Changes Without Prior Approval - Pharma

0 %
100 %
Information about Changes Without Prior Approval - Pharma
Business & Mgmt

Published on February 4, 2009

Author: siddharth4mba

Source: slideshare.net

Description

Changes Without Prior Approval - Pharma

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

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.

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

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

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

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.

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

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”

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.

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

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”

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 Need for Zero Tolerance Limits Increasing Process Understanding and Control

Continuous Improvement Post Approval Regulation Knowledge and Process Understanding

Current Paradigm Raw Material Product Variability Manufacturing Process Locked Process Variables

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.”

“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.”

“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.

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."

"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

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...

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...

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.

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]

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

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

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

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)

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

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.

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

Add a comment

Related presentations

Related pages

CHANGES WITHOUT PRIOR APPROVAL - PQRI: Product Quality ...

CHANGES WITHOUT PRIOR APPROVAL AN FDA PERSPECTIVE Dennis M. Bensley, Jr., Ph.D. ... Prior Approval CBE Annual CVM • A significant number of CMC changes are
Read more

Afnan to FDA: Simplify Post-Approval Changes, Spur ...

... it is vital to allow some manufacturing changes without prior FDA approval. ... Step Change Pharma. He can be reached at aafnan@stepchangepharma ...
Read more

PPT – Changes without Prior Approval PowerPoint ...

Changes without Prior Approval. Description: True risk comes from an assessment of whether product has changed from the ... To bundle or not to bundle.
Read more

Changes without Prior Approval

10/9/2003: Changes without Prior Approval . Changes without Prior Approval. Breakout Session Summary Rick Smith Aventis Pasteur, Inc. ...
Read more

Changes without Prior Approval

Changes without Prior Approval. Breakout Session Summary Rick Smith Aventis Pasteur, Inc. ...
Read more

The Pharma Compliance Blog: Your Space. For Your Space ...

The Pharma Compliance ... without prior review and approval ... Both prospective and retroactive changes can made without prior approval ...
Read more

The Pharma Compliance Blog: Your Space. For Your Space ...

The Pharma Compliance Blog is ... without prior review and approval ... window may proceed with the change without prior CMS approval ...
Read more

Model List of Variations (Changes) to Pharmaceutical ...

made without prior approval: a. The change should be one of those listed below as one that is allowable without prior approval,
Read more