# Presentation: 912637

## Changes Without Prior Approval

- How do we get there from here?

- Jon Clark
- Associate Director for Policy Development
- Office of Pharmaceutical Science
- Center for Drug Evaluation and Research, FDA
- ACPS Manufacturing Subcommittee July 21, 2004

## Overview

- The traditional system of approval and change control seems burdensome
- There should be a way to protect the public without slowing innovation
- Methods and standards for this are available
- Need to train ourselves into a new way of thinking and working

## Shared Concerns

- The pharmaceutical industry has one of the most technically advanced discovery organizations, but remains more conservative when it comes to using "cutting edge" technology in manufacturing.
- Concern over how regulatory agencies will react to using knowledge and technology
- Agency focus on changes with inconsequential impact on the product quality can result in delay.

## Complex Interaction

- Commitment to high quality products
- with
- Commitment to most rapid introduction to market

## When to Optimize the Process

- Optimization before approval
- Greatest cost may be time
- No baseline for measuring return on investment
- Provides immediate benefit to patient
- Continuous improvement
- Time element minimized
- Enables measured improvement
- Feed forward data and scope protocols
- Inclusion of development data helps, but can not equal knowledge obtained during routine production

## Points to Consider

- Raw Materials
- Process
- Measurement
- Steering the Process
- Variability

## Raw Materials

- Pharmaceutical raw materials are variable.
- Cannot assume that holding the inputs constant will always produce a constant product.
- Ergo:  Attempting process control through raw material control is futile.

##  Process

- Discovery and design suggest a process model
- The model should be designed so that its parameters can be measured in the real world
- As the model evolves measurement strategy evolves with it
- The effect of change can be better predicted with realistic models
- There is a lack of process models in applications

## Measurement

- Measurement is most effective when used to control the process in “real time”
- Traditional approach has been to sample the process and product,  then test for compliance with criteria via “Laboratory Determination”

## Steering the Process

- Change times, speeds, temperatures based on measurement to achieve target value for a product parameter.
- Discarding batches or portions of batches reveals failure to steer the process.

## Variability

- Variability reduction adds value
- increases process capability
- minimizes the risk of OOS
- prerequisite for investigation

## Situation Spectrum

**High Process Understanding and Control**
**Obviated **
**End Product Testing**

**Extensive Product Testing**
**Little Process Understanding**

- Increasing Desirability

## Therefore

- FDA focus on Laboratory Testing is not ideal for controlling a process
- Need to encourage Process Understanding and Engineering
- Focus resources on the manufacturing process instead of lab tests and criteria
- Avoid trap of “measure it because you can”

## Need for Zero Tolerance Limits 

## Continuous Improvement

## Current Paradigm

- Raw
- Material

- Product

**Variability**

## Dynamic System

- Manufacturing Process

- Measurement Dependant
- Process Variables

- Raw
- Material

- Product

**Input**
**Response**

**Endpoint**
**Response**

## P A TProcess Analytical Technology

- Manufacturing Process

- Critical Process Parameter (CPP)
- adjusted by measurement of
- Critical Quality Attributes (CQA)

- Raw
- Material

- Product

**Feed**
**Forward**

**Feedback**

## We are not AloneMIL-STD-1916  dated 1996

- “Process controls and statistical control methods are the preferable means of preventing nonconformances, controlling quality, and generating information for improvement.”
- “Sampling inspection by itself is an inefficient industrial practice for demonstrating conformance to the requirements of a contract and its technical data package.”
- “To the extent that such practices are employed and are effective, risk is controlled and, consequently, inspection and testing can be reduced.”

## More

- “The objective is to create an atmosphere where every noncompliance is an opportunity for corrective action and improvement rather than one where acceptable quality levels are the ... goals.”
- “The goal is to support the movement away from a [product]  inspection strategy to ... effective prevention-based strategies including a comprehensive quality system, continuous improvement and partnership with Government.”

## And More

- Process should be focus of quality system
- Consistently producing conforming product.
- Controlled as far upstream as possible.
- Robust to variation....
- Operated to constantly reduce variation.
- Utilization of equipment in a way that minimizes variability around target values
- Managed for continuous improvement
- Designed and controlled using a combination of practices and methods in order to ensure defect prevention and process improvement.

