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Generic product development and technology transfer : At a glance

The document outlines the challenges and remedies in generic product development and technology transfer, highlighting significant issues such as difficult product formulation and regulatory queries. It emphasizes the application of Quality by Design (QbD) principles, reverse engineering techniques, and specific case studies related to drug formulation and bioavailability. Through systematic approaches and thorough understanding of product and process, the text calls for efficient regulatory compliance and improved product quality assurance.

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Generic Product Development and Technology Transfer : At a Glance Girish Sonar, M. Pharm, PhD Novugen Pharma (Malaysia) Sdn. Bhd. Shah Alam, Selangor, Malaysia Email: girish.sonar@novugen.com Pharma Formulation & Regulatory Symposium Sept 06, 2018, Kuala Lumpur, Malaysia
Generic Product Development and Technology Transfer : At a Glance Generic product life cycle 2
Generic Product Development and Technology Transfer : At a Glance3 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance4 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance Scope of reverse engineering: o API particle size determination from reference product o Pellet layer thickness determination o Polymorph identification o Quantitative estimation of excipients o Polymer grade & ratio determination 5 Reverse Engineering
Generic Product Development and Technology Transfer : At a Glance6 API particle size determination from FP SiO2 Particles API used in in-house productAPI particle size from reference product tablets Confidential
Generic Product Development and Technology Transfer : At a Glance7 Pellets layer thickness determination -100 100 300 500 0 10 20 30 40 50 Size(µm) Size count Layer 1 (µm) Layer 2 (µm) Layer 3 (µm) Sphere size (µm) Parameter Layer-1 Layer-2 Layer-3 Sphere size Average size (µm) 49 22 88 292 Min size(µm) 32 15 78 240 Max size(µm) 62 29 95 374 Confidential
Generic Product Development and Technology Transfer : At a Glance8 Polymorph identification Confidential
Generic Product Development and Technology Transfer : At a Glance9 Quantitative estimation of excipients Category Excipient How to determine? Diluents Lactose Innovator disclose quantity in SmPC/PAR MCC Water insoluble matter, Chemical method Mannitol Chemical method Dicalcium phosphate Calcium content by flame photometry Binder HMPC Chromatographic method HPC Chromatographic method PVP Chemical method Copovidone Chemical method Disintegrant Sodium starch glycollate Sodium content by flame photometry Croscarmellose sodium Sodium content by flame photometry Wetting agent Sodium lauryl sulphate UV spectroscopy Polysorbate 80 Chemical method Confidential
Generic Product Development and Technology Transfer : At a Glance10 What is QbD? o Systematic and proactive approach to pharmaceutical development o Begins with predefined objectives o Emphasizes product and process understanding and process control o Based on sound science and quality risk management
Generic Product Development and Technology Transfer : At a Glance11 Why QbD? o Ensure higher level of assurance of product quality for patient • Improved product and process design & understanding • Monitoring, tracking, trending of product & process o More efficient regulatory oversight o Encouraged continuous manufacturing process improvements o Real-time quality control and reduced end-product release testing o Fewer lost batches o Fewer manufacturing deviations, saving costly investigative hours o Reduced out-of-specification results, reducing rework o Reduce post approval changes/Variations
