FDA Quality Metrics Guidance

Marlène García Swider, Ph.D., CQM, CSSBBInstitute of Validation Technology

Quality Metrics Conference

February 22 – 24, 2016

Coronado Island, San Diego, CA

Personal Claim

This presentation

does not reflect a position, official or

unofficial, of the FDA. Any reference to FDA information is based on author interpretation of public information.

Outline

Definitions

FDA Quality Metrics Guidance What FDA wants

Included products

Excluded products

Examples of Quality Tools and SP

Other FDA related guidance

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Definitions

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What is an FDA Guidance?

Agency’s interprets a policy/law/issue

Not legally binding

Show only one way to reach a goal

Posted in website and open for

commentsReport on FDA Good Guidance Practices

http://www.fda.gov/downloads/AboutFDA/Transparency/TransparencyInitiative/UCM285124.pdf

Fact Sheet: FDA Good Guidance Practices

http://www.fda.gov/downloads/AboutFDA/Transparency/TransparencyInitiative/UCM285344.pdf

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Definition of Quality

A subjective term.

Technical usage (2 meanings):

1) product/service able to satisfy a need

2) Product/service free of deficiencies

(The Certified Manager of Quality/Organizational Excellence

Handbook – 3rd Ed. , ASQ)

PMP’s Quality definition

The degree to which the project (product,

service, process) fulfills requirements.

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What are Quality Tools?

Instruments that facilitate ways to bring

quality to a process or product. These are

usually (but not necessarily) based on

objective data or measurable data or

metrics.

“… metrics are not solely indicative of the

state of quality…” (page 2) (e.g.

management commitment, quality culture,

etc.)

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7 Basic Quality Tools

Flowchart

Check Sheet

Cause-and-Effect Diagram

Pareto Chart

Control Charts

Histograms

Scatter Diagrams

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The Guidance

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What FDA wants?

Evidence that a process is capable of

consistently delivering quality product.

All products to U.S. are required to meet

the same standards as domestic goods –

must be pure, produced under sanitary

conditions and contain informative and

truthful labeling in English.

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The use of Quality Metrics in

FDA

Guidance Authority

Title VII of the Food and Drug

Administration Safety and Innovation Act

(FDASIA) Public Law No. 112-144

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Guidance only applicable to…

CDER and CBER products

Products inspected and approved by other

Centers have other guidance to follow.

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Guidance applies to which

products?

FDA approved products

Over-the-counter products

Marketed unapproved drug products

Certain foreign establishments (section

704(a)(4))

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What products

Subject to an approved application (505

FDA Act or the 351 PHS Act)

Marketed pursuant an OTC monograph

Unapproved marketed drug product

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Reports for drugs from reporting

establishments

One for FDF

One for API

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Excluded

Manufacturers of excipients or container/closure

(510)

Establishments not registered (per CFR 207.10)

Compounders (503 A)

Foreign establishments (data only)

Outsources facility (503 B)

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Excluded (Con’t)

Medical gas manufacturers

Positron emission tomography

Manufacturers. Blood and blood

components for transfusion

Vaccines

Cell therapy products

Gene therapy

Allergenic extracts

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Others not included

Tissues

Cellular

Tissue Based Products

Non-recombinant Version of plasma

derived products

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Who reports?

Owners and operators responsible for:

Manufacture

Preparation

Propagation

Compounding

Processing

(Sec 704)

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What FDA intends to do with

data collected

“… inform FDA’s risk-based drug

inspection scheduling and better detect

manufacturing conditions that may lead to

a shortage.” (Details in Section V)

Advice: Work as a partner with FDA! Exceed its expectations by

having data already analyzed, integer, and demonstrating continual

manufacturing process improvement.

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FDA depends on statistics…

To assure that batches of products meet

each appropriate specification and

appropriate statistical quality control

criteria as a condition for their approval

and release.

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FDA requires…

That statistical quality control criteria shall

include appropriate statistical quality

control criteria as a condition for their

approval and release.

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Statistics are no exception

“Where appropriate, each manufacturer

shall establish and maintain procedures

for identifying valid statistical

techniques…” – FDA Quality System Regulation (1996)

Statistical Methods & Quality

Tools

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Set of Quality Metrics FDA uses

Not an all-inclusive set of metrics

Compliance data (e.g. no. of recalls)

FDA encourages use of additional quality metrics beyond the ones described in guidance

Determining risk factors

Process validation data

What Quality Data to report

(under consideration)

Lot Acceptance Rage = 1 – x

Product Quality Complaint Rate

Invalidated Out-of-Specification (OOS) rate

Annual Product Review (APR) or Product

Quality Review (PQR) on Time Rate

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Ideal Risk Formula

Includes past inspections results, recalls,

Field Alert Reports, Biological Product

Deviation Reports.

