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Pharmaceutical Technology CPhI Supplement, September 2012

Modification of the solid form of a drug substance may be required for drug compounds that show poor solubility and bioavailability. The authors describe a solid form technology platform used to optimize salt selection, cocrystallization identification and modification, or the development of a free form. 

Evaluation of lead compounds targeted for use in a conventional solid oral formulation commonly employs drug-modification strategies that are focused on improving drug solubility. This is based on the recognition that the drug must be in a solution state to be absorbed across the gastrointestinal (GI) tract. Maximizing the amount of drug that dissolves and remains dissolved as it travels through the GI tract provides an increased likelihood that the absorption and bioavailability of the drug will be maximized. 

The early phases of development are often accompanied by efforts  to profile the physicochemical properties of the drug and attempts to measure its dissolution rate and solubility behavior to model the 

 performance of the drug (1). Predictive tools have been used to develop a general understanding of these attributes (2, 3). Empirical measurements (e.g., kinetic solubility and intrinsic dissolution rate), however, remain a mainstay. Data that reveal poor or suboptimal solubility/dissolution rate do not necessarily preclude the advancement of a drug. A progression strategy, however, often will need to explore an alternative delivery mode or modification on the drug substance as a means of enhancing solubility and bioavailability. The latter is often times the most straightforward and cost-effective approach. The options available for consideration require an understanding of how the molecule behaves (e.g., solubility and precipitation) in different regions of the GI tract. Some understanding on the intended formulation dose levels also can be helpful in evaluating potential options.   

 of the compound and its intrinsic solubility, it generally becomes clearer whether a salt can be used to afford an improvement in properties that can lead to an improvement in bioavailability (4). For molecules that have the potential to form stable salts, salt-screen studies are typically the most effective approach at surveying a wide range of acids, bases, and crystallization conditions. The screen also can be achieved in a material-efficient manner, an ever-important consideration during early development. 

Salt-screening studies performed using a solid-form technology platform (Optiform, Catalent Pharma Solutions) allow multiple diversity elements to be used in a high-throughput operation, which in turn maximizes the likelihood of producing and discovering crystalline salts. Diversity elements important to consider when screening for salts and available with the Optiform platform include acid–base stoichiometry, the method of drug dosing (e.g., dosing the drug as a solid or a solution), the method of counter-ion dosing (e.g., as a solid or a solution), crystallization solvent selection, and crystallization mode (e.g., cooling and antisolvent addition). Initial evaluation of the solubility of the parent as well as the feasibility of generating crystalline hydrochloride or sodium salts in a small set of experiments offer insight into potential solvents that can be used and provide a guide on the appropriate crystallization method. Effective mixing combined with a sample/vial format that permits individual samples to be cherry-picked from the array, isolated, and characterized using high-throughput isolation and analysis provides a material- and time-efficient screening methodology. 

For molecules that are either unionizable or do not form stable salts, cocrystals are often considered as a means of delivering a crystalline material that has the potential to enhance bioavailability in comparison to the free form of the compound. Similar to salt screening, identifying a suitable cocrystal requires combining the API with a stoichiometric amount of a second compound that is both a solid at room temperature and generally regarded as safe (GRAS). These combinations can be effectively constructed using the Optiform technology platform. The stoichiometric combinations are subjected to slurry-based ripening studies, solvent-drop grinding, and/or solution-based experiments as a means of promoting cocrystal formation. The ripening and solution-based experiments can be supported, in their entirety by the Optiform platform. High-throughput solvent-drop grinding, however, requires the use of specialized milling equipment.  High-throughput milling techniques have been partnered with the Optiform platform to show the effectiveness of the combination in conducting cocrystallization studies (5). 

