Pharma Polymers News

The newsletter of Evoniks Pharma Polymers & Services product line Issue 2 | 2012

Quality by Design (QbD) our expertise for your market success

Editorial
Dear Readers,
Weve changed our name! Now we are officially Evonik Pharma Polymers & Services. The addition of the word Services reflects our strong commitment to empower all aspects of modern drug delivery through close partnership with customers. Our comprehensive services around our well known functional polymers EUDRAGIT, RESOMER and LAKESHORE BIOMATERIALS range from formulation and process development to commercial manufacturing and support with regulatory and toxicological data. Keeping our clients at the forefront of innovation and enhancing their market success: that is

the goal of Evonik Pharma Polymers & Services. In order to maximize the reliability and quality of our products and services, we have implemented Quality by Design (QbD) standards into our technical services for polymer and formulation users. Our cover story will give you an in-depth view into a study demonstrating how the application of QbD principles resulted in the process optimization of a sustained release coating with EUDRAGIT NM 30 D. Additionally, it provides important facts about QbD requirements becoming mandatory soon. This edition of Pharma Polymers News also describes the scientific studies well present as posters at the AAPS Annual

Meeting in Chicago. Appropriately, one of them will introduce the above-mentioned QbD study. The variety and range of poster topics clearly demonstrates our main principle: to provide our customers with optimum support in order to ensure best success for their developments. Of course, you wont want to miss our regular features. Get the latest updates on our new team members and find out where the next shows and seminars will take place. So read on and enjoy! Warm regards,

Content Quality by Design (QbD) Page 2 New in the team Page 5 AAPS poster abstracts Page 6 Evonik workshops and trade shows Page 8

Dr. Thomas Riermeier Vice President Pharma Polymers & Services

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Quality by Design (QbD) our expertise for your market success

Quality by Design (QbD) is a hot topic in the worldwide pharmaceutical industry. The U.S. Office of Generic Drugs has made the enhanced QbD approach to product development mandatory for all generic applications beginning in January 2013.
The QbD guidelines Q8, Q9 and Q11, as established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), clearly state the intent of this initiative [1]. The key elements named therein are:
Table 1: Quality Target Product Profile (QTPP)
Product attribute Dosage form and route of adminstration Dose strength Identity Assay Content uniformity Degradation products Drug release Storage stability Target Oral modified release pellets 80 mg propranolol Implications Coated pellets Twice a day

Meeting compendial or other applicable quality standards Sustained release Drug release unchanged

Pharmacopoeial methods Dissolution over 12 h (> 80%) Dissolution testing

Risk management Scientific knowledge Process understanding

The FDA advises the use of these elements to reach the desired condition of a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight. [2] At Evonik our major principle is to support our clients with their development and production requirements. Hence, the QbD principles have become a crucial element in that aim, as they help to ensure the quality of our clients products.

In the following case study the application of QbD principles to process optimization is presented. As a model, fluid bed coating and subsequent inprocess curing of a sustained release coating with EUDRAGIT NM 30 D were chosen.

EUDRAGIT NM 30 D in sustained release coatings EUDRAGIT NM 30 D is one of the most highly flexible EUDRAGIT polymers, showing an elongation at break of ~ 600 %. Hence, it can be used to apply diffusion-controlled coatings for extended drug release multiparticulates on almost any substrate, no matter how the pellets, crystals or granules are shaped. In order to ensure stable functionality over the shelf life of the coated dosage form, the coalescence of the polymer latex particles must be completed. This can be realized by an in-process curing step directly after the coating.

Quality Target Product Profile As the first step of a pharmaceutical development, quality, safety and efficacy of the product have to be defined in a Quality Target Product Profile (QTPP see Table 1). It forms the basis for the development of the product, where drug release and stability are important drug product quality criteria. For functional coatings with EUDRAGIT NM 30 D these criteria are mainly defined by the film formation. Physics of film formation The formation of a film from any aqueous polymer dispersion can be described in four steps: 1. Evaporation of water and densification of latex particles 2. Deformation of latex particles 3. Fragmentation and segregation of hydrophilic shells 4. Interdiffusion of latex particles
Table 2: Risk analysis
Process step Failure mode Abrasion of pellets Preheating Abrasion of pellets Pellets sticking Pellets sticking No spraying Coating Preheating Production of fine parts Filter clogging Incomplete coalescence Curing Drying Incomplete coalescence Incomplete coalescence None

