Quality by DesignThe Challenge for Regulators

Summary of New ThinkingPath for Development of Review ConsiderationsNot yet FDA policy

Jon ClarkAssociate Director for Policy DevelopmentOffice of Pharmaceutical ScienceCenter for Drug Evaluation and Research, FDA

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 technology.

Agency study of potentially inconsequential impact on the product can result in delay.

Potential for Contradiction

Commitment to high quality products with

Commitment to most rapid introduction to market

Inclusion of development data helps, but can not equal knowledge obtained during routine production

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

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. You need to measure and model the process then

steer it. The model should be designed so that we can

measure the parameters used in the model to control the process.

As the model evolves measurement strategy evolves with it.

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.

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

Situation Spectrum

High Process Understanding and Control

No Need for 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 heuristic trap Don’t measure it just because you can

Need for Generic Rules Based Control

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Increasing Process Understanding and Control

Continuous ImprovementG

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Putative Post ApprovalRegulation Increasing

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 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 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

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Range

Process Designed to LimitProduct Variability

CQA

What Might FDA Reviewer See?Anna Thornton “Variation Risk Management”

Identification Key Characteristics (KC) Variation “Flowdown”

Assessment Which variations put CQA at risk

Mitigation Eliminate source Reduce impact

Key CharacteristicsInjection Delivery Device

Leaks

Contamination in fluid path

Contamination outside fluid path

Variation FlowdownContamination IN Path

Tube Luer lock Needle

Common Sources Supplier Handling Adhesive

Variation Flowdown Contamination Outside Fluid Path

Needle Tube Luer lock Roller clamp “Wings” or other handles

Variation Flowdown Leaks

Cracked needle base Cracked luer lock Unsealable luer lock

Flash Diameter

More...

Variation Flowdown More Leaks

Leak in Joints Needle tube connection Tube luer lock connection

UV cure time Adhesive application Correct diameters

Examples of evidence regarding process improvement

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]

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

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 mitigation. This is designed to place research 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.

Organization of CMC Staff

Current attachment to Clinical Staff doesn’t seem ideal

We are studying the best way to organize them

Training specific to new technologies and philosophies is needed

Supplement change control process needs work

Situation Spectrum

High Process Understanding and Control

No Need for End Product Testing

Extensive Product TestingLittle Process Understanding

Increasing Desirability

End

Thank you