Presentation of DR Sandip Tiwari

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)

Quality Target Product Profile 


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 


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 


List all Material Attributes and Process Parameters & 

Identify Quality Attributes 


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


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


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


Powder Characterization 

• Formulated powder blends with Propranolol HCl (30% Methocel K15M) 

Density (g/mL) Carr’s Sotax Flow LOD 


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.


Tablet Characterization 

• Propranolol HCl ER tablets with high polymer level (30% Methocel K15M) @ 15 kN 


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



• 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



• 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 % HP/ Low Level 

Low % HP/ Low Level 



Me echanical Stren ngth (MPa) 

4 

3 

2 

1 

0 

0 10 20 30 40 50 60 

Compression Pressure (MPa) 


Low Viscosity/ i High Level 

High % HP/ High Level 

Low % HP/ 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


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) 







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


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 


High %HP/ High Level 

Low %HP/ High Level 





• Drug release was consistent across HP range


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) 










•Drug release was significantly effected by coarser particle size distribution at the lower 

polymer level


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) 









• Drug release was consistent across viscosity range


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 


High %HP/ High Level 

Low %HP/ High Level 




•Drug release was consistent across HP range


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) 









•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 y y 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 i (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 d 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.


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 


• Blends of PEO N12K & 205 produced viscosity ~ POLYOX 1105 NF 

• M wt & polydispersity for blends were consistent with standard POLYOX


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) 


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% 


(UL-LL) @ 

50% 


(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 

(Quality by Design for ANDAs: An Example for Modified release Dosage Form)

Thank You

Presentation of DR Sandip Tiwari

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