrochloride. At coating levels between 4 mg/cm

, there is no release of the drug at pH 6.8 to 7.2 during 60 min. When you reduce the pH to 1.2, you will see complete drug release, and this is an ideal situation for tastemasking.  

 What are other applications of the product?   

 Smartseal 30 D is also very suitable for pellet and crystal coatings. We believe that these applications increase in importance due to the rise of innovative dosage forms, such as orally dispersible tablets. For example, caffeine pellets can be effectively tastemasked at a coating level of 5 mg/cm

. Acetaminophen crystals are effectively tastemasked at 30 % weight gain where there is no drug release at pH 6.8 –7.2 during 120 min. Some tastemasking is achieved even as low as 7.5% weight gain. In each example, the pellet and crystal coating can be visualized by including a pigment in the formulation. Kollicoat Smartseal 30 D has an additional benefit as it provides gloss. 

 How do you evaluate tastemasking performance, and what are the key characteristics to achieve tastemasking?   

Although it is good to show dissolution data, we really need to see it in reality whether you are achieving a tastemasking effect on the tablets themselves when you take them into your mouth. Using a professional panel for tastemasking is obviously important because they are trained to do just this exercise. 

In our analysis, we [BASF] compared Kollicoat Smartseal 30D with the commercially available butylated methyl acrylate copolymer and hydroxypropyl methylcellulose products. At different coating levels, the panelists provided their assessments of bitter taste. For example, with the Kollicoat Smartseal 30D, at 5 mg/cm

, all the panelists reported a complete absence of bitter taste for quinine hydrochloride compared to the other materials tested. Hence, Kollicoat Smartseal 30 D is a very effective tastemasking polymer at that coating level. 

In sum, Kollicoat Smartseal 30 D has extremely low water-vapor permeability, thereby providing the opportunity for moisture protection. It shows quick dissolution in acidic medium below pH 5.5 and a strong resistance at neutral pH. It is, therefore, deemed highly suitable for both tastemasking and moisture-protective coatings. One other advantage is it is an aqueous-based coating. No solvents are required. It has very low odor, and even more importantly, is not sticky, which can be a real advantage, especially on a manufacturing scale. It enables quick and simple preparation of the coating suspension. It has low viscosity and is easy to spray at high solids concentrations. It is effective at relatively low coating levels. Kollicoat Smartseal 30 D has been specifically designed to show exactly all of these characteristics to provide the solution the market was looking for. The result is tastemasking and moisture protection in combination with instant release and easy and economical film coating.  

For the editorial webcast, "Tastemasking in Formulation Development," see 

 1. "Tastemasking in Formulation Development" Webcast, 

Articles

A Q&A with BASF moderated by Patricia Van Arnum.

Excipients in Tastemasking

High-potency manufacturing is a niche, but specialized area that requires proper facility design, equipment selection, production processes,  and operator knowledge to safely handle and produce highly potent APIs (HPAPIs) and finished drug products containing HPAPIs. 

 conducted an industry roundtable to gain a perspective of these issues. Participating were: Joe Cascone, director of potent product pharmaceutical development at Metrics; Joe Nettleton, vice-president and director of operations at Cambrex's Charles City, Iowa, facility; Peter Müller, delegate of the Dishman board and member of the Carbogen Amcis' management team; Theodore Iliopoulos, chief scientific officer at Euticals; Paul Doherty, chemical engineer, Sigma Black Belt, and plant manager at Ferro Pfanstiehl Laboratories; and David Bormett director of operations at SAFC. 

A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process. What are the key considerations in designing a high-potency manufacturing facility and in selecting equipment?  

: High-potency containment structures address both cross-contamination requirements targeting patient safety, and at the same time, worker safety by maintaining occupational exposure limits (OELs) below 10 mcg (Band III) or 10 ng (Band IV) per cubic meter of air for an eight-hour weighted average. Exposure to just a small quantity of a highly potent HPAPI or highly potent compound can pose significant health risks.  

The challenge in designing a high-potency containment facility is to find the appropriate level of containment that should manage the exposure risk at a reasonable cost. It also is crucial that the operators and the production staff understand the need and proper use of engineering controls. Enclosed reactors, centrifuges, dryers, and highly dusty mills are key manufacturing assets in an API production line and, together with product-transfer systems, are key elements in a high-containment design. The most crucial issues in selecting the proper equipment are the containment of the process itself. In other words, one must ensure that no airborne particles are released to the ambient air and that product remains in the process piping used. Equipment and facility-engineering controls apply to all areas handling such compounds, not just manufacturing. It also refers to process-development and quality-control laboratories.  

 Manufacturing chemist in personal protective equipment handling material in fully contained glovebox isolator at SAFC's facility in Verona, Wisconsin. 			

 Proper initial design and engineering of a potent-compound handling facility is crucial to achieve the desired levels of containment. Consideration must be given for containment of the entire process, from weighing and charging of raw materials, to packaging of the final material. Key facility-design criteria include single-pass heating, ventilation, and air-conditioning (HVAC) systems, controlled access to areas, airlocks around potent-compound handling rooms for segregated gowning/degowning, proper room-pressure differentials for containment, degown misting showers, bag-in/bag-out filtration components, sufficient support utilities (such as supplied air), and proper waste-handling capabilities.  

