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In This Issue:
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| Application of QbD Principles to METHOCEL™ Premium Cellulose Ethers in Extended Release Matrices |
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Author: Ian Robertson Quality by Design Manager
Industrial and regulatory requirements are driving the adoption of Quality by Design (QbD), a systematic approach to pharmaceutical development. QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality.1 In the case of hydrophilic matrix tablets, consideration of the Critical Material Attributes (CMA) of the rate-controlling polymer, as well as the variability in API properties and processing conditions is essential.2
The Controlled Release Alliance partners, Colorcon and Dow Wolff Cellulosics (DWC) have developed a QbD sample service for METHOCEL™ premium cellulose ethers, K-chemistry (USP substitution type 2208) CR grade, to better assist the pharmaceutical formulator in matrix development.
Through continued investment, DWC has now refined the METHOCEL K-chemistry Premium CR grade manufacturing process control. This, in turn, has led to revision of the sales specification reflecting even tighter control of METHOCEL CMAs, namely particle size, methoxyl (%MeO) and hydroxypropoxyl (%HP) content. Polymer process trending that demonstrates to formulators where, within the specification, the polymer is routinely manufactured is available via Colorcon.
Through research and experience, particle size, viscosity, and hydroxypropoxyl content (% HP) have been identified as CMAs for METHOCEL high viscosity polymers. Formulators are required to demonstrate which, if any, of these attributes are important and identify any sensitivity to extended release (ER) matrix formulation robustness. Not only is this a key part of early formulation development, but also important during full development programs including scale-up, technical transfer and pivotal batch manufacture. Data to show that CMAs have been fully evaluated and validated to support filing is also now a regulatory expectation.
The QbD samples represent the specification extremes in METHOCEL K-chemistry (USP substitution type 2208) Premium CR grade for viscosity, hydroxypropoxyl content (% HP), and particle size (percent through a 230 mesh screen). These samples are designed to facilitate exploration and generation of formulation design space typically using a Design of  Experiments approach, accelerating the overall formulation development and yielding reduced risk for the ultimate drug manufacture.
Customers can now access the unique METHOCEL QbD service via their local Colorcon technical services representative. In addition to QbD samples, Colorcon offers an array of services supporting optimized matrix formulation inclusive of an extensive knowledge base and applications data, polymer and formulation consultancy, the HyperStart® oral solid dose starting formulation service and global regulatory support.
The recent webinar ‘Application of QbD Principles to METHOCEL Extended Release Matrices’ hosted by Colorcon and DWC was extremely popular with both innovator and generic formulators and proved to be a good forum to understand and discuss challenges and opportunities on this topic. Technical experts Sandip B. Tiwari, PhD, Senior Manager, Product Development, Colorcon, Inc. and Tim D. Cabelka, PhD, Senior Product Research Specialist, DWC presented a case study on the influence of hydroxypropoxyl (HP) substitution, viscosity, and particle size of METHOCEL, on performance of a hydrophilic matrix and how to manage the influence of inherent polymer variability.
As QbD becomes an increasingly important part of product development, Colorcon, as Your Formulation Partner™, will continue to extend service and support to assure your first time right pharmaceutical product development.
Contact us for more information!
METHOCEL™ is a trademark of The Dow Chemical Company.
1. Yu, L. X., Pharmaceutical Quality by Design: product and process development, understanding, and control. Pharmaceutical Research 2008:25(4): 781-791.
2. Cabelka, T., Faham, A., Bernthal, H., Rajabi-Siahboomi, A., Application of Quality by Design (QbD) principles to the formulation of a hydrophilic matrix tablet of a high dose/high solubility drug. AAPS annual meeting and exposition, Los Angeles, CA 2009.
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Introducing Opadry® 200, Performance Optimized Film Coating System
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Author: Kamlesh Oza General Manager, Film Coatings
In response to the market need for fast and easy-to-use film coating process, combined with improved protection of active ingredients, Colorcon is proud to announce the introduction of Opadry® 200, a new performance optimized film coating system.
Approved for global pharmaceutical use, Opadry 200 is a low tack, high-film strength, immediate release PVA (polyvinyl alcohol)-based system that combines the optimum benefits achieved with our established Opadry® II high productivity film coating and Opadry® amb moisture barrier film coatings.
Using Opadry 200, coating solutions can be applied at up to 25% solids, resulting in better productivity and shorter processing times. With less time spent in the coating pan, tablets are protected from spikes in temperature and moisture. The unique combination of polymers used in Opadry 200 provides an additional level of protection for sensitive active ingredients. The result is better productivity with improved stability especially when compared to HPMC-based systems.
Opadry 200 also adapts to a wider range of coating parameters, which makes it easy–to-use in various types of coating equipment. This is an added advantage when ease of transfer from site-to-site or maximizing the use of a company’s existing coating operation assets are concerns.
To find out more on how you can improve formulation stability, lower your total cost of production and reduce waste, contact your local Colorcon representative or visit us at the upcoming 2011 trade shows.
To view a copy of the Opadry 200 Characterization Study, please use the link below.
Study Link (PDF 198.47 KB)>>
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Notification of Change
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Author: Kevin McGlue Director, Quality Assurance
In recent times, the chemical industry has been in a state of flux with continual mergers, takeovers, and exercises to maximize efficiency. This has led to consolidation of products and/or changes in manufacturing sites. For Colorcon, this has meant frequent change notifications from suppliers regarding raw materials, over which we have little or no control, and subsequent change notifications provided to our customers.
Changes in raw materials included in Colorcon products, even though slight, may impact on our customers’ final products. Therefore we adhere strictly to the guidance of the ‘IPEC Significant Change Guide for Bulk Pharmaceutical Excipients’ with respect to the requirement to notify change.
Our aim is to minimize the impact and actions required for customers by ensuring that all changes are fully evaluated. On receipt of notification regarding change to a raw material, Colorcon will carry out a full assessment of the impact of that change on the affected products. This assessment includes both chemical and physical comparisons of pre and post change samples of the raw material. In addition to compendia or specification tests, Colorcon endeavors to include all relevant assessments (including for example morphology assessment by Scanning Electron Microscopy) that may indicate a difference or potential impact.
We will then evaluate the changed raw material in selected model products, looking for any functional or performance differences, and if appropriate, effects on stability. Conclusions and data are usually published as an Executive Summary that can be made available to customers upon request.
Colorcon understands the difficulties that notifications of change can bring. As a premier excipient supplier, our goal is to provide you the highest quality products and service in the market. To meet this goal we will continue to notify you of raw material changes as part of our overall service package. Be assured that Colorcon aims to reduce the potential impact of change on your final pharmaceutical product, wherever possible.
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Nutrateric® II Nutritional Enteric Coating System – Next Generation
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Author: Charlie Cunningham Senior Manager, Product Development
 Nutrateric® was a revolutionary alternative to traditional shellac-based systems for the enteric coating of dietary supplements when introduced to the North American market in 2003, and subsequently in Europe in 2008. Since then, users have benefited from the easy and reproducible application and improved consumer appeal through masking of products with a strong odor, eg, fish oil capsules and garlic tablets. An improved version of the coating system, Nutrateric II, is now available and offers demonstrable improvements in coating productivity.
Nutrateric II is based on Surelease®, aqueous ethylcellulose dispersion, and NS Enteric®, nutritional enteric component, the same key components as Nutrateric. However, the system has been reformulated to reduce coating time by over 40%, improving productivity and efficiency while maintaining the excellent enteric performance of the original system. This means greater throughput, more coating capacity, and, in coating constrained operations, the possible avoidance or delay of costly capital expenditure. Enteric/delayed release can usually be achieved at relatively low weight gains of 3 to 5% of Nutrateric II, keeping coating times and costs down.
Just like its predecessor, the enteric performance of Nutrateric II can be used to differentiate and add value to nutritional products such as preventing unpleasant odor or strong taste, enhancing consumer appeal and acceptance. It can also be used to protect sensitive actives such as enzymes from the harsh environment of the stomach with reliable and reproducible enteric protection. Both tablets and capsules can easily be coated using conventional processing equipment.
Nutrateric II complies with the US and EU regulations for nutritional and food supplements, meeting self-affirmed GRAS status in the USA and the EU Council Directive 2006/52/EC approving the use of the key ingredient ethylcellulose (E 462) as a food additive in Europe. Additionally, all raw materials are selected to meet the label friendly requirements for the nutritional market.
To request a sample of Nutrateric II, please click here.
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New Colorcon Formulation School for Osmotics
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Global industry interest continues to grow in osmotic pump technology for delivering clinical benefit as well as adding value through product differentiation and/or product life cycle extension. It is possible to deliver drugs at zero order release rate, independent of gastric pH and hydrodynamic conditions with osmotically controlled drug delivery systems. Colorcon recognizes the need for specialist support and training for osmotic pump formulation development, by providing subject matter expertise in the technology along with POLYOX™ Water Soluble Resins the key rate controlling polymers used in these applications. Consequently, we are now launching this special focus Formulation School® to provide valuable insight on the theory and practical approach to osmotic technology.
 The first School for Osmotics will be introduced in November 2011 at Colorcon’s Global Headquarters in Harleysville, PA, USA.
Bringing together leading experts from industry, academia and Colorcon Technical Centers, the School will provide an overview of formulation technology, best practices in granulation, tableting, film coating and laser drilling, inclusive of hands-on laboratory demonstrations for each unit operation.
To register your interest for this event, or another of Colorcon’s pharmaceutical training programs on formulation and coating technology, please click here.
POLYOX™ is a trademark of The Dow Chemical Company.
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| New Colorcon Film Coating Troubleshooting Charts Available Soon |
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Are you looking to identify ways to improve your film coating process efficiency?
Need suggestions to enhance finished product quality?
Whatever your coating question is, Colorcon’s new Film Coating Troubleshooting Chart has the answer!
 The new Troubleshooting Chart includes solutions to the more common problems our customers face, and provides practical suggestions on how tablet cores, coating formulation or process equipment setups can be adjusted to fix these quality challenges.
The 2011 edition will be available in the following sizes:
Poster (A1) 23.40 x 33.10 in.
Letter (A4) 8.27 x 11.69 in.
Both sizes will be available in English in early August. Chinese and Spanish will be available later in the year.
To order the English versions, click here.
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| Colorcon Brasil Wins Quality Award for Seventh Time |
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Colorcon do Brasil Ltda is the proud winner of the Sindusfarma (Syndicate of Pharmaceutical Industry in the State of São Paulo) 2011 Quality Award for Raw Materials Suppliers (APIs and Excipients). The award was created to recognize companies that help raise quality standards, ensure that drugs meet sanitary specifications and who provide products with the quality the public demands. This year marked Colorcon's seventh time being recognized in this category, an achievement recognizing our continued focus on overall product and service quality.
The most recent award was presented on Monday, May 23rd, during the Sindusfarma Quality Award Ceremony.
People featured in the photo receiving the award on behalf of Colorcon are: Daniel Aymard, General Manager Southern Region, Fernanda Fugii, Quality Assurance Manager & Dennis Cummings, President – Americas.
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| 2010 Lilly Global Supplier Award for Excellence |
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Colorcon was honored to receive the 2010 Lilly Global Supplier Award, presented to Colorcon executives in a ceremony at Lilly’s headquarters in Indianapolis, Indiana on April 12, 2011.
The award specifically recognized Colorcon’s unique Brand Enhancement™ Services for tablet design in support of Lilly’s strategic initiatives. Receipt of this prestigious award recognizes the contribution of the entire Colorcon team supporting Lilly, and confirms that our Brand Enhancement Service helps reduce product development times and provides the manufacturing and commercialization supporting our customers’ continuous process improvement objectives.
To learn more about Colorcon’s Brand Enhancement Service, please click here.
From left to right: Jim Ward, Lilly CPO, Dennis Cummings, Colorcon President – Americas, Jim Coward, Colorcon Vice President – Corporate Development, MaryAnn Hegedus, Colorcon Global Account Manager, Larry Taber, Lilly Director Lean Six Sigma.
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| Conversation with… |
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Dr. David Bain - General Manager, Formulation Technologies, Colorcon Inc.
 Continuing to Advance Controlled Release Technologies
Controlled release (CR) formulations play a critical role in establishing a balanced portfolio of solid dosage products with enhanced efficacy and improved patient compliance. As CR technologies are a key component of our own portfolio, Colorcon views its responsibility in several areas to:
• Increase our customers’ access to a full range CR technology options
• Improve existing CR polymer efficiencies through optimal blends and applications
• Help improve robustness of CR formulations in increasingly rigorous regulatory environments
• Constantly challenge the overall cost-in-use and reduce waste
These initiatives are directed at improving the overall competitiveness of our customers without compromising quality, patient safety or product efficacy.
General Manager of Formulation Technologies, David Bain says that “Colorcon is helping our global customer base remove some of the technical barriers to new dosage presentations by providing specialized polymers along with formulation capabilities, valuable reference data, and application expertise through dedicated subject matter experts. Our aim is to help customers move to the higher level technologies to effectively modulate drug release from the range of matrix tablet, multiparticulate and osmotic platforms”. Colorcon facilitates use of multiple CR technologies and develops first time right formulations through best practice guidelines. With in-depth applications experience, Colorcon also provides technical support to customers from formulation right through to scale-up and manufacturing.
Asked about the impact of the launch of the Controlled Release (CR) Alliance, with Dow Chemical Company now Dow Wolff Cellulosics (DWC), in July 2007, David states that “Colorcon has focused even more resources to advance the use of METHOCEL™ premium cellulose ethers, ETHOCEL™ premium ethylcellulose polymers, and POLYOX™ water soluble resins, in oral controlled release applications, with DWC providing premier polymer chemistry expertise in support of Alliance new product development”. He adds that “through the CR Alliance products, Colorcon has been able to extend the depth of technology options for our customers across the globe, developing best practice guidelines and minimizing formulation and process variability associated with barrier membrane coating and osmotic applications. Additionally, the CR Alliance has brought leadership in applying Quality by Design (QbD) principles to matrix formulations".
Process simplification is another means by which customers can simultaneously reduce cost and improve robustness. The introduction of METHOCEL™ DC, a directly compressible grade of METHOCEL specifically designed for matrix tablets further underlines our commitment. By improving tablet hardness without the need for additional flow-enhancing ingredients, METHOCEL DC provides simplified processing with direct compression vs. granulation, increasing throughput and ultimately a more cost effective manufacturing process.
Colorcon and DWC are committed to working together to continue advancing CR technologies across the oral solid dose platform globally.
METHOCEL™/ METHOCEL™ DC/ ETHOCEL™/ POLYOX™ are trademarks of The Dow Chemical Company.
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Colorcon at CRS 2011
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 Colorcon was pleased to again be a sponsor and contributor to the Annual Meeting & Exposition of the Controlled Release Society, held July 30 - August 3, 2011 at National Harbor, Maryland U.S.A.
Contributions to the scientific program included hosting one of the Releasing Technology Workshops on Consideration in Design and Security of Hydrophilic Matrix System, held Sunday 31st July, followed by a roundtable/focus group event Quality by Design for Oral Controlled Release Solids - Realities and Ambitions held on August 1st and co-chaired by Dr. Ali Rajabi-Siahboomi, Colorcon’s Director of Scientific Affairs.
Colorcon also presented eleven scientific posters on controlled release or related topics including osmotic pump technology, barrier membrane coating and mini-matrices. Click here to view all presented posters.
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Colorcon.com Extends Customer Service through Website Login
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We are pleased to offer a new login feature on the Colorcon website.
This login allows customers to enjoy an enhanced Services section of the website. The improvements include detailed order and sample tracking as well as access to valuable regulatory and quality documentation. Additional services will be added in the near future – stay tuned!
Click here to view additional details or visit our Services section to request access today!
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Regulatory Corner
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Polyvinyl Acetate Phthalate (PVAP) – New Safety Data Supports Higher Levels of Use in Pharmaceuticals
Polyvinyl Acetate Phthalate (PVAP) or co-processed PVAP-TiO2 has been used as a component in a number of Colorcon’s pH dependent enteric coating systems - Opadry® Enteric, Sureteric®, Coateric® and Opaseal®. These film coatings have been used in approved drug products in various countries for many years. PVAP is listed in the U.S. FDA’s Inactive Ingredient Database (IID), but no maximum potency has yet been listed in the public version of the document. The original PVAP safety studies conducted in the 1960’s only support a fairly low acceptable safe use level of approximately 60 mg per day.
Recently, there has been interest in using higher levels of PVAP and PVAP-TiO2 in new applications, especially where drug interaction may prevent other enteric polymers from being used or where PVAP can be used to enhance tablet binding, contribute to matrix extended release mechanisms, and/or increase solubility. Due to this increased interest in the polymer, Colorcon has conducted and completed a number of state of the art GLP toxicological studies and analytical studies to support higher levels of use in film coating and modified release dosage forms. These studies are listed below:
• Acute oral study (LD50) - PVAP and PVAP-TiO2
• 90-day dietary study in rats - PVAP
• Developmental study in rats - PVAP
• Bacterial mutation test - PVAP and PVAP-TiO2
• Chromosome aberration test - PVAP
• Detailed co-processed excipient analytical studies - PVAP-TiO2
IPEC’s New Excipient Safety Evaluation Procedure (for details, see http://ipecamericas.org/content/ipec-novel-excipient-safety-evaluation-procedure) was used to obtain an independent review of the safety of PVAP and co-processed PVAP-TiO2 based on the new studies. The independent expert safety panel, consisting of three world-class experts, concluded that PVAP and PVAP-TiO2 could safely be used in oral drug products up to 829 mg per day, a significant increase from 60mg/day.
All of this data was submitted to FDA in June 2011 in Colorcon’s new Type V PVAP DMF to support our customer’s applications and future FDA reviews.
To obtain more information about the results of these studies, contact the Colorcon Global Regulatory Affairs Department.
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