Adopting Technologies to Enhance Quality in Manufacturing

Adopting Technologies to Enhance Quality in Manufacturing Sandip B. Tiwari, Ph.D. March 18, 2012

Current Status of Quality in Pharma Manufacturing Pharmaceutical manufacturing techniques lag behind those of potato-chip and laundry soap makers. The Wall Street Journal, September 3, 2003

Outline What is Quality in Pharmaceutical Manufacturing Assurance of Quality: Changing Paradigm Quality by Testing (QbT) to Quality by Design (QbD) What is QbD Adopting QbD in Manufacturing (at Design Stage) Implantation of QbD Conclusions

Pharmaceutical Quality

Assurance of Quality: Changing Paradigm Quality by Testing Quality by Design Presentation by A. Raw on Quality by Design example of generic modified release products

What is Quality by Design (QbD) Design the product to meet patient requirements Design the process to consistently meet product critical quality attributes Understand the impact of starting materials and process parameters on product quality Identify and control the source of process variation Continually monitor and update the process to allow a consistent quality over time

Quality by Design Approach API Variability Excipient Variability Process Variability σ σ σ σ 2 2 2 2 = + + + Product API Excipients Process σ 2 Interactions Ref: C. Moreton, 2009 QbD: design product & process to ensure robust formulation Need to fully understand all starting materials and influence of batch variability on end product Quality - Design of Experiments (DoE) - Risk Assessment - Process Analytical Technology

Why is QbD important? High level of assurance of product quality Cost saving and efficiency for industry and regulators Increase manufacturing efficiency, reduce cost and product rejects Minimize potential compliance actions, costly penalties and recalls Enhance opportunities for first cycle approval Streamline post approval manufacturing changes and regulatory processes Opportunities for continual improvement Reducing variability (or its effects) = Quality & Cost

Implementation of QbD Design Stage Scale up/ commercial scale manufacturing? Target----------------------------->Design--------------------------------------> Implantation Yu. Pharm. Res. 25:781-791 (2008)

Basis of QbD: Begin with End in Mind QbD asks Manufacturer to define their Quality Target Product Profile (QTPP) Presentation by A. Raw on Quality by Design example of generic modified release products

QbD Implementation: An Example

Quality Target Product Profile Source: www.fda.gov; (Quality by Design for ANDAs: An Example for Modified release Dosage Form)

Implementation of QbD Target----------------------------->Design--------------------------------------> Implantation Yu. Pharm. Res. 25:781-791 (2008)

Formulation Development Schematic Diagram of MR Product Development

Formulation Manufacturability Traditional/ Classical Approach Manufacturable at scale up level? QbD Approach Are the right excipients selected to ensure robust process Does this mean that a robust formulation o has been developed e that can be manufactured with consistent quality, over and again? Does the ER coating polymer offer flexibility to film to withstand t compression force? If not, does the addition of cushioning agent help? If yes, how much level is required?

Formulation Manufacturability: Preliminary Evaluations Source: www.fda.gov; (Quality by Design for ANDAs: An Example for Modified release Dosage Form)

Process Development/ Scale Up Traditional/ Classical Approach Scale up batch production record QbD Approach Risk assessment/ DoE 10X Scale up, Same Equipment/ Same operating principle Full commercial scale batches Can one guarantee reliable and reproducible commercial scale manufacturing? Determine critical process parameters/ non critical process parameters in unit operation Define design space for the process parameter Increased likelihood of success at commercial scale manufacturing

List all Material Attributes and Process Parameters & Identify Quality Attributes Source: www.fda.gov; (Quality by Design for ANDAs: An Example for Modified release Dosage Form)

Apply DoE Screening Design to Investigate which High Risk Parameters are Critical to ER Coating Performance

Compile Summary of DoE Study to Identify Design Space Experimental Design and Product Characteristics for Pilot Scale Batch

Updated Risk Management: ER Coating Variables

Typical Hydrophilic Matrix Formulation Material Critical Considerations Drug Low to high (dose/solubility) Polymer (METHOCEL ) Types/levels l Filler Type/level/solubility Glidant Low (0.2 1%) Lubricant Low (0.5 1%) Release modifiers/buffering agents/solubilizers/stabilizers Film coating Conventional IR/Functional MR Decision on choice and level of polymer and filler depends on drug properties and desired release profiles

Chemical Structure of HPMC n-2 hydroxypropoxyl substitution methoxyl substitution HPMC polymers are semi-synthetic materials derived from cellulose Performance indicators for METHOCEL (Viscosity, Substitution & Particle size)

