Quality by Design nella cristallizzazione degli API

Transcription

1 Quality by Design nella cristallizzazione degli API (QbD in API crystallization process) Marino Nebuloni (REDOX srl Monza)

2 Content Recent ICH and FDA Guidelines ICH Q8, Q9 and Q10 Quality by Design (QbD) Example Approach to QbD QbD for API crystallization Examples of Implementing QbD Concluding and Remarks

3 ICH & FDA Guidances Product Design Process Design Manufactu ring Process Monitoring/ Continuous Verification ICH Q8/Q8(R)- Pharmaceutical Development FDA PAT Guidance ICH Q9 - Quality Risk Management ICH Q10 - Pharmaceutical Quality Systems

4 ICH Q8 Guidance Provide guidance on Pharmaceutical Development Describe good practice for pharmaceutical product development Introduce the concepts of: Designe Space Flexible regulatory approaches Quality Risk Management (Q9)

5 QbD Definition (ICH Q8(R)) A systematic approach to development, that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management

6 Why QbD? High level of assurance of product quality Cost saving and efficiency for industry Increase efficiency of manufacturing process Minimize/eliminate potential compliance actions Provide opportunities for continual improvement Facilitate innovation More efficient regulatory oversight Enhance opportunities for first cycle approval More focused PAI and post approval cgmp inspections

7 Quality Risk Management Process

8 Role of Quality Risk Management in Development & Manufacturing

9 Quality by Design Approach Target Design Implementation

10 6 Steps -QbDProcess for Crystallization Product Development

11 Crystallization Strategy Exploration Exploitation Crystallization Development Strategy Exploration:Existing Knowledge not sufficient to solve the problem identified. New knowledge needs to be created and acquired to contribute to the existing body of knowledge Exploitation:Utilization of existing knowledge for innovative problem solving

12 CQAs & CPPs in Crystallization Critical Quality Attribute (CQAs) A CQA is a physical, chemical, property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. API Particle Size, Purity, dissolution, polymorphism, stability, Critical Process Parameter (CPPs) A process parameter, e.g. temp, time, speed, when variable it can affect the CQA of a product or process Critical Process Parameters (CPP) identified using a risk analysis investigated extensively using a DOE. Non-Critical Process Parameters A process parameter identified as low risk which leads to low probability of product failure

13 CQAs for a Solid API properties (Example) CQAs Polymorphism Particle Size Distribution Morphology Flowability Density (apparent / packed) Specific Surface Area Melting Point Form I d10, d50, d90 plates specification specification specification specification Target

14 CQAs for Solid API Stability (Example) CQAs Target Drying Temperature Packaging behaviour Coalescience Humidity Light Milling / Micronization Range values Compression value Storage temperature Range of % RH Exposure Lux value Polymorphism/amorphous Etc.

15 CPPs (Example Mixing Unit Operation) 1. Mixing Time 2. Mixing Speed 3. Process temperature in crystallization 4. Drying Temperature 5. Grinding Process

16 Risk Assessment (General Approach)

17 Simple Risk assessment in crystallization (example) Quality Attribute of DS, or Unit Operation CPP Potential Risk Probability of Occurrence (Lo, Med, Hi) Potential Impact to the Quality Risk Reduction /Mitigation DS Solid State Form New polymorph of DS formed Med More complex formulation DS solvates New Impurities Hi Instability on storage Reduction PS distribution Temperature Change in Dissolution New polymorph Hi Reduction product shelflife Develop a back-up formulation Perform process optimization Change in grinding process Lo OOS Define process Temperature

18 CQAs Unit Operation Relationship in crystallization (Example)

19 Variability is the Problem A process CANNOT have a constant output from a fixed process and variable input

20 Conceptual Representation of Knowledge, Design and Control Spaces 1. Specifications 2. Continuous Improvement without Regulatory Approval

21 Design Space: crystallization and Drying Unit Operation (Example) Physical Properties (or ) Unit Operation CPP Polymorphism Crystallization Temperature Rate of coprecipitate Drying time & Temperature Drying Time & vacuum value & Temperature Form I or Form II Design Space Range (> 5 C - < 60 C) Range 2 4 L/min Time 4-6 hours C Range of time vstemperature vs vacuum

22 Example I QbD application to prevent API crystallization in injectable DP 1.Solubilization of the API at defined ph 2.pH correction 3.Storage the solution before the dispensing in vials (time temperature influence) 4. Filtration of the solution 5. Final Control of particle presence