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Figure 1: Contour plot for all responses at 15 min curing time

Dissolution 3 hours
50 45 Temperature 40 35 30 30 22 24 28 26 20 Temperature 18 50 45 40 35 64 30 62 60 54

Dissolution 6 hours
50 52 Temperature 50 45 40 35 84 30 80 82 78

Dissolution 10 hours
74 76 MODDE 9.1 35 40 45

58

56

35

40

45

35

40

45

Relative humidity [%]

Relative humidity [%]

Relative humidity [%]

Step 2 happens under the condition of T>MFT, where T is the product temperature and MFT is the minimum filmforming temperature. Step 4 happens under the condition of T>Tg, where Tg is the glass transition temperature of the polymer. In step 4 the appearance of the film does not change, but elongation at break, dielectrical resistance and diffusability properties do. With the application of a sustained release coating, step 4 obviously has a major impact on the quality of the coated drug product, especially since the Tg of EUDRAGIT NM 30 D is only 9C. To control this step, a thermal treatment (curing) is done after coating, conventionally conducted on trays in a circulating air cabin at 40 C over 24 hours. As an efficient alternative and more adequately suited for production, the curing can be performed in the coating equipment.

Relative humidity, temperature and curing time have been identified as factors influencing the curing process [3]. Prior studies on the curing behavior of sustained release formulations have shown an operating range of 4045 C product temperature and 4550% relative exhaust air humidity for 30 minutes to be ideal for EUDRAGIT NE and NM coatings [4, 5].

material attributes and process parameters have an impact on Critical Quality Attributes (CQAs) of the product. Table 2 shows the risk assessment for the sustained release product using failure mode effects analysis as a tool. Curing has been identified as a significant parameter and was studied through Design of Experiments (DoE) to achieve a higher level of process understanding.

Risk assessment A risk assessment begins with a review of the entire process. For each step the possible modes of failure are considered. Therefore, prior knowledge and expertise are of great importance. To ensure the best possible outcome, it is vital that a cross-functional team of experts with product knowledge, formulation expertise and process knowhow performs the review. This risk assessment helps in identifying which

Design of Experiments As part of the control strategy, DoE was used to gain knowledge on the curing process. Batches of 3 kg pellets were coated in a fluid bed coater (Unilab, Httlin GmbH, A Bosch Packaging Group, Schopfheim, Germany) in bottom spray mode with a sustained release coating formulation based on EUDRAGIT NM 30 D. After-

(S: Severity, O: Occurance, D: Detectability, RPN: Risk Priority Number) Failure effects Drug release out of spec due to incorporation of drug particles in SR coating Drug release out of spec due to incorporation of drug particles in SR coating Drug release out of spec; if pellets stick together surface area will change and hence release rate Drug release out of spec; if pellets stick together surface area will change and hence release rate No coating No coating Interruption of batch Instable release profile over time Instable release profile over time Instable release profile over time N/A Causes of failure mode Preheating time too long Inlet air volume too high Inlet air temperature too high Process humidity too high Nozzles blocked Spray drying due to too high inlet air temperature Filter clogging Inlet air temperature too low Process humidity too low Curing time too short N/A Controls None None Product temperature sensor Humidity sensor Spraying suspension weight control Product temperature sensor Pressure difference Product temperature sensor Exhaust air humidity sensor None N/A S 8 8 9 9 6 4 0 10 10 10 0 O 1 1 3 3 1 1 1 1 2 1 0 D 1 1 2 2 9 1 1 10 10 10 0 RPN 8 8 54 54 54 4 0 100 200 100 0 Actions Preheat coater without pellets Preheating time set to 2 min Inlet air volume set to 300 m/h Product temperature set to 2023C Inlet air volume set to exhaust air humidity of max. 60% r. h. Stirring of coating suspension to avoid sedimentation of talc Product temperature set to 2023C Change filter to rougher type Inlet air / product temperature Spray rate for water Time None

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Figure 2: Design Space plot

Risk of failure [%]

Humidity [% r. h.] CuringTime = 7

Humidity [% r. h.] CuringTime = 26

Humidity [% r. h.] CuringTime = 45 MODDE 9.1

Conclusion The principles of QbD paid off, delivering a reliable model explaining the correlation of the carefully selected parameters at a reasonable number of trials. Thus, enhanced knowledge regarding the process was obtained and allowed for control of the parameters during production. Operating within the Design Space results in higher process safety and a product that meets the defined quality. The size of the Design Space depends on the risk one is willing to take, while a smaller risk gives a smaller Design Space. As an element of the proposed manufacturing process it can be included in the submission.

Temperature [C]

Temperature [C]

wards, the coated pellets were cured at different conditions in the fluid bed coater. For this in-process curing, product temperature, exhaust air humidity and curing time were investigated as factors in the DoE. Drug releases after 3, 6 and 10 hours were established as responses. MODDE software (Modde v. 9.1, MKS Umetrics AB, Sweden) was used to estimate a design space and thus, a safe region of operability in which the desired response profile could realistically be met. With this software it was possible to display the estimated probability of failure at the specified risk level. The limits of the DoE design were set according to prior knowledge [6, 7]. Product temperature was set between 32 and 54 C. Relative exhaust air humidity ranged from 28 to 54 %. Reflecting the heating capacity of common fluid bed coaters, the design had to be limited to an enthalpy of 140 kJ/kg. The design plan resulted in 11 trials. As the actual curing process parameters differed slightly from the designed factor levels, the experimental process parameters were used for the interpretation of the data with MODDE 9.1.

Results and discussion The software predicted a robust model over the full area which is visualized for three time points (Figures 1+2). The contour plots show the influence of temperature and humidity (Figure 1).
Entering the criteria for dissolution time points into the optimizer function of MODDE 9.1 allows a risk of failure estimation utilizing a Monte Carlo Simulation. This results in a Design Space as required in an enhanced QbD approach for an Abbreviated New Drug Application (ANDA) registration. It also shows how the working range increases with prolonged curing time (Figure 2).

Temperature [C]

REFERENCES
1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH): Quality Guideline Q8 on Pharmaceutical Development, page 9, at: www.ich.org 2. Woodcock: The Desired State: A Mutual Goal of Industry and Regulators. ISPE Annual Meeting, November 7, 2005 3. Amighi et al.: Influence of curing conditions on the drug release rate from EUDRAGIT NE 30 D film-coated sustained release theophylline pellets, STP Pharma Sciences, 2/2007 4. Dassinger et al.: Scale-up Study of Propranolol Sustained Release Pellets Coated with EUDRAGIT NE 30 D, APV, 2011 5. Albers et al.: Storage Stable, In-process Cured Sustained Release Coatings Based on EUDRAGIT NM 30 D, AAPS, 2011 6. Br, H.: Untersuchung des Curings- und Alterungsverhaltens von EUDRAGIT NM 30 D Filmberzgen auf Metoprololtartrat Pellets, University of Applied Science. Bingen, 2009 7. Hensel et al.: Development of Storage Stable, Sustained Release Coatings Based on EUDRAGIT NM 30 D, APV, 2012

Transfer to other equipment The conditions of in-process curing mainly depend on the polymer and its formulation. However, different pieces of equipment will have different heat loss via the product container, and the sensors for product temperature and exhaust air humidity will need to be placed in different locations. By doing this, any curing design space is dedicated to the equipment. However, previous transfers have shown that ranges overlap almost entirely between different equipment.

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New in the team

Dr. Frank Nerenz joined Evoniks Health Care business line in April 2012 as Sales Manager for Southern Germany and Switzerland. Prior to joining Evonik he worked in custom research at ASM (Germany) focusing on business development, R&D projects and management, as well as supply chain excellence. Before this, Frank worked in R&D and technical marketing for Honeywell Specialty Chemicals Seelze GmbH (Germany) and in technology transfer at an Allied Signal/PFC (Bahamas) cGMP production site. His academic experience includes a postdoctoral internship at the School of Pharmacy of the University of Wisconsin-Madison (USA) and a Ph.D. in Organic Chemistry from Leibniz University, Hannover (Germany). Moreover, he authored and co-authored several research papers, text book chapters and patents.

Dr. Frank Nerenz

Sales Manager Southern Germany and Switzerland

Dr. Alexandra Steckel joined Evoniks Health Care business line as Sales Manager for Northern Germany in February 2012. Her industrial career started at Losan Pharma GmbH (Germany) where she worked as Business Development Manager and was responsible for new projects and customer acquisitions as well as out-licensing activities. Alexandra studied Pharmacy at the State University of St. Petersburg (Russia) and continued her education at the University of Kiel (Germany) where she received a M.Sc. degree for her scientific work on nebulizer solutions. For her Ph.D. she worked on topical pharmaceutical dosage forms and their formulations and characterization.

Dr. Alexandra Steckel

Sales Manager Northern Germany

Dr. Knut Kreuzer

Dr. Knut Kreuzer joined Evoniks product line Pharma Polymers & Services in June 2011 as Regulatory Affairs Manager for the AsiaPacific region. As a certified toxicologist, Knut is predestined to evaluate the safety profiles of Evoniks pharmaceutical polymers and to prepare drug master files for non-clinical data. Prior to joining Evonik he worked for an international consulting company in regulatory affairs and product safety, thereby mainly focusing on the toxicological and eco-toxicological assessment of chemicals. Knut studied Biology and received his Ph.D. in ecology from the Technical University in Darmstadt (Germany). While working for his previous employer, he successfully pursued a post-graduate degree in toxicology at the University of Leipzig (Germany).

Regulatory Affairs Manager Asia-Pacific

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AAPS 2012 scientific poster abstracts

We look forward to meeting you at the poster presentations and at the Evonik booth (No. 2224). All our scientific posters will be available for downloading by October 16, 2012 at www.evonik.com/e-lab
AAPS Poster # T2092 Tuesday, October 16, 2012, 11:30 am 12:30 pm AAPS Poster # T2212 Tuesday, October 16, 2012, 11:30 am 12:30 pm AAPS Poster # T2230 Tuesday, October 16, 2012, 11:30 am 12:30 pm

Effect of desiccant on the stability of lansoprazole delayed release pellets

Proton pump inhibitors (PPIs) like lansoprazole are susceptible to degradation in the presence of moisture. For this reason, the impact of a desiccant on the degradation stability of lansoprozole delayed release pellets was examined. Dissolution behavior, impurity profile and appearance were evaluated over storage.

Formulation strategies for the control of drug polymorph formation in sustained-delivery microparticles
A major challenge in the development of sustained release microparticles is the control of drug polymorphs. Several formulation strategies can be used to control their formation. This work demonstrates how these strategies were applied to a sustained release microparticle product containing nimodipine.

Preparation of micron-sized solid lipid particles for sustained release injections

Lipid nanoparticles for intravenous administration have been the subject of recent research. For subcutaneous and intramuscular injections, particles in the micron size range would be advantageous to mitigate opsonification. In these experiments, various lipids and lipidexcipient combinations were used to prepare lipospheres between 1100 m using bupivacaine base.

Results: Lansoprazole delayed release pellets coated with EUDRAGIT L 30 D-55 were stable with and without desiccants. This shows that EUDRAGIT L 30 D-55 can be applied for protecting sensitive drugs from acid as well as from degradation caused by moisture.

Results: Polymorph and amorphous component formation in the nimodipine microparticle formulations were shown to impact in-vitro release profiles. Additionally, a conversion of the amorphous component to Crystalline Form II caused aggregation of the resultant product, ultimately impacting injectability of the formulation. In this application, amorphous content formation was minimized with the control of formulation parameters such as polymer and solvent choice and drying rate. This resulted in a product with improved stability and performance.

Results: Resultant materials were freeflowing powders syringeable through appropriate needle sizes. Particle size was easily controlled by surfactant selection and concentration. Controlled release was more evident when bupivacaine concentrations were low or an additional excipient was used to solubilize the drug. These studies demonstrated solid lipid particles as a viable sustained release platform.

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polymer matrix at a molecular level prior to extrusion processing. The goal of this work was to compare the proposed method to traditional blend methods of API dispersion by evaluating implant product performance.

AAPS Poster # W4111 Wednesday, October 17, 2012, 11:30 am 12:30 pm

Solubility enhancement using melt extrusion: Role of ionic interactions

Polymer selection is a critical step in formulation development using melt extrusion. In this study, the role of ionic interactions in the dissolution enhancement of melt extruded formulations containing naproxen was investigated. Melt extrusion was performed at 30 % naproxen loading with five commonly used pharmaceutical polymers with distinct chemistries.