Control Materials: HPMC as a Polymeric Rate Controlling Polymeric Excipient- Critical Specification Variables HPMC (METHOCEL premium cellulose ethers) Viscosity Assay % HP & % Methoxy Moisture (LOD) Functionality Related Characteristics (EP*) - Molecular mass distribution - Particle-size distribution - Powder flow Substritution Type 2208 Methoxy (%) Hydroxypropoxy (%) Min. Max. Min. Max. 19 24 4 12 * EP - Supplement 5.7 of the European Pharmacopoeia 2007 The information contained in this presentation is proprietary to Colorcon Inc and may not be used or disseminated

Process trend data: viscosity experience Hypromellose 2208 4000 mpa.s 6000 5500 5000 Historical production range Viscos sity 4500 4000 3500 USP range Vis cp Vis cps 3000 2500 2000 Time of Manufacture It may not be practical to keep one variable constant and vary the other. It may not be practical to obtain samples at extremes of specifications.

Process trend data: methoxy and HP experience Hypromellose 2208 4000 mpa.s 25.0 23.0 MeO 21.0 USP range MeO % 19.0 17.0 15.0 Historical production range 13.0 HPO 11.0 9.0 USP range HPO % 7.0 5.0 Time of Manufacture It may not be practical to keep one variable constant and vary the other. It may not be practical to obtain samples at extremes of specifications.

Case Studies Objective: Study influence of HP substitution, viscosity and particle size on performance of a hydrophilic matrix using METHOCEL K15M premium CR Polymer concentrations 15% low level 30% recommended level Model API s Metformin HCl (freely soluble drug, 500 mg/ml, 500 mg dose) AAPS poster 2009 available on Colorcon and DWC websites Propranolol HCl (soluble drug, 50 mg/ml, 160 mg dose) Theophylline anhydrous (slightly soluble drug, 8.3 mg/ml160 mg dose)

Physicochemical properties of METHOCEL K15M Premium CR Hypromellose Batch 2% Viscosity (mpa.s) % through 230 mesh % HP % MeO High viscosity 24856 57.7 9.1 23.1 Low viscosity 13413 55.0 9.6 22.9 High % thru 230 mesh 17054 62.8 9.5 22.4 Low % thru 230 mesh 20156 52.6 9.4 23.1 High % HP 16698 56.2 10.5 22.5 Low % HP 16833 56.2 8.4 22.9 Center point 19036 57.5 9.4 22.6 Powder properties for all seven samples of METHOCEL K15M Premium CR were comparable

METHOCEL K15M Premium CR Formulation and Testing Methods Composition of Propranolol Hydrochloride ER formulations Ingredient % Composition Propranolol Hydrochloride 45.7 Methocel K15M Premium CR 15.0 or 30.0 Microcrystalline Cellulose (Emcocel 90M) 38.8 or 23.8 Magnesium Stearate 0.5 Total 100.00 Tablet weight 350 mg Direct compression method - 3/8" round, standard biconvex, Dissolution method: USP Apparatus II, 100 rpm, with sinkers, 1000 ml ph 6.8 phosphate buffer

METHOCEL K15M Premium CR Formulation and Testing Methods Composition of Theophylline ER formulations Ingredient % Composition Theophylline 45.2 Methocel K15M Premium CR 15 or 30 Lactose (FastFlow) 38.88 or 23.8 Magnesium Stearate 0.5 Silicon dioxide 0.5 Total 100.0 Tablet weight 352 mg Direct compression method - 3/8" round, standard d biconvex, Dissolution method: USP Apparatus II, 100 rpm, with sinkers, 1000 ml purified water

METHOCEL K15M Premium CR Powder Characterization Formulated powder blends with Propranolol HCl (30% Methocel K15M) Density (g/ml) Carr s Sotax Flow LOD Hypromellose Batch Bulk Tapped Index (%) (g/sec) (%) High viscosity 0.44 0.64 31.25 5.2 1.8 Low viscosity 0.45 0.66 31.82 4.8 1.7 High % thru 230 mesh 0.44 0.65 32.31 5.9 1.8 Low % thru 230 mesh 0.43 0.63 31.75 5.0 2.0 High % HP 0.45 0.64 29.69 4.8 1.8 Low % HP 0.44 0.64 31.25 5.2 2.4 Center point 0.43 0.65 33.85 5.0 1.7 All formulated propranolol blends exhibited comparable bulk/ tapped densities, powder flow and moisture levels.

METHOCEL K15M Premium CR Tablet Characterization Propranolol HCl ER tablets with high polymer level (30% Methocel K15M) @ 15 kn Hypromellose Batch Hardness Tensile Thickness Friability (kp) strength (MPa) (mm) (%) High viscosity 14.30 ± 0.7 2.81 ± 0.14 5.16 ± 0.03 0.00 Low viscosity 15.40 ± 0.7 3.02 ± 0.14 5.07 ± 0.02 0.01 High % thru 230 mesh 15.50 ± 01 0.1 311 3.11 ± 020 0.20 5.10 ± 004 0.04 000 0.00 Low % thru 230 mesh 14.40 ± 0.7 2.85 ± 0.14 5.14 ± 0.02 0.03 High % HP 15.00 ± 0.7 2.99 ± 0.14 5.12 ± 0.02 0.00 Low % HP 15.00 ± 1.2 2.99 ± 0.24 5.12 ± 0.04 0.00 Center point 15.40 ± 0.5 3.00 ± 0.10 5.19 ± 0.02 0.00 All tablet formulations exhibited comparable tablet hardness, tensile strength, thickness and friability values

METHOCEL K15M Premium CR Tablet Characterization Propranolol HCl ER tablets: compression force vs. hardness profiles 15% Polymer level 30% Polymer level 20 20 15 15 Hardness (k kp) 10 Hardness (k kp) 10 5 0 High Viscosity/ Low Level Low Viscosity/ Low Level High % HP/ Low Level Low % HP/ Low Level High % thru 230 mesh/ Low Level Low % thru 230 mesh/ Low Level Center Point/ Low Level 0 5 10 15 20 25 Compression force (kn) 5 High Viscosity/ High Level Low Viscosity/ High Level High % HP/ High Level Low % HP/ High Level High % thru 230 mesh/ High Level Low % thru 230 mesh/ High Level Center Point/ High Level 0 0 5 10 15 20 25 Compression force (kn) All tablet formulations exhibited comparable compression force vs. hardness profiles

METHOCEL K15M Premium CR Tablet Characterization Propranolol HCl ER tablets: compression pressure vs. mechanical strength profiles 15% Polymer level 30% Polymer level 5 5 Mec chanical Streng gth (MPa) 4 3 2 1 0 0 10 20 30 40 50 60 Compression Pressure (MPa) High Viscosity/ Low Level Low Viscosity/ Low Level High % HP/ Low Level Low % HP/ Low Level High % thru 230 mesh/ Low Level Low % thru 230 mesh/ Low Level Me echanical Stren ngth (MPa) 4 3 2 1 0 0 10 20 30 40 50 60 Compression Pressure (MPa) High Viscosity/ High Level Low Viscosity/ High Level High % HP/ High Level Low % HP/ High Level High % thru 230 mesh/ High Level Low % thru 230 mesh/ High Level All tablet formulations exhibited comparable compression pressure vs. mechanical strength profiles

Powder and Tablet Property Summary METHOCEL K15M Premium CR batches studied had comparable powder properties All formulations containing propranolol or theophylline (15 or 30% polymer) exhibited similar bulk/ tapped densities, powder flow and moisture levels exhibited comparable tablet hardness, tensile strength, thickness and friability values

METHOCEL K15M Premium CR Drug Release Propranolol HCl release: effect of viscosity 100 f 2 = 66.90 % PP P dissolved 80 60 40 15% polymer 30% polymer f 2 = 74.21 20 0 0 120 240 360 480 600 720 Time (min) High Viscosity/ Low Level Low Viscosity/ Low Level Center Point/ Low Level High Viscosity/ High Level Low Viscosity/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Higher polymer level lower variability Drug release was consistent across viscosity range

METHOCEL K15M Premium CR Drug Release Propranolol HCl release: effect of % HP content % PP P dissolved 100 80 60 40 15% polymer 30% polymer f 2 = 84.99 f 2 = 94.83 20 0 0 120 240 360 480 600 720 Time (min) High %HP/ Low Level Low %HP/ Low Level Center Point/ Low Level High %HP/ High Level Low %HP/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Higher polymer level lower variability Drug release was consistent across HP range

METHOCEL K15M Premium CR Drug Release Propranolol HCl release: effect of particle size % PP dissolved d 100 80 60 40 20 15% polymer 30% polymer f 2 = 48.23 f 2 = 94.14 0 0 120 240 360 480 600 720 Time (min) High % thru 230 mesh/ Low Level Low % thru 230 mesh/ Low Level Center Point/ Low Level High % thru 230 mesh/ High Level Low % thru 230 mesh/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Higher polymer level lower variability Drug release was significantly effected by coarser particle size distribution at the lower polymer level

