Application of Quality by Design (QbD) in product development James E. Polli jpolli@rx.umaryland.edu September 16, 2015
Pharmaceutical Equivalence Same active ingredient(s) Same dosage form Same route of administration Identical in strength or concentration Meet compendial or other applicable standards of strength, quality, purity, and identity May differ in shape, excipients, packaging...
What is Pharmaceutical Quality? Free of contamination and reproducibly delivers the therapeutic benefit promised in the label Pharmaceutical Quality = ƒ (Drug substance, excipients, manufacturing, and packaging) ICH Q8 R(2) The suitability of either a drug substance or a drug product for its intended use Quality cannot be tested into products; quality can only be built into products
Quality by Design ICH Q8(R2) 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) Risk assessment
Quality by Design (QbD) and Questionbased Review (QbR) FDA s Pharmaceutical Quality for the 21 st Century QbD Initiative, ICH Q8, Q9, Q10, and Q11. Q12 in-process. Applicant: Implementing QbD in development, manufacturing, and control FDA: Developed a system that assesses applicant s QbD NDAs and ANDAs 5
QbD: Required or Optional? Required Quality target product profile (QTPP) Including critical quality attributes (CQAs) of the drug product Product design and understanding Critical material attributes (CMAs) of the drug substance and excipients Process design and understanding Critical process parameters (CPPs) Control strategy, including justification Optional Design Space Process Analytical Technology
Overview of QbD Labeled Use Safety and Efficacy DEFINE Quality Target Product Profile DESIGN Formulation and Process IDENTIFY Critical Material Attributes and Critical Process Parameters CONTROL Materials and Process TARGET DESIGN and UNDERSTANDING Yu. Pharm. Res. 25:781-791 (2008) IMPLEMENTATION
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
Target Product Profile (TPP) Organized according to key sections in the product s 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
Quality Target Product Profile (QTPP) A natural extension of Target Product Profile for product quality A prospective summary of the quality characteristics of a drug product that will ideally be achieved to ensure the desired quality (performance) Guide to establish formulation strategy and keep the formulation effort focused and efficient
What Does Quality Target Product Profile Include? Intended use in clinical setting Route of administration, dosage form (delivery systems), and container closure system Quality attributes of drug product Appearance, Identity, Strength, Assay, Uniformity, Purity/Impurity, Stability, and others Active pharmaceutical ingredient release or delivery and attributes affecting pharmacokinetic characteristics (Safety and efficacy) Dissolution, aerodynamic performance
Basis for Establishing QTPP Pharmaceutical equivalence and bioequivalence Analysis of the reference listed drug product Clinical use Pharmacokinetics Drug release Physicochemical characterization Product labeling/administration
Critical Quality Attributes of Drug Product Quality attributes of drug product can be critical or non-critical ICH Q8 R(2) CQA is 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 Critical Quality Attributes (CQAs) of drug product are those that can be impacted by formulation and manufacturing processes For example: Identity and dosage form are not CQAs, but assay and content uniformity are
Overview of QbD Labeled Use Safety and Efficacy DEFINE Quality Target Product Profile DESIGN Formulation and Process IDENTIFY Critical Material Attributes and Critical Process Parameters CONTROL Materials and Process TARGET DESIGN and UNDERSTANDING Yu. Pharm. Res. 25:781-791 (2008) IMPLEMENTATION
Drug Substance Property Physical properties Physical description Appearance, shape, particle size, and distribution Salt form, polymorphism Melting point Aqueous solubility as function of ph Hygroscopicity Density (Bulk, Tapped, True) Flow property Others Solubility (mg/ml) 125 124 123 122 121 Aqueous Solubility Profile 120 0 2 4 6 8 ph Solubility of Z
Drug Substance Property Chemical properties pka Chemical stability in solid states (crystalline & amorphous), and in solution Degradation pathways Photolytic Stability Oxidative Stability Others
Drug Substance Property Biological properties Partition coefficient, membrane permeability, and/or pharmacokinetic information Biopharmaceutics Classification System Biopharmaceutics Class Solubility Permeability I High High II Low High III High Low IV Low Low
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 Enhance any other attribute of the overall safety, effectiveness, or delivery of the drug during storage or use
Excipient Physical property Particle size, shape, density, hygroscopicity, aqueous solubility, pka, and viscosity of polymer dispersion. Chemical property Chemical identity, purity, incompatibility with drug substance Biological property Mechanical property Excipient quality
Steps for Product Understanding 1. Identify all possible drug substance and excipient attributes that could impact the performance of the product 2. Use risk assessment to identify high risk drug substance and excipient attributes 3. Determine levels or ranges of these attributes to be investigated 4. Use Design of Experiments (DoE) to design experiments 5. Conduct actual experiments 6. Analyze experimental data to determine appropriate ranges of these attributes (design space)
Overview of QbD Labeled Use Safety and Efficacy DEFINE Quality Target Product Profile DESIGN Formulation and Process IDENTIFY Critical Material Attributes and Critical Process Parameters CONTROL Materials and Process TARGET DESIGN and UNDERSTANDING Yu. Pharm. Res. 25:781-791 (2008) IMPLEMENTATION
Critical Material Attribute and Critical Process Parameter Critical Material Attribute (CMA) A physical, chemical, biological or microbiological property or characteristic of an (input) material that should be within an appropriate limit, range, or distribution to ensure the desired quality of drug substance, excipient, and in process materials Critical Process Parameter (CPP) A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality
Relationship of CMA, CPP, and CQA CPPs CMAs Input Materials Pharmaceutical Unit Operation CQAs Output Materials or Product A CQA of an output material may become a CMA if it becomes an input material of another unit operation
Process Understanding: Linking CMAs and CPPs to CQAs I N P U T S (X) Material Process Y = ƒ(x) Priori knowledge Risk Assessment Mechanistic models DoE Inputs to the process control variability of the Output Y OUTPUT
Steps for Process Understanding 1. Identify all possible process parameters and material attributes that could impact the performance of the process 2. Use risk assessment to identify high risk parameters and/or attributes 3. Determine levels or ranges of these high risk parameters and attributes 4. Use appropriate DOE to design experiments 5. Conduct actual experiments 6. Analyze the experimental data to determine if a process parameter or material attribute is critical A process parameter/material attribute is critical when a realistic change in that process parameter/material attribute can cause the product to fail to meet CQAs For critical parameters or attributes, define acceptable ranges (Design Space). While for non critical parameters or attributes, the acceptable range is the range investigated
Design Space Design Space The multidimensional combination and interaction of input variables (e.g. Material Attributes) and process parameters that have been demonstrated to provide assurance of quality Use sound science, design space developed at lab or pilot scale can be proposed for commercial scale, but it needs to be verified at production scale, 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.
Scale Effect on Design Space 10 Fold Generation? = Confirmation Lab Scale Design Space Commercial Scale Design Space
Design Space of What? Lab scale design space Pilot scale design space Commercial scale design space Only commercial scale design space can have meaningful regulatory flexibility as defined in ICH Q8(R2)
Overview of QbD Labeled Use Safety and Efficacy DEFINE Quality Target Product Profile DESIGN Formulation and Process IDENTIFY Critical Material Attributes and Critical Process Parameters CONTROL Materials and Process TARGET DESIGN and UNDERSTANDING Yu. Pharm. Res. 25:781-791 (2008) IMPLEMENTATION
ICH Q8 Control Strategy Input material control (specification) Product control (specification) Manufacturing process (unit operation) control In-process control or real-time release testing (RTRT) in lieu of end-product testing A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models
Control Strategies Level of Level 1: Extensive end product testing + Fixed Critical Process Parameters (CPPs) Control Level of Freedom 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
QbD Tools
Risk Assessment Variables and Unit Operations DP CQA Pharmacy weighing IR granulation ER beadsdrug layering Sieving I ER coating Sieving II Final blending Compression Appearance Low Low Low Low Low Low High Medium Assay Medium Low High Low Low Low Medium Medium Content Uniformity Drug Release (IR portion) Drug Release (ER portion) Drug Release (whole tablets) Drug Release (whole tablets vs. half tablets) Low Low Medium Low Low Low High High Low High Low Low Low Low Medium High Low Low Medium Low High Medium Medium High Low High Medium Low High Medium Medium High Low Low Low Low Low Low Low High Alcohol Induced Dose Dumping Low Low Low Low High Low Low High Relative risk ranking: Low risk: no further investigation is needed. Medium risk: further investigation may be needed. High risk: further investigation is needed.
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 Box-Behnken design D-optimal DOE etc.
Predictive In Vitro Dissolution for IR Products For BCS Class I and III drugs formulated in IR dosage forms, in vitro dissolution can be a good surrogate for in vivo performance For BCS Class II and IV drugs formulated in IR dosage forms, in vitro dissolution is expected to be predictive of in vivo performance. Therefore, ANDA applicants should make effort to develop predictive in vitro dissolution Effect of different particle size
Predictive In Vitro Dissolution for MR Products For MR products, in vitro dissolution is expected to be predictive of in vivo performance. Therefore, ANDA applicants should make effort to develop predictive dissolution Effect of slow, medium, and fast dissolution
Conclusion Quality by Design Define quality target product profile Identify drug product critical quality attributes 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 DOE and risk assessment are tools to facilitate the implementation of QbD AND and ANDA applicants should make every effort to develop predictive dissolution for IR products of poorly soluble drugs and MR products