Pharmaceutical QbD is a systematic approach to product development that begins with predefined objectives in the form of Quality Target Product Profile (QTPP) and emphasizes product and process understanding in the form of Critical Material Attributes (CMAs), Critical Processing Parameters (CPPs) & Critical Quality Attributes (CQAs) and its controls based on sound science and quality risk management
01. Definition of Quality Target Product Profile - QTPP
In QbD, “What We Want?” should be defined from first & Quality Target Product Profile (QTPP) defines Voice of the Customers i.e. Requirements of (i) Pharmacist (ii) Physician (iii) Patient for that particular product. QTPP is a prospective summary of the quality attributes of a drug product that ideally will be achieved to ensure the desired Quality, taking into account Safety & Efficacy of the drug product.
02. Determination of Critical Quality Attributes? - CQAs
From Quality Attributes (QAs) of QTPP, Critical Quality Attributes (CQAs), i.e. physical, chemical, biological & microbiological attributes that should be within an appropriate limit, range, or distribution to ensure the desired product quality are identified on the basis of :
a. Impact analysis by change in formulation attributes &/or process variables & b. Severity of its harm to patient when that CQA fail to meet its specs.
03. Risk Assessment of Material Attributes & Processing Parameters - RA After determination of all in process & finished product CQAs, Risks related to individual MAs &/or PPs will be identified, analyzed & evaluated step wise on the basis of preliminary experiments, prior arts & scientific rationale :
a. RISK IDENTIFICATION : First all the Material Attributes (MAs) of Formulation Composition & Process Parameters
(PPs) of Manufacturing Process are identified & listed out step wise in Process Map with respect to individual CQAs. b. QUALITATIVE ANALYSIS : Then, All the MAs & PPs are qualitatively analyzed by ‘Relative Risk Matrix’ with respect to CQAs & categorized as High, Medium & Low Risk factors. c. QUANTITATIVE ANALYSIS : After qualitative analysis, MAs & PPs are quantitatively analyzed by ‘Failure Modes Effects Analysis (FMEA)’ & prioritized as per Probability, Severity & Detectability Scores (Severity x Probability x Detectability =Risk Priority Number RPN) of risk factors.
04. Design of Experiments (DoE) & Development of Design Space
After Risk Assessment of all Material Attributes & Process Parameters with respect to CQAs, Design of Experiments (DoE) has been carried out as a systematic series of experiments, In which purposeful changes are made to input factors to identify causes i.e. CMAs & CPPs, for significant changes in the output responses i.e. CQAs & Determining the relationship between factor(s) i.e. CMAs & CPPs & response(s) i.e. CQAs, in the form of regression model equation, to evaluate all the potential factors simultaneously, systematically and speedily; with complete understanding of the process to assist in better product development & subsequent process scale-up with pretending the finished product quality & performance
a. DEFINITION : Objective of the experiment is defined as per Identification of Factors & its Levels for Selection of Experimental Designs for Optimization of Factors;
b. MEASUREMENT : Dependent Responses (CQAs) are measured for different combination of factors (CMAs &/or
CPPs) in all the experimental runs with or without Randomization, replication & blocking of Design Point Runs;
c. ANALYSIS : After measurement of all the responses, Regression Models are thoroughly analysed with ANOVA with Goodness & Lack of Fit Statistics, Residual Diagnostics plots along with 2D & 3D Model Graphs
d. DEVELOPMENT of the Design Space (Multidimensional combination & interaction of input variables i.e. CMAs & CPPs), where all the specifications for the individual responses i.e. CQAs met to the predefined targets through Numerical Optimization as per Composite Desirability & Graphical Optimization as per Sweet spot in Overlay plot
e. VERIFICATION of the Design Space through Minimum 3 Confirmatory Runs within design space for Correlation between Observed Results with Model Predicted Results by means of CI & PI
05. Implementation of Control Strategy for commercial manufacturing
On the basis of prior art, scientific rationale & OFAT/DoE based Proven Acceptable Ranges & Design Space for different CMAs & CPPs; Control Strategy for each & every CMAs & CPPs are proposed for future Commercial Manufacturing to ensure batch to batch consistency in product quality. Control Strategy is a planned set of controls derived from current product and process understanding during lab Scale Developmental Stage, Scale Up Exhibit-Submission Stage that ensures consistent process performance and product quality during Commercial Manufacturing.
During ‘Implementation of Control Strategy’, Actual Ranges for Critical Factors (CMAs & CPPs) at ‘Lab Scale’ & ‘Exhibit Scale’ are reviewed & Control Ranges are proposed for future ‘Commercial Manufacturing’ to ensure batch to batch consistency in product quality. All the ranges are tabulated systematically with respect to past, present & future i.e. a. PAST : Which were the ranges studied during Lab Scale Developmental batches? b. PRESENT : Which are the ranges studied during Exhibit- Submission batches? c. FUTURE: Which will be the ranges proposed for Commercial Manufacturing?
06. Continual Improvement for Product Lifecycle Management After Exhibit batches & Validation batches, Continuous Risk Review & Risk Communication was done during Routine Commercial Manufacturing between Stockholders of all the departments i.e. FR&D, AR&D, DRA, Production, QC & QA. For Continual Trend Analysis of Process behavior by Process Control Charts that assures the process remains in a state of control (the validated state) during commercial manufacture for excellent Product Lifecycle Management Control Charts’ analyze the process trend, past process performance indices (Pp/Ppk) & future process capability indices (Cp/Cpk) for each CQAs over the time with OOC & OOS data points for ‘Continual improvement’ of Commercial Manufacturing Process.
Thus, In QbD based Formulation and Process Development, first all the CQAs are determined according to predefined goals of QTPP, then all the risk factors (CMAs &/or CPPs) are identified according to its impact analysis & then a mathematical model will be established in between CMAs, CPPs & CQAs through DoE for development of design space within which all the CQAs will met with predefined goals using risk assessment tools. From Design Space along with Proven Acceptable Ranges & Edges of Failures, Control Strategies are proposed for each & every CMAs & CPPs to ensure batch to batch consistency in CQAs during commercial manufacturing. The resulting formulation and manufacturing process developed through QbD will be more robust along with better product quality, reduced process variability, reduced product defects, enhanced process understanding, higher process capability, faster approvals, regulatory flexibility, fewer regulatory queries, fewer post launch issues, more rapid resolution of post approval change managements and increased flexibility to implement continuous improvement changes.
Very well explanation sir
Very well explained in concise manner. Thank you.
Excellent -Very focused, easy to understand language (steps wise technical explanation), short communication but gives you a detailed picture in mind.
The concept of QbD presented in a simple way of Understand for beginners.
Will be excited for more to read from your Blogs.
Cheers to Dr. Shivang and His Team efforts.
As all know, you are most crazy scientist who is always give the better version of knowledge sharing - crisp and short but, contains all information one needs and thank you so much for this. Your this short technical review is excellent and will be handy guidelines for entry level to expert level understanding.
Thanks for everything Dr. Shivang
Good work shivangbhai