Presented By: Vipul Patel Quality By Design Presented By: Vipul Patel

Syllabus QbD and PAT: Elements of QbD, QbD tools, significance of QbD Design of experiments –Methods and applications of optimization techniques to assure quality in product, critical quality attributes, critical process, Process analytical technology (PAT) in Pharmaceutical manufacturing. Goal of PAT, Benefits of PAT, PAT tools, Process Analyzer, Application of PAT in chemical and pharmaceutical industry.

HISTORY In 2007 FDA received an 5000 supplements, it was actually a striking raise in the number of manufacturing supplements to applications of New Drug Applications (NDAs), Biological License Applications (BLAs) and Abbreviated New Drug Applications (ANDA’s). FDA recognized that there is an increase in lapse of NDA or ANDA submissions by the firms, large number of a supplemental application for every manufacturing change were received. In both original applications and supplements the data mainly focused was on chemistry. And the least attention was given on other important aspects of the manufacturing, such as engineering, product development. Eventually, the FDA acknowledged that more and more controls were required for drug manufacturing processes for efficient drug product and no doubt for better regulatory decision making. It resulted in more stringent regulatory upbringing. To solve this issue in 2002, the FDA implemented changes through the Pharmaceutical cGMP (good manufacturing practice) for the 21st Century.

Facilities and equipment What is QbD? Integrated, systematic and scientific approach to design, development and delivery of performance attributes that ensure consistent delivery of specific quality, safety and efficacy objectives. People Product Facilities and equipment Process Ref.: ICH Q8 (R2)

DEFINITION Systematic, holistic and proactive approach to pharmaceutical development. Begins with predefined objectives Emphasizes product and process understanding and process control Based on sound science and quality risk management

Quality by Design (QbD) is a concept first outlined by well-known quality expert Joseph M. Juran who believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned in the first place. Proactive & risk based approach for predictable & predefined quality Planning quality into the process. A leading indicator for better controls & to handle quality crises and problems early in the cycle. Quality by Design means –designing and developing formulations and manufacturing processes to ensure a predefined quality

Benefits of QBD Eliminate batch failures Minimize deviations and costly investigations Avoid regulatory compliance problems Organizational learning is an investment in the future QbD is good Science Better development decisions Empowerment of technical staff Efficient, agile, flexible system Increase manufacturing efficiency, reduce costs and project rejections and waste Build scientific knowledge base for all products Ensure consistent information Incorporate risk management

Enhances scientific foundation for review. Improves information in regulatory submissions. Ensures decisions made on science and not on empirical information. Provides for better coordination across review, compliance and inspection.

Interpretations of Quality Meeting Specifications Features Perception Easy Maintenance Fitness for use Cost Time Satisfaction QUALITY Safety Standards compliance Regulations Experience Look & Feel Aesthetics Performance Quality by Design (QbD), FICCI, 19th Jan 2012

Target Quality Profiling- A Perspective Market Regulations Corporate Social Responsibility Customer Research HRM) Installation & Service Business insights Engineering Manufacturability Suppliers Purchasing Competitor(s)

Overview of QbD Quality Target Product Profile Ref.: ICH Q8 (R2) Product Design and Understanding Process Design and Understanding Control Strategy Continuous Improvement Ref.: ICH Q8 (R2)

Elements of QbD Elements of QbD Different elements of pharmaceutical development include, Defining an objective Determination of critical quality attributes (CQA) Risk assessment Development of experimental design Designing and implementing control strategy Continuous improvement

Defining an objective (QTPP) Elements of QbD Defining an objective (QTPP) Quality target profile (QTP) forms the basis of QbD, which is in relation to the predefined objective criteria mentioned in the definition of QbD. Considerations for the Quality Target Product Profile could include: Intended use in clinical setting, route of administration, dosage form, delivery Systems. Dosage strength(s), Container closure system. Therapeutic moiety release or delivery and attributes affecting, Pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance). Drug product quality criteria like sterility, purity, stability and drug release as appropriate for dosage form the intended for marketing

Elements of QbD QbD requires a Target Product Profile; it may be called as Quality Target Product Profile (QTPP) which defines the expectations in final product. In case of analytical method development it is called as analytical target profile (ATP), it is also called as Target Product Profile (TPP). The TPP will help to identify critical quality attributes such as potency, purity, bioavailability or Pharmacokinetic profile, shelf-life, and sensory properties.

