Drug product manufactured at many different facilities, changes in the process, different manufactures,…
Uncertainty, Variability and Risk
Quality – Clinical Connection
Uncertainty
Variability
Risk
Pharmaceutical Equivalent
Need for Bioequivalence
Assessment
Same active, identical amount, same dosage form, and route of administration. Identity, Strength Quality, Purity.
Similarity with reference label, medication errors.,,
Certain differences due to changes in the manufacturer, distributor, pending exclusivity issues, or other characteristics
Executed batch record and master batch record (e.g., 10X) – application commitment
Post-approval process validation and stability commitment
“Market Standards”
Science of Design + Manufacturing Science = Quality by Design
Risk/Benefit and Quality
Label
Harm
Acceptable Risk/Benefit
Quality
No benefit (placebo effect)
Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.
Management Goals
Improving quality and ensuring availability Optimal use of our resources
In decision making there are many advantages in distinguishing between uncertainty, variability (random variation) and risk
Goals and Characteristics of a Quality Decision System: Example
Normal healthy subjects, cross-over design, fasting (and fed) conditions
Common for all oral drugs – i.e., procrustean
To cover “worst case” scenarios If mean is 100% and 90% CI is outside 80- 125 say 85 - 126.5?
A Systems Approach
Science of Design
Manufacturing Science
Deபைடு நூலகம்iver Quality by Design
State of Control & Continuous Improvement
Quality can not be tested into a product; it has to be by design
Managing Pharmaceutical Quality
Quality of a new molecular entity (a potential drug)
Intrinsic pharmacological & toxicological attributes
Identity
Complexity A range of uncertainty with respect to identity of “active moiety”, purity and stability of materials used in evaluation of pharmacological and toxicological attributes (if a mixture; variability adds additional uncertainty) Variability in the extent and rate of delivery of “active moiety” to the sites of action and variability in the pharmacological & toxicological response and measurement systems further adds uncertainty
Characteristics important to desired performance must be derived from a combination of prior knowledge and experimental assessment during product development.
Managing Pharmaceutical Quality
Quality of a drug product
For establishing proposed therapeutic claim (label)
Drug product manufactured for clinical trials
Prior Knowledge (NDA)
Post Approval: Monitoring program
Such as MedWatch Consumer Complaints Therapeutic
Inequivalence Coordinating Committee
Adequately Labeled
A systems approach to CMC review and CGMP investigations
Based on knowledge and process understanding
Achieving “quality by design” Demonstrating “science of design” Continuous learning and improvement through
Generally 1bio-batch
Bioequivalence goal post 80-125%
90 % Confidence Interval for the Test/Reference ratio for Cmax and AUC in between the goal post
What is Quality?
What is pharmaceutical quality?
consistent delivery of the label performance and lack of contamination.
operationalzed via a set of pre-specified quality attributes (e.g., specifications, limits) and through the CGMP regulations.
Do not present a known or potential bioequivalence problem. Acceptable
in vitro standard
Present a known or potential bio problem. Appropriate bioequivalence
FDA, in its quality definition, is standing in for the customer—and it is apparent that health care practitioners and patients highly value an additional drug attribute: product availability
Manufactured in conformance to
CGMP's
Process Validation and Quality System
Deviations, Out of Specifications,...
ANDA Applications: Limited Information
Content (e.g., IR Capsule)
After successful demonstration of therapeutic claim (acceptable risk-to-benefit ratio)
Drug product manufactured for commercial distribution
Life cycle of the product (shelf-life, exclusivity period, generic competition, post-approval changes,…)
Goal: expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling