FMEA, DoE & PAT : Three Inseparable Organs of Quality Risk Management (QRM) Body for Pharmaceutical Product Development with QbD

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Information about FMEA, DoE & PAT : Three Inseparable Organs of Quality Risk Management...
Health & Medicine

Published on March 4, 2014

Author: shivang47

Source: slideshare.net

FMEA DoE PAT Three Inseparable Organs of Quality Risk Management Body SHIVANG CHAUDHARY Formulation Scientist (Pharma-QbD Associate) M.S. Pharm (Pharmaceutics)- NIPER P.G.D (Patents Law)- NALSAR Email ID: shivaniper@gmail.com Contact No: +91-9904474045 © Copyrighted by Shivang Chaudhary

QRM/QbD EXAMPLE FROM PHARMA INDUSTRY Generic Immediate Release Uncoated Scored Tablet © Copyrighted by Shivang Chaudhary€€

Define QTPP (Quality Target Product Profile) QUALITY TARGET PRODUCT PROFILE On the basis of THERAPEUTIC EQUIVALENCE for Generic Drug Product = PHARMACEUTICAL EQUIVALENCE (same dosage form, route of administration, strength & same quality) + BIO-EQUIVALENCE (same pharmacokinetics in terms of Cmax, AUC to reference product) Determine CQAs (Critical Quality Attributes) CRITICAL QUALITY ATTRIBUTES Considering QUALITY [Assay, Uniformity of Dosage units,], SAFETY [Impurities (Related substances), Residual Solvents, Microbiological limits], EFFICACY [Dissolution & Absorption] & MULTIDISCIPLINARY [Patient Acceptance & Compliance] Quality Risk Assessment of CMAs & CPPs by DESIGN OF EXPERIMENTS PROCESS ANALYTICAL TECHNOLOGY CONTROL STRATEGY © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS (1) RISK IDENTIFICATION: by Ishikawa Fishbone (2) RISK ANALYSIS by Relative Risk based Matrix Analysis (3) RISK EVALUATION by Failure Mode Effective Analysis DoE & Generation of Design Space DoE For SCREENING & OPTIMIZATION of CMAs & CPPs with respect to CQAs by superimposing contour plot to generate OVERLAY PLOT (Proven acceptable Ranges & Edges of failure ) based upon desired ranges of Responses PAT Development of PAT System For continuous automatic analyzing & controlling critical processing through timely measurements of CMA & CPAS by INLINE ANALYZERS WITH AUTO SENSORS with the ultimate goal of consistently ensuring finished product quality with respect to desired CQAs Implementation of Control Strategy For CONTROLS OF CMAs, CPPs within Specifications, by Real Time Release Testing, Online Monitoring System * Inline PAT Analyzers [based upon previous results on development, Scale Up. Exhibit/ Validation batches] Continual Improvement CONTINUAL IMPROVEMENT FMEA based upon CONTINUAL RISK REVIEW & RISK COMMUNICATION BETWEEN PLANT, QA, QC, RA, R&D, AR&D during routine commercial manufacturing experience © Copyrighted by Shivang Chaudhary <<(QRM)>>

PHARMACIST’S POINT OF VIEW QUALITY TARGET PRODUCT PROFILE PHYSICIAN’S POINT OF VIEW PATIENT’S POINT OF VIEW QTPP Element Dosage FORM © Copyrighted by Shivang Chaudhary PROCESS ANALYTICAL TECHNOLOGY Oral Dosage STRENGTH DESIGN OF EXPERIMENTS Immediate Release Uncoated Tablet ROUTE of Administration RISK ASSESSMENT OF CMAS & CPPS Tablet Dosage DESIGN CRITICAL QUALITY ATTRIBUTES Target x mg Drug Product QUALITY ATTRIBUTES Description Assay Uniformity Impurities Dissolution Microbiological Limits Water Content Residual Solvents PRIMARY PACKAGING QTPP Element Pharmaco-KINETICS QTPP Element CONTROL STRATEGY EASE OF STORAGE & DISTRIBUTION STABILITY & SHELF LIFE CONTINUAL IMPROVEMENT PATIENT ACCEPTANCE & PATIENT COMPLIANCE Justification Pharmaceutical equivalence requirement: same dosage form Immediate release design needed to meet label claims Pharmaceutical equivalence requirement: same route of administration Pharmaceutical equivalence requirement: same strength Pharmaceutical equivalence requirement: Must meet the same compendia or other applicable reference standards (i.e., identity, assay, purity and quality). Plastic Container & Closure/ Metal Blister system Needed to achieve the target shelf-life and should be qualified as suitable for drug product with to ensure product integrity during shipping desired appropriate compatibility & stability Target Fasting Study and Fed BE Study 90 % confidence interval of the PK parameters, AUC0-2, AUC2-24, AUC0-∞ and Cmax, should fall within bioequivalence limits of 80-125 Justification Bioequivalence requirement needed to ensure rapid onset and efficacy Target Justification Can be stored at real time storage condition as a normal practice with desired stability & can be Required to handle the product easily distributed from the manufacturer to end user same with suitable accessibility as per Reference Product. Should be stable against hydrolysis, oxidation, photo Equivalent to or better than degradation & microbial growth. At least 24-month Reference Product shelf-life shelf-life is required at room temperature Should be suitably flavored & colored for possessing acceptable taste ( in case of soluble/ dispersible/ Required to achieve the desired patient effervescent tablet) similar with Reference Product. acceptability & suitable compliance Can be easily administered/used similar with Reference Product labeling © Copyrighted by Shivang Chaudhary

MULTIDIS CIPLINARY QUALITY TARGET PRODUCT PROFILE Quality Attributes of Drug Product QUALITY SAFETY EFFICACY Yes Size Similar to reference product No Scored Yes* Identification Positive for drug Yes* Assay 90.0 to 110.0 % of labeled claim. Yes Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout formulation and process development. Yes Variability in content uniformity will affect safety and efficacy. Both formulation and process variables impact content uniformity, so this CQA will be evaluated throughout formulation and process development. Yes if drug is sensitive to moisture, it will impact stability & ultimately safety & efficacy. If drug is not sensitive to moisture, it will not impact stability Physical Attribut es © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS PROCESS ANALYTICAL TECHNOLOGY Color and shape should acceptable to the patient. No visual tablet defects should be observed. Score configuration DESIGN OF EXPERIMENTS Is this a CQA? Appearance CRITICAL QUALITY ATTRIBUTES Target Conforms to USP <905> Uniformity of Weight Variation/ Dosage Units: 90.0-110.0 % of Content Uniformity labeled claim with Acceptance Value: NMT 15.0; RSD : NMT 5.0% Water Content Impurities As per In house specification according to stability data As per ICH Q3A& Q3B Yes Justification Color, shape and appearance are not directly linked to safety and efficacy. Therefore, they are not critical. But to ensure patient acceptability it should be similar with reference product For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the target for tablet dimensions is set similar to the reference product If reference product is a scored tablet; then, the generic tablet should be scored. Score configuration is also critical for half-dosing & ease of splitting for generic drug product design.. Though identification is critical for safety and efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. Formulation and process variables do not impact identity. Therefore, this CQA will not be discussed during formulation and process development. Degradation products can impact safety and must be controlled based on compendial/ICH requirements or reference product characterization to limit patient exposure. The limit for total impurities is also based on reference product analysis. The target for any unknown impurity is set according to the ICH identification threshold for this drug product. Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development. Residual solvents can impact safety, but as it will be primarily controlled during drug substance & drug product manufacturing by drying, so Formulation and process variables are unlikely to impact this CQA. CONTINUAL IMPROVEMENT Residual Solvents Conforms to USP <467> option 1 Yes* Microbiological Limits CONTROL STRATEGY Conforms to USP <61 & 62> Yes* Non-compliance with microbial limits will impact patient safety, but as it will be primarily controlled during drug substance & drug product manufacturing, so formulation and process variables are unlikely to impact this CQA. Dissolution NLT X % (Q) of labeled amount of drug is dissolved in y Minutes in pH Z buffer, 900 ml, Apparatus I/II, 50/100 rpm. Yes Failure to meet the dissolution specification can impact bioavailability (efficacy). Both formulation and process variables affect the dissolution profile. This CQA will be investigated throughout formulation and process development. © Copyrighted by Shivang Chaudhary