Generic Product Development and Technology Transfer : At a Glance12 QbD Program QTPP CQA Risk Mitigation Design Space Quality Risk ManagementControl Strategy INITIAL Risk Assessment Drug Substance Formulation variables Process Packing UPDATED Risk Assessment Drug Substance Formulation variables Process Packing
Generic Product Development and Technology Transfer : At a Glance13 QbD examples December 2011 April 2012
Generic Product Development and Technology Transfer : At a Glance14 QbD Software QbD-Expert™ Software
Generic Product Development and Technology Transfer : At a Glance15 Systematic QbD flow in product development
Generic Product Development and Technology Transfer : At a Glance16 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance Category : Overactive bladder Dosage form : Extended-release tablets BCS : III Dissolution media (QC) : USP I/900mL pH 6.8 Phosphate buffer/100 rpm Tmax : 3 - 4 hrs 17 Case study
Generic Product Development and Technology Transfer : At a Glance18 Multimedia dissolution of Product ‘X’ USP I/900 mL pH 6.8 Phosphate buffer/ 100 rpm Time Reference Product Test Product 1 Test Product 2 Mean (%) 1 h 8 8 10 3 h 32 29 31 5 h 59 52 53 7 h 83 75 80 8.5 h 94 89 88 10 h 97 101 99 12 h 97 102 101 F2 - 64 70 USP I/900 mL pH 4.5 Acetate buffer/ 100 rpm Time Reference Product Test Product 1 Test Product 2 Mean (%) 1 h 14 15 16 3 h 41 42 44 5 h 70 69 67 7 h 92 94 93 8.5 h 99 99 100 10 h 100 101 101 12 h 100 102 100 F2 - 89 83 USP I/900 mL 0.1 N HCl/ 100 rpm Time Reference Product Test Product 1 Test Product 2 Mean (%) 1 h 22 22 20 3 h 59 55 54 5 h 88 85 84 7 h 101 99 98 8.5 h 102 101 100 10 h 100 100 101 12 h 99 100 101 F2 - 82 75 Confidential
Generic Product Development and Technology Transfer : At a Glance19 Bio results 0.0 5.0 10.0 15.0 20.0 25.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Concentration(ng/mL) Time (h) Mean Plasma Concentration Vs Time Profile Mean Plasma Concentration Test_(T1) Mean Plasma Concentration Reference_(T2) Mean Plasma Concentration Reference_(R) Study design : 3-way crossover, Fasted N = 18
Generic Product Development and Technology Transfer : At a Glance20 Human GIT & biorelevant dissolution medias Physiology of the GI tract of healthy humans in FASTED state pH-gradient preprandial Segment of GI tract Transit time (h) pH Biorelevant media pH Stomach 1-2 1.5-1.9 FaSSGIF 1.6 Duodenum 3.6 6.5 FaSSIF-V2 6.5 Jejunum 6.8 Half-FaSSIF 7.0 Ileum 7.2 FaSSIF-sans 7.5 Colon 7-20 6.5 SCoF 5.8 Physiology of the GI tract of healthy humans in FED state pH gradient postprandial Segment of GI tract Transit time (h) pH Biorelevant media pH Stomach 1.4-4.0 3-7 FeSSGF 5.0 Duodenum 3.8 5.1-5.4 FeSSIF-V2 5.8 Jejunum 5.2-6.0 Half-FeSSIF 6.5 Ileum 7.5 FeSSIF-sans 7.5 Colon - 5.0 SCoF 5.8
Generic Product Development and Technology Transfer : At a Glance21 Dissolution in Bio-relevant media Time Reference Product Test Product 1 Test Product 2 USP I/ 900 mL FaSSGF (pH 1.6)/ 75 rpm/2 h 1 h 17 26 15 2 h 30 43 28 USP I/ 900 mL FaSSIF (pH 6.5)/ 75 rpm/12 h 3 h 47 60 44 4 h 58 71 53 5 h 69 81 64 6 h 77 91 75 7 h 86 100 88 8 h 97 101 101 10 h 100 100 99 12 h 103 102 100 The closer the dissolution test conditions to the physiology, the better the chances of predicting in vivo performance. Confidential
Generic Product Development and Technology Transfer : At a Glance22 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CPP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance23 CPP study (1) Process variables involve in WET GRANULATION based manufacturing process Steps Granulation Drying Sizing and Milling Blending and Lubrication CPP HS Granulation o Impeller speed o Chopper speed o Binder addition time o Granulation time o Wet milling Fluid Bed Granulation o Spray rate o atomization air pressure o Air flow o Product temperature o Granulation time o Product temperature o Air flow o LOD o Type of screens (Plain/Grater) o Screen size o Mill speed o Blending time o Lubrication time o Blender type