Model Quality Target Product Profile (QTPP)

Model Quality Target Product Profile (QTPP)

Prepare Quality Target Product Profile for following Dosage form Immediate Release tablet, Control Release tablet, Hard Gelatine capsule, Cream, Insitu gelling System

Determination of critical quality attributes (CQA) Elements of QbD Determination of critical quality attributes (CQA) According to ICH Q8 R2 ‘‘A 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’’. QAs are generally linked with the drug substance, excipients, intermediates (in process materials) and drug product. For example CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability whereas for Parenterals they are Sterility and clarity. The CQAs can additionally include properties like particle size distribution, bulk density that affect drug product. Mostly CQAs are derived from the Quality Target Product Profile and/or prior knowledge is used to guide the product and process development and Subsequently CQAs are accessed for risk management.

Elements of QbD Dissolution test is crucial for a controlled release drug product and on other hand dissolution test for an immediate release drug product which belongs to the high aqueous solubility and high permeability i.e. BCS class I drug will not prove as critical attribute for quality control viewpoint.

Basic Terminology: (CQA Can be independent or dependent) In scientific language those attributes are called as variables.. Independent variables Conc. Of Polymer, Agitation Speed Binder (%), Granulation time Dependent variables Friability, hardness Pharmacological activity

Independent variable: Significant variable More important.. Go on changing level.. E.g. Polymer Conc, Granulation time Insignificant variable Not that much importance you can keep it at constant level also.. E.g. Effect of lubricant on floating tablet Independent variable may positive or negative result on to the dependent variable

Dependent variable Also Known as Response variable. Its output of our experiment. Not limit for dependent variable. This variable depends on independent variable. Keep as many as you wish. e.g. Angle of repose, Disintegration time, Friability, Hardness.

QTPP and CQAs QTPP components CQAs Assay (Efficacy) Dosage Form Route of administration Strength Pharmacokinetics Stability Appearance Identity Assay Impurities Residual Solvents/Monomers Adhesion Test(Peel Test, Peel from Liner Test , Probe Tack) Cohesion Test(Shear) Drug Release CQAs Assay (Efficacy) Adhesion (Efficacy) Impurities (safety) Residual Monomer(Safety) Stability (Efficacy)

What factors affect drug product CQAs? Properties of Input Materials - Identify Critical Material Attributes (CMAs) Properties of in-process materials - CQAs of one step become CMAs for a downstream unit operation Manufacturing process parameters - Identify Critical Process Parameters (CPPs) Input Materials CMA1 Output Materials Product CQAs CPP1 Unit Operation 1 Unit Operation 2 CMA2 CPP2

Critical Material Attributes (CMA)

Critical Process Parameters (CPP) Critical process parameters Unit operations Critical process parameters Mixing Mixing speed Mixing time Product temperature Addition rate Coating drying and lamination Zone temperature Blower speed Residence time Lamination pressure Web tension Slitting Machine speed Slit roll width Printing and die cutting Patch dimension

Activity Prepare list of all possible quality attributed for following pharmaceutical unit operation: (i) Drying, Mixing, (ii) Size reduction, Wet granulation, (iii) Compression, Pan coating

Risk assessment Elements of QbD It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Risk assessment helps to increase quality of method or process. Also it is determinant for effect of input variable on method or processes. From risk assessment one can recognize critical attributes that are going to affect final quality of product. A risk assessment is helpful for effective communication between FDA and industry, research/development and manufacturing and among multiple manufacturing sites within company. There may be risk and uncertainty in validation of bioanalytical method though the guidelines for validation are given by various regulatory bodies there may be a variation in interpretation of those guidelines and hence in experimental method designing which leads to unfit method development for intended purpose.

Principles of quality risk management are: Scientific knowledge based evaluation of the risk to quality which eventually links to the protection of the patient. Adequate effort should be taken; formality and documentation of the quality risk management process should be done with the level of risk involved. Risk management is joint responsibility of quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics and clinical department

QbD Tools - Risk Assessment Risk Identification “What might go wrong?” A systematic use of information to identify hazards historical data theoretical analysis informed opinions concerns of stakeholders

Risk Analysis QbD Tools - Risk Assessment “What is the likelihood it will go wrong?” The estimation of the risk associated with the identified hazards. A qualitative or quantitative process of linking the likelihood of occurrence and severity of harm Consider detectability if applicable (used in some tools)

Risk Evaluation QbD Tools - Risk Assessment “What is the risk?” Compare the identified and analyzed risk against given risk criteria Consider the strength of evidence for all three of the fundamental questions What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)?

Risk Control: Risk Reduction QbD Tools - Risk Assessment Risk Control: Risk Reduction “Decision-making activity” Is the risk above an acceptable level? What can be done to reduce or eliminate risks? Are new risks introduced as a result of the identified risks being controlled? Focus actions on severity and/or probability of harm; don’t forget detectability

Risk Control: Risk Acceptance QbD Tools - Risk Assessment Risk Control: Risk Acceptance Discuss the appropriate balance between benefits, risks, and resources Focus on the patients’ interests and good science/data Risk acceptance is not Inappropriately interpreting data and information Hiding risks from management / competent authorities

QbD Tools - Risk Assessment Risk Communication Bi-directional sharing of information about risk and risk management between the decision makers and others Communicate at any stage of the QRM process Communicate and document the output/result of the QRM process appropriately Use existing channels as specified in regulations, guidance and SOP’s

Risk review QbD Tools - Risk Assessment Review the output / results of the QRM process Take into account new knowledge and experience Utilize for planned or unplanned events Implement a mechanism to review or monitor events Reconsideration of risk acceptance decisions as appropriate

QbD Tools - Risk Assessment Risk Ranking and Filtering Steps in Risk Ranking & Filtering Potential Risks are identified The probability is estimated (Qualitative/Quantitative) The severity of the harm is estimated (Qualitative/Quantitative) Each individual risk is assigned a specific score, based on the Probability & Severity. Based on this score the overall score is determined for each identified potential risk. Risks are ranked and filtered, using criteria specific to the circumstances.

Risk Ranking and Filtering QbD Tools - Risk Assessment Risk Ranking and Filtering Risk Ranking/Score > 6 High 3-4 Medium 1-2 Low Probability 3 6 9 2 4 1 Severity Low Broadly acceptable risk. No further investigation is needed. Medium Risk is accepted. Further investigation may be needed in order to reduce the risk. High Risk is unacceptable. Further investigation is needed to reduce the risk.

What happening With Trial And Error Method Traditional Trend Randomized fashion of research Required More number of trials.., Take more time Cant predict the extension… i.e. cant say what happen if such change are made within that particular system.

Activity Derived Possible number of experimentation for following formulation optimization . e.g. In process of Extrusion Spheronization, Three attributes… Binder (%) (1 % to 20 %) Granulation time (Min) (1 min to 500 min) Spheronization speed (RPM) (5 RPM to 1000 RPM)

Is there Any alternative?? Optimization Designing experiments to yield the most information from the fewest runs Reduce the number of trial to minimum but in logical manner Carry out research in systematic way Identify the characteristic you want in your product

Development of experimental design Elements of QbD Development of experimental design Experimental design is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Design space is proposed by the applicant and is subject to regulatory assessment and approval of ICH Q8 (R2).

Various technique for optimization., Factorial design Fractional Factorial design Simplex lattice design Plackett-burman design Central composite design Constrained mixture design Box Behnken design

FACTORIAL DESIGN Basic Terminology: In scientific language those attributes are called as variables.. Independent variables Conc. Of Polymer, Agitation Speed Binder (%), Granulation time Dependent variables Friability, hardness Pharmacological activity

Independent variable: Significant variable More important.. Go on changing level.. E.g. Polymer Conc, Granulation time Insignificant variable Not that much importance you can keep it at constant level also.. E.g. Effect of lubricant on floating tablet Independent variable may positive or negative result on to the dependent variable

Dependent variable Also Known as Response variable. Its output of our experiment. Not limit for dependent variable. This variable depends on independent variable. Keep as many as you wish. e.g. Angle of repose, Disintegration time, Friability, Hardness.

LEVEL What is level?? Level of factor are the values or designations assigned to the factors. In General Factor and Level are keep below 3. No of trial depend upon... No of independent variable No of level So choosing the independent variable and no of level that is the crucial step in optimization.