23 Investigation approach

24 Critical Quality Paramiters Concentration ph Solid state FBRM on line Filtrability Induction Time

25 FBRM application for monitoring the API crystallization particles

26 Time 0 time Nucleation Growing Induction Time

27 Information collected on the time during the crystallization

28 Laboratory Scale-up Production F.B.R.M. F.B.R.M. Definition of CQAs Quality Control P.A.T. Optimization

29 Experimental Data N particelle Particelle 1-3 um Particelle 3-5 um Particelle 5-10 um Particelle um Particelle um Particelle um N totale di particelle Inizio 2h Tempo (h)

30 ph= 6.7 concentration : A mg/ml Poor filtrability Design Of Experiment Filtrazione F 7 A F 7 B F 6.7 A F 6.7 B NO F 7 A ph NO F 7 B NO F 6.7 A NO F 6.7 B Concentrazione

31 um 3-5 um 5-10 um um um um N totale particelle N particelle N particelle totali Inizio 3h tempo (h)

32 Final Result Filtrability F 7 A F 7 B 3 h F 6.7 A 2 h F 6.7 B NO F 7 A ph NO F 7 B 0.5 h NO F 6.7 A 0 h NO F 6.7 B Concentration Time

33 Results of Investigation Critical Parameters (CQAs) and Process Parameters (CPPs) to be strectly controlled in the Storage solution before and after filtration: 1. Reduce the solution evaporation (fix the concentration limits-range) 2. Define the filtration temperature 3. Control the filtration time and the presence of crystals traces (< 3 microns) by on line method 4. Control the final ph before the dispensing. 5. Avoid any cooling conditions yhay induces nucleation - definition of Temperature limits

34 Example II QbD application to prevent API crystallization into undesired polymorphic form. 1.Two polyomorphic Forms (Form A & Form B) 2. Form A dissolution in specification 3.Influence of temperatura in the Crystallization process 4.Morphology and Filtration 5.Final Control of Particle Size Distribution

35 Control Crystalliazion of a active polymorphic Form by on-line Raman spectroscopy Polymorphic Form A Polymorphic Form B high melting temperature (active form) low melting temperature (OOS form)

36 Form A XRPD pattern 4,1 4,0 1342,8 3,5 3,0 2, %T ,0 1667,2 1580,6 1,5 1621,5 1473, ,6 1193,2 1,0 1698,7 1391, ,3 849,94 949,14 834,2 582,24 0,5-0, Raman spectrum

37 Form A -Crystal Morphology

38 Form B XRPD pattern 3,5 3, ,2 3,0 1348,7 2,8 2,6 2,4 2, %T 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 0,4 1614,8 1495,3 1694,5 1582, ,5 1531,5 1437,4 1209,3 1115,2 1095,3 1165,9 829,19 642,74 592,05 Raman spectrum ,2 0, Raman Shift / cm-1

39 Form B-Crystal Morphology (aggregates)

40 1649,8 Forma B pura Forma A pura Reference band %T 1666,5 1697,3 1707,6 1693,6 1496,9 Banda di quantificazione 1003,3 Form B quantification by Raman spectrum Raman Shift / cm ,8 1,6 1, ,4 1,2 1,0 % T 1666,5 %T 0,8 1697,3 0,6 1707,6 1693,6 0,4 0, Raman Shift / cm , Raman Shift / cm-1

41 Quantification of Form B in production batches Form B % T 1497 Lotto Nome Descrizione Raman Shift / cm-1 From aria ratio, Form B present about 12% Specification from DMF: < 10 %

42 Lab Scale Experiments Raman & FBRM (Lasentec) into RC1 calorimeter Probe Immagine RC1 FBRM RC1

43 Crystalliztion control by on-line spectroscopy Forma B 1666 cm-1 Raman shift Forma A 1497 cm-1 Raman shift

44 Polymorphyc concentration of Form A and Form Bduring the crystallization process & Particle Counting N totale di particelle (Lasentec) Forma A 1497 Raman shift Forma B 1666 Raman shift

45 Is QbDreally a new concept in crystallization? QbD is not a new concept from the technology perspective QbD is new relative to regulatory review and submission QbD is optional and should not become a regulatory requirement as agreed to in ICH Q8 QbD will not necessarily be included in all submissions Generation of QbD information during the process phases should be at industry benefict

46 FDA: What is the advantage of QbD? Emphasizes product and process understanding and process control

47 Conclusion Full implementation of Quality by Design is a benefit for: Manufacturers less regulatory examination and lower manufacturing costs Regulators less regulatory severity without sacrificing quality Patients increase in availability of high quality pharmaceuticals

48 QbD in API crystallization process Thanks for the Attention M. Nebuloni