## Product Sampling and QualityDr. W. Edwards Deming

- "Cease dependence on inspection [laboratory determination] to achieve quality. Eliminate the need for inspection on a mass basis by building quality into the product in the first place."
- "Depending on inspection is like treating a symptom while the disease is killing you. The need for inspection results from excessive variability in the process. The disease is variability.”
- "Ceasing dependence on inspection means you must understand your processes so well that you can predict the quality of their output from upstream activities and measurements."

## Target Critical Quality Attributes 

- Range of Raw Material
- and
- Facility Attributes

- Range

- Process Designed to Limit
- Product Variability

- CQA

## Variation ControlAnna Thornton “Variation Risk Management”

- Identification
- Key Characteristics (KC)
- Those that assure achieving CQA
- Variation “Flowdown”
- Assessment
- Which variations put CQA at risk
- Mitigation
- Eliminate source
- Reduce impact

## Examples of evidence regarding process understanding MIL-STD-1916  dated 1996

- Process flow charts showing the key control points for action to prevent defective product
- Identification of process improvement techniques...
- Identification of measures used, e.g., trend analysis
- Results of improvements from using these...
- Results of experiments that led to reduced variability...

## Examples of evidence regarding process control	

- Identification of the scope of use of process control techniques...
- Process control plans, including improvement goals...
- Approaches and supporting data used to determine if suppliers have adequate controls...
- Descriptions of the required training ...
- Identification of departmental interrelations
- Rationale for establishing subgroups
- Identification of key parameters used in lieu of specified characteristics
- More...

## Examples of evidence regarding process control (continued)

- Identification of personnel responsible for process related corrective action.
- Proper gage measurement studies showing measurement variations relative to total variation.
- Traceability of the product and process corrective action(s) taken when the process went out of control, showing how the root cause was identified and eliminated.

## Examples of evidence regarding product conformance

- Control chart showing the process in statistical control in accordance with the criteria...
- Records of product and process corrective action(s) taken when nonconformances occur.
- Process capability studies consisting of correct calculation and interpolation of [attribute measures]
- History of product inspection results reinforced by statistical data and analysis.
- Results from in-process control methods, such as [automation applications]

## Contribution ofExperience and Quality System

- Institutionalization of Knowledge is a Quality Concern
- Need to apply “solutions” wherever they provide improvement
- Prior regulatory approval for every improvement defeats this goal

## Application w/o supplements?

- What are quality critical attributes, the means of monitoring and controlling them
- What are the fundamental scientific mechanisms of the physical changes?
- How do formulation and process factors affect product performance?
- Control of the operation using mechanistic scientific principles; Directly!
- Demonstrate a range of operating ranges, controls and principles
- History of manufacturing success with similar drugs or similar operating principles or similar site operations

## More Information

- Significance of the site location and environment on the quality of the finished product
- Drug product specification based on attributes critical to product performance experienced by the patient
- Process control relationships to finished product quality

## Operational Freedom

- This process understanding knowledge leads to greater freedom from narrow operating procedures and allow focus on drug product quality
- Provide for use of alternatives to any application requirements
- components
- manufacturing and packaging procedures
- in-process controls
- analytical procedures
- 21 CFR 314.50 (d)(1)(ii)

## Focus on process science and understanding

- The FDA wishes to avoid allowing the submission of great operating procedure detail with equipment specifications to create a "safe harbor" for processes that do not consistently result in quality of product suitable for use
- Batch records should not be used as manufacturing process control specifications or change control restrictions
- Stability analysis is more valuable than raw data
- Understanding of degradation mechanism helps predict impact of change

## Commercial Batch Research Data

- Agency acknowledges concern that process research data may indicate a problem when the product still meets its approved release methods.
- FDA began using a "research data exemption" concept in several guidance documents.
- Doesn’t protect one that knowingly does harm without attempting corrective action.
- This is designed to place this information outside the scope of a “normal” inspection.
- Shouldn’t impact on the ability to release products that meet all aspects of the company's current registered quality control strategy.

## Situation Spectrum

**High Process Understanding and Control**
**Obviated **
**End Product Testing**

**Extensive Product Testing**
**Little Process Understanding**

- Increasing Desirability

## End

- Thank you