Development by Design Best Practices in Pharmaceutical Development José Luís Santos, PhD

Transcription

1 Development by Design Best Practices in Pharmaceutical Development José Luís Santos, PhD November 2014

2 Agenda Advanced Tools in Development and Manufacturing Excellent Development and Manufacturing Quality by Design at Hovione

3 Advanced Tools in Development and Manufacturing DEVELOPMENT Risk Assessment Design of Experiments Modeling Tools Scale-Up Methods Scale-Down / Miniaturization Process Analytical Technology MANUFACTURING Lean 6 Sigma Visual Stream Mapping Failure Mode and Effect Analysis Multivariate Analysis 8D Poka-Yoke OEE

4 Modeling Tools Adjust model complexity Concept Development Solution Domain (Problem statement) 1st principles models Fundamentals captured (months) Mechanistic models Main mechanisms captured (weeks) Statistical models Behaviour captured (days) Best modeling approach: considering the problem statement, keep things as simple as possible, but not simpler

5 Modeling Tools Case-study: chemical synthesis Problem statement (troubleshooting) catalyst catalyst During an alkylation reaction, the content of raw material increased after IPC (upon scale-up). V = 0.1 L Hypothesis: poor mixing leading to un-reacted raw material accumulation; detailed analysis needed. Approach Axial & radial mixing patterns should be compared in detail for the lab and commercial-scale reactors. 1 st principles V = 2000 L For the 2000 L reactor, ~ zero velocity (stagnant fluid) is observed in the region below the impeller. Impeller was re-designed; problem was solved.

6 Scale-up Case-study: spray drying Droplet size correlations Thermodynamic space Heat and mass balance CFD Scale-up methodology

7 Scale-down Case-study: spray drying Commercial unit Lab unit D v 50 = 82 mm span = 1.7 bulk density = 0.29 kg/l tap density = 0.40 kg/l solvent = 5% w/w D v 50 = 83 mm span = 1.5 bulk density = 0.34 kg/l tap density = 0.42 kg/l solvent = 7% w/w

8 Process Analytical Technology Chemical Processes Handheld NIR Raw materials identification and qualification UV photometry Refractometry Concentration and end-point determination FBRM Crystals growth dynamics Raw material dispensing Reaction Purification Crystallization Drying Raman spectroscopy Reaction conversion and polymorphs formation FT-IR spectroscopy Reaction conversion and polymorphs formation Prediction XR02036 % (w/w) y = x R 2 = R = 0.97 O-H O-H C-OH C-OH C-OH Raman and FT-IR spectroscopy Concentration and polymorph conversion NIR spectroscopy Drying end-point and solid state characterization XR02036 % (w/w)

9 Process output Process output (actual) Multivariate Analysis Raw materials Synthesis Downstream Final product Quality attributes (e.g.: purity) or process performance indicators (e.g.: yield) Process inputs Impact of process inputs on a process output Higher the absolute value => greater impact Process output (predicted)

10 Statistical Process Control Control Chart

11 How to use FMEA? FMEA PROCESS Team Definition Present Context Purpose to the team Failure identification risk evaluation Corrective / Preventive actions definition New risk evaluation Document risk analysis Actions implementation Follow up final evaluation - List ALL possible failures - Classification and quantification (1 to 10) of failures based on: Frequency (F)/ probability of failure occurs Severity (S) of the effect Detection (D) of the failure (capacity to detect) - Prioritization by calculating Risk Priority Number: RPN = F x S x D

12 Agenda Advanced Tools in Development and Manufacturing Excellent Development and Manufacturing Quality by Design at Hovione

13 Excellent Development and Manufacturing New approach at Hovione Established methodologies: Britest, QbD, Lean State-of-the-art tools Throughout project life-cycle Site independent Accessible by everyone Aligned with regulators (FDA & EMA)

14 Industrialization (QbD) Manufacturing (LEAN) Technical screening (BRITEST) Excellent Development and Manufacturing Guidelines New project Technical / Business Evaluation FAMILIARIZATION Stage #1 Technical Screening BRITEST driven Receive a Chemical Structure Route Scouting (change conditions) Receive Chemical Process (route defined) Familiarization Receive an API and target specification Lab scale formulation development N for Chem Does it work? PRELIMINARY RISK ASSESSMENT N for SD Technical / Business Evaluation Definition of pcma s pcqa s pcpp s Preliminary PIH & PHA LAB SCALE DEVELOPMENT and PILOT SCALE Stage #2 Industrialization QbD driven No No INDUSTRIALIZATION Lab Scale Development HAZOP and What If, Ok? Final Process OK for Pilot Scale? Pilot Scale Campaign Technical Evaluation Yes Any Campaign Issues? Technical Evaluation PROCESS DESIGN SPACE Design & Full PHA, Operating HSEE Space Aspects Business Evaluation VALIDATION and MANUFACTURING Stage #3 Manufacturing LEAN driven Demo or engineering batch Validation Batches 1 st Commercial Batch MANUFACTURING Continuous Improvement (3P, LEAN, PQLI) QbD Filling Report / Technical / Business Evaluation

15 Agenda Advanced Tools in Development and Manufacturing Excellent Development and Manufacturing Quality by Design at Hovione

16 QbD at Hovione 1st project under QbD 2nd project 3rd project 4th project 5th project Sucesfull PAI on QbD submission Approved Approved 6th 7th 8th projects Britest tools used in CRD Lean implementation QbD implementation EDaM implementation (Britest + QbD + Lean) Relevant Milestones Hovione s PAT and QbD speakers in International Conferences

17 QbD at Hovione Science and Risk based Target profile (quality, safety, efficacy) Regulatory filing & approval CQA definition (critical quality attributes) Risk assessment I (rank process parameters) Process Development (statistical, mechanistic) PAT Strategy Change control & implementation PAT Implementation Design space & NOR (feasible & preferable) Process control strategy Criticality analysis Risk assessment II (process FMEA)

18 QbD at Hovione Development by Design 1 st QbD filing 2 nd QbD filing Today # Runs at full scale ~ 270 ~ 60 ~ 9 Material needed ~ 900 kg (~ $9 MM*) ~ 200 kg (~ $2 MM*) ~ 40 kg (~ $0.4 MM*) Time required at full scale ~ 4 months ~ 4 weeks ~ 4 days * Assumed $10,000/kg of API as reference

19 10 Years of Commercial Spray Drying The most extensive commercial spray drying facilities in the world

20 Thank you for your attention. José Luís Santos, Particle Engineering Services hovione.com