Quality Assurance in Pharmaceuticals and Challenges it faces in 21st Century By: Muhammad Naeem Quality Assurance and Regulatory Manager CCL Pharmaceuticals (Pvt.) Ltd.

Quality Assurance Quality assurance is a wide ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. QA is the heart and soul of quality control QA = QC + GMP

QA GMP QC

Is that part of Quality Assurance aimed at ensuring that products are consistently manufactured to a quality appropriate to their intended use GMP

Is that part of GMP concerned with sampling, specification & testing, documentation & release procedures which ensure that the necessary & relevant tests are performed & the product is released for use only after ascertaining it’s quality QC

Public Health Expectations Every unit, Every Batch, Every Day.. “We rely upon the manufacturing controls and standards to ensure that time and time again, lot after lot, year after year the same clinical profile will be delivered because the product will be the same in its quality… We have to think of the primary customers as people consuming that medicine and we have to think of the statute and what we are guaranteeing in there, that the drug will continue to be safe and effective and perform as described in the label.”

Pharmaceutical Manufacturing Current State Conventionally Pharmaceutical mfg is a batch process operation with laboratory testing conducted on collected samples to evaluate quality Quality assurance is ensured by end-product testing, i.e., quality by testing and inspection and not by design Regulatory uncertainty-often cited reason for industry’s hesitancy to introduce innovative systems Significant opportunities exist for improving pharmaceutical development, manufacturing, and quality assurance through innovation in product and process development, process analysis, process control, and automation

Current State of Pharmaceutical Manufacturing: A snapshot…

Quality Issues: Examples Potency questioned Oversize tablet Capsule fill caries Volume/quantity questioned Dosage unit missing Empty capsule units Discoloration Precipitation Cloudy Clumping Odor/taste abnormal Microbial contamination Visible growth Container/closure defects Syringe malfunction Aerosol non-function Pump malfunction Excessive spray Adhesion lacking Patient reaction Death Foreign particulates Chipped, cracked

Pharmaceutical Manufacturing Desired State Product quality and performance ensured through the design of effective and efficient manufacturing processes Product and process specifications based on a mechanistic understanding o f how formulation and process factors affect product performance Continuous real time quality control and assurance Regulatory policies and procedures tailored to accommodate the most current level of scientific knowledge Risk-based regulatory approaches recognize the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product

Desired State: Systematic Approaches Innovation in manufacturing Incorporation of Quality by Design approaches based on sound science, engineering and risk management principles Drug Development, Manufacture and Quality Assurance Engineering Quality Continuous processing (Manufacturing) Implementing effective Pharmaceutical Quality System Process performance and Product Quality Monitoring System CAPA System Change Management System Knowledge & Quality Risk management Systems Management review of Process performance and Product Applying integrated systems approach to quality assessment both by industry and regulators R&D, Production, and QA CMC review and GMP compliance

Quality By Design A systematic approach to development that begins with predefined objectives and emphasizes process and product understanding and process control, based on sound science and quality risk management. It is a Scientific, risk-based and proactive approach to pharmaceutical development. It is a Full understanding of how product attributes and process relate to product performance. It is a Quality Risk Management in Development & Manufacturing of drug product. It is a building in Quality and Flexibility from day one.

Significance of QbD

Elements of QbD Approach

QbD Approaches Creating a design space during product development. Process Analytical Technology (PAT) implementation.

Design Space Definition Design Space Determination 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 Determination First-principles approach combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performance Non-mechanistic/empirical approach statistically designed experiments linear and multiple-linear regression Scale-up correlations translate operating conditions between different scales or pieces of equipment Risk Analysis determine significance of effects Any combination of the above

Application of QbD Applications of QbD by establishing a Design Space during Product Development: Lactose monohydrate is used in place of (defined) Lactose anhydrous. Experiment with different mesh sizes of API. Experiment with different container/closure system. Experiment with different equipment as defined in proposed formulation.

Approaches to Pharmaceutical Development

Benefit of QbD Increased understanding of formula and process. Greater understanding of excepients. Meaningful specifications. Excepients come from variety of sources is acknowledged. Excepients’ compatibility testing allows to determine the level of interaction between a given active pharmaceutical ingredient (API) and a selection of excepients.

ICH Guidance Q8–Pharmaceutical Development Q8(R) Describes good practices for pharmaceutical product development Introduces concepts of design space and flexible regulatory approaches Q8(R) Addendum to original Q8 Includes concepts of Quality by Design and examples of design space

ICH Guidance (Cont.) Q9: Quality Risk Management Describes a systematic process for the assessment, control, communication and review of quality risks Applies over product lifecycle: development, manufacturing and distribution Includes principles and examples of tools for quality risk management Q10: Pharmaceutical Quality Systems Describes systems that facilitate establishment and maintenance of a state of control for process performance and product quality Facilitates continual improvement Applies to drug substance and drug product throughout product lifecycle

Process Analytical Technology (PAT)-1 “A system for designing and controlling manufacturing through timely measurements/testing/analyzing (i.e. during processing) of critical quality and performance attributes for raw and in-process materials and also processes with the goal of ensuring final product quality”. PAT facilitates the implementation of QbD QbD and PAT = Tremendous benefits to industry, regulatory and the public! So the goal is ‘product quality’ and NOT just meeting specifications Quality Attributes: Identity, purity, strength and efficacy

Process Analytical Technology (PAT)-2 Need of PAT “The goal of PAT is to understand and control the critical manufacturing processes (critical quality attributes and performance attributes)”. “Quality cannot be tested into final products; it should be built-in by design”.

Process Analytical Technology (PAT)-3 Types of Testing In-line (Real-time)Testing (actual PAT) On-line Testing (Container sensor installed at equipment, Unit counter, Automatic removal of broken tablets on blister) At line (In-process control) Off-line (Lab Testing on final stage or final product)

Application of PAT Inline analysis of uniform distribution of materials during mixing in cone blender or mixer through FTNIR / Raman Spectroscopy. Inline drying process monitoring in FBD. Inline cleaning status of equipment during cleaning through TOC or UPLC.

PAT and QbD

Closing Remarks Successful implementation of QbD & PAT relies on industry’s adoption of innovative approaches to Development that are based on sound (material) science, engineering, and quality risk management principles Manufacturing Process through process understanding and timely process monitoring implementing risk-commensurate process control strategy to prevent/mitigate risk to product quality and performance Quality Assurance through validated processes (state of control) Continuous Process/Quality Verification Real Time Release

Acknowledgements Thanks Questions??

References Guidance for Industry: PAT —A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, September 2004 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, September 2006 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070337.pdf Guidance for Industry: Q9 Quality Risk Management, June 2006 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdf Guidance for Industry: Q8(R2) Pharmaceutical Development Revision 2, November 2009 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073507.pdf Guidance for Industry: Q10 Pharmaceutical Quality System, April 2009 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073517.pdf Guidance for Industry: Process Validation: General Principles and Practices, January 2011 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf