1. Molecule-to-Market-Place Quality
Dawn Sanchez-Barona, PhD
Senior Director, Quality Control
Quality Operations
Eisai Inc.

2. Overview Role of Quality Operations Principles of Quality Management
Example of Quality Operations Organization
Responsibilities of Each Quality Department
Quality Operations in Pharmaceutical and Analytical Development
Quality Strategy in Pharmaceutical Development

3. References
Q7A – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Q8 – Pharmaceutical Development
Q9 – Quality Risk Management
The Gold Sheet, Vol. 40, August 2006

4. Role of Quality Operations
Ensure (Eisai) patients receive clinical or commercial products that are safe, pure, and fit for their intended use, and comply with all regulatory requirements.

5. Principles of Quality Management
All persons involved in manufacturing pharmaceutical products are responsible for quality.
Each manufacturer should establish, document, and implement an effective system for managing quality that requires the commitment and active participation of management and staff at all levels in the company – as well as the company’s suppliers, contractors, and distributors.
There should be a quality unit(s) that is independent of production and that fulfills the quality assurance (QA) and quality control (QC) responsibilities.
Quality-based decisions are based on sound scientific judgment and evaluation and require defined processes to implement.

6. Example of Quality Operations Organization

7. Responsibilities – Manufacturing QA
Broadly responsible for implementation and adherence to GMPs, product disposition, and quality systems associated with these functions:
Document Control
Auditing/Vendor Certification
Training
Product Dispositions
Deviations/Investigations/Corrective Actions/Preventative Actions
Change Control
Label Review and Disposition
Reserve/Retain Sample Management
Complaints
Trending
Annual Product Reviews
Contract Manufacturing Organizations

8. Responsibilities – QC
Broadly responsible for laboratory controls associated with product disposition and quality systems required for this function:
Sampling/Disposition Raw Materials and Packaging Components
GMP Laboratory Management
Release Testing
Stability Testing and Program Management
Document Control/Evaluation
Out-of-Specification Investigation
Reference Standard Management
Analytical Technology Transfer/Validation
Analytical Evaluation of Post-Market Changes
Investigation Support

9. Responsibilities – Validation
Broadly responsible for establishing a validation program and compliant documentation and execution of all qualification and validation activities, including:
Equipment Qualification
Computer System Validation
Cleaning Validation
Process Validation
Periodic Review of Validated Systems
Risk Assessment

10. Responsibilities – Clinical QA
Broadly responsible for ensuring clinical trials are conducted in accordance with GCPs, and that data are generated, documented, and reported accurately and in compliance with all applicable regulatory requirements.

11. Quality
Manufacturing QA
Clinical QA QC
Validation

12. Quality Operations in Pharmaceutical and Analytical Development

13. The New Drug Development Process Steps from Test Tube to New Drug Application Review

14. Quality Operations in Pharmaceutical and Analytical Development
Goals are same; i.e, role of Quality Operations and principles of Quality Management does not change.
Tactics for implementing quality can be different.
Controls used in the manufacture of active pharmaceutical ingredients (APIs) and drug products should be consistent with the stage of development.
Process and test procedures should be flexible to provide for changes as knowledge of the process increases, and clinical testing of a drug product progresses from pre-clinical through clinical stages.

15. Responsibilities – Manufacturing QA
Broadly responsible for implementation and adherence to GMPs, product disposition, and quality systems associated with these functions:
Document Control
Auditing/Vendor Certification
Training
Product Dispositions
Deviations/Investigations/Corrective Actions/Preventative Actions
Change Control
Label Review and Disposition
Reserve/Retain Sample Management
Complaints
Trending
Annual Product Reviews
Contract Manufacturing Organizations

16. Responsibilities – Analytical Development
Testing functions commonly performed by QC can be performed within other organizational unit, such as Analytical Development (AD).
In this example, AD would be broadly responsible for laboratory controls associated with clinical product disposition and quality systems required for this function:
Sampling/Disposition Raw Materials and Packaging Components
GMP Laboratory Management
Release Testing
Stability Testing and Program Management
Document Control/Evaluation
Out-of-Specification Investigation
Reference Standard Management
Analytical Technology Transfer/Validation
Analytical Evaluation of Post-Market Changes
Investigation Support

17. Responsibilities – Validation
Broadly responsible for establishing a validation program and compliant documentation and execution of all qualification and validation activities, including:
Equipment Qualification
Computer System Validation
Cleaning Validation
Process Validation
Periodic Review of Validated Systems
Risk Assessment

18. Quality Strategy in Pharmaceutical Development
Theme – Quality by Design (QbD)
Knowledge of process (design space)
Identification of steps critical to quality of drug substance or drug product
Control strategies for synthesis/formulation choices justified

19. Background
PD Goal – Design a quality product and manufacturing process to consistently deliver the intended performance of the product.
Information and knowledge gained from pharmaceutical development studies provide:
Scientific basis for establishing the formulation design space, specifications, and manufacturing controls
Rationale for quality risk management

20. Background Design Space
Multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Proposed in (NDA) filing and subject to regulatory (FDA) assessment.
Working within design space not considered a change.
Movement out of design space considered a change and would initiate a typically regulatory post-approval filing.

21. Establishing Design Space: Gains
Creates higher degree of understanding of material attributes, manufacturing processes and their controls within your company and with FDA.
Facilitates understanding of differences between the manufacturing processes used to make drug product for pivotal clinical trials/stability studies and vs. commercial product
Provides potential opportunities for risk-based regulatory decisions (reviews and inspections)
Facilitates manufacturing process improvements without further regulatory review (if stay within design space) and may reduce number of post-approval submissions
Provides potential for real-time quality control and reduction of end-product (QC) release testing

22. Establishing Design Space: Challenges
Establishing appropriate/expected level of detail in regulatory submissions
Establishing balance between QbD-based vs. traditional demonstration of quality
Achieving regulatory flexibility while assuring product quality
Sharing proprietary information with FDA
FDA pilot program – more work to be done!