FDA Medical Device Industry Coalition

Quality System Survival:

Success Strategies for

P&PC and CAPA An Educational Forum

15 April 2016

FDA Medical Device Industry Coalition

Introduction

Disclaimers, housekeeping, logistics,

laws, regulations, and guidance

documents

Disclaimer

The information provided in this forum does

not take the place of the laws and

regulations enforced by FDA

Any reference to a commercial product,

process, service, or company is not an

endorsement or recommendation by the

U.S. government, HHS, FDA or any of its

components

Disclaimer

FDA is not responsible for the contents of

any outside information referenced in this

forum

This forum does not convey any waiver of

responsibility to the firm, nor impart any

immunity to the firm for violations that may

occur, even if you implement our

recommendations as per 21 CFR 10.85(k)

No Smoking

Cell Phones, Pagers and PDA’s

Please make sure your

cell phones, pagers,

and other devices are

set on silent mode

Please step outside if

you must answer or

make a call

Logistics

Restrooms

Breaks

Lunch

Questions

Evaluation form

Certificate of

Attendance

FDA Medical Device Industry Coalition

Quality System Overview

John C. Criscione, MD, PhD

Associate Professor

Department of Biomedical Engineering

Texas A&M University, College Station

Big Picture

High Quality Product!

High Quality Definition of Quality

What is Quality?

High Quality Definition of Quality

Quality is “Realizing Expectations”

A Quality Product or Service will Perform as

Expected

A Low Quality Item Fails to Meet

Expectations

High Quality Definition of Quality

Quality is “Realizing Expectations”

A Quality Product or Service will Perform as

Expected

Expectations for Food, Drugs,

Cosmetics and Devices

Quality System

A Systematic Approach to Achieving Quality

Without Quality Assurance there is no

Quality System…

Is a Quality System Necessary

Yes!

Low Risk of

Injury or Death

High Risk of

Injury or Death

Few Procedures

Few People Maybe Yes

Many Procedures

Many People Yes Absolutely

Is a Quality System Necessary

Yes!

Low Risk of

Injury or Death

High Risk of

Injury or Death

Few Procedures

Few People Maybe Yes

Many Procedures

Many People Yes Absolutely

Bottom Line: If a product or service has a

high impact then quality must be assured…

Is a Quality System Necessary

Yes!

Low Risk of

Injury or Death

High Risk of

Injury or Death

Few Procedures

Few People Maybe Yes

Many Procedures

Many People Yes Absolutely

High Quality Attitude

The Most Critical Component to Attaining

Quality Products and Services

Basis of TQM—Total Quality Management

High Quality Attitude

Quality Attitude Attenuates Down the

Leadership Ladder

Executive Officers Production Staff

High Quality Attitude

In a Company that Values Quality, a Quality

Attitude will Lead to Promotion…

Executive Officers Production Staff

High Quality Attitude

If a Company Does Not Value Quality, There

are Worse Things than a Warning Letter…

Executive Officers Production Staff

High Quality Attitude

Having a High Quality Attitude is Difficult

AND Necessary

Can You Say “Thank You” when a Co-Worker

Inspects Your Work and Reports the Flaws?

It is Human Nature to be Defensive when

Criticized, and yet “to Err is Human”…

Sec. 820.20 Management responsibility.

(a) Quality policy. Management with executive responsibility shall establish its policy and objectives for, and commitment to,

quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and

maintained at all levels of the organization.

(b) Organization. Each manufacturer shall establish and maintain an adequate organizational structure to ensure that devices

are designed and produced in accordance with the requirements of this part.

(1) Responsibility and authority. Each manufacturer shall establish the appropriate responsibility, authority, and interrelation

of all personnel who manage, perform, and assess work affecting quality, and provide the independence and authority

necessary to perform these tasks.

(2) Resources. Each manufacturer shall provide adequate resources, including the assignment of trained personnel, for

management, performance of work, and assessment activities, including internal quality audits, to meet the requirements of

this part.

(3) Management representative. Management with executive responsibility shall appoint, and document such appointment of,

a member of management who, irrespective of other responsibilities, shall have established authority over and responsibility

for:

(i) Ensuring that quality system requirements are effectively established and effectively maintained in accordance with this

part; and

(ii) Reporting on the performance of the quality system to management with executive responsibility for review.

(c) Management review. Management with executive responsibility shall review the suitability and effectiveness of the quality

system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality

system satisfies the requirements of this part and the manufacturer's established quality policy and objectives. The dates and

results of quality system reviews shall be documented.

(d) Quality planning. Each manufacturer shall establish a quality plan which defines the quality practices, resources, and

activities relevant to devices that are designed and manufactured. The manufacturer shall establish how the requirements for

quality will be met.

(e) Quality system procedures. Each manufacturer shall establish quality system procedures and instructions. An outline of the

structure of the documentation used in the quality system shall be established where appropriate.

Sec. 820.25 Personnel.

(a) General. Each manufacturer shall have sufficient personnel with the

necessary education, background, training, and experience to assure that all

activities required by this part are correctly performed.

(b) Training. Each manufacturer shall establish procedures for identifying

training needs and ensure that all personnel are trained to adequately

perform their assigned responsibilities. Training shall be documented.

(1) As part of their training, personnel shall be made aware of device defects

which may occur from the improper performance of their specific jobs.

(2) Personnel who perform verification and validation activities shall be made

aware of defects and errors that may be encountered as part of their job

functions.

Sec. 820.50 Purchasing controls.

Each manufacturer shall establish and maintain procedures to ensure that all purchased or

otherwise received product and services conform to specified requirements.

(a) Evaluation of suppliers, contractors, and consultants. Each manufacturer shall establish and

maintain the requirements, including quality requirements, that must be met by suppliers,

contractors, and consultants. Each manufacturer shall:

(1) Evaluate and select potential suppliers, contractors, and consultants on the basis of their ability

to meet specified requirements, including quality requirements. The evaluation shall be

documented.

(2) Define the type and extent of control to be exercised over the product, services, suppliers,

contractors, and consultants, based on the evaluation results.

(3) Establish and maintain records of acceptable suppliers, contractors, and consultants.

(b) Purchasing data. Each manufacturer shall establish and maintain data that clearly describe or

reference the specified requirements, including quality requirements, for purchased or otherwise

received product and services. Purchasing documents shall include, where possible, an agreement

that the suppliers, contractors, and consultants agree to notify the manufacturer of changes in the

product or service so that manufacturers may determine whether the changes may affect the

quality of a finished device. Purchasing data shall be approved in accordance with 820.40.

Sec. 820.70 Production and process controls. (Slide 1 of 2)

(a) General. Each manufacturer shall develop, conduct, control, and monitor production processes to ensure that a

device conforms to its specifications. Where deviations from device specifications could occur as a result of the

manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any

process controls necessary to ensure conformance to specifications. Where process controls are needed they shall

include:

(1) Documented instructions, standard operating procedures (SOP's), and methods that define and control the manner

of production;

(2) Monitoring and control of process parameters and component and device characteristics during production;

(3) Compliance with specified reference standards or codes;

(4) The approval of processes and process equipment; and

(5) Criteria for workmanship which shall be expressed in documented standards or by means of identified and

approved representative samples.

(b) Production and process changes. Each manufacturer shall establish and maintain procedures for changes to a

specification, method, process, or procedure. Such changes shall be verified or where appropriate validated

according to 820.75, before implementation and these activities shall be documented. Changes shall be approved in

accordance with 820.40.

(c) Environmental control. Where environmental conditions could reasonably be expected to have an adverse effect

on product quality, the manufacturer shall establish and maintain procedures to adequately control these

environmental conditions. Environmental control system(s) shall be periodically inspected to verify that the system,

including necessary equipment, is adequate and functioning properly. These activities shall be documented and

reviewed.

