Qulaity by Design

– The pharmaceutical Quality by Design (QbD) is 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 Quality by Design Tools – – – Design of experiments (DoE) (DoE) Risk assessment Process analytical technology (PAT) 3 Overview of QbD Labeled Use Safety and Efficacy DEFINE Target Product Quality Profile DESIGN Formulation and Process IDENTIFY Critical Material Attributes and Critical Process Parameters CONTROL Materials and Process.

TARGET DESIGN IMPLEMENTATION 4 2 Define Target Product Quality Profile 5 Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool U. S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2007 6 3 Target Product Profile Beginning with the end in mind A summary of the drug development program described in terms of labeling concepts Mainly focus on the safety and efficacy Dynamic as it will change as knowledge of the product increases 7 Target Product Profile.

Organized according to key sections in the product’s product’ labeling – – – – – – – – – – – – – Description Clinical Pharmacology Indications and Usage Contraindications Warnings Precautions Adverse Reactions Drug Abuse and Dependence Overdosage Dosage and Administration How Supplied Animal Pharmacology and/or Animal Toxicology Clinical Studies 8 4 Target Product Quality Profile A natural extension of Target Product Profile for product quality – Quality characteristics (attributes) that the drug product should possess in order to reproducibly deliver the therapeutic benefit promised in the label.

Guide to establish formulation strategy and keep the formulation effort focused and efficient 9 Target Product Quality Profile Dosage Form Characteristics – Appearance, shape, size etc. Target product quality profile includes CQAs of drug product Critical Quality Attribute (CQA) – A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality Identity Strength Assay Uniformity Purity/Impurity Stability, and Dissolution/Disintegration – Pharmacokinetics and bioequivalence.

Others 10 5 Target Product Profile versus Target Product Quality Profile Target Product Profile – – – – – – – – – – – – Description Clinical Pharmacology Indications and Usage Contraindications Warnings Precautions Adverse Reactions Drug Abuse and Dependence Overdosage Dosage and Administration How Supplied Animal Pharmacology and/or Animal Toxicology – Clinical Studies Target Product Quality Profile – Dosage Form – Appearance – – – – – – – Shape, size etc. Identity Strength Assay Uniformity Purity/Impurity Stability, and Dissolution/Disintegration Pharmacokinetics and bioequivalence.

– Others EMEA and ICH Q8(R) uses Target Product Profile 11 Target Product Quality Profile Quality Attribute of Drug Product Dosage Form Appearance Identity Strength Assay Uniformity Impurities Target Immediate release capsule Oval, white Ranitidine 150 mg 95 – 105% Meets USP Impurity 1: NMT 0. 5% Impurity 2: NMT 0. 2% Others: NMT 0. 1% Total: NMT 1. 0% pH 1. 2: NLT 85% in 30 min pH 4. 5: NLT 85% in 30 min pH 6. 8: NLT 85% in 30 min Bioequivalence to RLD 12 Dissolution Bioavailability/Bioequivalence 6 Design Formulation and Process 13 Drug Substance Property.

Physical properties – Physical description Particle size, shape, and distribution – – – – – – – Salt form, polymorphism Aqueous solubility as function of pH Hygroscopicity Aq u e o u s So lu b ility Pro file Density (Bulk, Tapped, True) 1. 2 1 Intrinsic dissolution 0. 8 rate 0. 6 Wettability 0. 4 Others 0. 2 Solubility (mg/mL) 0 0 2 4 pH 6 8 14 7 Drug Substance Property Chemical properties – pKa – Chemical stability in solid state and in solution Degradation pathways % Degradation product – Photolytic Stability – Oxidative Stability – Others.

Stability in Solution 40 deg C 5 4 3 2 1 0 0 1 2 Weeks 3 4 15 Drug Substance Property Biological properties – Partition coefficient, membrane permeability, and/or pharmacokinetic information – Biopharmaceutics Classification System Biopharmaceutics Class I II III IV Solubility High Low High Low Permeability High High Low Low 16 8 Mechanical Property? Elasticity (Young’s Modulus of Elasticity) Plastic Deformation Pressure (Hardness) Tensile Strength Brittle Fracture Index Bonding Index Degree of Viscoelasticity 17.

Excipient Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form – – – – Aid in the processing of the dosage form during its manufacture Protect, support, or enhance stability, bioavailability, or patient acceptability Assist in product identification or Enhance any other attribute of the overall safety, effectiveness, or delivery of the drug during storage or use 18 9.

Excipient Property and Quality Physical property – Particle size, shape, polymorph, hygroscopicity, aqueous solubility, pKa, and density Chemical property – Chemical identity, purity, incompatibility with drug substance Excipient quality 19 Drug-Excipient Compatibility Generally acceptable methods – Thermal analysis – Isothermal stress; HPLC analysis Minimize unexpected stability problems Advantages – Maximize the stability of a formulation – Enhance understanding of drug-excipient interactions 20 10 Formulation: BCS as a Tool.

Class I: High Solubility High Permeability Class II: Low Solubility High Permeability Formulations Designed To Overcome Solubility or Dissolution Rate Problems • No major challenges for immediate release dosage forms • Salt formation • Precipitation inhibitors • Controlled Release dosage forms may be needed to limit rapid absorption profile • Metastable forms • Solid Dispersion • Complexation • Lipid Technologies • Particle Size Reduction Class III: High Solubility Low Permeability Class IV:

Low Solubility Low Permeability Approaches To Improve Permeability • Formulation would have to use a combination of approaches identified in • Prodrugs Class II and Class III to overcome • Permeation Enhancers dissolution and permeability problems • Ion Pairing • Strategies for oral administration are not • Bioadhesives really viable. Often use alternative delivery methods, such as intravenous administration.

Class V: Metabolically or Chemically Unstable Compounds Approaches To Stabilize Or Avoid Instability • Prodrugs • Enteric Coating (protection in stomach) • Lipid Vehicles (micelles or emulsions/microemulsions) • Enzyme Inhibitor • Lymphatic Delivery (to avoid First Pass Metabolism) • Lipid Prodrugs • P-gp efflux pump inhibitors Ref: Amidon, He, Hageman, Burgers Medicinal Chemistry, 6th Edition, Vol 2, Ch. 18 (2004) 21 Formulation Robustness Studies Formulation Factors – – – – Lactose/MCC ratio Dinintegrant level Lubricant level Binder level Factors Lactose/ MCC ratio Disintegrant Target 2. 6 Range 2. 4-2. 8 2. 4- 3% 2. 5-4. 0% 2. 5- Responses.

– Dissolution – Uniformity Lubricant 0. 5% 0. 25-0. 75% 0. 25- Binder 3% 2. 0-4. 0% 2. 0- 22 11 Design Drug Product Physical Chemical Mechanical Components & Amounts API Properties Excipient Properties Physical Chemical Mechanical Formulation Process Process Steps Small-scale Manufacture Scale-up Greg Amidon 23 Process Selection based on Physical Properties DC = Direct Compression, WG = Wet Granulation, DG = Dry Granulation + High Crystallinity Low Crystallinity Low Melting Point Poor Particle Size, Shape, Dist High Hygroscopicity High Aqueous Solubility Poor Mechanical properties DC WG DG DC DG DC DG WG DG DG DC DC DG WG DG WG WG DC WG WG DC Greg Amidon 24 12.

Computer-aided Process Design Widely used in other industries – chemical and oil industries Currently, CAPD and process simulation are largely used in drug substance manufacturing The application of CAPD and process simulation in drug product design is currently limited 25 Identify Critical Material Attributes and Process Parameters 26 13 Critical Material Attribute and Critical Process Parameter Critical Material Attribute (CMA) – A physical, chemical, biological or microbiological property or characteristic of a material that should be within an appropriate limit, range, or distribution to ensure the desired product quality Critical Process Parameter (CPP).

– A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality 27 CMAs and CPPs: an Example Process Parameters Speed Forces Depth of fill Punch penetration depth Moisture Feeder Hopper Mixing Compression Material Attributes Before Compression Blend uniformity Particle size Density Moisture Flow Properties Material Attributes After Compression Core tablet weight Uniformity Hardness Thickness Porosity Friability Visual attributes Identity Assay Purity/Impurity Dissolution (Disintegration) 28 14 Process Identification and Understanding: Concept Process I N P U Measurement T S (X) Material Y = ? (X) Priori knowledge Risk Assessment Design of Experiments.

Inputs to the process control variability of the Output Y OUTPUT Environment 29 Design Space Design Space – The multidimensional combination and interaction of input variables (eg. Material attributes) and process (eg. parameters that have been demonstrated to provide assurance of quality Regulatory Implication – Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval 30 15.

Design Space Determination Design of Experiment – Factors: Raw material attributes (e. g. , particle size) and process parameters (e. g., speed and time) – Responses: outputs are the critical quality (material) attributes such as blend uniformity, tablet hardness, thickness, and friability Prior knowledge and risk assessment to identify potential critical input and output variables and process parameters to be investigated Based on the acceptable range of CQAs, the design space of raw material attributes and process parameters are determined 31 Design Space Determination:

Blend Uniformity 1. Prior knowledge and risk assessment to determine potential critical factors and responses Factors: API and MCC particle sizes, load level, number of rotations Response: Blend uniformity Input attributes API (d90) MCC (d90) Revolution Scale Range 10-30 micron 1030-90 micron 30>100 Any 2. 3. 4. DoE.

