Changes Without Prior Approval

How do we get there from here?

Jon ClarkAssociate Director for Policy DevelopmentOffice of Pharmaceutical ScienceCenter 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 TestingLittle 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 N

eed

for Z

ero

Tole

ranc

e Li

mits

Increasing Process Understanding and Control

Continuous ImprovementPo

st A

ppro

val

Reg

ulat

ion

Knowledgeand Process Understanding

Current Paradigm

RawMaterial

ProductManufacturing Process

LockedProcess Variables

Variability

Dynamic System

Manufacturing Process

Measurement DependantProcess Variables

RawMaterial

Product

InputResponse

EndpointResponse

P A TProcess Analytical Technology

Manufacturing Process

Critical Process Parameter (CPP)adjusted by measurement of

Critical Quality Attributes (CQA)

RawMaterial

Product

FeedForward Feedback

We are not AloneMIL-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 QualityDr. 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 R

ange

of R

aw M

ater

ial

and

Faci

lity

Attr

ibut

esRange

Process Designed to LimitProduct Variability

CQA

Variation ControlAnna 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 ofExperience 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 TestingLittle Process Understanding

Increasing Desirability

End

Thank you