Quality by Design

Quality by Design It is a systematic approach to Product & Process Design and Development. Product Quality and Performance can be assured by designing efficient mfg process. QBD is thorough understanding of the process to achieve quality product for safety of patient. Quality has to be build in the product as well as services through proper planning, so that forth coming failure can be avoided. Mere Analysis of the final product will not work but the quality should by designed in the product. Quality associated problems have their origin in the way which quality was planned in the first place.

FDA Perspective FDA asks CMC demonstrating application of QBD as part of NDA. QBD involves thorough understanding of the process, a goal, or objective is defined before actual start of the process. ICH in its Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, Q10 Pharmaceutical Quality System gives stringent requirements regarding quality of the product. FDA’s view of QBD is a systematic approach to Product & Process Design and Development.

Patient safety and Product efficacy is focused. Advantages of QBD Patient safety and Product efficacy is focused. Critical Quality Attributes are identified and their effect on final quality of product is analyzed. Science based risk assessment is carried out Scientific understanding of Pharmaceutical process & method is done It involves product design and process development It offers robust method or Process.

Overview of QBD Product Design and Understanding Quality Target Product Profile Product Design and Understanding Process Design and Understanding Control Strategy Continuous Improvement

1. Defining an objective i.e. Quality Target Product Profile (QTPP) Elements of QBD 1. Defining an objective i.e. Quality Target Product Profile (QTPP) 2. Define Critical Quality Attributes (CQAs) 4. Development of Experimental Design. 5. Design and implement a control strategy 3.Perform Risk assessment 6.Manage product lifecycle, including continuous improvement.

Quality Target Product Profile-QTPP What is QTPP? A set of elements that defines the drug product The target or goal set in advance A guide to Drug Product development What forms the basis for QTPP? The RLD and its label Applicable regulatory guidelines When to define QTPP? At the start of development Knowledge gained in development may change some elements

Components of QTPP Components related to safety, efficacy, identity, purity and potency Critical and non-critical components, e.g. Critical: Assay, content uniformity Non-critical: Appearance Fixed and variable components Fixed elements must be present e.g. Dosage form, strength Variable elements may have a range of acceptable values e.g. Tablet weight, assay. Specific requirements in QTPP Scored tablets Weight variation between two halves Dissolution of half tablet Orally Disintegrating tablets Hardness Disintegration time Container closure QTPP components for IR tablet Dosage Form Route of administration Strength Weight Pharmacokinetics Appearance Identity Assay Impurities Content uniformity Friability Dissolution Residual solvents

Critical Quality Attributes – CQAs CQA is a physical, chemical, biological or microbiological property or characteristics that should be within an limit to ensure desired product quality. CQAs are a subset of the QTPP Include critical parameters that are likely to change based upon variations in raw materials and processes -Identity test for dosage form – Not a CQA -Assay, Content uniformity – CQAs CQAs are monitored throughout the DP development. CQAs ensure that DP remains within safe and effective levels. Ex. Dissolution is critical for CR tablet but for IR tablet it is not if drug is BCS class I.

Route of administration Dissolution (efficacy) QTPP and CQAs QTPP components Dosage Form Route of administration Strength Weight Pharmacokinetics Appearance Identity Assay Impurities Content uniformity Friability Dissolution Residual solvents CQAs Assay (efficacy) Impurities (safety) C.U. (efficacy) Dissolution (efficacy)

Why risk assessment in product development? It is a combination of the probability of occurrence of harm & severity of that harm, it helps to increase quality of method or process. Ex. In analytical method development small changes in method like reagents, instruments,, analysts , labs, days, temp, humidity are included in risk assessment. If primary method fails a back up method is used which is risk assessed. Why risk assessment in product development? To identify relative risk levels at the beginning of product development To prioritize limited development resources To assess the needs of additional studies for scale up and technology transfer To identify appropriate specifications, critical process parameters and manufacturing controls To decrease variability of critical quality attributes

Risk Assessment Risk assessment for Formulation – starting material properties, levels of components Manufacturing process Steps for risk assessment List out all components / processes Prepare the process flow chart Identify all potential failure modes for each item with risk query (what might go wrong?) Risk analysis Risk evaluation Various formal methodologies available for risk assessment Failure Mode Effects Analysis & Failure Mode Effects & Criticality Analysis Hazard & Operability Analysis Supporting statistical tools

QBD for ANDAs: Example for Immediate-Release Dosage Forms Risk Assessment QBD for ANDAs: Example for Immediate-Release Dosage Forms Generic product development for Acetriptan Tablets, 20 mg. Acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range. It exists in three different polymorphic forms which may affect dissolution. Polymorph III is the most stable polymorph. Drug product is prepared with roller compaction process.