Central composite response surface Determine design space based on the outcome of DoE Evaluate scale effect 32 16 Control Materials and Process 33 Control Strategies Level of Level of Control Freedom Level 1: Extensive end product testing + Fixed Critical Process Parameters (CPPs) Level 2: Reduced end product testing + Flexible manufacturing process within fixed design space Level 3: PAT, Real-time automatic “engineering control”+ Flexible manufacturing process Increase 34 17 Level 1 Control API, fixed particle size MCC, grade specified Croscarmellose Na Mg stearate Drug product Test Appearance Identity Assay Uniformity Impurities Tablet weight Hardness Friability Dissolution.

Blend Uniformity Testing Fixed order of addition Fixed load level Fixed # of revolutions Fixed pre-compression force preFixed compression force Fixed press speed Fixed feeder speed 35 Level 2 Control WDS = Within Design Space API, particle size WDS MCC, particle size WDS Croscarmellose Na Mg stearate Test Appearance Identity Assay Uniformity Impurities.

Tablet weight Hardness Friability Dissolution Drug product Blend Uniformity Testing Fixed order of addition WDS load level WDS # of revolutions Testing may be reduced if predicted from input and process parameters WDS pre-compression force preWDS compression force WDS press speed WDS feeder speed 36 18 Level 3 Control UFC = Under Feedback Control API, Flexible particle size MCC, Flexible particle size Croscarmellose Na Mg stearate Drug product PAT “PAT” PAT” “” = …

Flexible order of addition Flexible load level UFC # of revolutions UFC pre-compression force preUFC compression force UFC press speed UFC feeder speed 37 Control Variability There is uncharacterized variability in the excipients and process – Level 1 handles variability by excessively testing – Level 2 handles variability by limited testing and establishing design space for critical material attributes and process parameters – Level 3 is a robust process that can ensure quality in the presence of uncharacterized variability 38 19 QbD Tools 39 Process Analytical Technology (PAT).

A system for designing, analyzing, and controlling manufacturing through timely measurements (i. e., during processing) of critical quality and performance attributes of raw and inprocess materials and processes with the goal of ensuring final product quality The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner 40 20 PAT versus Design Space? Blend uniformity is determined by on-line NIR at commercial scale Value of design space?

41 Design of Experiment (DoE) A structured, organized method for determining the relationship between factors affecting a process and the output of that process For example – Plackett and Burman design – Factorial design – Central composite design etc. 42 21 Risk Assessment Risk – Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Risk Assessment.

– A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards 43 Risk Assessment Questions What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)? 44 22 Formulation Composition Risk Assessment DPQP API Particle Size Appearance Identity Assay Impurities Content Uniformity Dissolution L L L L H H Formulation Attributes Lactose DisDisintegrant L L L L L H MCC particle Size L L L L H L Mg St. Level H L L L L H 45 L L L H H H Unit Operation Risk Assessment.

DPQP Blending Appearance Identity Assay Impurities Content Uniformity Dissolution L L L L H L Unit Operation Roller Compaction L L L L H H Milling L L L L H H LubicaLubication H L L L L H CompresCompression H L H L H H 46 23 Continual Improvement 47 Process Capability Process capability is a statistical measure of the inherent process variability for a given output characteristic.

Process capability index (CpK) is the value of the tolerance specified for a particular characteristic divided by the process capability CpK = upper limit – lower limit 6 standard deviation Robust process if the CpK value is significantly greater than one, the process is deemed capable 48 24 Process Improvement (Variability Reduction) Define: Clearly state the intended improvement Measure: The critical attributes are measured to see if they are out of the limit.

The out of the limit data are analyzed and used to determine the sigma level of the process Analyze: When the sigma level is below the target, steps should be taken to increase it, starting by identifying the most significant causes of the excessive variability Improve: The process is redesigned and/or process controls should be incorporated to eliminate or attenuate the significant root causes of variance Control:

The improved manufacturing process should be evaluated and maintained 49 Conclusion Quality by Design – Define target product quality profile – Design and develop formulation and process to meet target product quality profile – Identify critical raw material attributes, process parameters, and sources of variability – Control raw materials and process to produce consistent quality over time PAT, DoE, and risk assessment are tools to facilitate the implementation of QbD 50 25.

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