Quality Assurance in Pharmaceuticals and

Challenges it faces in 21st Century

By: Muhammad NaeemQuality Assurance and Regulatory ManagerCCL Pharmaceuticals (Pvt.) Ltd.

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Quality AssuranceQuality 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

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QC

GMP

QA

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Is that part of Quality Assurance aimed at ensuring that products are consistently

manufactured to a quality appropriate to their intended

use

GMP

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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

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Public Health ExpectationsEvery 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.”

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Pharmaceutical ManufacturingCurrent 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

o pharmaceutical development, manufacturing, and quality assurance through innovation in o product and process development, process analysis, process control, and

automation

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Current State of Pharmaceutical Manufacturing: A snapshot…

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Quality Issues: Examples 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

Potency questioned Oversize tablet Capsule fill caries Volume/quantity

questioned Dosage unit missing Empty capsule units Discoloration Precipitation Cloudy Clumping Odor/taste abnormal

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Pharmaceutical ManufacturingDesired 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

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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

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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.

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Significance of QbD

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Elements of QbD Approach

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QbD Approaches Creating a design space during product

development.

Process Analytical Technology (PAT) implementation.

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Design Space Definition

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

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Application of QbDApplications 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.

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Approaches to Pharmaceutical Development

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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.

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ICH Guidance Q8–Pharmaceutical Development

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

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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

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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

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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”.

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Process Analytical Technology (PAT)-3Types 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)

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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.

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PAT and QbD

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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

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Acknowledgements

Thanks

Questions??

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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