If neither salts nor cocrystal modifications can be successfully obtained, then the free form of the compound can be modified to impart a change in the solubility and dissolution rate and, correspondingly, the bioavailability of the compound. This modification can be achieved by size reduction to increase surface area through various means,  including mechanical milling under ambient or cryostatic conditions. Conversion of the highly ordered crystalline state to a solid form that has low (i.e., poorly crystalline) or negligible long-range order (i.e., amorphous) is an approach generally considered to improve bioavailability. This option can be explored by performing a range of crystallization studies on the free form of the drug substance, typically by employing experiments that lend themselves to producing less ordered or highly energetic forms (e.g., fast desupersaturation methods). Other techniques that can produce amorphous materials include lyophilization, spray-drying, and/or rapid solvent evaporation. In almost all cases, knowledge of the drug solubility is required to allow for a well-designed study. Optiform technology platform uses the solubility information to create experimental designs and execute those designs in a parallel manner. 

is a principal scientist, both of Optiform Technologies, Catalent Pharma Solutions, 160 Pharma Drive, Morrisville, NC, 

* To whom all correspondence should be directed.  

 3. S. R. Carino, D.C. Sperry, and M. Hawle

The authors describe a solid form technology platform used to optimize salt selection, cocrystallization identification and modification, or the development of a free form.

Developing the Optimal Solid Form

Can you explain how the Freiburg and Illertissen facilities complement each other in terms of scale and capabilities?  

Holger Weyhers, director of pharmaceutical operations, Pfizer Illertissen

: Pfizer has two Centers of High Containment (HC) Excellence in Germany. The Product and Process Development  (PPD) facility in Freiburg focuses on product development, scale-up, and clinical supply. The Illertissen facility is focused on commercial-scale manufacture and packaging. Pfizer CentreSource (PCS), a commercial unit of Pfizer Global Supply, provides contract manufacturing and development-stage outsourcing services through these facilities. PCS recently expanded its suite of HC services to support earlier stage development in addition to commercial supply. Services and support available through PCS include drug-product formulation development, excipient studies, material characterization, compatibility studies, analytical method development, process analytical technology, product enhancement, ICH stability studies, and clinical supply. 

A weighing isolator in the Pfizer facility in Freiburg, Germany, is used for dispensing highly potent compounds. (Image Courtesy of Pfizer)  

Bernd Schuemmelfeder, director, PPD business development, Pfizer Freiburg

: At PPD Freiburg, the focus is on highly potent solid dosage form development to ensure a smooth process transfer from laboratory (5–15 kg) 

 pilot (70 g) to commercial scale (150 kg). Our DevCon (Development Containment) facility was designed as a multiple module facility to provide flexibility during product development at scales of  5–150 kg. Pfizer's strategy is to have capacities in place to support early-stage candidates when limited tox data are available. Pfizer handles such early-phase compounds by default as Occupational Exposure Band (OEB ) 4 compounds. According to the Pfizer nomenclature, OEB 4 refers to compounds with an occupational exposure limit of smaller than 10 µg/m

: The Illertissen site focuses on HC manufacturing and specialized packaging operations; the facility can handle compound classes,  including highly active compounds, cytotoxics, and hormones. Our three containment suites accommodate a portfolio of medium- to large-volume products, with batch sizes of 80–700 kg. Containment facilities are highly automated, and follow the "engineered containment" philosophy (i.e.,  a best-in-class environmental health and safety approach in line with current regulatory requirements). The processes in the NEWCON facility and our smaller scale ICON facility are fully automated and remotely controlled, thus there is no contact whatsoever between operator and product.   

The Illertissen facility received ISPE's 2008 "Facility of the Year Award" for process innovation and garnered the overall ISPE 2008 "Facility of the Year Award." The facility's innovative "cell concept" layout (in contrast to the more traditional modular design) and the automated remotely run production processes previously described incorporate the current aspects of process visualization, manufacturing execution systems, process visualization, masterbatch recording, and electronic batch recording.  

: Can you describe the containment approach at the Freiburg facility and its sustainability features?   

: DevCon has been designed as a multiple module facility to provide best flexibility during product development ranging from 1 to 150 kg. Our PPD group, and its facilities are an integral part of Pfizer's manufacturing site in Freiburg, which received the ISPE 2011 Facility of the year Award for Sustainability. The design of the Freiburg facility incorporates a range of eco-friendly technologies, such as geothermal energy for cooling and heating, adiabatic cooling , and other sustainable building design elements (photovoltaics, energy monitoring, and performance windows, for example.) We also introduced greener laboratory techniques. Subsequently, we have achieved notable improvements in HVAC (heating, ventilation, air conditioning) energy consumption levels. As a result, we are now generating some 93% of total plant energy from renewable energy technologies.

Pfizer has two manufacturing facilities in Germany for high-potency manufacturing, respectively in Freiburg and Illertissen. Pharmaceutical Technology's Executive Editor Patricia Van Arnum visited the facilities and spoke to the company about the design and operation of these facilities.

Plant Focus: High-Potency Manufacturing and Sustainability at Pfizer

Coating tablets involves selecting a specific color and gloss that are used to distinguish a drug product and build brand identity for that product. In addition to the issue of color and gloss, the coating must have appropriate surface-slip properties and adequately adhere to the tablet. The coating process and the materials used in the coating system can be optimized using a quality-by-design (QbD) approach to meet these requirements. The authors describe a QbD study that was performed to optimize a coating system.

Critical quality attributes (CQAs) for a tablet coating are color, slip, gloss, and adhesion. A quality-by-design (QbD) study that uses a statistical design and data analysis can identify the critical process parameters (CPPs) needed to obtain the desired CQAs. 

CPPs include both the material composition (i.e., formula) and parameters in the coating process. In this study, quality function deployment (QFD) was used to identify the expected effects of material composition on the CQAs. QFD can be used to minimize the number of experiments, which limits experimental error.  Based on the QFD shown in 

) and a red dye were identified as the CQAs for color, and it was determined that a mixture design was not necessary to test the effect of material composition on color.  Instead, a three-factor full factorial with a center point for color effect was chosen as a practical design of experiment (DOE).  

Table I: Quality function deployment for effects of material on coating properties (Spectrablend II Pink, Sensient  Pharmaceutical Coating Systems). (ALL TABLES ARE COURTESY OF THE AUTHORS)			

The coating system compositions were studied. The level of red dye (Red 40 Lakes, 12–14% concentrate) and the level of TiO

were varied to set the design space for the color effect. Medium-chain triglyceride (MCT) levels were adjusted to maintain the mass balance. 

lists the temperature and spray-rate process variables used to test each of the nine coating-system compositions.  

Table II: Experimental coating conditions.			

A 1200-g batch of placebo tablets was coated with each of the nine coating systems. After spray coating, 3 and 5% weight-gain samples were collected and rolled in the coating pan for additional 5 min. The percentage of weight gain was based on theoretical coating solution consumption and did not account for coating efficiency. A total of 45 coating experiments were conducted, and 90 samples were collected. Samples were tested, with five replicates, for color, gloss, slip, and adhesion. 

Colorimetry was used to measure the color shade. The L* value is the white/black color space. The a* value is the red/green space, and the b* value is the blue/yellow space. Target L*, a*, and b* values are listed in 

. The total color difference (ΔE*) is calculated from the differences between L*, a*, and b* values and the target by taking the square root of the sum of differences squared. Specifications for L*, a*, and b* values were defined based on ΔE* < 2.0.  

Table III: Target colorimetry values (Spectrablend II Pink, Sensient Pharmaceutical Coating Systems).			

All 450 samples were analyzed by regression to detect the factors that had a significant L* value. The data analysis revealed that all six factors (i.e., level of titanium dioxide, red dye, and MCT in the  coating system, and percentage of weight gain, coating exhaust temperature, and spray rate) had significant effect on the L* value. The regression model had a R

  (adjusted) of 92.10% and a lack-of-fit p-value of 0.000. The relative effect of the variables is shown in 

 and red dye had the most significant effect; both exhaust temperature and spray rate also had a significant effect on L*.  

Figure 1: Pareto chart of the standardized effects of the experimental variables on the L* value, which describes the white/black color space,  Alpha = 0.10. (ALL FIGURES ARE COURTESY OF THE AUTHORS)			

A similar regression analysis was performed to identify the factors that may have significant effect on the a* value. The data analysis revealed that the same six factors had significant effect on the a* value. The regression model had a R

  (adjusted) of  91.57% and a lack-of-fit p-value of 0.000. The relative effect of the variables is shown in 

. The data analysis revealed that the levels of  TiO

 and red dye had the most significant effect; both exhaust temperature and spray rate also had significant effect on the a* value.  

Figure 2: Pareto chart of the standardized effects of the experimental variables on the a* value, which describes the red/green color space,  Alpha = 0.10.			

Lastly, a similar regression analysis was performed to identify the factors that may have a significant effect on the b* value. The data analysis revealed only four factors (i.e., TiO

 and red dye levels, percentage of weight gain, and coating exhaust temperature) had significant effect on the b* value. The regression model had a R

  (adjusted) of 86.6% and the lack-of-fit p-value of 0.000. The relative effect of the variables is shown in 

and red dye levels had the most significant effect; both exhaust temperature and spray rate also had a significant effect on b* value.  

Figure 3: Pareto chart of the standardized effects of the experimental variables on the b* value, which describes the blue/yellow color space,  Alpha = 0.10. 			

An optimization of the factors targeted for the L*, a*, and b* value was calculated using multiregressional analysis. Optimal material and process factors are highlighted in red in 

 which shows that the colorant level had a larger effect on color shade compared with the process effects (e.g., exhaust temperature and spray rate). For the optimized solution at 3% weight gain, the predicted L*, a*, and b* values were 75.86, 32.21, and 9.07, respectively. The predicted ΔE* was 0.0, which is a perfect match. A process specification of the TiO

 and red dye was also calculated based on the lower and upper percentage limits of both ingredients. The white area of the plot in 

is the allowable level of the color ingredient that would meet ΔE* < 2.0. A different color specification can be determined by using the same design space.  

Figure 4: Contour plot of calorimetry measurements (L*, a*, and b* values) in relation to red dye and titanium dioxide concentrations in the formulation.  Variables held constant were weight gain (3%), medium chain triglyceride concentration (7.0%), exhaust temperature (40 Â°C), and spray rate (10 g/min). 			

Gloss is a measure of the proportion of light that has a specular reflection from the surface. A smooth surface has a high gloss, while a rougher surface has less, because the light reflected is diffused. High percentages of solid in the dry blend can make a rougher surface that can affect the gloss. Process conditions, such as coating temperature and spray rate, may also have a significant effect on the film surface rheology, which can affect the gloss. A novo-curve gloss meter was used to measure the film-coating gloss on the tablet coating with 60° light reflection. 

Regression analysis showed a weak model with R

 (adjusted) of 40.45% even though the lack-of-fit p-value was 0.000. A low R

  (adjusted) means that other significant factors were not accounted for or that the process is not in control. A weak model resulted in low predictability. It is known, however, that the gloss can be induced by the batch weight and the pan rolling time after the spraying is completed.  

The statistical summary of the gloss data showed a broad range of gloss results. Analysis of variables (ANOVA) was used to deduce the main effect. Based on the ANOVA result, high levels of  TiO

 and red dye had a negative effect on the gloss. High percentage of weight gain had a positive effect on gloss. High temperature and high spray rate had a positive effect on gloss but had no effect above a 45 °C exhaust temperature and a 20 g/min spray rate. High solids percent is expected to cause more roughness, which can affect the light reflection. MCT level did not show a significant effect on gloss. The requirement for color matching constrains the TiO

and red dye levels, but a minimum coating exhaust temperature of 45 °C and spray rate of 20 g/min are recommended to achieve the maximum gloss. 

Slip (i.e., surface friction) of the film coating was measured using a texture analyzer. Five tablets were measured for each experiment (i.e., a total of 2250 samples) to obtain a statistical justification, and the data were analyzed by regression. The R

  (adjusted) of 68.80% was marginally acceptable. Regression analysis indicated that spray rate, exhaust temperature, and level of MCT also have a significant effect on slip. The regression model predicted that a minimum slip of 27.56 g-force could be achieved with the recommended material composition and process conditions. Because the material composition must keep constant to match the target color, the optimal response was adjusted using weight gain and titanium dioxide and red-dye levels. 

Adhesion quality was determined by measuring the tension force on a tablet. A tablet was placed on a piece of double-sided tape adhered to the top of the texture analyzer's flat platform. Another piece of tape was pressed flat to the bottom of a 25-mm, stainless-steel, cylindrical probe, compressed to 800-g force onto the tablets for 10 s, then pulled apart at 1 mm/s. Regression analysis had a R

  (adjusted) of 59.04%, which suggested unaccounted-for factors or high experimental error. The data distribution for the adhesion data was a non-Gaussian distribution, which was fitted as a 3-parameters Weibull distribution. The probability of failure based on the design space was estimated to be low (0.94%), which indicated that adhesion was not sensitive to material factors (i.e., TiO

, red dye, and MCT levels) or process factors (i.e., exhaust temperature and spray rate).  

A typical QbD exercise is to outline the process flow diagram and construct the process mapping to identify the key process input variables (KPIVs) and key process output variables (KPOVs). The relative importance of the KPIVs and KPOVs were assessed with a cause-and-effect (C&E) matrix. The KPOVs with the highest scores (e.g., in the top 20th percentile) were considered to be CQAs for which process specifications needed to be defined. The C&E matrix result showed that the blending uniformity before and after the addition of MCT was critical. The blend uniformity before MCT addition determined the blend uniformity after MCT addition. Therefore, there was only one CQA in the blending process. The detection sensitivity needed to determine the blend uniformity was based on visual detection by obtaining a blend drawdown. Visual detection under magnification, which can further ensure uniformity quality, is recommended. From the C&E matrix, the KPOVs with high scores (i.e., raw material charge and sample checking for blend uniformity) were defined as the CPPs. It is important to control the CPPs to achieve desirable quality. A failure mode effect analysis (FMEA) was performed based on the CPPs identified. 

Based on the FMEA assessment, the risk-priority number (RPN) was generated, and the raw-material charge had a high RPN. Corrective action plans were developed to control the raw-material charge procedure and ensure accuracy and execution of the production procedure. Similarly, the drawdown step was also a CPP. The RPN was not as severe compared with the raw material charge step, and a process-control procedure was also proposed. The C&E assessment indicated a completely dispersed Spectrablend II pink in water was a CQA. This CQA could be controlled by visual testing. All KPIVs were CPPs. The coating process had six process variables (i.e., coating temperature, spray rate, pan speed, atomization pressure, AIR pattern, and air flow).  

The C&E assessment suggested coating efficiency, drying efficiency, and coating quality were the CQAs. Drying efficiency is a visual observation during coating and is dependent on the operator's experience. Coating quality can be quantitatively measured by colorimetry and other rheological tests. The C&E assessment suggested all six KVIPs had a significant effect. A FMEA assessment was performed.  

Tablet charge, air flow, coating temperature, spray rate, and pan speed needed to be controlled. Tablet-charge amount should be maximized according to the pan-coater design. Air flow was correlated to coating temperature and should be adjusted to the optimal setting to stabilize the coating temperature. Pan speed should be adjusted to have an ideal flow without excessive tumbling to cause tablet or coating chipping. The coating temperature and spray rate effect were more subjected to the coating material as previously described. 

Critical quality attributes, such as color shade, gloss, slip, and adhesion, can be controlled by proper material and process specification. A QbD approach is a practical tool to understand and control quality and the process. 

is formulations scientist, all at Sensient Pharmaceutical Coating Systems, Saint Louis, MO, tel. 314.286.7135, 

To whom all correspondence should be addressed. 

The authors describe a QbD study that was performed to optimize a coating system.

Achieving Process Understanding and Control in Film Coating

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, 

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

Excipients in Tastemasking

The pharmaceutical industry is under severe pressure to make its API processes greener, lower costs, minimize waste, and shorten existing syntheses. The need for economical, robust, scalable, and reliable processes for the synthesis of chiral APIs and intermediates has resulted in process chemists tuning their skills at the interface of chemistry and biology and embracing biocatalysts and biocatalytic processes in organic synthesis. This shift has resulted in biocatalysis becoming the workhorse of the chemists' toolbox for chiral chemistry. 

Why has there been a surge in the application of this green technology? The key difference in using biocatalysis today compared with 10 years ago is that now all the supporting technologies that can make a difference in enzyme development, such as bioinformatics, enzyme evolution, and high-throughput screening, allow for an efficient turnaround in process development and enzyme evolution. Libraries of enzymes in the form of screening panels that contain all the materials required to screen against a given substrate can be used as an efficient way to identify and use biocatalysts for a given process. For example, the biocatalysis group at Almac has developed the selectAZyme platform, a proprietary platform that consists of a range of enzyme types, including hydrolases, carbonyl reductases, transaminases, P450 monooxygenases, nitrile hydratases, and nitrilases, to provide access to a broad range of chiral compounds, such as acids, esters, alcohols, amines,  and amides. 

 illustrates typical transformations performed by the selectAZyme platform. 

 FIgure 1: Possible transformations using biocatalysis (selectAZyme platform, Almac).			

The timeline for selection of a given biocatalyst, scale-up, and manufacture of a given product is similar to that of the timelines for conventional chemistry optimization and scale-up. Typical timelines are shown in 

Figure 2: Example of a timeline for implementation of an enzyme platform (selectAZyme, Almac) involving enzyme selection, scale-up, and commercial manufacture.			

To illustrate the improvements in a synthesis that can be made using biocatalysis, take the example of Phase IIb compound in which nine steps of chemistry resulted in the formation of three chiral centers of a registered starting material with a global yield of 7.4%. The project was initiated with certain key objectives: 					

Increase productivity of the process > 50% kg/L/day

Remove heavy metals and subsequent contamination 

Remove the necessity for specialized equipment (e.g., original synthesis used high-pressure hydrogenation)

Develop a process with consistent quality of product

The original chemistry involved a myriad of steps, including a late-stage classical resolution using an expensive amine resolving agent and high-pressure hydrogenation using metal catalysis. The late-stage resolution resulted in large volumes having to be processed to step seven in the original synthesis. Almac's challenge was to make a scalable lower-volume route that had green and cost incentives for changing the process. Almac completed route invention, proof-of-concept demonstration, scale-up of hundreds of kilograms, and final commercial production of metric tons. The revised route consisted of five steps using three different selectAZyme enzymes with a global yield of 23.4%. 

Innovation was achieved by delivering a green process that was scalable, derived from readily available feedstocks, and used off-the-shelf selectAZyme enzymes. From retrosynthetic analysis, it was shown that the registered starting material could be made from feedstocks that would not have any long-term supply issues and could be sourced readily from India and China. Having the proposed route on paper, the next step was to synthesize the key intermediates and begin enzyme screening. 

Plant focus: High-potency manufacturing and sustainability at Pfizer 			

The project involved an early-stage bioresolution that resulted in a carboxylic acid product with > 96% enantiomeric excess (ee). From this point, a bioreduction step introduced another chiral center. Key to this enzyme screening was to find a carbonyl reductase (CRED) enzyme that was able to stereospecifically reduce the ketone of the desired enantiomer feedstock and not the undesired (2% ee) enantiomer from the bioresolution step. The CRED identified resulted in a stereospecific reduction and subsequent biopolish of the diastereomeric mixture. The remaining undesired ketone was easily removed using conventional work-up at the next step. The process ran from start to finish using two solvent combinations. Having developed the process, all stereoisomers (seven different products) were synthesized readily from other key selectAZyme enzymes, so analytical development could be undertaken to determine the fate of these potential impurities. The summarized advantages of the green enzyme process are shown in 

Table I: Comparison of process conditions and efficiencies for a selected synthesis when made from a chemical route and a biocatalytic route.			

It is clear from the example described herein that biocatalysis offers an attractive approach for a synthesis, which can result in greener processes and lower API costs. Advances in evolution technologies and metagenomic programs help to further enhance biocatalysis as a tool in chemical syntheses. Biocatalysis is a maturing technology and aids in the supply and delivery of chiral intermediates, fine chemicals, and APIs. 

* is head of biocatalysis and isotope chemistry, and 

is biocatalysis senior chemist, both at Almac, Stranmillis Road, Belfast, Northern Ireland, BT95AG, 

*To whom correspondence should be addressed. 

The authors explain chemical transformations that are achievable through certain biocatalytic routes.

Making API Synthesis Greener

The late Dr. Louis Lasagna, visionary father of the field of clinical pharmacology and founder of the Tufts University Center for the Study of Drug Development (CSDD), used to refer to the "cruel irony" of developing life-saving, breakthrough drugs that patients can't afford. In many respects, this conundrum isplaying itself out across many major pharmaceutical markets around the world.  

Open markets, which allow for more flexible pricing strategies, offer a significant incentive to drug companies to seek approval in that region, thereby leading to a greater number of medicines reaching the marketplace despite the fact that some of these medicines may be unaffordable to some patients. At the other extreme, closed markets, which more closely regulate pharmaceutical prices and reimbursement, may lead to fewer new medicines reaching the marketplace. Those products, however, may be more affordably priced and, therefore, accessible to a greater number of patients.  

The basic question for healthcare strategists and policymakers is the following: Do you want more drugs, knowing that some patients who need them may not be able to afford them, or do you want fewer drugs, which are affordable to all?  

To explore this issue, Tufts CSDD conducted a study that looked at access to cancer drugs in the United States and the European Union and reviewed pricing and reimbursement restrictions in each region. The findings of the study, which was led by a co-author of this article, Joshua Cohen, were published in a recent issue of 

Briefly, the study found that in the past decade, FDA approved more cancer drugs than its European counterpart, EMA, and for those drugs approved in both markets, the FDA approved them more quickly. Moreover, third-party payers in the US, both private and public, approved a larger percentage of marketed drugs for reimbursement, but with a much higher patient-cost sharing than in Europe. In contrast, whereas fewer cancer drugs were approved in Europe, the prices of those drugs were, on average, 9% lower than in the US.   

Although the study did not assess whether better access to the newest cancer drugs led to better health outcomes, the results highlight a key challenge for policy makers. Given that the annual tally of relatively expensive new cancer drugs is increasing, reimbursement will continue to be a significant concern in all healthcare systems. In this regard, policymakers may be well served by cautiously drawing lessons from the experiences, both positive and negative, of systems that have integrated economic evaluations into the prescribing and reimbursement decision-making process. 

Of course, this conclusion begs the questions: Why were more new cancer drugs approved in the US than in Europe, and among the 29 drugs common to both regions, why were all of them approved and marketed first in the US? The answer is that approvals are, in part, a function of both regulatory policy (e.g., access to priority review and accelerated approval procedures) as well as institutional features, such as whether an environment is more conducive to the marketing of products. The US has fewer price controls and has less institutionalization of cost-effectiveness assessments as a possible barrier to market access. Consequently, pharmaceutical companies are more likely to seek approval and market their products first in the US.   

If the following policy goal is presupposed—that is, to maximize aggregate health outcomes subject to a budget constraint—then the European scenario of granting less access to medicines deemed to offer less value (i.e., less cost-effective) may make sense. This scenario, however,  is a societal or payer perspective and may not represent the best interests of individual patients, who are unlikely to care much about average, aggregated data. To them, having more immediate access offers hope, a chance at an extension of life,  or an improvement in quality of life.   

There may be a trade-off between access and pricing: greater access at the expense of higher, possibly unaffordable prices to patients. It's a "cruel irony." 

, is assistant professor, both at the Tufts Center for the Study of Drug Development, Tufts School of Medicine, 

* To whom all correspondence may be addressed. 

 1.  K.I. Kaitin, Ed., "US Offers Patients Faster, Greater Access to Cancer Drugs than Europe", 

Policymakers must balance fundamental issues involving access to medicines and pricing.

Weighing Access and Affordability

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

There are many elements of project management that are generic across both project and industry types; however, there are some specific challenges within the pharmaceutical industry. The 

ISPE Good Practice Guide: Project Management for the Pharmaceutical Industry 

This article presents an overview of ISPE's guide on project management.

Pharmaceutical Technology-09-01-2012