RISK IDENTIFICATION QUALITY TARGET PRODUCT PROFILE RISK ANALYSIS RISK EVALUATION CRITICAL QUALITY ATTRIBUTES GRANULATION & DRYING RISK ASSESSMENT OF CMAS & CPPS PROCESS ANALYTICAL TECHNOLOGY © Copyrighted by Shivang Chaudhary DESIGN OF EXPERIMENTS IMPELLER/ MIXER SPEED CHOPPER/GRANULATOR SPEED COMPRESSION LIQUID ADDITION RATE FEEDER SPEED TOTAL GRANULATION TIME PRESS TURRET SPEED ENVIRONMENT PRECOMPRESSION FORCE TEMPERATURE FLUIDIZATION AIR VELOCITY COMPRESSION FORCE RELATIVE HUMIDITY ATOMIZATION AIR PRESSURE INLET AIR TEMPERATURE API PSD & SOLUBILITY MILLING SPEED INLET AIR TEMPERATURE ATOMIZATION PRESSURE DILUENT PSD & LOD MILLING SCREEN SIZE (SIEVE NO:ASTM/BSS#) SOLUTION SPRAYING RATE COATING PAN SPEED SOLUTION CONC. BINDER TYPE & CONC. BLENDER SPEED-RPM BLENDING TIME DISINTEGRANT CONC. LUBRICANT CONC. RAW MATERIAL SIZING & BLENDING COATING CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

RISK IDENTIFICATION QUALITY TARGET PRODUCT PROFILE RISK ANALYSIS RISK EVALUATION CRITICAL QUALITY ATTRIBUTES RISK ASSESSMENT OF CMAS & CPPS PROCESS ANALYTICAL TECHNOLOGY © Copyrighted by Shivang Chaudhary DESIGN OF EXPERIMENTS Physical Assay Uniformity Impurities Dissolution Particle size Low Low High Medium High Flow Properties Low Low High Low Low FP CQAs Diluent Binder Physical Assay Uniformity Impurities Dissolution Low Medium High Medium Low Low Low Low Low High FP CQAs Residual Solvent Low Low Low Medium Low Granulating Disintegrant Agent Low Low Low Low Low Low Low Low High High Solid state Solubility /Polymorph High Low Low Low Low Low Low Low High High Wetting Agent Low Low Low Medium High Glidant Low Low High Medium Low Process Impurity Low High Low High Low Antiadherant High Low Low Low High Chemical Stability Low High Low High Low Lubricant High Low Low Low High CMAs of Inactive Ingredient (Excipients) CONTROL STRATEGY CONTINUAL IMPROVEMENT Moisture content Low Low Low Medium Low Low Medium High Broadly acceptable risk. No further investigation is needed Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk. Risk is unacceptable. Further investigation is needed to reduce the risk. © Copyrighted by Shivang Chaudhary CRITICAL MATERIAL ATTRIBUTES (CMAs) CMAs of Active Pharmaceutical Ingredient (API)

QUALITY TARGET PRODUCT PROFILE PhysicoChemical Property of Actives Failure Mode (Critical Event) Solid Sate Form CRITICAL QUALITY ATTRIBUTES Critical Material Attribute (CMAs) Different Polymorph/ form CONTROL STRATEGY © Copyrighted by Shivang Chaudhary PROCESS ANALYTICAL TECHNOLOGY High water content Hygroscopicity High water content Residual Solvents High residual solvent Solubility Chemical Property Poor flow Different Salt/ Form Process Impurities Less Purity Chemical Stability DESIGN OF EXPERIMENTS Flow Properties Moisture content Physical Property RISK EVALUATION Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode) Particle Size Higher PSD Distribution (PSD) RISK ASSESSMENT OF CMAS & CPPS RISK ANALYSIS poor Different Solubility of drug substance= Dissolution of drug product may be affected= Bioavailability/Efficacy may got compromised BCS Class II/IV drug = Dissolution of drug product can be affected= Bioavailability/Efficacy may got compromised Poor blend uniformity in simple dry mixing process= uncertainty in uniformity of dosage units due to possible segregation = Quality may got compromised Rate of degradation may be affected = Impurity profile may be affected = Safety may got compromised Rate of degradation may be affected = Impurity profile may be affected = Safety may got compromised Residual solvents are likely to interact with drug substance= Impurities may be affected = Safety may got compromised Dissolution of the drug product can be affected = Bioavailability/Efficacy may got compromised Assay & impurity profile of drug product may be affected = Quality & Safety may got compromised Susceptible to dry heat/oxidative/hydrolytic/UV light degradation- impurity profile may get affected = Quality & Safety may got compromised Probability* Severity** Detect ability*** Very Unlikely Occasional Repeated Regular Minor Moderate Major Extreme Always Detected Regularly Detected Likely not Detected Normally not Detected Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure. CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary S P D RPN (=S*P*D) 4 4 4 64 4 4 4 64 4 4 3 48 3 2 2 12 3 2 2 12 3 2 2 12 3 2 3 18 3 2 3 18 3 2 3 18 Score 01 02 03 04 FMEA of Active’s CMAs RISK IDENTIFICATION

QUALITY TARGET PRODUCT PROFILE Critical Excipient Material (Inactive Attribute ingredient) (CMAs) CRITICAL QUALITY ATTRIBUTES Particle Size Distribution Failure Mode (Critical Event) Uneven Diluent Moisture Content High DESIGN OF EXPERIMENTS PROCESS ANALYTICAL TECHNOLOGY CONTROL STRATEGY © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS More than optimum Binder/ Granulating agent Amount of Binder Disintegrant Amount of Disintegrant Less than optimum Glidant Concentration of Glidant Less than optimum Anti-adherant Concentration of Anti-adherant Less than optimum Lubricant Coloring/ Flavor/ Sweetener agent Concentration of Lubricant Concentration Less than optimum Less than optimum Higher than Optimum Lower than optimal Higher than optimum RISK ANALYSIS Effect on IP & FP CQAs with respect to QTPP (Justification of Failure Mode) Flow properties of the blend may be affected (in dry mixing process) = Uniformity of dosage units may be affected = Quality/ Safety may got compromised Impurity profile may be affected (in case of moisture sensitive drugs) = Safety may got compromised Produces hard granules= Produces tablet / capsule with greater disintegration time & retarded dissolution= Efficacy may got compromised Loose granules will be formed, which may produce friable Tablet = Patient acceptance/ Patient compliance got compromised Desired Dissolution cannot be achieved (in case of immediate release product) = Efficacy may got compromised Flow of granules or powder from hopper to die by reducing friction between particles may be affected = = Uniformity of dosage units may affected =Quality may got compromised Ejection of finished product from tooling may be difficult= Material get stuck to the surface of filling die= Sticking may be observed = patient acceptance/ compliance may got compromised Material get stuck to the surface of punches/toolings = Picking may be observed = Patient acceptance/ compliance may got compromised Hydrophobic lubricant may surface coat the drug particle = dissolution may got retarded = Efficacy may got compromised Shade variation/ Mottling may be observed = Patient compliance may got compromised Safety may got compromised Probability* CONTINUAL IMPROVEMENT RISK EVALUATION Severity** Detect ability*** Very Unlikely Occasional Repeated Regular Minor Moderate Major Extreme Always Detected Regularly Detected Likely not Detected Normally not Detected Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure. © Copyrighted by Shivang Chaudhary S P D RPN (=S*P*D) 3 3 2 18 3 3 2 18 4 4 2 32 4 4 2 32 4 4 2 32 3 3 2 18 3 3 2 18 3 3 2 18 3 3 3 27 3 3 1 9 3 3 3 27 Score 01 02 03 04 FMEA of In active's CMAs RISK IDENTIFICATION

RISK IDENTIFICATION QUALITY TARGET PRODUCT PROFILE RISK ANALYSIS RISK EVALUATION CRITICAL QUALITY ATTRIBUTES PROCESS ANALYTICAL TECHNOLOGY CPPs of Wet Granulation Process FP CQAs Co-sifting Blending Description Assay Impurities Uniformity Dissolution Low Medium Low Medium Low Low High Low High Low Rapid Mixing Granulation Low Low Low Low High Fluid Bed Drying Low Low High Low Low Sizing High Medium Low Medium Low Lubrication Compression High High Low High High High Low Low High High CONTROL STRATEGY CONTINUAL IMPROVEMENT Low Medium High Broadly acceptable risk. No further investigation is needed Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk. Risk is unacceptable. Further investigation is needed to reduce the risk. © Copyrighted by Shivang Chaudhary CRITICAL PROCESSING PARAMETERS (CPPs) DESIGN OF EXPERIMENTS © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS

QUALITY TARGET PRODUCT PROFILE Unit Operations Critical Process Parameter (CPPs) Sifting CRITICAL QUALITY ATTRIBUTES Sifting Dry Mixing DESIGN OF EXPERIMENTS PROCESS ANALYTICAL TECHNOLOGY © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS Granulation in Rapid Mixer Granulator Drying in Fluid Bed Drier Sizing (Milling & Screening) Lubrication & Blending Compression / Filling Coating CONTROL STRATEGY CONTINUAL IMPROVEMENT Rate of Impeller / Mixer Rate of Chopper/ Granulator Binder-Granulating agent spraying rate Inlet Temperature Fluidizing Air Flow rate RISK EVALUATION Failure Mode Effect on IP & FP CQAs with respect to (Critical QTPP (Justification of Failure Mode) Event) Larger Sieve size. Lower RPM & Shorter Time High RPM & Longer Time Low RPM & Shorter Time High RPM High Product Temperature Higher CFM Comil Speed Increase Speed Comil Screen Larger # Size Blending Rate High RPM & High Time Turret/ Feeder Speed Compression Force /Tamping force Bed Temperature Spraying rate Atomizing Pressure RISK ANALYSIS High Speed High Force High Temp. Higher Rate Lower pressure S P D RPN (=S*P*D) Uneven PSD = Uncertainty in Uniformity 02 02 03 12 Lesser No. of total Revolutions = Uncertainity in Uniformity 02 02 03 12 04 04 03 64 04 04 03 48 04 04 03 48 02 02 03 12 02 02 03 12 02 02 03 12 02 02 03 12 02 02 03 12 04 03 03 36 04 03 02 24 02 03 02 02 03 02 03 01 01 12 09 04 Produce Larger granules (forms agglomerate/lumps)= Dissolution of Tablet / Capsule can be increased= Efficacy/ Bioavailability may got compromised Rate of degradation may be affected = Impurity profile may be affected Increased attrition & evaporation produces fines = process efficiency may be compromised Fines may be generated = Poor flow leads to uncertainty in uniformity of dosage units Uneven PSD leads to uncertainty in Uniformity Larger granules = Dissolution may be increased Increase No. of total Revolutions = Dissolution may be increased Weight Variation may be observed= Uniformity of dosage units may be bargained Hardness of Tablet/ Slug will be increased = Disintegration/ Dissolution may be increased Impurity profile affected Appearance affected Appearance affected Probability* Severity** Detect ability*** Very Unlikely Occasional Repeated Regular Minor Moderate Major Extreme Always Detected Regularly Detected Likely not Detected Normally not Detected Total Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure. © Copyrighted by Shivang Chaudhary Score 01 02 03 04 CRITICAL PROCESSING PARAMETERS (CPPs) RISK IDENTIFICATION

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE ANOVA DIAGNOSTICS MODEL GRAPHS DESIGN SPACE FOR OPTIMIZATIONS OF IR TABLET FORMULATION & KNEADING IN GRANULATION PROCESS CRITICAL QUALITY ATTRIBUTES NO. OF FACTORS: 3 NO. OF LEVEL: 3 CMAs DESIGN OF EXPERIMENTS PROCESS ANALYTICAL TECHNOLOGY CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 CPP CQAs Factor 1 Factor 2 Factor 3 Response 1 A: B: C:KNEADING BINDER DISINTEGRANT Time HARDNESS (in %) (in %) (in minutes) (in N) 4 3 2 46 4 5 4 52 4 1 4 55 4 3 6 58 7 3 4 70 7 1 6 72 7 3 4 68 7 3 4 70 7 3 4 72 7 3 4 68 7 1 2 65 7 5 2 62 7 5 6 74 10 3 6 92 10 5 4 86 10 3 2 83 10 1 4 88 Response 2 Response 3 Response 4 DISINTEGRATION DRUG FRIABILITY TIME DISSOLVED (in %) (in min) (in %) 0.24 5 95 0.21 5 97 0.18 9 87 0.16 7 91 0.11 6 99 0.10 11 90 0.10 6 100 0.12 6 97 0.09 6 100 0.08 6 99 0.13 10 92 0.14 5 98 0.09 6 95 0.06 9 82 0.07 4 89 0.08 8 88 0.08 12 86 DESIGN: BOX-BEHNKEN TOTAL RUNS: 17 ORDER: QUADRATIC MODEL: POLYNOMIAL © Copyrighted by Shivang Chaudhary

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE ANOVA DIAGNOSTICS MODEL GRAPHS DESIGN: BOX-BEHNKEN CRITICAL QUALITY ATTRIBUTES DESIGN SPACE NO. OF FACTORS :3 NO. OF LEVELS :3 TOTAL RUNS :17 (0,+1,+1) (-1,0,+1) PROCESS ANALYTICAL TECHNOLOGY 0 (7%) (0,-1,+1) (+1,+1,0) (-1,+1,0) BINDER (in %w/w) DESIGN OF EXPERIMENTS +1 (10%) © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS (+1,0,+1) (0,0,0) (+1,-1,0) (-1,-1,0) +1 (6 min) (0,+1,-1) 0 (4 min) (-1,0,+1) CONTROL STRATEGY CONTINUAL IMPROVEMENT -1 (4%) (+1,0,-1) -1 (2 min) (0,-1,-1) SUPER DISINTEGRANT (in % w/w/) -1 (1%) 0 (3%) © Copyrighted by Shivang Chaudhary x +1 (5%)

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE CRITICAL QUALITY ATTRIBUTES Analysis of Variance (ANOVA) For Each factor, their interactions & curvatures on Individual Response RISK ASSESSMENT OF CMAS & CPPS ANOVA DIAGNOSTICS MODEL GRAPHS DESIGN SPACE Predicted Effect Equation of Each factor, their interactions & curvatures on Individual Response © Copyrighted by Shivang Chaudhary PROCESS ANALYTICAL TECHNOLOGY HARDNESS = +69.60+17.25A-0.75B+5.00C+0.25AB-0.75AC+1.25BC +1.08A2-0.42B2-0.93C2 Model F-value: 27.49 Model Value: Significant Significant Model Terms: A, C, A2 FRIABILITY = +0.100-0.063A+2.500E-003B-0.023C-0.010AB+ 0.015AC-5.000E-003BC+0.027A2+7.500E-003B2+7.500E-003C2 Model F-value: 37.34 Model Value: Significant Significant Terms: A,B,C, AB, B2, C2 DISINTEGRATION TIME = +6.00+0.87A-2.75B+0.63C-1.00AB-0.25AC+0.000BC +0.37A2+1.13B2+0.88C2 Model F-value: 23.67 Model Value: Significant Significant Terms: A,B,C, A2, B2, C2 DESIGN OF EXPERIMENTS Model F-value: 128.93 Model Value: Significant Significant Model Terms: A, C DRUG DISSOLVED = +99.00-3.12A+3.00B-1.88C-1.75AB-0.50AC-0.25BC -7.00A2-2.25B2-3.00C2 CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE ANOVA DIAGNOSTICS MODEL GRAPHS DESIGN SPACE 2D Contour plots Plots for Individual Responses with respect to Binder(A) & Kneading Time(C) 2D CONTOUR PLOTS CRITICAL QUALITY ATTRIBUTES PROCESS ANALYTICAL TECHNOLOGY 3D RESPONSE SURFACE PLOTS 3D Response Surface Methodology (RSM) Plots for Individual Responses with respect to Binder(A) & Kneading Time (C) 4D Cube Plots for Individual Responses with respect to Binder(A) & Kneading Time(C) 4D CUBE PLOTS DESIGN OF EXPERIMENTS © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE Factors (Variables) A BINDER (%) B DISINTEGRANT (%) C KNEADING TIME (min) Responses (Effects) Y1 HARDNESS (N) Y2 FRIABILITY (%) Y3 DISINTEGRATION (min) Y4 DISSOLUTION (%) CRITICAL QUALITY ATTRIBUTES ANOVA DIAGNOSTICS MODEL GRAPHS Levels of Factors studied 0 5%w/w 3%w/w 4min Goal for Individual Responses To achieve tablet hardness in the range from 60 to 80N To achieve minimum friability nearest to 0.00% To achieve tablet DT in the range from 5 to 10 minutes To achieve maximum dissolution nearest to 100% -1 3%w/w 1%w/w 2min DESIGN SPACE +1 7%w/w 5%w/w 6min PROCESS ANALYTICAL TECHNOLOGY OVERLAY PLOT WITH SWEET SPOT DESIGN OF EXPERIMENTS © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE ANOVA DIAGNOSTICS MODEL GRAPHS DESIGN SPACE 2D Contour plots Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B) 2D CONTOUR PLOTS CRITICAL QUALITY ATTRIBUTES PROCESS ANALYTICAL TECHNOLOGY 3D RESPONSE SURFACE PLOTS 3D Response Surface Methodology (RSM) Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B) 4D Cube Plots for Individual Responses with respect to Binder (A) & Superdisintegrant (B) 4D CUBE PLOTS DESIGN OF EXPERIMENTS © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

