hallenges, benefits, case study
Pharmaceutical development phases overview The new paradigm for development: Quality by Design (QbD) hallenges Benefits ase study losure and Q&A»»»»»» D. eriani Meet MINITAB, Milano 2/04/206 2
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D. eriani Meet MINITAB, Milano 2/04/206 Pharmaceutical development phases MEDIAL NEED MARKET ANALYSIS 4
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you. The need for inspection results from excessive variability in the process. The disease is the variability. easing dependence on inspection means you must understand your processes so well that you can predict the quality of their output from upstream activities and measurements. To accomplish this you must have a thorough understanding of the sources of variation in your processes and Pharmaceutical development phases Depending on inspection is like treating a symptom while the disease is killing then work toward reducing the variation. easing dependence on inspection forces you to reduce variability D. eriani Meet MINITAB, Milano 2/04/206 7
Pharmaceutical Development Quality Risk Management Pharmaceutical Quality System Development and Manufacture of Drug Substances (chemical/biological entities): in progress - Q8: - Q9: - Q0: - Q: Develop a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science I: International onference of armonization D. eriani Meet MINITAB, Milano 2/04/206 8
The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products, i.e., quality should be built in by design D. eriani Meet MINITAB, Milano 2/04/206 9
» Risk: defined as the combination of the probability of occurrence of harm, the severity and the detectability of that harm» Management: Systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. D. eriani Meet MINITAB, Milano 2/04/206 Pharmaceutical development phases» Quality: Degree to which a set of inherent properties of a product, system or process fulfills requirements (in vivo efficacy and safety, formulation stability, patient compliance...) 0
D. eriani Meet MINITAB, Milano 2/04/206 Pharmaceutical development phases Quality Target Product Profile (QTPP) Quality Risk Management (QRM) Design of Experiments (DoE) ritical Quality Attribute (QA) Knowledge Management (KM) ritical Process Parameter (PP) ontrol Strategy (S) Process Analytical Technology (PAT) Lifecycle Management (LM) ontinuous Improvement (I)
Pharmaceutical development phases D. eriani Meet MINITAB, Milano 2/04/206 2
Pharmaceutical development phases D. eriani Meet MINITAB, Milano 2/04/206 dc 3
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Factors that influence safety and efficacy: Absorption Distribution Metabolism Excretion Protein binding D. eriani Meet MINITAB, Milano 2/04/206 6
Organizational changes (cross functional team, ad hoc department creation, ) Need for employees training Need for new hardware and software Need for a change of mind of the upper managment D. eriani Meet MINITAB, Milano 2/04/206 7
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More innovation= intellectual property Reduced time to market More efficient production process = less batch failure. More flexible regulatory approaches Reduced time to approval Reduced inspection frequencies D. eriani Meet MINITAB, Milano 2/04/206 9
onsistent efficacy onsistent safety onsistent quality Reduced sale price? D. eriani Meet MINITAB, Milano 2/04/206 20
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Pharmaceutical development phases D. eriani Meet MINITAB, Milano 2/04/206 22
API content: Impurities profile: topical immediate liquid stratum corneum permeation no unpleasant smell good spreadability good spraying properties % w/w unknown 0.% specified known 0.5 to % 24 months (world wide long term=30 ) 30 ml Stability: Pack size: Efficacy Patient ompliance Route of admin.: Release type: Form: Biopereformance: Subjective properties: D. eriani Meet MINITAB, Milano 2/04/206 Safety Market needs 23