SAFC uses an overall potent-compound handling system that incorporates five levels of cascading protection, with the first two being the primary methods of material isolation/containment:  					

: using closed-system glassware and reactors and alpha-beta/split butterfly valves 

: glovebox isolators, ventilated laminar-flow enclosures, rapid-transfer ports, local exhaust ventilation, and closed-system cleaning through clean-in-place (CIP) systems 

: proper air pressurization, high number of air changes, single-pass air, restricted room access, airlocks, safe-change filters, and misting showers 

: As a secondary precaution, Saranex coveralls and hoods, powered air respirators or supplied air, proper glove selection, and chemical suits when needed for solvents/reagents 

: training, written procedures/policies, education, and employee-health monitoring.

: In pharmaceutical manufacturing, there are two primary objectives for containment: to protect product quality and prevent worker exposure. There are underlying design principles that apply to all pharmaceutical manufacturing and analytical facilities at Cambrex. The operational goal is to maintain process isolation using isolators, sealed process vessels, dedicated piping, and single-pass, high-efficiency particulate air (HEPA)-filtered airflow. It also is crucial to design the ventilation system so that potentially contaminated air will flow downstream and away from the process area. Ingress and egress also are controlled to ensure both air and worker traffic moves in a single direction with minimal turbulence. Gowning/degowning vestibules, material pass-throughs, and misting showers also are integrated into the flow. Upon ingress, disposable garments are donned, and upon egress, workers are misted with water to tack particulates to disposable garments, which are then discarded before exiting. 

With respect to exposure prevention, in many instances, the design strategy for quality protection is the same as exposure prevention. Process isolation using isolators, sealed reactors and dryers, and HEPA-filtered airflows all are important. In some cases, however, pressure differentials that protect pharmaceutical quality may not be protective of worker exposure. For example, when opening an isolator, positive pressure in the isolator will prevent cross-contamination, but the pressure release will potentially expel particulate material toward the worker. In these cases, the engineering strategy may include a bag in/out system. It also may be appropriate to include extra personal protective equipment when transferring toxic or potent compounds. 

Manufacturing chemist in personal protective equipment attaching a hose to the powder-transfer system below a glovebox on a Nutsche filter dryer at SAFC's facility in Verona, Wisconsin. 			

Mockups, training, and verification also are key. Because all manufacturing processes are different, it is important to verify that a given process design will function correctly and that operators are familiar with the process before a pharmaceutical product is actually manufactured. At Cambrex, it is common for the manufacturing team to develop and conduct mock handling exercises. These mock exercises may include the handling of surrogate pharmaceutical compounds followed by an assessment of potential releases and cross-contamination using wipes, air sampling, and appropriate analytical detection. Naproxen is typically used as a surrogate because it has an extremely low detection limit and is easy to clean. At completion, mock exercises will demonstrate that process and containment equipment performs as expected, provide process ownership and training for operators, and identify potential need for design modifications to prevent cross-contamination or worker exposure. Cambrex routinely conducts equipment maintenance and equipment performance verification to ensure isolators, hoods, balance enclosures, airlocks, and HEPA systems are working properly. 

: Carbogen Amcis has more than one site and has more than one production facility at its headquarters site in Bubendorf, Switzerland, but the concepts pursued with regard to containment are governed by one common philosophy regarding the handling of HPAPIs: the risks to be controlled regard the patient, the worker, and the environment. Therefore, we are analyzing the whole lifecycle from the purchasing of raw materials (which may eventually be highly potent compounds) to the delivery of products and to the creation of waste, the whole set of buildings and installations involved, and the whole series of applicable procedures and measures. 			

The containment requirements are defined in view of the toxicological category (performance-based exposure control limit [PBCEL], OEL, or acceptable daily exposure [ADE], respectively), whereby Carbogen Amcis is working with a four-categories approach, and strict requirements are applied in case of Categories 3 and 4. They involve with regard to production separation of the ventilation (room and/or reactor exhaust, i.e. systems), HEPA-filtration of exhaust air, separation of the room (airlocks), pressure cascades, partial dedication of specific equipment to HPAPIs, completely closed processing, and separation of the wastestreams. The focus is on avoiding carryover as well as contamination of the workers and the environment through production equipment (cleaning), through space, and through infrastructure systems. The respective considerations are applied along the whole sequence of activities (i.e., the lifecycle). The details cannot be outlined here, but it can be said in a summary that they include gloveboxes or isolators, respectively, barrier isolation benches, laminar flows, and flexible containment with all the activities subjected to their specific risk analysis. Personal protective equipment is eventually used as a safety backup during critical operations.  

 The facility and equipment constitute the barriers between the high-potent active agents and their surroundings. A facility designed with one-pass air and multiple airlocks with cascading negative pressure differentials will, in conjunction with other controls, mitigate cross-contamination. Hard- and soft-wall isolation technology demonstrates sufficient containment for the manufacture of solid-oral dosage forms containing compounds deemed to fall within an occupational exposure band of 10 mcg /m

  (TWA). These systems may be verified by recognized industrial hygiene practices, such as the

 ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment 

Enclosing a particular process or unit operation is reasonably well-established by most equipment manufacturers and isolation specialists. A key challenge is linking the unit operations together with the proper conveyance technology. This is particularly daunting if there is a wide variety of equipment makes and models. It is generally easy to contain powders within a bowl or vessel. Charging and discharging those powders and transporting them to other pieces of equipment is more complex. Examples of conveyance technology that may offer solutions include vacuum conveyance and continuous-liner 'bag-out' systems. 

Another challenge related to isolation and containment centers on powder sampling. Process intermediates (e.g., blends and granules) need to be sampled  to characterize in-process attributes and/or comply with prescribed regulations. Access to the product 

 properly designed and contained sample ports is essential. 

: First and foremost is the principle to not rely on 'moon suits' for the operators and instead have a strategy and philosophy to use engineering controls to provide proper containment. The key considerations are the OEL of the substance to be handled and, particularly for a CRO/CMO, the stage of the API and the scale of operation.  The organization should have a system in place that uses the OEL to establish the acceptable options available for facility design and equipment selection. For a CRO/CMO, the best and most economical means to handle a potent substance depend significantly on the stage (preclinical, clinical, or commercial) and scale.  For example, the best means of producing a preclinical small-scale API might be a combination of dedicated laboratory-scale equipment, disposables, and a small isolator. In contrast, a commercial product produced at a 50-kg scale might require plant-scale equipment with validated cleaning procedures and test methods.   

Risk assessment, evaluation, and mitigation

What are key considerations in risk assessment, revaluation, and mitigation in high-potency manufacturing, including the metrics used to monitor risk? 

: Conducting a thorough risk assessment is the best practice to achieve a desired level of containment. It is important to note that 'more' containment may not be a 'desired level' of containment. Rather, the desired level of containment is derived from the need to protect employees and mitigate cross-contamination of drug products. The level of containment required in any instance should be technical and quantifiable. It is not speculative or derived from interpretation or opinion. 

A comprehensive risk assessment will determine what engineering, facility, and administrative controls are required. A risk matrix may be developed for each step of the process. Each matrix will identify associated potential adverse events. Each potential adverse event should be quantified by calculating the product of its probability of occurrence by its severity. Risks cannot be monitored during a process, but actual events and exposures can. Proper feedback tools are essential to ensure the 'desired level' is appropriate and effective. 

 Utilization of properly designed engineering controls is the primary means for achieving the desired level of containment. It is important to understand the OELs or potential OEL of development compounds, for the product to be handled in the facility, and then design and test to meet 50% of the lowest OEL. Planning for containment at 50% of the OEL allows for variability that may occur due to different operators, process scales, material densities, and/or equipment use. Proper containment should be confirmed by obtaining industrial hygiene air/surface samples and conducting testing for the specific compound being handled, or using a representative surrogate product. Data generated during industrial hygiene testing should be used to assess areas of greatest potential risk for exposure to allow for improvements and changes to be implemented to minimize the risk. Testing must be repeated over time to evaluate containment systems and processes and to ensure that equipment continues to operate at expected levels.  

Another key area for consideration is equipment cleaning following use with potent compounds. An effective and verified cleaning program is critical to prevent potential cross-contamination, especially in a multi-use facility. Equipment cleaning also can be an activity for potential employee exposure. Therefore, CIP systems should be employed when possible, and monitoring should be performed during cleaning activities to verify that the OEL requirements are being met.  

Facilities handling highly potent compounds should have a compound evaluation and categorization system in place in order to conduct appropriate risk assessments and communicate hazards. This is especially critical when working on developmental  compounds that may not have an established OEL. The categorization can be used to determine proper handling and containment requirements for the compound based on the systems in place within the facility.  

: A proper facility to handle HPAPIs should be designed considering technologies such as isolators, laminar flow hoods, and local exhaust ventilation systems with air filtered before released to the ambient air. The air supplied to the rooms should be single-pass with proper air-pressure differentials to keep product-exposed areas negative to all adjacent areas or airlocks. Appropriately validated cleaning procedures should secure no cross contamination with the next compound to be produced using same equipment or piping. ISPE launched the 

Risk-Based Manufacture of Pharmaceutical Products

, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross-contamination (2, 3). EMA followed with a concept paper, published in Oct. 2011, and suggests using "a more scientific approach...to establish threshold values" (4).   

In instances when the toxicity of a compound is not known, it must be treated as Band IV compound. Obviously, the best would be to determine the toxicity of a given compound prior to embarking in high-cost production set-ups. To minimize the risk and for extra safety purposes even if engineering controls are in place, personnel working with highly potent compounds should wear suitable personal protective equipment, including respiration equipment. Best practices in dealing with HAPIs are the availability and checking of material safety data sheet (MSDS) data for any compound used in the process, process-hazard analysis, start-up, safety review, training, change control, emergency planning and response. Measurement of the dust during operation in the production areas is a key parameter in defining and checking the safety level at the operational level.  

: Risk management at Cambrex begins with training. All Cambrex employees granted access to areas that manufacture potent or toxic APIs must participate in training and become certified. Training follows a detailed risk assessment and risk-management framework that was developed in collaboration with the Cambrex toxicologist who is board certified and has extensive experience in risk assessment and with the Cambrex occupational nurse. Project-specific risk management recommendations are formalized by the toxicologist into a document known as a Project Safety Dossier (PSD). PSDs are formally reviewed by the manufacturing team before beginning work. In high-containment areas, new process designs are evaluated by certified Cambrex manufacturing teams in mock exercises that verify and document containment. Cambrex is guided by a four-band occupational exposure band (OEB) framework. Every molecule used to synthesize the API is evaluated separately and assigned an OEB. In some cases, where data are unavailable for a particular synthetic intermediate, Cambrex may conduct 

When making risk-management recommendations and decisions, Cambrex is cognizant that safeguards must balance the conflicting goals of mitigating exposure risk, minimizing the ergonomic hazards imposed by unnecessarily conservative exposure controls, and quality considerations. Safeguards include integration of API-specific toxicodynamic factors into risk-management decisions, appropriate use of personal protective equipment, and containment verification with good hygiene practices. 

: The best practices to be applied depend on the category and amount of the material handled and on the frequency and complexity of the operation in question. For Carbogen Amcis, we are working with dedicated equipment that is firmly installed in many instances and working with flexible containment approaches in others (e.g., when having to dismantle equipment in the context of cleaning or when having to be sure that eventual leakage could be controlled). A realistic assessment of the risk in question is important.  

Key practices in analytical monitoring involve swabbing surfaces (e.g., in the laboratory) as well as air-sampling during critical operations. Thereby, we are normally working with a combination of IOM samplers carried by the worker and of stationary samplers adequately placed to provide an idea of the eventual emission's distribution in space. We use surrogates right after installing new equipment and periodically perform analogous sampling and analyzing (i.e., high-performance liquid chromatography) of the true highly potent materials to control routine operations later on. The key parameter to be realistically determined is the exposed person's potential daily up-take in micrograms   

 Before moving forward with any project work, a process hazard analysis (PHA) should be conducted. This PHA will evaluate all aspects of the technical challenge and incorporate information, such as safety data sheets, product use, OELs, short-term exposure limits, odor threshold, industrial-hygiene monitoring method and analysis, irritant or sensitizer, toxicological data, primary toxic effect, route/mechanism of exposure, warning signs of exposure, treatment for exposure, cleaning procedures, acceptable surface residual levels, deactivation procedures, flammability/combustability, applicability of transportation regulations, waste disposal consideration, and other regulatory impacts.  

Even with the best facility design and equipment selection, the level of containment can be largely determined by operational practices. Therefore, a considerable amount of effort needs to be devoted to writing solid operating procedures, and providing operator training. The organization should have a system in place that uses the OEL to establish the acceptable options for handling procedures and practices. In addition, industrial-hygiene monitoring should be used to verify that the combination of facility design, equipment selection, and operational practices is providing the expected level of containment. Medical monitoring of employees should be included as a verification of the adequacy of the industrial-hygiene sampling program.  

 What are some recent technological advances in facility and equipment design for high-potency manufacturing? 

 Many equipment vendors are pre-engineering their equipment to be contained whereas in the past this was considered an optional upgrade. New equipment is more modular in nature. Product-contact modules can be cleanly removed from drive units and disassembled and cleaned in remote washing areas. This reduces downtime and exposure risks.  

 There has been an increasing interest idisposable containment options for potent-compound handling, especially for larger-scale operations. Disposable systems reduce the time for cleaning and can eliminate the potential for cross-contamination. They also may be used as secondary isolation around fixed equipment to improve overall containment of the process to meet lower OELs. Improvements in local exhaust systems, with proper filtration for potent-compound capture, also have been implemented to further reduce potential exposure to employees or the facility. The integration of two types of equipment, in some instances by two different equipment vendors, also is an area that has seen improvement. This could include engineering glovebox isolation equipment onto Nutsche filter/dryers or lyophilizers to allow for containment during discharge of potent compounds. 

: There is a growing trend in powder processing. Closed systems for powder handling and special valves are being developed along with engineering advances in the equipment used to contain the highly potent APIs or hazardous compounds. The term containment itself directs engineers in developing methodologies and structures to isolate the highly potent compounds. Charging materials to reactors, discharging a centrifuge, charging of a mill and packaging in closed systems are becoming popular practices in dealing with highly hazardous substances produced in multipurpose facilities. Traditional technologies are not easy to clean, and the risk of material remaining on the surfaces is too high. Disposables used in the closed system solve these problems, but have limitations with some solvents. Some examples of currently used isolation technologies using disposables are drum-sampling, dispensing, transfer sleeves, filter-change containment, decontamination, and cleaning containment. The benefit is that with low investment, one can achieve the desired containment level. I am sure that the future development will be focused in the development of isolation technologies at the level of dust generation. 

 With improved awareness and hazard recognition related to high-potency API development and manufacturing, there is a greater appreciation of proper risk management associated with HPAPI handling in general. Industry leaders are working to move away from administrative containment strategies to more robust engineering conrols. Specifically in regards to micronization of HPAPIs, Cambrex maintains GMP micronization suites equipped with high-level containment engineering controls. These containment systems units have demonstrated performance to 1 ng/m

What I am seeing is a lot of small improvements to potent-handling equipment, such as better means of cleaning split butterfly valves that provide continuous improvement in containment. These small improvements should not be underestimated in their beneficial impact.  

 ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment (

 Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP)

Concept Paper on the Development of Toxicological Guidance for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities

An industry roundtable representing Metrics, Cambrex, Carbogen Amcis, Euticals, Ferro Pfanstiehl, and SAFC.

Strategies for High-Containment

On Oct. 1, 2012, the Generic Drug User Fee Act (GDUFA), which was signed into law by President Barack Obama on July 9, 2012, goes into effect and provides important changes for generic-drug manufacturers and producers of generic APIs. The law imposes generic-drug user fees, payable by producers of generic finished drugs and APIs, to provide additional funding to FDA to improve the regulatory review process, including inspections for drug-manufacturing facilities, for generic drugs. These measures, which are supported by the generic-drug and fine-chemical industries, are intended to speed the delivery and ensure the quality of generic drugs (1).  

Under the GDUFA, FDA will receive $299 million annually (adjusted for inflation) during the five-year authorization of GDUFA from Oct. 1, 2013 to Sept. 30, 2017 (i.e., fiscal year [FY] 2013 to FY 2017) (2). The user fees required by the GDUFA are:  					

A one-time fee for original abbreviated new drug applications (ANDAs) pending on Oct. 1, 2012 (also known as backlog applications)

Annual fees for API and final dosage-form facilities

Fees for new ANDAs and prior approval supplements (PASs)

A one-time fee for drug master files (DMFs) (1). 

Seventy percent of the GDUFA fees will be derived from annual facility fees for facilities producing or pending review to produce APIs or finished dosage forms for a generic-drug application, and approximately 30% of the user fees will be derived from one-time application fees (DMF fees and ANDA and PAS fees). Overall fees were structured to reflect the respective weight in the supply chain, so that 80% of the fees are paid by finished dosage form manufacturers and 20% by API manufacturers. In the first year of the program, $50 million of the total GDUFA user-fee funding will be generated by the one-time backlog fee for ANDAs pending (except for ANDAs that are pending but have received tentative approval) on Oct. 1, 2012. Overall, it is estimated that FDA will receive the funding through approximately 750 ANDAs per year submitted electronically, 750 PASs, 350 newly referenced DMFs per year, and 2000 facilities associated with ANDAs (2). 

With the additional funding provided by generic-drug user fees under the GDUFA, FDA is obligated to meet certain performance goals with respect to its regulatory review of generic drugs. The GDUFA outlines goals in five main program areas. 

: By the end of FY 2017, FDA will review and act on 90% of complete electronic ANDAs within 10 months after the date of submission. Certain amended applications may have differing metrics.  

: FDA will review and act on 90% of all ANDAs, ANDA amendments, and ANDA PASs of current review status (whether electronic, paper, or hybrid) pending on Oct. 1, 2012, by the end of FY 2017.

: FDA will conduct risk-adjusted biennial cGMP surveillance inspections of generic API and generic finished dosage form manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic firms in FY 2017.

: FDA will implement various efficiency enhancements, which include efforts by industry and FDA to populate and maintain databases as necessary for facilities, fee assessments, efficiency, and other enhancements. FDA also will make DMF- and inspection-based enhancements as well as create a current chemistry manufacturing, and controls (CMC) records database to aid in the efficiency of reviews and inspections.

: FDA will continue or begin various regulatory-science initiatives. Some key issues are continuing quality-by-design initiatives for generic drugs, including developing science-based recommendations for product development, raw material, API and process controls, and life-cycle management of complex dosage forms (e.g., orally inhaled drug products and modified-release dosage forms). Another key goal is to develop a risk-based understanding of potential adverse impacts to drug-product quality resulting from changes in API manufacturing and controls. This effort will aid in the ability to predict the potential impact manufacturing changes will have on product quality, so manufacturers can target assessments and controls on high-risk areas and regulators can focus their reviews on these areas (2).  

Industry response to the GDUFA has been largely positive with groups, such as the Generic Pharmaceutical Association (GPhA), the European Fine Chemicals Group (EFCG), and the Bulk Pharmaceuticals Task Force (BPTF), an affiliate of the Society of Chemical Manufactures & Affiliates (SOCMA), supporting the passage of the GDUFA and offering input throughout the legislative process.  

"The historic user-fee legislation—the most important pharmaceutical legislation since the 1984 Hatch-Waxman Act—will provide FDA with additional resources and ensure all participants in the US generic-drug system, whether US-based or foreign, comply with our country's strict quality standards," said Ralph G. Neas, president and CEO of GPhA, in a July 9, 2012, GPhA press release. The new fees are expected to reduce the average review time for most generic-drug applications by nearly two years—from more than 30 months today to 10 months by the end of the program's fifth year, according to GPhA, and will provide increased funding for generic-drug manufacturer facility inspections.   

For fine-chemical and API producers, one of the key provisions of the GDUFA is the adoption of a risk-based inspection process to achieve parity in facility inspection between US and foreign manufacturers, a point made by FDA Commissioner Margaret Hamburg earlier this year (3). "Under the GDUFA, FDA will also ensure that manufacturers—foreign or domestic—who participate in the US generic drug market are held to the same, consistent, high quality standard," said Hamburg at the GPhA Annual Meeting on Feb. 23, 2012 (3). "We will conduct risk-adjusted biennial surveillance inspections of all generic API and finished form manufacturers—with the goal of achieving parity of inspection frequency between foreign and domestic firms by year five. Having the resources to undertake these regular inspections will level the playing field for foreign and domestic manufacturers..."(3). 

The fine-chemicals industry agrees. "The Congressionally mandated inspection frequency of every two years has been very difficult to achieve due to insufficient resources within FDA and the rapid globalization of generic-drug manufacturing," says BPTF Executive Director John DiLoreto. "While US facilities have been inspected approximately every 2.5 years, many foreign facilities have never been inspected at all. Successful implementation of the GDUFA will result in the identification and registration of all drug-production facilities," he explains. "Previously, FDA even had difficulty determining how many facilities were producing generic drugs that enter the supply chain every day," he said. By the end of the first five years of the GDUFA, it is expected that all foreign and domestic facilities will be inspected at the same nominal rate of every two years. "This will level the playing field for foreign and domestic producers and establish a balance in drug quality by ensuring that all manufacturers are implementing cGMPs," says DiLoreto.  

Under the GDUFA, FDA will conduct risk-adjusted biennial cGMP surveillance inspections of generic API and generic finished dosage-form manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic firms in FY 2017. FDA will prioritize inspections of establishments associated with ANDAs that are otherwise approvable or eligible for tentative approval except for an outstanding inspection, as well as establishments associated with ANDAs that have not been inspected previously. In appropriate circumstances, FDA can rely on a routine surveillance inspection in lieu of an application-specific inspection. Generally, FDA relies on a previous inspection of a finished product site occurring within two years of the cGMP evaluation for a pending application, three years for an API site or a control testing laboratory, and four years for a packaging-only site (2). There are exceptions to this general practice, which are usually related to the nature of the drug being processed or the complexity of the associated processing operations. Under the GDUFA, FDA intends to continue the practice of using a risk-based assessment in determining the length of time since the last inspection, guided by a two-year cycle for finished dosage product sites and a three-year cycle for API sites with consideration of the type of finished product or API in the application. For making decisions about pending applications for which FDA does not have current inspection information within the time period indicated, FDA may use previous FDA inspection information and/or use inspection information from another regulatory authority as appropriate (2).  

 "Risk-based inspections will have a positive effect on FDA and generic-drug manufacturers," says DiLoreto. "In managing resources most efficiently, FDA will be able to focus on those manufacturers having the most difficulty in implementing and maintaining quality drug-production programs. Manufacturing facilities that have never been inspected will be considered high risk, and manufacturers with a history of active successful quality programs will be considered to be lower risk," he explains.  

Carla Vozone, business development director at Hovione and industry representative of the EFCG during the negotiation process for the GDUFA, also points to the benefit of the GDUFA in "correcting the mismatch that existed in the inspection schedule and the actual supply chain." Although approximately 80% of APIs for drugs marketed in the US come from India or China, inspections of drug-manufacturing facilities in these countries are not proportional to these levels, explains Vozone. "Parity in inspections is critical to ensure safety of generic medicines," she says. She also points to the value in the provisions of the GDUFA that provide for a risk-adjusted surveillance inspections system to prioritize inspections of higher-risk facilities.  

Also of significance is increased authority for FDA to deal with low-quality and counterfeit drugs. "Prior to the GDUFA, FDA had little authority to prevent low-quality and counterfeit drugs from entering the supply chain," explains DiLoreto. As of Oct. 1, 2012, FDA will have the authority to consider misbranded any drugs not produced in a registered and inspected manufacturing facility. All drugs considered misbranded may be destroyed rather that returned so they will not be allowed to enter the supply chain through different supply chain channels, he explains.  

As the quality bar for generic drugs and APIs are raised under the GDUFA, the supply chain for generic drugs also may be affected, notes Vozone. "Generic-drug manufacturers will have to do a risk assessment of their supply chains," she says. Issues, such as increasing secondary sourcing or further evaluations of existing suppliers, will come into play. She also notes that the amount of the user fees, which are still being  determined, will oblige producers to evaluate their cost structures for supplying a given generic API, and as a result, certain producers may exit the market for that product or the sector. These issues will be important to take into consideration in the sourcing strategies for generic-drug manufacturers.   