AAPS Poster # W4317 Wednesday, October 17, 2012, 11:30 am 12:30 pm

Quality by Design approach to optimize in-process curing of EUDRAGIT NM 30 D

Storage stability for EUDRAGIT NM 30 D coatings can be achieved via curing in the fluid bed at specific conditions. Aim of this study was to identify and investigate the influence and correlation of critical process parameters for in-process curing. To achieve this objective, a Quality by Design approach was used.

Results: The molecular dispersion technique showed improved blend and drug content uniformity compared to the traditional dry blending technique. Additionally, a more sustained in-vitro release profile was obtained for implants produced using the molecular dispersion technique. These advantages can significantly increase efficiency and reproducibility of the final extrusion product.

AAPS Poster # W5205 Wednesday, October 17, 2012, 3:30 pm 4:30 pm

New EUDRAGIT E PO formulation for moisture protection and taste masking for pharmaceutical and nutraceutical applications
EUDRAGIT E PO (basic methacrylate copolymer) based coating systems have largely been used over years for moisture protection and taste masking of solid pharmaceutical dosage forms. This study describes a newly developed EUDRAGIT E PO formulation, where the sodium lauryl sulphate used as surfactant in the standard pharmaceutical formulation is replaced by tartaric acid, which is GRAS listed and has an E-number.

Results: Formulations with EUDRAGIT E PO exhibited a solubility enhancement of 5-fold in acidic pH which none of the other polymers achieved. FTIR scans showed ionic interactions between the carboxylic acid group of the naproxen molecule and the dimethylaminoethyl group of the EUDRAGIT E PO, which is absent in the other formulations evaluated. Faster onset of action of naproxen and improved bioavailability are expected, due to the increased solubility of EUDRAGIT E PO extrudates in acidic pH.

Results: As critical factors for in-process curing, product temperature, exhaust air humidity and curing time were identified. Following the QbD approach, the empirically developed process conditions were confirmed and even broadened. A robust and cost efficient process was achieved.

AAPS Poster # W5070 Wednesday, October 17, 2012, 3:30 pm 4:30 pm

Improved extrusion product using molecularly dispersed macrospheres

Active pharmaceutical ingredients (API) vary between multiple lots, making formulation especially challenging in the initial development stages of an implantable formulation. A method was examined here for dispersing the API within the

Results: The newly developed EUDRAGIT E PO formulation with tartaric acid provides excellent moisture protection which is comparable to the standard EUDRAGIT E PO formulation. It shows fast disintegration and complies to the requirement of USP dissolution tests for dietary supplements, both in HCl and in water. Similar to the standard EUDRAGIT E PO formulation, it is advantageous compared to HPMC and PVA based coatings.

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Workshops
EUDRAGIT Compact Course October 17 18, 2012 Buenos Aires, Argentina EUDRAGIT Compact Course November 7, 2012 Piscataway, NJ, USA Focus on PLGA applications: Parenteral drug delivery and medical devices November 27, 2012 Milan, Italy EUDRAGIT Basic Workshop November 29 30, 2012 Darmstadt, Germany EUDRAGIT Basic Workshop November 30, 2012 Ahmedabad, India EUDRAGIT Compact Course December 5, 2012 Dubai, United Arab Emirates

Log in to our online platform e-Lab at www.evonik.com/e-lab to register for our workshops in just a few easy steps.

Trade shows
Visit us at these upcoming trade shows.
AAPS October 14 18, 2012 Chicago, IL, USA Supply Side West November 6 8, 2012 Las Vegas, NV, USA CPhI India November 21 23, 2012 Mumbai, India MD&M West February 11 14, 2013 Anaheim, CA, USA AAOS March 19 23, 2013 Chicago, IL, USA SfB Annual Meeting & Exposition April 10 13, 2013 Boston, MA, USA

Imprint
This is a publication of Evoniks Pharma Polymers & Services product line Published by Evonik Industries AG Kirschenallee 64293 Darmstadt Germany phone +49 6151 18-4019 fax +49 6151 18-3520 eudragit@evonik.com www.eudragit.com www.evonik.com/e-lab www.evonik.com/biomaterials Responsible for content Dr. Brigitte Skalsky Layout MLW KommunikationsForm GmbH Werbeagentur, Worms = registered trademarks EUDRAGIT and RESOMER are registered trademarks of Evonik Industries or its subsidiaries.

All dates and locations are subject to change Pharma Polymers News 2 | 2012