METHOCEL K15M Premium CR Drug Release Theophylline release: effect of viscosity 100 80 15% polymer f 2 = 61.82 2 % TP dissolved 60 40 30% polymer f 2 = 62 20 0 0 120 240 360 480 600 720 Time (min) High Viscosity/ Low Level Low Viscosity/ Low Level Center Point/ Low Level High Viscosity/ High Level Low Viscosity/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Drug release was consistent across viscosity range

METHOCEL K15M Premium CR Drug Release Theophylline release: effect of % HP content % TP dissolved 100 80 60 40 15% polymer 30% polymer f 2 = 74.16 f 2 = 63.79 20 0 0 120 240 360 480 600 720 Time (min) High %HP/ Low Level Low %HP/ Low Level Center Point/ Low Level High %HP/ High Level Low %HP/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Drug release was consistent across HP range

METHOCEL K15M Premium CR Drug Release Theophylline release: effect of particle size 100 80 15% polymer f 2 = 62.57 P dissolved % T 60 40 30% polymer f 2 = 82.68 20 0 0 120 240 360 480 600 720 Time (min) High % thru 230 mesh/ Low Level Low % thru 230 mesh/ Low Level Center Point/ Low Level High % thru 230 mesh/ High Level Low % thru 230 mesh/ High Level Center Point/ High Level The similarity factor (f 2 ) was calculated by comparing high vs. low end of the selected physicochemical property Higher polymer level slower drug release Drug release was consistent across particle size range

Case Study Conclusions Ranges of viscosity, HP % and particle size of METHOCEL K15M Premium CR had no effect on physical properties of two model formulations and tablets Drug release profiles from METHOCEL matrices were slower when polymer concentration was increased from 15% to 30% w/w At 30% w/w polymer level, drug release profiles were similar despite variations in viscosity, %HP and particle size At 15% w/w polymer level, drug release profiles were generally more variable St ti P i t th C t ll d R l Alli ll d Starting Point - the Controlled Release Alliance generally recommends 30% polymer concentrations in HPMC hydrophilic matrices

The Next Step - Upgrade to CR Sales Specifications Process control and understanding of critical quality attribute impact on dosage form performance has led to tightening of the following criteria Methoxyl content Hydroxypropoxyl content Particle size percent through a 230 U.S. Std sieve In addition to existing 40 and 100 mesh specifications All other specifications remain unchanged Change effective January 7, 2011 No impact to PREMIUM grades or customer specifications

Upgrade to CR Sales Specifications METHOCEL K Premium Controlled Release Grades Specifications for METHOCEL E Premium CR grades and METHOCEL K Premium DC grades are also available

Value Add - Upgrade to CR Sales Specifications Decreases variability, increases METHOCEL CR reliability Robust, consistent dosage form performance Minimize excursions in product attributes Defines a realistic, achievable design space Permits QbD samples to be identified, captured and provided to users upon request Facilitates increased regulatory acceptance - increased speed to market Responds to the needs of the industry Reinforces the Controlled Release Alliance s commitment to understanding and fulfilling the needs of our customers Enhances potential to increase compliance and quality, while decreasing costs!!!

The Controlled Release (CR) Alliance Extension of a relationship between Colorcon and Dow since the 1970 s. Combines Colorcon, an acknowledged world leader in application development support Dow Wolff Cellulosic's, global experts in polymer and material science To deliver Unparalleled technical support in the development of controlled release dosage forms for the pharmaceutical industry

Strategies to Reduce Observed Variability Question is related to what solutions exist if variability is observed during investigation of a formulation design space Colorcon has previously shown that combinations of METHOCEL and Starch 1500 work in a synergistic manner to control drug release from matrices More recent studies have highlighted that similar combinations can be used to reduce the variability a specific critical quality attribute may be providing to a dosage form In particular, particle size can be a very important attribute when working with low solubility drugs, and matrix systems governed by erosion mechanisms

The Effect of Starch 1500 as A Filler in METHOCEL K100LV Formulations Hydrochlorothiazide (HCTZ) release: Effect of particle size and filler (30% Polymer Level) 100 80 High polymer level, Low viscosity, Medium %HP % HCTZ disso olvede 60 40 20 Low %thru 230 mesh (Starch 1500) High %thru 230 mesh (Starch 1500) Low %thru 230 mesh (Lactose) High %thru 230 mesh (Lactose) Filler f 2 Lactose 39.9 Starch 1500 81.1 0 0 2 4 6 8 10 12 Time (hours) This effect is generally observed across a range of dose-solubility combinations

Summary so far Applications data highlighting the critical quality attributes of METHOCEL and potential impacts on drug release was provided A service intended to provide samples and process trend data to build robust formulation design spaces was discussed Starch 1500 as a filler was demonstrated as an option to reduce the variability observed when evaluating METHOCEL samples of varying particle size One of the many benefits of accessing the Controlled Release Alliance has been demonstrated Stay in touch as options are developed for E-chemistry and premium grades

QbD Alliance Approach for POLYOX POLYOX general properties H H - C C O H H n Free flowing, nonionic, highly swelling Linear chain, typical particle size 150 μm Soluble in water, stable at ph 1.2-12 High crystallinity and thermoplastic Courtesy of Dow Chemical Company

POLYOX : Critical Specification Variables USP specifications for POLYOX Test USP Identification (A) + Identification (B) + Loss on Drying + Residue on Ignition (silicon dioxide and non-silicon dioxide) + POLYOX Viscosity Functionality Related Characteristics Silicon Dioxide + - Molecular mass distribution Heavy Metals + - Particle-size distribution - Powder flow Free Ethylene Oxide +

POLYOX Available Viscosity Grades POLYOX NF Viscosity Grades Viscosity Range at 25 C, cp Approximate* POLYOX NF Grades Molecular Weight 5% Solution 2% solution 1% Solution WSR N-10 NF 100,000 30-50 WSR N-80 NF 200,000 55-90 WSR N- 750 NF 300,000 600-1,200 WSR 205 NF 600,000 4,500-8,800 WSR - 1105 NF 900,000 8,800-17,600 WSR N-12K NF 1,000,000 400-800 WSR N-60K NF 2,000,000 2,000-4,000 WSR - 301 NF 4,000,000 1,650-5,500 WSR Coagulant NF 5,000,000 5,500-7,500 WSR-303 NF 7,000,000 7,500-10,000 Blends may offer the potential answer to generate QbD samples at viscosity extremes that may otherwise be difficult to obtain if working with just the intended grade. Courtesy of Dow Chemical Company

Case Study with POLYOX Formulation Objective: To investigate the effect of polyethylene oxide blends on polymer viscosity and formulation robustness Theophylline (sparingly soluble API) Diltiazem HCl (soluble API) Two standard PEO polymers -POLYOX 205 & POLYOX N-12K were used to develop the viscosity specification range of another standard product (POLYOX 1105) Polymer viscosity, molecular weight, tablet mechanical strength, and drug dissolution were determined to evaluate the effect of PEO blends on excipient performance in hydrophilic ER matrix tablets. L Hote-Gaston et al, Polyethylene Oxide Mixtures to Study Formulation Robustness in Hydrophilic Extended Release Matrix Tablets, AAPS 2009 Formulations consisted of 40% w/w API, 30% w/w polymer or polymer blend, 29.5% w/w MCC, and 0.5% w/w magnesium stearate.

Case Study with POLYOX Formulation 17600 8800 17600 8800 Properties of PEOs, PEO blends, and tablets prepared from theophylline and diltiazem HCl formulations Sample Brookfield Viscosity (cp) M w (Daltons) M n (Daltons) PDI Theophylline Hardness (scu) Diltiazem HCl POLYOX 1105 (A) 11520 1.17 X 10 6 2.59 X 10 5 4.52 26.2± 0.9 19.4±0.7 POLYOX 1105 (B) 9250 1.09 X 10 6 2.09 X 10 5 5.21 25.7±1.0 18.8±0.6 POLYOX 1105 (C) 9120 1.05 X 10 6 1.83 X 10 5 5.74 25.2±1.6 18.4±0.5 POLYOX 205 NF 6690 9.76 X 10 5 2.50 X 10 5 3.91 - - POLYOX N-12K 430 1.32 X 10 6 2.61 X 10 5 5.03 - - 25/75 POLYOX 205: N-12K (D) 17700 1.25 X 10 6 2.82 X 10 5 4.46 26.9±1.0 21.8±0.6 50/50 POLYOX 205: N-12K (E) 12720 1.13 X 10 6 2.59 X 10 5 4.35 27.5±1.1 22.1±0.4 75/25 POLYOX 205: N-12K (F) 9630 1.04 X 10 6 2.41 X 10 5 4.32 27.1±0.9 21.4±0.9 PDI: polydispersity index L Hote-Gaston et al, Polyethylene Oxide Mixtures to Study Formulation Robustness in Hydrophilic Extended Release Matrix Tablets, AAPS 2009 Blends of PEO N12K & 205 produced viscosity ~ POLYOX 1105 NF M wt & polydispersity for blends were consistent with standard POLYOX

Case Study with POLYOX Formulation Theophylline release from matrices containing PEO or PEO blends Diltiazem HCl release from matrices containing PEO or PEO blends 100 100 90 90 Th heophylline Releas sed (%) 80 70 60 50 40 30 20 10 0 POLYOX 1105 (A) POLYOX 1105 (B) POLYOX 1105 (C) 25/75 POLYOX 205:N-12K (D) 50/50 POLYOX 205:N-12K (E) 75/25 POLYOX 205:N-12K (F) 0 60 120 180 240 300 360 420 480 540 600 660 720 Time (min) Ditiazem HCl Releas sed (%) 80 70 60 50 40 30 20 10 0 POLYOX 1105 (A) POLYOX 1105 (B) POLYOX 1105 (C) 25/75 POLYOX 205:N-12K (D) 50/50 POLYOX 205:N-12K (E) 75/25 POLYOX 205:N-12K (F) 0 60 120 180 240 300 360 420 480 540 600 660 720 Time (min) L Hote-Gaston et al, Polyethylene Oxide Mixtures to Study Formulation Robustness in Hydrophilic Extended Release Matrix Tablets, AAPS 2009 The viscosity of PEO, whether as an individual product or a blend, did not significantly affect the drug dissolution (f 2 > 75) within the evaluated range.

Conclusions Blends of PEO N12K & 205 produced viscosity across the range of POLYOX 1105 NF. Molecular weight and polydispersity for PEO blends were consistent with the standard POLYOX product. The viscosity of PEO, whether as an individual product or a blend, did not significantly affect drug dissolution (f2 > 75) within the evaluated range, both for theophylline and diltiazem HCl. This study demonstrates an approach to assess the impact of POLYOX variability in matrix formulation by blending standard PEO grades.

Summary & Conclusions Pharmaceutical manufacturing changing paradigm from QbT to QbD Implementation of QbD in drug product development will help the industry as well as well as end customer i.e. patient Risk assessment and Design of Experiment (DoE) are the tools to use during design, development and ultimate manufacturing of pharmaceutical products Control on process variables and raw material quality is critical during the manufacturing Implementation of QbD in drug product design will ensure compliance with cgmp

Frequently Asked Questions: Hydrophilic Matrices Typical customer questions Are QbD samples available for METHOCEL controlled release E-chemistry grades? What types of customers have inquired most frequently for QbD support for high viscosity METHOCEL? How are the batches that will be sampled to users selected? General questions from regulatory bodies Demonstrate your product performance across the viscosity specifications of the selected controlled release polymer. What are the critical quality attributes t of your excipient(s)/ i process(es)?. Provide practical data to support the selection of your design space.

Frequently Asked Questions : General Source: www.fda.gov/downloads/drugs/newsevents/ucm237512.pdf

FAQ: Effect of Viscosity on Drug Release (Theoretical Considerations) Expected differences in % drug released over a range of HPMC viscosity specification Δ UL LL 0.24 0.24 ( Drug Release ) = b ( M M ) at x% at x% LL UL = x M M UL LL 0.24 1 M w 1 Ln (2% viscosity ) 1.2631 0. 8216 1.0778 viscosity = 0.0002 METHOCEL Type η 2% (cp) ln η, 2% (cp) Mw (Daltons) Δ Drug release (UL-LL) @ 20% Δ Drug release (UL-LL) @ 50% Δ Drug release (UL-LL) @ 80% Low limit 11250 9.33 447882 K15M 044 0.44 110 1.10 174 1.74 High limit 21000 9.95 489938 Theoretically, an expected difference in % drug released over a range of HPMC viscosity specification is minimal. Ref. Mitchell SA, and Balwinski KA 2008. J. Pharm Sci. 97:2277-2285

Frequently Asked Questions: General Source: www.fda.gov/downloads/drugs/newsevents/ucm237512.pdf

Frequently Asked Questions: General Source: www.fda.gov (Quality by Design for ANDAs: An Example for Modified release Dosage Form)

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