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When and Where…

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FDA Globalizes

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No matter where you are…

The same FDA guidance apply to all

the inspections done by the Agency

(in U.S. or any other country.)

Quality Metrics part of Validation

Have a Quality Program in place that can:

Help understand variation (Pareto Analysis)

Detect presence and degree of variation (DOE, sampling)

Impact of variation on process and product (Force field Analysis, Fish Diagram)

Control variation in relation to risk

presented (Control Charts, Monte Carlo)

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What is Process Validation?

According to FDA, process validation is

the collection and validation of data, from

the process design stage throughout

production…

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Process Validation – 3 Stages

Process Design

Process Qualification

Continuous Process Verification

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How it is done - Example 1

Process Design

DOE

Risk Analysis (screening potential

variables)

Models of the commercial process

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How it is done - Example 2

Process Qualification

Design of facility and equipment/utilities

qualification

Process Performance Qualification (PPQ)

Intra-batch and inter-batch metrics

Comparison and Evaluation of process

measures, in-process and final product

attributes

How it is done - More Examples

Bayesian Statistics

Learning from evidence as it accumulates.

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How it is done - More Examples

Process Control Techniques

SPC Techniques (probability, multivariate

statistics, and statistical control charts)

Process Analytical Techniques (PAT)

Process Capability Studies

Control Charts

Comparison of CPK and CQA

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Additional metrics under

consideration

Data reflecting robustness and Senior

Management commitment to quality:

APR or PQR

CAPA Effectiveness based on re-design

and re-development of the process

What percentage of corrective actions

involved re-training vs. re-development

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Additional information under

consideration

Process Capability Performance

Meaningful specifications to achieve

desired results enabling science and

risk-based quality risk management

Yes or no to process capability or

performance index foe each CQA

Yes or not having a policy for CAPAS

and if yes, triggering performance index

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How to avoid FDA inspections?

Highly controlled manufacturing process

Understand risk-based principles (use of

SWOT, gap analysis, internal audits, QbD

Have a plan & measures in case of

disruption to manufacturing takes place

Avoid inconsistent data

Communication plan in place

Avoid at all cost not-reporting!(raise flags)

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Effective Strategy to report

Create a good reputation!

Develop a rapport, network with your

FDA’s contacts

Bring FDA from the beginning

Train-the-trainer session

Communicate, communicate

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Advice No. 1

Know your product!

Ensure that a statistician or person with

adequate training develops statistical

process control techniques.

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Advice No. 2

Develop data collection plans and

statistical methods and procedures for

measuring and evaluating process stability

and process capability

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Advice No. 3

Describe how trending and calculations

are performed and detect unintended

process variability

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Advice No. 4

Collect production data to evaluate

process stability and capability

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Advice No. 5

Understand the role of the quality unit and

review process

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Advice No. 6

Identify variability in the process and/or

signal potential process improvements

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Advices

Invest in a good record-keeping

Process Validation that can ensure

products with the desired attributes

Studying your products

Collect & analyze data to keep control

(what tools then) (e.g. Annual Product

Review)

Trained personnel

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More Advices

Correctly validated sampling process

Maintenance program (e.g. calibration

program running like a clock)

Collect, calculate and evaluate Real Time

metrics

Data tabulation and presentation (e.g.

Minitab)

Tools used for risk analysis

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In Conclusion

Study and familiarize yourself with FDA

policies and regulation in order to comply

Network and participate on forums like this

one to keep in top of changes and trends

Inform yourself through researching

literature

References

FDA 2011 Process Validation Guidance

FDA, Quality Systems Approach to

Pharmaceutical CGMP Regulations, Guidance

for Industry, 2006

Case Study: Use of Statistical Process Control

to Detect Process Drift (Torbeck, 2011)

Guidance for the Use of Bayesian Statistics in

Medical Device Clinical Trials

www.fda.gov

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Contacts

Guidance:

Office of Communication CDER at

855-543-3784 or 301-796-3400 or

druginfo@fda.hhs.gov

Office of Communication CBER at

800-835-4709 or 240-402-7800 or

ocod@fda.hhs.gov