 1. FDA, "Agency Information Collection Activities; Proposed Collection; Comment Request; Generic Drug User Fee Cover Sheet; Form FDA 3794,"  

Human Generic Drug Performance Goals and Procedures Fiscal Years 2013 through 2017

www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf

 3. M. Hamburg, "Challenges and Opportunities for the Generic Drug Industry Remarks," presented at the GPhA Annual Meeting, Orlando, FL, Feb. 23, 2012.  

The author discusses the key provisions of GDUFA as they relate to the pharmaceutical supply chain, including parity of inspections between domestic and foreign sites for both finished dosage forms and APIs of generic drugs.

Moving to Risk-Based Inspections

Eli Lilly has received $1.3 billion for payment of financial obligations from Amylin Pharmaceuticals following Bristol-Myers Squibb’s acquisition of Amylin Pharmaceuticals earlier this month. 

Bristol-Myers Squibb acquired the biopharmaceutical company Amylin Pharmaceuticals for a purchase price of $5.3 billion and an additional $1.7 billion for assuming Amylin’s net debt and a contractual payment obligation to Eli Lilly based on Amylin’s recently terminated agreement with Eli Lilly over the diabetes drug exenatide. Following the closing of the acquisition of Amylin by Bristol-Myers Squibb, AstraZeneca made a $3.2-billion payment to Bristol-Myers Squibb as part of the companies’ previously formed diabetes-drug collaboration.

Amylin has paid to Lilly $1.259 billion in satisfaction of its revenue-sharing obligation with respect to exenatide. As a result, Lilly will recognize income in the third quarter of 2012 of approximately $790 million (pretax). Lilly also expects to recognize income in 2013 related to this payment of approximately $425 million (pretax) contingent upon transfer of exenatide commercial rights outside the United States to Amylin. Currently, Lilly anticipates these rights will be transferred to Amylin over the course of 2013. In addition, Amylin also has repaid in full to Lilly a $165 million loan and accrued interest.

Amylin and Eli Lilly had partnered for developing exenatide, the active ingredient in the diabetes drug Byetta, which was approved in the US in 2005, and for developing a once-a-week version of exenatide, Bydureon, which was approved in the European Union in June 2011 and in the US in January 2012. In November 2011, Amylin and Eli Lilly terminated their alliance for exenatide, with worldwide development and commercialization rights transitioning back to Amylin, starting with the US in 2011 and progressing to all markets by the end of 2013. As part of that termination, Amylin agreed to make a one-time, upfront payment to Eli Lilly of $250 million and pay future revenue-sharing payments to Eli Lilly based on global net sales of exenatide products. 

AstraZeneca and Bristol-Myers Squibb Extend Diabetes Alliance

Bristol-Myers Squibb Agrees to Acquire Amylin for $5.3 Billion

Eli Lilly has received $1.3 billion for payment of financial obligations from Amylin Pharmaceuticals following Bristol-Myers Squibb's acquisition of Amylin Pharmaceuticals earlier this month.

Eli Lilly Receives $1.3 Billion Following Bristol-Myers Squibb's Acquisition of Amylin Pharmaceuticals

Myriad Genetics reported that a US federal appeals court has ruled that the company's composition of matter claims covering isolated DNA of the BRCA1 and BRCA2 genes are patent-eligible material under federal patent law. The court, however, denied the company's effort to patent methods of "comparing" or "analyzing" DNA sequences.

The US Federal Circuit Court of Appeals upheld Myriad’s right to patent the isolated genes, BRCA1 and BRCA2, which are linked to hereditary breast and ovarian cancers. These genes serve as the basis for the intellectual property for the company’s BRACAnalysis test, a predictive test for assessing a woman’s risk for developing hereditary breast and ovarian cancer.

The key issue before the court related to the patentability of isolated DNA molecules and whether and to what degree such molecules are considered products of nature. Isolated DNA is a freestanding portion of a larger, natural DNA molecule. Isolated DNA has been cleaved or synthesized to consist of a fraction of a naturally occurring DNA molecule. Myriad contended that isolated DNA does not exist in nature and that isolated DNAs, unlike native DNAs, can be used as primers and probes for diagnosing cancer. The plaintiffs in this case, which included the Association for Molecular Pathology, contended that to be patent-eligible a composition of matter must also have a distinctive name, character, and use, making it “markedly different” from a natural product. In this case, the plaintiffs asserted that because isolated DNAs retain part of the same nucleotide sequence as native DNAs, they do not have any “markedly different” characteristics.

In ruling in favor of Myriad, the US federal appeals court agreed that “isolated DNA molecules before us are not found in nature. They are obtained in the laboratory and are man-made, the product of human ingenuity,” said the court in its 

. “While they are prepared from products of nature, so is every other composition of matter. All new chemical or biological molecules, whether made by synthesis or decomposition, are made from natural materials. “For example, virtually every medicine utilized by today’s medical practitioners, and every manufactured plastic product, is either synthesized from natural materials (most often petroleum fractions) or derived from natural plant materials. But, as such, they are different from natural materials, even if they are ultimately derived from them. The same is true of isolated DNA molecules.”

Myriad supported the court’s decision. "We are very pleased with the favorable decision the Court rendered today which again confirmed that isolated DNA is patentable," said Peter Meldrum, president and CEO of Myriad Genetics, in a company 

. "Importantly, the Court agreed with Myriad that isolated DNA is a new chemical matter with important utilities which can only exist as the product of human ingenuity."

Myriad owns or has exclusive license rights to 525 claims in 24 US patents relating to BRAC analysis testing. These patents contain multiple claims, including claims relating to compositions of matter on isolated BRCA1 and BRCA2 nucleic acids, compositions of matter on probes and primers, methods of detecting genetic mutations in the BRCA1 and BRCA2 genes, the use for diagnosing a predisposition to breast or ovarian cancer, and general molecular diagnostic technology applicable to BRAC analysis testing.

The genesis of the litigation dates back to 2009 when the Association for Molecular Pathology and other plaintiffs brought a lawsuit against Myriad in federal district court seeking a declaratory ruling that 15 claims of seven Myriad patents relating to the BRCA1 and BRCA2 genes were invalid.  The district court ruled against Myriad, and Myriad appealed the decision. In July 2011, a federal court of appeals reversed the district court’s decision in part, holding that nine composition claims relating to isolated DNA molecules and one method claim relating to screening potential cancer therapeutics were are patent-eligible, but affirmed the lower court’s decision that the remaining five method claims were patent-ineligible. In December 2011, the Association for Molecular Pathology and other plaintiffs in the case filed a petition for a writ of certiorari with the US Supreme Court of the United States seeking the Supreme Court’s review of the decision of the federal court of appeals. In March 2012, the Supreme Court granted the writ of certiorari and remanded the case back to a federal court of appeals for reconsideration in light of the US Supreme Court’s recent decision in 

in which the US Supreme Court ruled that the relationship between the concentrations of blood metabolites and response to a therapeutic drug in two patents owned by Prometheus Laboratories were unpatentable.

In its ruling last week on upholding the patentability of isolated DNA molecules, the federal appeals courts also upheld that Myriad’s method claim to screening potential cancer therapeutics 

 changes in cell growth rates of transformed cells is patent-eligible. The federal appeals court, however, ruled that Myriad’s method claims directed to “comparing” or “analyzing” DNA sequences are patent-ineligible because such “claims include no transformative steps and cover only patent-ineligible abstract, mental steps,” said the court.

Myriad Genetics reported that a US federal appeals court has ruled that the company's composition of matter claims covering isolated DNA of the BRCA 1 and BRCA 2 genes are patent-eligible material under federal patent law. The court, however, denied the company's effort to patent methods of "comparing" or "analyzing" DNA sequences.

Myriad Genetics Receives Favorable Ruling on Gene Patentability

Pfizer has resolved with the US Department of Justice (DOJ) and Securities and Exchange Commission (SEC) matters related to certain improper payments in the operations of two of its subsidiaries outside the United States.

A Pfizer subsidiary (Pfizer H.C.P. Corporation) will enter into a deferred prosecution agreement with the DOJ and pay a fine of $15 million. Under the terms of a civil settlement with the SEC, Pfizer agreed to a disgorgement of profits of $16 million and prejudgment interest of $10.3 million. The DOJ declined to bring a criminal action against Pfizer. The DOJ settlement with Pfizer H.C.P. Corporation covers improper conduct in Bulgaria, Croatia, Kazakhstan, and Russia. The Pfizer SEC civil settlement covers improper conduct in all of these countries as well as in Italy, China, the Czech Republic, and Serbia. As part of its agreement with the DOJ, Pfizer H.C.P. Corporation will continue to cooperate with the DOJ for a period of two years in connection with its settlement.

In a separate civil settlement with the SEC, Pfizer’s Wyeth subsidiary has agreed to a disgorgement of profits of $17.2 million and prejudgment interest of $1.66 million to resolve issues involving certain improper payments in the operations of four subsidiaries outside the US. Pfizer conducted a risk-based Foreign Corrupt Practices Act due-diligence review of Wyeth’s global operations after it acquired the company in late 2009, and voluntarily disclosed these issues to the US government, according to an Aug. 7, 2012, 

. Pfizer’s postacquisition due diligence review of Wyeth identified certain improper payments in China, Saudi Arabia, Indonesia, and Pakistan.

“There is no allegation by either DOJ or SEC that anyone at Pfizer’s or Wyeth’s corporate headquarters knew of or approved the conduct at issue before Pfizer took appropriate action to investigate and report it, “ said Pfizer in its release. “As soon as these local activities came to the attention of Pfizer’s corporate headquarters, they were voluntarily brought to the attention of the DOJ and SEC. Today’s settlements are focused solely on these local activities.”

All the conduct at issue was investigated by Pfizer and voluntarily disclosed to the US government, according to the company. Pfizer began self-reporting to the US government in 2004 after the discovery of certain improper payments that had been made by employees of a recently acquired Pfizer affiliate in Croatia. Pfizer legal and compliance staff, outside counsel and auditors, conducted an internal investigation and regularly briefed DOJ and SEC on its findings, said Pfizer in its release.

An internal investigation and voluntary disclosure by Pfizer led to a settlement with the US Department of Justice and Securities and Exchange Commission.