Formulation Variables Risk assessment for formulation components Risk assessment of DP manufacturing process Drug Product CQA Formulation Variables Drug Substance PSD MCC/Lactose Ratio CCS Level Talc Level Magnesium Stearate Level Assay MEDIUM LOW Content Uniformity HIGH Dissolution Degradation Products Drug Product CQAs Process Steps Pre-RC* Blending and Lubrication Roller Compaction Milling Final Blending and Lubrication Compression Assay MEDIUM LOW Content Uniformity HIGH Dissolution Degradation Products

Design of experiments (DoE) Useful for screening of variables with significant impact on DP CQAs Classical approach uses OFAT (One Factor At A Time) Limited number of experiments gives limited information. “DOE” helps study effects of interaction of multiple factors at a time. Used in optimization studies, enables creation of “design space” “Design space” is proposed by the applicant and subject to regulatory assessment and approval. “Design space” developed at lab or pilot scale can be proposed for commercial scale, but needs to be verified at production scale for scale dependant parameters.

Design of experiments (DOE) Branch of applied statistics deals with planning, conducting, analyzing and interpreting controlled tests to evaluate the factors that control the value of a parameter or group of parameters. A strategically planned and executed experiment may provide a great deal of information about the effect on a response variable due to one or more factors. Many experiments involve holding certain factors constant and altering the levels of another variable. This One–Factor–at–a–Time (or OFAT) approach to process knowledge is, however, inefficient when compared with changing factor levels simultaneously. Useful for screening of variables with significant impact on DP CQAs Limited number of experiments gives limited information. DOE helps study effects of interaction of multiple factors at a time

Design of experiments (DoE) “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. Working within the design space is not considered as a change. 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.

Design of experiments (DoE) “Control space” Control space is within the Design space. It is the upper and lower limit for raw material or a process within which parameter & material are regularly controlled, which assures quality of the product. If “Control space” Control space is smaller than the Design space it is considered as Robust.

Design of experiments (DoE) Variables Independent variables : The independent variables are under the control of the formulator. These might include the compression force or the die cavity filling or the mixing time. Dependent variables : The dependent variables are the responses or the characteristics that are developed due to the independent variables. The more the variables that are present in the system the more the complications that are involved in the optimization.

Parameter 1 has a range of 44 and 53 Parameters 1 and 2 are factors of a granulation operation that affect the dissolution rate of a tablet (e.g., excipient attribute, water amount, granule size.) The approach in Figure 1 allows the maximum range of operation to achieve the desired dissolution rate. In Figure 1, the design space is defined as a smaller range, based on a linear combination of parameters. Parameter 1 has a range of 44 and 53 Parameter 2 has a range of 0 and 1.1 Figure 1: Design space for granulation parameters, defined by a linear combination of their ranges, that delivers satisfactory dissolution (i.e., >80%).

Designing & Implementing Control Strategy The control strategy is “a planned set of controls, derived from current product and process understanding, that assures process performance and product quality. Control Strategy is designed to ensure that a product of required quality will be produced consistently . It is important that set method performs as intended and consistently gives accurate results. For that purpose control on method is required. A factor identified to have risk has to be controlled. More attention is given to the high risk factors. System suitability can be checked and verified time to time by having control over it. Control Strategy includes following elements which contribute to final product quality . Input material attributes (e.g. drug substance, excipients, container closure) Equipment operating conditions (process parameters) In-process controls Finished product specifications Controls for each unit operations Methods and frequency of monitoring and control.

Surface response Plots

Example QbD IR Tablet Pharmaceutical Development Control Strategy

Product Life Cycle Management & Continuous Improvement Throughout the product lifecycle, the manufacturing process performance will be monitored to ensure that it is working as anticipated to deliver the product with desired quality attributes. Process stability and process capability will be measured and evaluated. Inventive approaches to improve quality. If any unexpected process variability is detected, appropriate actions will be taken to correct, anticipate, and prevent future problems so that the process remains in control. The additional knowledge gained during routine manufacturing will be utilized for adjustment of process parameters as part of the continual improvement of the drug product. As a commitment, the regulatory agency will be notified in accordance with CFR 314.70 regarding each change in each condition beyond the variability already provided in this application.

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