Generic Product Development and Technology Transfer : At a Glance24 CPP study (2) Process variables involve in ROLLER COMPACTION based manufacturing process Steps Granulation Sizing CPP 1. Type of roller 2. Compaction force 3. Roller gap 4. Roller speed 5. Feed speed 1. Type of screens (Plain/Grater) 2. Screen size 3. Mill speed
Generic Product Development and Technology Transfer : At a Glance25 CPP study (3) Process variables involve in MUPS TABLETS manufacturing process Steps Pellets coating Compression CPP o Air flow rate o Spray rate o Atomization air pressure o Product temperature o Dew point o Curing temperature and time o Pre-compression force o Main compression force o Feeder speed o Turret speed o Feed frame design o Tooling design
Generic Product Development and Technology Transfer : At a Glance26 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance27 Case 40°C/75% RH – 6 months RS test failure 1 FD of FP Oxidation sensitive API Use oxygen scavenger 2 Open exposure at 75% RH – 1W Moisture sensitive API Protective pack
Generic Product Development and Technology Transfer : At a Glance28 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance29 Case Study Reference Product : Amlodipine / Valsartan 10 mg/160 mg (Exforge®) Strengths : 10 mg/ 160 mg, 5 mg/160 mg, 5 mg/80 mg Linearity : Amlodipine and valsartan exhibit linear pharmacokinetics Tmax : Valsartan : 3 hrs, Amlodipine : 6-8 hrs Absolute bioavailability : Valsartan : 23%, Amlodipine : 64 to 80% Elimination half-life : Valsartan : 6 hrs, Amlodipine : 30 to 50 hrs Confidential
Generic Product Development and Technology Transfer : At a Glance30 Generic 1 / Winthrop Pharma UK (Zentiva) Reference Product : Amlodipine / Valsartan 10 mg/160 mg (Exforge®) Analyst : Valsartan Reference : Public assessment report, MHRA, UK/H/5856-7/001-3/DC Confidential Confidential
Generic Product Development and Technology Transfer : At a Glance31 Generic 2/ Apotex Europe B.V. Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®) Analyst : Valsartan Reference : Public assessment report, NL/H/3447/001-003/DC, 13 January 2017 Confidential Confidential
Generic Product Development and Technology Transfer : At a Glance32 Generic 3/ Mylan Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®) Analyst : Valsartan Reference : Assessment report, EMA/CHMP/182030/2016, 28 January 2016 Confidential Confidential
Generic Product Development and Technology Transfer : At a Glance33 Generic 4/ Genericon Pharma Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®) Analyst : Valsartan Reference : Public assessment report, SE/H/1573/01-03/DC, LAKEMEDELSVERKET Medical Products Agency Confidential Confidential
Generic Product Development and Technology Transfer : At a Glance34 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance35 Regulatory agencies expectations
Generic Product Development and Technology Transfer : At a Glance Explanation Development batches • Formula optimization • Process optimization (partial) Scale-up batches • Process optimization (Scale dependent process) Bio batches • No optimization Commercial batches • No optimization
Generic Product Development and Technology Transfer : At a Glance37 Process Optimization Process optimization planned based on knowledge of – 1. Scale dependent equipment/Process parameter 2. Scale independent equipment/Process parameter If R&D scale and commercial scale equipment have same mechanism, same geometry and scalable based on scientific basis, then process optimization batches can be perform in R&D scale equipment. If not, then process optimization batches will be performed in commercial scale equipment.
Generic Product Development and Technology Transfer : At a Glance38 Process optimization – Study plan (1) # Equipment Scalable process parameters Recommended Remark 1 Wurster (Bottom spray) Spray rate, atomization air pressure, air flow volume, dew point ADP area is considered to calculate the scale up factor and apply to all critical process parameter except dew point and product temp Scale independent 2 HSG Impeller speed, Chopper speed, Granulation time Tip velocity : Low speed = 3.0-3.5m/sec, High Speed = 6.0-7.0m/sec at the R&D scale and commercial scale Scale independent 3 FBP (Top Spray granulation) Spray rate, atomization air pressure, air flow volume, dew point Calculate the scale up factor based on vendor’s recommendation and apply for critical process parameters Scale independent 4 Multimill Milling screen opening, mill speed and direction Screen size/impeller direction/ mill speed should be same Scale independent 5 Co-mill screen opening, mill speed and direction Screen size/impeller direction/ mill speed should be same. Apply scale factor as per vendor’s recommendation Scale independent
Generic Product Development and Technology Transfer : At a Glance39 Process optimization – Study plan (2) # Equipment Scalable process parameters Recommended Remark 6 Blender No of revolutions, Blender geometry Blending : 300 ± 10 revolutions, Lubrication: 50 ± 5 revolutions. Calculate the blender rpm and time based on Froude no calculation. Scale independent 7 Roller Compaction Roller speed, roller gap, compaction force, milling parameters Scaling up factor varies from mechanism of roller compaction and follow vendor’s guideline for scale-up Scale independent most of the time 8 Compression machine Turret speed, feeder speed, pre-compression force, main compression force, dwell time Optimize the process parameters wrt compression machine at manufacturing site Scale dependent 9 Coating Spray rate, atomization air pressure, product temp, gun to bed distance, pan rpm Optimize the process parameters wrt coating machine at manufacturing site Scale dependent
Generic Product Development and Technology Transfer : At a Glance40 Risk Management Tools 1. Basic risk management facilitation methods (flowcharts, check sheets etc.) 2. Failure Mode Effects Analysis (FMEA) 3. Failure Mode, Effects and Criticality Analysis (FMECA) 4. Fault Tree Analysis (FTA) 5. Hazard Analysis and Critical Control Points (HACCP) 6. Hazard Operability Analysis (HAZOP) 7. Preliminary Hazard Analysis (PHA) 8. Risk ranking and filtering 9. Supporting statistical tools
Generic Product Development and Technology Transfer : At a Glance41 Basic Risk Management Facilitation Methods 1. Flowcharts; 2. Check Sheets; 3. Process Mapping; Cause and Effect Diagrams (Ishikawa diagram or fish bone diagram)
Generic Product Development and Technology Transfer : At a Glance42 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance43 Frequently asked queries Elemental impurities data Discriminato ry power of dissolution media 1. Implement QbD approach during product development and technology transfer 2. Understand regulatory agencies interest 3. Extrapolated regulatory agencies expectation to pipeline products 4. Implement requirements covered in new/ revised guideline and so on …
Generic Product Development and Technology Transfer : At a Glance44 Conclusion # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
Generic Product Development and Technology Transfer : At a Glance Girish Sonar, M. Pharm, PhD Manager – Generic formulation R&D Novugen Pharma (Malaysia) Sdn. Bhd. Shah Alam, Selangor, Malaysia. Email : girish.sonar@novugen.com Skype : girish.sonar1 LinkedIn : https://www.linkedin.com/in/girishsonar/ Questions?

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Generic product development and technology transfer : At a glance

  • 1.
    Generic Product Developmentand Technology Transfer : At a Glance Girish Sonar, M. Pharm, PhD Novugen Pharma (Malaysia) Sdn. Bhd. Shah Alam, Selangor, Malaysia Email: girish.sonar@novugen.com Pharma Formulation & Regulatory Symposium Sept 06, 2018, Kuala Lumpur, Malaysia
  • 2.
    Generic Product Developmentand Technology Transfer : At a Glance Generic product life cycle 2
  • 3.
    Generic Product Developmentand Technology Transfer : At a Glance3 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 4.
    Generic Product Developmentand Technology Transfer : At a Glance4 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 5.
    Generic Product Developmentand Technology Transfer : At a Glance Scope of reverse engineering: o API particle size determination from reference product o Pellet layer thickness determination o Polymorph identification o Quantitative estimation of excipients o Polymer grade & ratio determination 5 Reverse Engineering
  • 6.
    Generic Product Developmentand Technology Transfer : At a Glance6 API particle size determination from FP SiO2 Particles API used in in-house productAPI particle size from reference product tablets Confidential
  • 7.
    Generic Product Developmentand Technology Transfer : At a Glance7 Pellets layer thickness determination -100 100 300 500 0 10 20 30 40 50 Size(µm) Size count Layer 1 (µm) Layer 2 (µm) Layer 3 (µm) Sphere size (µm) Parameter Layer-1 Layer-2 Layer-3 Sphere size Average size (µm) 49 22 88 292 Min size(µm) 32 15 78 240 Max size(µm) 62 29 95 374 Confidential
  • 8.
    Generic Product Developmentand Technology Transfer : At a Glance8 Polymorph identification Confidential
  • 9.
    Generic Product Developmentand Technology Transfer : At a Glance9 Quantitative estimation of excipients Category Excipient How to determine? Diluents Lactose Innovator disclose quantity in SmPC/PAR MCC Water insoluble matter, Chemical method Mannitol Chemical method Dicalcium phosphate Calcium content by flame photometry Binder HMPC Chromatographic method HPC Chromatographic method PVP Chemical method Copovidone Chemical method Disintegrant Sodium starch glycollate Sodium content by flame photometry Croscarmellose sodium Sodium content by flame photometry Wetting agent Sodium lauryl sulphate UV spectroscopy Polysorbate 80 Chemical method Confidential
  • 10.
    Generic Product Developmentand Technology Transfer : At a Glance10 What is QbD? o Systematic and proactive approach to pharmaceutical development o Begins with predefined objectives o Emphasizes product and process understanding and process control o Based on sound science and quality risk management
  • 11.
    Generic Product Developmentand Technology Transfer : At a Glance11 Why QbD? o Ensure higher level of assurance of product quality for patient • Improved product and process design & understanding • Monitoring, tracking, trending of product & process o More efficient regulatory oversight o Encouraged continuous manufacturing process improvements o Real-time quality control and reduced end-product release testing o Fewer lost batches o Fewer manufacturing deviations, saving costly investigative hours o Reduced out-of-specification results, reducing rework o Reduce post approval changes/Variations
  • 12.
    Generic Product Developmentand Technology Transfer : At a Glance12 QbD Program QTPP CQA Risk Mitigation Design Space Quality Risk ManagementControl Strategy INITIAL Risk Assessment Drug Substance Formulation variables Process Packing UPDATED Risk Assessment Drug Substance Formulation variables Process Packing
  • 13.
    Generic Product Developmentand Technology Transfer : At a Glance13 QbD examples December 2011 April 2012
  • 14.
    Generic Product Developmentand Technology Transfer : At a Glance14 QbD Software QbD-Expert™ Software
  • 15.
    Generic Product Developmentand Technology Transfer : At a Glance15 Systematic QbD flow in product development
  • 16.
    Generic Product Developmentand Technology Transfer : At a Glance16 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 17.
    Generic Product Developmentand Technology Transfer : At a Glance Category : Overactive bladder Dosage form : Extended-release tablets BCS : III Dissolution media (QC) : USP I/900mL pH 6.8 Phosphate buffer/100 rpm Tmax : 3 - 4 hrs 17 Case study
  • 18.
    Generic Product Developmentand Technology Transfer : At a Glance18 Multimedia dissolution of Product ‘X’ USP I/900 mL pH 6.8 Phosphate buffer/ 100 rpm Time Reference Product Test Product 1 Test Product 2 Mean (%) 1 h 8 8 10 3 h 32 29 31 5 h 59 52 53 7 h 83 75 80 8.5 h 94 89 88 10 h 97 101 99 12 h 97 102 101 F2 - 64 70 USP I/900 mL pH 4.5 Acetate buffer/ 100 rpm Time Reference Product Test Product 1 Test Product 2 Mean (%) 1 h 14 15 16 3 h 41 42 44 5 h 70 69 67 7 h 92 94 93 8.5 h 99 99 100 10 h 100 101 101 12 h 100 102 100 F2 - 89 83 USP I/900 mL 0.1 N HCl/ 100 rpm Time Reference Product Test Product 1 Test Product 2 Mean (%) 1 h 22 22 20 3 h 59 55 54 5 h 88 85 84 7 h 101 99 98 8.5 h 102 101 100 10 h 100 100 101 12 h 99 100 101 F2 - 82 75 Confidential
  • 19.
    Generic Product Developmentand Technology Transfer : At a Glance19 Bio results 0.0 5.0 10.0 15.0 20.0 25.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Concentration(ng/mL) Time (h) Mean Plasma Concentration Vs Time Profile Mean Plasma Concentration Test_(T1) Mean Plasma Concentration Reference_(T2) Mean Plasma Concentration Reference_(R) Study design : 3-way crossover, Fasted N = 18
  • 20.
    Generic Product Developmentand Technology Transfer : At a Glance20 Human GIT & biorelevant dissolution medias Physiology of the GI tract of healthy humans in FASTED state pH-gradient preprandial Segment of GI tract Transit time (h) pH Biorelevant media pH Stomach 1-2 1.5-1.9 FaSSGIF 1.6 Duodenum 3.6 6.5 FaSSIF-V2 6.5 Jejunum 6.8 Half-FaSSIF 7.0 Ileum 7.2 FaSSIF-sans 7.5 Colon 7-20 6.5 SCoF 5.8 Physiology of the GI tract of healthy humans in FED state pH gradient postprandial Segment of GI tract Transit time (h) pH Biorelevant media pH Stomach 1.4-4.0 3-7 FeSSGF 5.0 Duodenum 3.8 5.1-5.4 FeSSIF-V2 5.8 Jejunum 5.2-6.0 Half-FeSSIF 6.5 Ileum 7.5 FeSSIF-sans 7.5 Colon - 5.0 SCoF 5.8
  • 21.
    Generic Product Developmentand Technology Transfer : At a Glance21 Dissolution in Bio-relevant media Time Reference Product Test Product 1 Test Product 2 USP I/ 900 mL FaSSGF (pH 1.6)/ 75 rpm/2 h 1 h 17 26 15 2 h 30 43 28 USP I/ 900 mL FaSSIF (pH 6.5)/ 75 rpm/12 h 3 h 47 60 44 4 h 58 71 53 5 h 69 81 64 6 h 77 91 75 7 h 86 100 88 8 h 97 101 101 10 h 100 100 99 12 h 103 102 100 The closer the dissolution test conditions to the physiology, the better the chances of predicting in vivo performance. Confidential
  • 22.
    Generic Product Developmentand Technology Transfer : At a Glance22 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CPP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 23.
    Generic Product Developmentand Technology Transfer : At a Glance23 CPP study (1) Process variables involve in WET GRANULATION based manufacturing process Steps Granulation Drying Sizing and Milling Blending and Lubrication CPP HS Granulation o Impeller speed o Chopper speed o Binder addition time o Granulation time o Wet milling Fluid Bed Granulation o Spray rate o atomization air pressure o Air flow o Product temperature o Granulation time o Product temperature o Air flow o LOD o Type of screens (Plain/Grater) o Screen size o Mill speed o Blending time o Lubrication time o Blender type
  • 24.
    Generic Product Developmentand Technology Transfer : At a Glance24 CPP study (2) Process variables involve in ROLLER COMPACTION based manufacturing process Steps Granulation Sizing CPP 1. Type of roller 2. Compaction force 3. Roller gap 4. Roller speed 5. Feed speed 1. Type of screens (Plain/Grater) 2. Screen size 3. Mill speed
  • 25.