Smell Viscosity Assay Impurities level Stratum corneum permeation D. eriani Meet MINITAB, Milano 2/04/206 PEG peroxyde level Polymeric thickener Solvents API ontainer closure system Filter mesh Mixing time Mixer speed Oxygen presence Spindle type Mixer filling volume RITIAL QUATY ATTRIBUTES Material attributes and process parameters Spraying Spreading 24
Mixing speed (rpm) VOLUME (l) NITROGEN (bar) SPINDLE TYPE PEROX PEG (PPM) MIX TIME (h) FILTER RE SIZE (µm) 200 5 2 BASE 2 4.5 0 400 3.75 0 SMIT 0 8 00 LEVELS Mixing speed VOLUME SPINDLE PEROX PEG NITROGEN MIX TIME FILTER MES 2 3 4 5 6 7 8 RUN # D. eriani Meet MINITAB, Milano 2/04/206 25
Assay + impurities level 2 weeks 3 weeks month 2 months 3 months X X X X X 60 X X 40 /75% R Storage cond. Time week D. eriani Meet MINITAB, Milano 2/04/206 26
Main Effects Plot for Means Data Means VELO VOLUME 0.45 0.5 0.00 2 PEG 0.60 Mean of Means 0.30 0.60 SPINDLE 2 T MIX 2 FILTRO 0.45 0.30 0.5 27 0.00 2 D. eriani Meet MINITAB, Milano 2/04/206 2 2
VOLUME 0.3588 0.3483 0.00375 2.5 SPINDLE 0.3525 0.34875 0.00250 5 SPEED 0.35063 0.34937 0.0025 6 Level - Delta Rank D. eriani Meet MINITAB, Milano 2/04/206 PEG NITROGEN 0.03938 0.35000 0.66063 0.35000 0.6225 0.00000 7 Response Table for Means Linear Model Analysis: factors ranking MIX TIME FILTER 0.34875 0.3483 0.3525 0.3588 0.00250 0.00375 4 2.5 28
EXLUDED PARAMETERS 0.03 0.6 0.29 0.03 0.000 0.6 0.000 0.06 0.05 0.000 0.05 0.06 Estimated Model oefficients for Means ase study 4/6/205 NITROGEN, SPEED, SPINDLE P tail ( =0.05) mix speed volume spindle nitrogen mix time filter PEG NITROGEN, SPEED NITROGEN, SPEED, SPINDLE, MIX TIME Term oef onstant 0.350000 VOLUME 0.00875 PEG PEROX -0.30625 FILTER -0.00875 S = 0.002652 D. eriani Meet MINITAB, Milano 2/04/206 SE oef 0.000937 0.000937 0.000937 0.000937 R-Sq = 00.0% T 373.333 2.000-33.333-2.000 P 0.000 0.6 0.000 0.6 R-Sq(adj) = 00.0% 29
Main Effects Plot for Means Data Means V E LO V O LU M E 0.2 2 A ZO TO 2 TE M P O M IX 0.2 PEG 0.4 0.0 2 2 2 F ILTRO 0.4 4/6/205 2 Mean of Means ase study 0.0 S P IN D LE 0.4 0.2 0.0 2 D. eriani Meet MINITAB, Milano 2/04/206 30
SPEED 0.202500 0.200000 0.002500 4.5 VOLUME 0.200000 0.202500 0.002500 4.5 SPINDLE 0.200000 0.202500 0.002500 4.5 PEG 0.000000 0.402500 0.402500 NITROGEN 0.200000 0.202500 0.002500 4.5 MIX TIME 0.202500 0.200000 0.002500 4.5 FILTER 0.202500 0.200000 0.002500 4.5 Level - Delta Rank Response Table for Means Linear Model Analysis: factors ranking D. eriani Meet MINITAB, Milano 2/04/206 3
EXLUDED PARAMETERS SPEED, VOLUME, SPINDLE 0.423 0.423 0.423 0.423 0.000 0.374 0.374 0.000 0.39 0.39 0.39 0.000 P tail ( =0.05) mix speed volume spindle nitrogen mix time filter PEG SPEED, VOLUME NITROGEN, SPEED, SPINDLE, MIX TIME Estimated Model oefficients for Means Term onstant PEG PEROX MIX TIME FILTER oef 0.20250-0.20250 0.00250 0.00250 S = 0.003536 SE oef 0.00250 0.00250 0.00250 0.00250 R-Sq = 00.0% D. eriani Meet MINITAB, Milano 2/04/206 T 6.000-6.000.000.000 P 0.000 0.000 0.374 0.374 R-Sq(adj) = 00.0% 32
a content in peroxides in raw material 2 ppm is mandatory PEG supplier choice based on raw material quality PEG container/closure and holding time from opening study (on going) PEG peroxides level is critical to product quality and safety D. eriani Meet MINITAB, Milano 2/04/206 33
Design space: spindle type doesn t matter Design space: nitrogen pressure in vessel between 0 and 2 bars Design space: mixer speed between 200 and 400 rpm D. eriani Meet MINITAB, Milano 2/04/206 34
Design space: mixer filling volume between nominal and 75% of nominal Design space: mix time between 4,5 and 8 h Design space: filter pore size between 0 and 00 µm D. eriani Meet MINITAB, Milano 2/04/206 35
Technology transfer and scale up process Process validation PAT implementation for real time release D. eriani Meet MINITAB, Milano 2/04/206 36
Pharmaceutical development steps Quality by design and Design Space are.. a powerful approach to obtain excellent medicines for the patients a chance to improve employees process awareness a stimulus to innovation and intellectual property D. eriani Meet MINITAB, Milano 2/04/206 37
D. eriani Meet MINITAB, Milano 2/04/206 WILAM EDWARDS DING 38
D. eriani Meet MINITAB, Milano 2/04/206 DANIELA ERIANI EAD, DEVELOPMENT LABORATORY LUGANO 39