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

2. 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

3. QA
GMP QC

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

5. 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

6. 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.”

7. 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

8. Current State of Pharmaceutical Manufacturing: A snapshot…

9. 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

10. 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

11. 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

12. 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.

13. Significance of QbD

14. Elements of QbD Approach

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

16. 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

17. 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.

18. Approaches to Pharmaceutical Development

19. 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.

20. 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

21. 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

22. 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

23. 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”.

24. 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)

25. 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.

26. PAT and QbD

27. 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

29. Acknowledgements Thanks Questions??

30. References
Guidance for Industry: PAT —A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, September
Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, September
Guidance for Industry: Q9 Quality Risk Management, June
Guidance for Industry: Q8(R2) Pharmaceutical Development Revision 2, November
Guidance for Industry: Q10 Pharmaceutical Quality System, April
Guidance for Industry: Process Validation: General Principles and Practices, January