EXPERIMENTAL DESIGN QUALITY TARGET PRODUCT PROFILE Factors (Variables) A BINDER (%) B DISINTEGRANT (%) C KNEADING TIME (min) Responses (Effects) Y1 HARDNESS (N) Y2 FRIABILITY (%) Y3 DISINTEGRATION (min) Y4 DISSOLUTION (%) CRITICAL QUALITY ATTRIBUTES ANOVA DIAGNOSTICS MODEL GRAPHS Levels of Factors studied 0 5%w/w 3%w/w 4min Goal for Individual Responses To achieve tablet hardness in the range from 60 to 80N To achieve minimum friability nearest to 0.00% To achieve tablet DT in the range from 5 to 10 minutes To achieve maximum dissolution nearest to 100% -1 3%w/w 1%w/w 2min DESIGN SPACE +1 7%w/w 5%w/w 6min PROCESS ANALYTICAL TECHNOLOGY OVERLAY PLOT WITH SWEET SPOT DESIGN OF EXPERIMENTS © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

PAT FOR TABLET MANUFACTURING LINE QUALITY TARGET PRODUCT PROFILE CRITICAL QUALITY ATTRIBUTES API / EXCIPIENT PURITY by In Line BRUKER FT-NIR API / EXCIPIENT PARTICLE SIZE DISTRIBUTION by In line Lasentec FBRM DESIGN OF EXPERIMENTS PROCESS ANALYTICAL TECHNOLOGY CONTROL STRATEGY CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS RAPID MIXER GRANULATOR FLUID BED DRYER SIFTER CUM MULTI MILL SIFTER FOR DELUMPING BIN BLENDER COMPRESSION MACHINE RATE OF DRY MIXING & RATE OF DRYING (Temperature / RATE OF BLENDING GRANULATION Time) FOR by In Line FT-NIR (Speed/ Time) by (Speed / Time) by In Line In Line FT-NIR Lasentec FBRM or PVM & AES (Acoustic Emission Spectroscopy) FOR GRANULES RATE OF SIZING / MILLING (Speed/ Force) by In Line Lasentec FBRM FOR GRANULES OR At Line Malvern PSA © Copyrighted by Shivang Chaudhary RATE OF COMPRESSION (Speed & Hardness ) by In Line Compression Force Sensor with Servo motor in Se-Jong/Fette for Auto matic control of Weight & Hardness OR Bruker Tandem FT-NIR

CONTROL OF CMAs QUALITY TARGET PRODUCT PROFILE Factor(s) CMAs CONTROL OF CPPs Ranges studied at Actual data for Proposed range for lab scale Exhibit batch Commercial batch Purpose of control API Attributes Polymorphic Form CRITICAL QUALITY ATTRIBUTES DESIGN OF EXPERIMENTS © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS Xx, yy, zz 2Ө values D25: Particle Size Distribution D50: (PSD) D90: Excipient Attributes Microcrystalline Cellulose Particle Size distribution (Avicel PH 102) Moisture content Crospovidone Level in Formulation (Polyplasdone XL 10) Specific surface area Polyvinylpyrolidone Level in Formulation (Pladone K 29/32) K Value Colloidal silicone Dioxide Specific surface area (Aerosil 200 Pharma) Magnesium Stearate Specific surface area (vegetable Grade) Factor(s) CPPs Pre-mixing time Granulation fluid quantity Solution addition rate Xx, yy, zz Xx, yy, zz To ensure batch to batch consistency in drug product Dissolution NMT 10 um NMT 35 um NMT 50 um NMT 10 um NMT 35 um NMT 50 um NMT 10 um NMT 35 um NMT 50 um To ensure batch to batch consistency in Blend uniformity & Dissolution d50: NMT 100 um NMT 5.0% 4%-10% 1.2-1.4 m2/g 1-5% 29-32 d50: NMT 100 um NMT 5.0% 7.5% 1.2-1.4m2/g 2.5% 30 d50: NMT 100 um NMT 5.0% 7.5% 1.2-1.4m2/g 2.5% 30 175-225m2/g 200m2/g 200m2/g 10-20m2/g 10-20m2/g 10-20m2/g Ranges studied at Actual data for Proposed range for lab scale Exhibit batch Commercial batch 10-20 min 15 min 15 min Granulation Process 2 min 4 min (Impeller: 50 rpm; Chopper: 1500 rpm) 45-55°C 2 min 4 min (Impeller: 50 rpm; Chopper: 1500 rpm) 45-55°C Water Content 0.5-5.0% 1.5-3.0% 1.5-3.0% Milling Speed Mill Screen Size 800-1200 rpm 1-2 mm 50-150 revolutions (10 RPM, 5-15 min) 30-70 revolutions (10 RPM, 3-7 minutes) 3-7 RPM 10-30 RPM 40-80N 1000 rpm 1.5 mm 100 revolutions (10 RPM, 10 minutes) 50 revolutions (10 RPM, 5 minutes) 3-7 RPM 15-25 RPM 50-70N Milling Process 1000 rpm 1.5 mm 100 revolutions (10 RPM, 10 minutes) 50 revolutions (10 RPM, 5 minutes) 3-7 RPM 15-25 RPM 50-70N Blending Rate in Pre Lubrication stage Blending Process Blending Rate in Pre Lubrication stage CONTINUAL IMPROVEMENT Compression Process Purpose of control 25% 2 min 2-6 min (Impeller: 50 rpm; Chopper: 1500 rpm) 40-50°C Rate of Wet Mass Mixing & Granulation Drying Process CONTROL STRATEGY 25% Drying temerature PROCESS ANALYTICAL TECHNOLOGY 20-30% To ensure consistency in dry mixing for wet granulation To ensure consistent disintegration of tablet into granules To give consistent binding functionality to granules To promote consistent flow property of granules from hopper to die To ensure consistent lubrication &smooth ejection of tablet from die. Feeder speed Turret Speed Compression hardness © Copyrighted by Shivang Chaudhary To ensure IR granule CQAs (PSD & bulk as well as tapped density) are met consistently To ensure low water content in order to prevent microbial growth & compression defects To ensure IR granule PSD is met consistently To ensure batch to batch consistancy in Blend Uniformity To ensure all tablet CQAs (Assay, CU & drug release) are met consistently

QUALITY TARGET PRODUCT PROFILE CONTINUAL RISK REVIEW & RISK COMMUNICATION BETWEEN STACKHOLDERS OF: CRITICAL QUALITY ATTRIBUTES REGULATORY AFFAIRS DESIGN OF EXPERIMENTS PROCESS ANALYTICAL TECHNOLOGY CONTROL STRATEGY © Copyrighted by Shivang Chaudhary RISK ASSESSMENT OF CMAS & CPPS FORMULATION R&D QUALITY CONTROL ANALYTICAL R&D QUALITY ASSUARANCE MANUFACTURING PLANT DURING ROUTINE COMMERCIAL MANUFACTURING CONTINUAL IMPROVEMENT © Copyrighted by Shivang Chaudhary

QRM/QbD EXAMPLE FROM FAST FOOD INDUSTRY World Famous McDonald’s French Fries © Copyrighted by Shivang Chaudhary

CMA McDonald’s passion for quality meant that every single ingredient was tested, tasted and perfected to fit the operating system 2. Special varieties of potato, like the “RUSSET BURBANK” which is chosen for its quality, taste and long shape when cut 3. 100 Circle Farms grows the perfect potatoes in circles so big around, they’re visible from space. CQAs 1. Even Light Golden blond Crispy & Soft Exterior Fluffy & Intact Interior Stay crisp & tasty for long time FREEZING in freezer for at least 4 hours FINISHING (FINAL FRYING) at 275-375ͦC for about five minutes, gives golden brown color CPPs Washing & Peeling of Potatoes RINSING & PLACING in Water-Vinegar mixture to remove extra starch for at least 12 hours BLANCHING (PRE FRYING) for 45 to 60 seconds at 390 degrees in canola blend oil Average McDonald's restaurants in the US sells 87,600 pounds of fries per year, 1.05 billion pounds of French fries nationwide. © Copyrighted by Shivang Chaudhary

Focus on Quality, Not on Money; Quality Automatically Brings Money. Thank You So much for Your Attention. SHIVANG CHAUDHARY Formulation Scientist (Pharma-QbD Associate) M.S. Pharm (Pharmaceutics)- NIPER; P.G.D (Patents Law)- NALSAR Email ID: shivaniper@gmail.com Contact No: +91-9904474045 © Copyrighted by Shivang Chaudhary

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