# Presentation: 702396

## Challenges and Opportunities in Enhancement of the CMC Section of NDAs: Quality – by - Design 

- Ajaz S. Hussain, Ph.D.
- Deputy Director
- Office of Pharmaceutical Science
- CDER, FDA

## Opportunity

- For companies that acquire extensive understanding about their product and manufacturing process and share this with the regulators
- Enhanced science and risk-based regulatory quality assessment will be possible
- Setting specifications
- Reduction in the volume of data to be submitted – replaced by more knowledge based submissions
- Flexible post approval continuous improvement

## Janet Woodcock, M.D.

**Janet Woodcock, M.D.**
**May 19, 2004**

## Without adequate product and process development and/or knowledge sharing

- Without “design” consideration, high level of uncertainty with respect to critical attributes, “representative” test sample, and adequacy of risk coverage (e.g., compendail tests) to assure batch quality [*Regulatory Concern/Risk*]
- Reduce concern/risk by covering all _apparent_ attributes with acceptance criteria based on capability of test methods and/or manufacturing process plus very inflexible SOP’s [*Current Regulatory Risk Mitigation Strategy*]

## To illustrate the current state: A “Case Study” – Dissolution Attribute The “case study” attempts to connect many dots 

**ICH Q6A**

**ICH Q8**

**Dissolution**

**SUPAC**

**BCS**

**BA/BE**

**1**

**2**

**4**

**5**

**3**

**Desired State**

**Desired State **

**Current**
** ****State**

**Testing to**
**Document Quality**

**Quality By Design**

## How do we currently establish dissolution specifications

- ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION

**What specific test conditions and acceptance criteria are appropriate? [IR]**

**dissolution significantly****affect BA?**

**Develop test conditions and acceptance**
**  ****distinguish batches with **unacceptable BA

**YES**

**NO**

**YES**

**NO**

**YES**

**NO**

**Do changes in****formulation or****manufacturing variables ****affect dissolution?**

**Are these changes controlled****by another procedure **
**and acceptance****criterion?**

**Adopt appropriate test conditions****and acceptance criteria without **
**regard to discriminating power, to**
**pass clinically acceptable batches.**

**Adopt test conditions and acceptance **
**criteria which can distinguish **
**these changes. Generally, single point **
**acceptance criteria  are acceptable. **

**How?**

**What?**

**Why?**

**Why?**

**Why?**

## Without adequate product development and/or knowledge sharing we debate frequently ......

**And then, have CGMP problems?**

## This can be catastrophic for the business and availability of

**This can be catastrophic for the business and availability of**
**Important drugs**

**A Warning Letter**

## OOS or Exceptions Further Increase Cycle Times (Source: G. K. Raju, M.I.T.FDA Science Board Meeting, November 16, 2001)

- OOS or Exceptions Further Increase Cycle Times (Source: G. K. Raju, M.I.T.FDA Science Board Meeting, November 16, 2001)

- Dissolution

## Testing to Document Quality: Requires Less Variable Test Methods 

- The current USP 10-mg Prednisone Calibrator Tablets exhibit slower dissolution over time
- If the acceptable test equipment calibration limit is 28-54; what can we say about use of f2 criteria (~mean profile difference of 10%) as a way to document unchanged quality (e.g., SUPAC)?

| Lot | Date | Mean (n=6) | SD (%) | USP Limit (%) |
| --- | --- | --- | --- | --- |
| M | 4/00 | 34.8 | 2.2 | 28-42 |
| M | 10/00 | 28.9 | 0.9 | 28-42 |
| N | 12/01 | 35.7 | 1.6 | 28-54 |
| N | 11/02 | 35.4 | 1.4 | 28-54 |
| N | 6/03 | 28.0 | 0.7 | 28-54 |
| DPA/FDA Data using Apparatus 2; data from only one apparatus shown. Note the USP adjusts the limits of each new lot of calibration tablets to reflect the anticipated decrease in dissolution. |  |  |  |  |

## Dissolution Experience at the FDA Division of Pharmaceutical Analysis

- Dissolution testing with USP Apparatus 1 and 2  requires diligent attention to details: mechanical and chemical
- Dosage forms can respond differently to small variations in apparatus set up or degassing
- Large differences in dissolution results are possible unless all parameters are carefully controlled
- The experience at DPA indicates that differences in reproducibility can often be traced to improper mechanical calibration and/or degassing

## False Positives and False Negatives!!! 

- False Positives and False Negatives!!!

- Test/Ref. Mean

- I. J. MacGilvery.  Bioequivalence: A Canadian Regulatory
-  Perspective. In, Pharmaceutical Bioequivalence
- . Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York,  (1992)).

## Do we need a dissolution specification of every solid oral drug product? No ICH Q6A: Decision Tree #7 (1)

- Modified release?

- High solubility?

- Rapid dissolution?

- Relationship between
- Disintegration - Dissolution?

- No

- Yes

- Yes

- Generally single-point
- dissolution acceptance criteria
- with a lower limit

- Generally disintegration
- acceptance criteria with
- an upper limit

- Establish drug release
- acceptance criteria:
- ER: Multiple time point
- MR: Two stage, parallel
- or sequential

- Yes

- No

- No

- No

- Yes

***How?***
***Test – Test Comparison?***

## Disintegration - Dissolution Relationship

*10# screen*

*Fraction *
*dissolved*

***Note: Disintegration and dissolution process in a dissolution apparatus may differ ***
***from that in a disintegration apparatus (different hydrodynamics and other conditions)***

## “Testing to Document Quality”

- The phrase has many dimensions
- In-process and end-product release and stability testing
- Reliability of specifications (attribute, test method, and acceptance criteria)
- Managing post approval changes/continuous improvement (e.g., reduce variability, improve efficiency,..)
- Product and process knowledge acquisition and generalization

## How can pharmaceutical development knowledge help?

- Demonstrate quality was designed in?
- Specifications based on mechanistic understanding?
- Continuous "real time" assurance of quality?
- Flexible continuous improvement?

## CMC: Why?

- ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION

**What specific test conditions and acceptance criteria are appropriate? [IR]**

**dissolution significantly****affect BA?**

**Develop test conditions and acceptance**
**  ****distinguish batches with ****unacceptable BA**

**YES**

**NO**

**YES**

**NO**

**YES**

**NO**

**Do changes in****formulation or****manufacturing variables ****affect dissolution?**

**Are these changes controlled****by another procedure **
**and acceptance****criterion?**

**Adopt appropriate test conditions****and acceptance criteria without **
**regard to discriminating power, to**
**pass clinically acceptable batches.**

**Adopt test conditions and acceptance **
**criteria which can distinguish **
**these changes. Generally, single point **
**acceptance criteria  are acceptable. **

**Overall Risk-based **
**CMC:** **Why?**

**Overall CMC Systems approach (e.g., link to morphic form, **
**particle size, stability failure mechanisms) CMC:**** ****Why? Then **How?

**Clin. Pharm.**
**What?**

**Design of **
**Manufacturing**
**and Controls**
**How (reliable)?**

**Product**
**Design **
- (Postulate -
- Confirmed
- Based on mechanism
- and/or empirically)** **
** **

***So what?***

## Based on Quality of Pharmaceutical Development Knowledge can we not evaluate

- Overall CMC Systems approach (e.g., link to morphic form, particle size, stability failure mechanisms) and address concerns and risks
- Is a dissolution specification needed?
- Instead of wet dissolution test, can we use disintegration test?
- Real time release and stability based on process controls, and NIR test for capsules?

## Not all information “mandatory”

- We are okay with this
- But we wish to avoid confusion and the potential vocabulary that may evolve from this – “two different systems”
- Instead we see this as one system with different levels of QbD
-  we will use the “process understanding – predictive ability” vocabulary as a means to create a continuous framework and avoid “two different systems”

**March 2004 ICH Q8 Meeting: FDA’s Goals**

## Challenges we face

- Common approach to, and more clear articulation of
- Not all information “mandatory”
- Improved process understanding and control technologies may be afforded reductions in regulatory requirements
- An inverse relation is expected between the effectiveness of the Quality by Design and the risk to a patient being exposed to product that is not fit for use
- Ensuring continuous improvement and a process for continuous learning and updating of the knowledge base

**March 2004 ICH Q8 Meeting: FDA’s Goals**