    Generic Product Developmentand Technology Transfer : At a Glance25 CPP study (3) Process variables involve in MUPS TABLETS manufacturing process Steps Pellets coating Compression CPP o Air flow rate o Spray rate o Atomization air pressure o Product temperature o Dew point o Curing temperature and time o Pre-compression force o Main compression force o Feeder speed o Turret speed o Feed frame design o Tooling design
  • 26.
    Generic Product Developmentand Technology Transfer : At a Glance26 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 27.
    Generic Product Developmentand Technology Transfer : At a Glance27 Case 40°C/75% RH – 6 months RS test failure 1 FD of FP Oxidation sensitive API Use oxygen scavenger 2 Open exposure at 75% RH – 1W Moisture sensitive API Protective pack
  • 28.
    Generic Product Developmentand Technology Transfer : At a Glance28 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 29.
    Generic Product Developmentand Technology Transfer : At a Glance29 Case Study Reference Product : Amlodipine / Valsartan 10 mg/160 mg (Exforge®) Strengths : 10 mg/ 160 mg, 5 mg/160 mg, 5 mg/80 mg Linearity : Amlodipine and valsartan exhibit linear pharmacokinetics Tmax : Valsartan : 3 hrs, Amlodipine : 6-8 hrs Absolute bioavailability : Valsartan : 23%, Amlodipine : 64 to 80% Elimination half-life : Valsartan : 6 hrs, Amlodipine : 30 to 50 hrs Confidential
  • 30.
    Generic Product Developmentand Technology Transfer : At a Glance30 Generic 1 / Winthrop Pharma UK (Zentiva) Reference Product : Amlodipine / Valsartan 10 mg/160 mg (Exforge®) Analyst : Valsartan Reference : Public assessment report, MHRA, UK/H/5856-7/001-3/DC Confidential Confidential
  • 31.
    Generic Product Developmentand Technology Transfer : At a Glance31 Generic 2/ Apotex Europe B.V. Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®) Analyst : Valsartan Reference : Public assessment report, NL/H/3447/001-003/DC, 13 January 2017 Confidential Confidential
  • 32.
    Generic Product Developmentand Technology Transfer : At a Glance32 Generic 3/ Mylan Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®) Analyst : Valsartan Reference : Assessment report, EMA/CHMP/182030/2016, 28 January 2016 Confidential Confidential
  • 33.
    Generic Product Developmentand Technology Transfer : At a Glance33 Generic 4/ Genericon Pharma Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®) Analyst : Valsartan Reference : Public assessment report, SE/H/1573/01-03/DC, LAKEMEDELSVERKET Medical Products Agency Confidential Confidential
  • 34.
    Generic Product Developmentand Technology Transfer : At a Glance34 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 35.
    Generic Product Developmentand Technology Transfer : At a Glance35 Regulatory agencies expectations
  • 36.
    Generic Product Developmentand Technology Transfer : At a Glance Explanation Development batches • Formula optimization • Process optimization (partial) Scale-up batches • Process optimization (Scale dependent process) Bio batches • No optimization Commercial batches • No optimization
  • 37.
    Generic Product Developmentand Technology Transfer : At a Glance37 Process Optimization Process optimization planned based on knowledge of – 1. Scale dependent equipment/Process parameter 2. Scale independent equipment/Process parameter If R&D scale and commercial scale equipment have same mechanism, same geometry and scalable based on scientific basis, then process optimization batches can be perform in R&D scale equipment. If not, then process optimization batches will be performed in commercial scale equipment.
  • 38.
    Generic Product Developmentand Technology Transfer : At a Glance38 Process optimization – Study plan (1) # Equipment Scalable process parameters Recommended Remark 1 Wurster (Bottom spray) Spray rate, atomization air pressure, air flow volume, dew point ADP area is considered to calculate the scale up factor and apply to all critical process parameter except dew point and product temp Scale independent 2 HSG Impeller speed, Chopper speed, Granulation time Tip velocity : Low speed = 3.0-3.5m/sec, High Speed = 6.0-7.0m/sec at the R&D scale and commercial scale Scale independent 3 FBP (Top Spray granulation) Spray rate, atomization air pressure, air flow volume, dew point Calculate the scale up factor based on vendor’s recommendation and apply for critical process parameters Scale independent 4 Multimill Milling screen opening, mill speed and direction Screen size/impeller direction/ mill speed should be same Scale independent 5 Co-mill screen opening, mill speed and direction Screen size/impeller direction/ mill speed should be same. Apply scale factor as per vendor’s recommendation Scale independent
  • 39.
    Generic Product Developmentand Technology Transfer : At a Glance39 Process optimization – Study plan (2) # Equipment Scalable process parameters Recommended Remark 6 Blender No of revolutions, Blender geometry Blending : 300 ± 10 revolutions, Lubrication: 50 ± 5 revolutions. Calculate the blender rpm and time based on Froude no calculation. Scale independent 7 Roller Compaction Roller speed, roller gap, compaction force, milling parameters Scaling up factor varies from mechanism of roller compaction and follow vendor’s guideline for scale-up Scale independent most of the time 8 Compression machine Turret speed, feeder speed, pre-compression force, main compression force, dwell time Optimize the process parameters wrt compression machine at manufacturing site Scale dependent 9 Coating Spray rate, atomization air pressure, product temp, gun to bed distance, pan rpm Optimize the process parameters wrt coating machine at manufacturing site Scale dependent
  • 40.
    Generic Product Developmentand Technology Transfer : At a Glance40 Risk Management Tools 1. Basic risk management facilitation methods (flowcharts, check sheets etc.) 2. Failure Mode Effects Analysis (FMEA) 3. Failure Mode, Effects and Criticality Analysis (FMECA) 4. Fault Tree Analysis (FTA) 5. Hazard Analysis and Critical Control Points (HACCP) 6. Hazard Operability Analysis (HAZOP) 7. Preliminary Hazard Analysis (PHA) 8. Risk ranking and filtering 9. Supporting statistical tools
  • 41.
    Generic Product Developmentand Technology Transfer : At a Glance41 Basic Risk Management Facilitation Methods 1. Flowcharts; 2. Check Sheets; 3. Process Mapping; Cause and Effect Diagrams (Ishikawa diagram or fish bone diagram)
  • 42.
    Generic Product Developmentand Technology Transfer : At a Glance42 Challenges & Remedies # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 43.
    Generic Product Developmentand Technology Transfer : At a Glance43 Frequently asked queries Elemental impurities data Discriminato ry power of dissolution media 1. Implement QbD approach during product development and technology transfer 2. Understand regulatory agencies interest 3. Extrapolated regulatory agencies expectation to pipeline products 4. Implement requirements covered in new/ revised guideline and so on …
  • 44.
    Generic Product Developmentand Technology Transfer : At a Glance44 Conclusion # Challenges Remedies 1. Difficult-to-develop product Reverse Engineering /Deformulation, QbD approach 2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API 3. Reproducibility results CCP study 4. Early stability confidence Short term stability indicative study, Pack characterization 5. Bio study Thorough literature search Right study design 6. Scale-up Scale-up factor implementation, QbD approach 7. Regulatory agency’s queries Understand requirement and start practicing
  • 45.
    Generic Product Developmentand Technology Transfer : At a Glance Girish Sonar, M. Pharm, PhD Manager – Generic formulation R&D Novugen Pharma (Malaysia) Sdn. Bhd. Shah Alam, Selangor, Malaysia. Email : girish.sonar@novugen.com Skype : girish.sonar1 LinkedIn : https://www.linkedin.com/in/girishsonar/ Questions?