Example of level in actual value and in a form of coded value: Coding of level Example of level in actual value and in a form of coded value: Variable Level Actual value Coded value Temp 2 level 30 ° & 50 ° c -1 & +1 3 level 30°, 40° & 50 °c -1, 0, & +1 4 level 30°, 40° , 50 ° and 60 ° c -2,-1 & +1, +2

Polynomial Equation Y = β0 constant + β1X1 + β2X2 + β3X3 main effects + β11X12 + β22X22 + β33X32 curvature + β12X1X2 + β13X1X3 + β23X2X3 interaction + ε error

Contour Plot Contour plot is formed by: Horizontal axis: Independent variable 1 Vertical axis: Independent variable 2 Lines: iso-response values

Designing and implementing control strategy Elements of QbD Designing and implementing control strategy Control strategy is required to ensure that material and process are within the expected lower and upper limits. Parameter and material are routinely controlled during production in order to assure reproducibility. The control space should be within the design space. Generally scale up is trial and error basis. During scale up processes parameters may differ but attributes which affect quality remain the same hence control strategy is required. QbD gives trace on reproducibility and robustness. Process capability index expresses reproducibility of process.

Continuous Improvement throughout product life cycle Elements of QbD Continuous Improvement throughout product life cycle Product quality can be improved throughout the product life cycle; companies have opportunities to opt inventive approaches to improve quality. Process performance can be monitored to make sure consistency in quality. Additional experience and knowledge is gained during routine manufacture which contributes to method/process development. Periodic maintenance can be done within a company’s own internal quality system; but design space should be unchanged. The QbD approach avails the continuous improvement throughout products’ life cycle this is distinguishing point from the conventional method which is much frozen process.

Problems in adoption of QbD PAT and QbD require collection of data, to act on that, and capitalize indicators and parameters but when a company does not own the equipment, it is often difficult to implement. Internal unwillingness in company Lack of belief in a business case. It is assumed that QbD would require more time to file generic products or that the amount of clinical trials necessary to implement QbD for drug substance production Lack of technology to implement. Alignment with third parties. It is difficult to manage a multipart supply chain that includes both suppliers and contract manufacturers. Inconsistent treatment of QbD across FDA. It is believed that FDA may not review filings in a consistent manner. Lack of concrete guidance for industry. Companies wanted clarification from FDA on matters such as acceptable methods, criteria to select critical quality attributes, standards by which to judge adequacy of controls, and criteria for analytical method substitution. Presented regulatory benefits does not inspire to follow QbD Misalignment of international regulatory bodies.

Quality by Design Tools : Design of experiments (DoE) Risk assessment Process analytical technology (PAT) Design of Experiments (DOE) : Design of Experiments (DOE) Structured, organized method for determining the relationship between factors affecting a process and the response of that process. DOE Methodology (1) Choose experimental design (e.g., full factorial, d-optimal) (2) Conduct randomized experiments (3) Analyze data (4) Create multidimensional surface model.

Risk assessment : As discussed earlier

Process Analytical Technology(PAT) 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 in process 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.

Example: Current Tablet Production Raw Material : Dispensing, Blending Compression Identification Tests (Chemical Only) Test Product Quality for Release (Active Only) End- Product Focused Testing to Document Quality Process at Risk

PAT Tablet Production : Compression Functional Tests (Chemical and Physical) Validate Process Control Control Blending (Particle Size & Disintegrant Distribution) Process Focused Mitigate the Process Risk Predictive Models

QbD Tools - Process Analytical Technology (PAT) Off-line Analysis performed in laboratory Day At-line Analysis performed on factory floor Minutes On-line Automated sampling and analysis seconds In-line No sampling- in process instrument < 1 second Time delay Frequency of sampling

PAT in Tablet manufacturing Stage Technique Measurement Dispensing NIR / Raman Identification of raw materials Wet Granulation NIR Moisture distribution Drying Moisture content Blending Blend Uniformity Compression Strain gauges Compression force Content Uniformity

PAT Examples Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD without any dryer modification.

Real-time Blend Uniformity by using TruProcess™ Analyzer PAT Examples Real-time Blend Uniformity by using TruProcess™ Analyzer

QbD: Required or Optional? Quality target product profile (QTPP) including critical quality attributes (CQAs) of the drug product and including Product design and understanding 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