(d) Personnel. Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal

practices, and clothing of personnel if contact between such personnel and product or environment could reasonably

be expected to have an adverse effect on product quality. The manufacturer shall ensure that maintenance and other

personnel who are required to work temporarily under special environmental conditions are appropriately trained or

supervised by a trained individual.

Sec. 820.70 Production and process controls. (Slide 2 of 2)

(e) Contamination control. Each manufacturer shall establish and maintain procedures to prevent contamination of

equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.

(f) Buildings. Buildings shall be of suitable design and contain sufficient space to perform necessary operations,

prevent mixups, and assure orderly handling.

(g) Equipment. Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified

requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance,

adjustment, cleaning, and use.

(1) Maintenance schedule. Each manufacturer shall establish and maintain schedules for the adjustment, cleaning,

and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities,

including the date and individual(s) performing the maintenance activities, shall be documented.

(2) Inspection. Each manufacturer shall conduct periodic inspections in accordance with established procedures to

ensure adherence to applicable equipment maintenance schedules. The inspections, including the date and

individual(s) conducting the inspections, shall be documented.

(3) Adjustment. Each manufacturer shall ensure that any inherent limitations or allowable tolerances are visibly

posted on or near equipment requiring periodic adjustments or are readily available to personnel performing these

adjustments.

(h) Manufacturing material. Where a manufacturing material could reasonably be expected to have an adverse effect

on product quality, the manufacturer shall establish and maintain procedures for the use and removal of such

manufacturing material to ensure that it is removed or limited to an amount that does not adversely affect the

device's quality. The removal or reduction of such manufacturing material shall be documented.

(i) Automated processes. When computers or automated data processing systems are used as part of production or

the quality system, the manufacturer shall validate computer software for its intended use according to an

established protocol. All software changes shall be validated before approval and issuance. These validation activities

and results shall be documented.

Sec. 820.72 Inspection, measuring, and test equipment.

(a) Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all

inspection, measuring, and test equipment, including mechanical, automated, or electronic

inspection and test equipment, is suitable for its intended purposes and is capable of producing

valid results. Each manufacturer shall establish and maintain procedures to ensure that equipment

is routinely calibrated, inspected, checked, and maintained. The procedures shall include

provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for

use are maintained. These activities shall be documented.

(b) Calibration. Calibration procedures shall include specific directions and limits for accuracy and

precision. When accuracy and precision limits are not met, there shall be provisions for remedial

action to reestablish the limits and to evaluate whether there was any adverse effect on the

device's quality. These activities shall be documented.

(1) Calibration standards. Calibration standards used for inspection, measuring, and test equipment

shall be traceable to national or international standards. If national or international standards are

not practical or available, the manufacturer shall use an independent reproducible standard. If no

applicable standard exists, the manufacturer shall establish and maintain an in-house standard.

(2) Calibration records. The equipment identification, calibration dates, the individual performing

each calibration, and the next calibration date shall be documented. These records shall be

displayed on or near each piece of equipment or shall be readily available to the personnel using

such equipment and to the individuals responsible for calibrating the equipment.

Verification Vs. Validation

User Requirement or

Process Functionality

Assumption

Testable Specification

Test Data

Functionality Results

Verification Validation

Sec. 820.75 Process validation.

(a) Where the results of a process cannot be fully verified by subsequent

inspection and test, the process shall be validated with a high degree of

assurance and approved according to established procedures. The validation

activities and results, including the date and signature of the individual(s)

approving the validation and where appropriate the major equipment

validated, shall be documented.

(b) Each manufacturer shall establish and maintain procedures for monitoring

and control of process parameters for validated processes to ensure that the

specified requirements continue to be met.

(1) Each manufacturer shall ensure that validated processes are performed by

qualified individual(s).

(2) For validated processes, the monitoring and control methods and data, the

date performed, and, where appropriate, the individual(s) performing the

process or the major equipment used shall be documented.

(c) When changes or process deviations occur, the manufacturer shall review

and evaluate the process and perform revalidation where appropriate. These

activities shall be documented.

Sec. 820.80 Receiving, in-process, and finished device acceptance.

(a) General. Each manufacturer shall establish and maintain procedures for acceptance activities. Acceptance activities

include inspections, tests, or other verification activities.

(b) Receiving acceptance activities. Each manufacturer shall establish and maintain procedures for acceptance of incoming

product. Incoming product shall be inspected, tested, or otherwise verified as conforming to specified requirements.

Acceptance or rejection shall be documented.

(c) In-process acceptance activities. Each manufacturer shall establish and maintain acceptance procedures, where

appropriate, to ensure that specified requirements for in-process product are met. Such procedures shall ensure that in-

process product is controlled until the required inspection and tests or other verification activities have been completed, or

necessary approvals are received, and are documented.

(d) Final acceptance activities. Each manufacturer shall establish and maintain procedures for finished device acceptance to

ensure that each production run, lot, or batch of finished devices meets acceptance criteria. Finished devices shall be held in

quarantine or otherwise adequately controlled until released. Finished devices shall not be released for distribution until:

(1) The activities required in the DMR are completed;

(2) the associated data and documentation is reviewed;

(3) the release is authorized by the signature of a designated individual(s); and

(4) the authorization is dated.

(e) Acceptance records. Each manufacturer shall document acceptance activities required by this part. These records shall

include:

(1) The acceptance activities performed;

(2) the dates acceptance activities are performed;

(3) the results;

(4) the signature of the individual(s) conducting the acceptance activities; and

(5) where appropriate the equipment used. These records shall be part of the DHR.

Sec. 820.90 Nonconforming product.

(a) Control of nonconforming product. Each manufacturer shall establish and maintain

procedures to control product that does not conform to specified requirements. The

procedures shall address the identification, documentation, evaluation, segregation, and

disposition of nonconforming product. The evaluation of nonconformance shall include a

determination of the need for an investigation and notification of the persons or

organizations responsible for the nonconformance. The evaluation and any investigation shall

be documented.

(b) Nonconformity review and disposition.

(1) Each manufacturer shall establish and maintain procedures that define the responsibility

for review and the authority for the disposition of nonconforming product. The procedures

shall set forth the review and disposition process. Disposition of nonconforming product shall

be documented. Documentation shall include the justification for use of nonconforming

product and the signature of the individual(s) authorizing the use.

(2) Each manufacturer shall establish and maintain procedures for rework, to include

retesting and reevaluation of the nonconforming product after rework, to ensure that the

product meets its current approved specifications. Rework and reevaluation activities,

including a determination of any adverse effect from the rework upon the product, shall be

documented in the DHR.

Sec. 820.100 Corrective and preventive action.

(a) Each manufacturer shall establish and maintain procedures for implementing corrective and

preventive action. The procedures shall include requirements for:

(1) Analyzing processes, work operations, concessions, quality audit reports, quality records,

service records, complaints, returned product, and other sources of quality data to identify existing

and potential causes of nonconforming product, or other quality problems. Appropriate statistical

methodology shall be employed where necessary to detect recurring quality problems;

(2) Investigating the cause of nonconformities relating to product, processes, and the quality

system;

(3) Identifying the action(s) needed to correct and prevent recurrence of nonconforming product

and other quality problems;

(4) Verifying or validating the corrective and preventive action to ensure that such action is

effective and does not adversely affect the finished device;

(5) Implementing and recording changes in methods and procedures needed to correct and prevent

identified quality problems;

(6) Ensuring that information related to quality problems or nonconforming product is disseminated

to those directly responsible for assuring the quality of such product or the prevention of such

problems; and

(7) Submitting relevant information on identified quality problems, as well as corrective and

preventive actions, for management review.

(b) All activities required under this section, and their results, shall be documented.

Sec. 820.100 Corrective and preventive action.

(a) Each manufacturer shall establish and maintain procedures for implementing corrective and

preventive action. The procedures shall include requirements for:

(1) Analyzing processes, work operations, concessions, quality audit reports, quality records,

service records, complaints, returned product, and other sources of quality data to identify existing

and potential causes of nonconforming product, or other quality problems. Appropriate statistical

methodology shall be employed where necessary to detect recurring quality problems;

(2) Investigating the cause of nonconformities relating to product, processes, and the quality

system;

(3) Identifying the action(s) needed to correct and prevent recurrence of nonconforming product

and other quality problems;

(4) Verifying or validating the corrective and preventive action to ensure that such action is

effective and does not adversely affect the finished device;

(5) Implementing and recording changes in methods and procedures needed to correct and prevent

identified quality problems;

(6) Ensuring that information related to quality problems or nonconforming product is disseminated

to those directly responsible for assuring the quality of such product or the prevention of such

problems; and

(7) Submitting relevant information on identified quality problems, as well as corrective and

preventive actions, for management review.

(b) All activities required under this section, and their results, shall be documented.

FDA Medical Device Industry Coalition

Getting It Wrong:

Warning Letter Learnings

Jeff R. Wooley, Compliance Officer

Dallas District, FDA

Common Challenges

Scope

Systemic Corrective Actions

Risk

Poor Inputs

Scope

CAPA should identify scope of impacted

product

Initial determination and review due to new

information

Should be documented and supported.

Investigators will evaluate this.

Scope

Preamble Comment 158

“These procedures must provide for control and

action to be taken on devices distributed, and

those not yet distributed, that are suspected of

having potential nonconformities.”

Scope

Distributed

Recall?

Safety Notice?

Revised labeling?

All evaluations or decisions should be

documented and supported.

Consider HHE or risk analysis

Scope

In-Process or Awaiting Distribution

Rework?

Additional testing or inspections?

Quarantine?

Cessation of production?

Any rework should be controlled

Decisions documented and supported

Scope

Timeframes of problem

Timeframes for manufacture/distribution

Product families

Multiple products made on same line

Multiple products made with same

components

Documentation is critical

Scope

Failure to establish procedures for corrective and

preventive action, as required by 21 CFR

820.100(a)…Specifically, your firm removed your

Liquid Bone Glue lot number 1111 from the

market due to your CAPA investigation

identifying contamination in the raw material,

used in the manufacture of this finished device.

However, your firm did not take any corrective

action with respect to Liquid Bone Glue lot 2222

that was also manufactured with the same lot of

raw material.

Warning Letter Citations…

“… Your firm’s CAPA investigation did not

review and evaluate additional lots of raw

material in similar drums to ensure all

affected drums/lots were identified…”

Scope

Firm’s CAPA procedure and records do not

specifically address scope

Firm did not address other lots that may

have been impacted

Firm did not consider other component lots

may have been impacted.

As a result, firm’s corrective action and

response to 483 was incomplete and

received WL.

Systemic Corrective Actions

CAPA intended to link data from multiple

subsystems

Intended to correct potential for multiple root

causes across quality system and subsystems

Rare for complete corrective action to be

limited to one process or procedure.

Systemic Corrective Actions

Consider mechanism to review previous

investigations

Distinguish symptoms from root causes

Fishbone

Cause and effect diagrams

5 Why’s

Systemic Corrective Actions

Bone Glue

Contaminated finished product sent to

customers. CAPA confirmed raw material

contaminated.

Purchasing Controls?

Incoming Acceptance?

Finished Product Acceptance?

Nonconforming Material Process?

Investigation (complaint & CAPA)?

Risk

Regulation does not specifically require risk

assesments, etc. as part of CAPA.

However, FDA is clear in preamble you

cannot effectively implement CAPA program

without assessing risk.

Risk

Preamble Comment 159

“…FDA does expect the manufacturer to develop

procedures for assessing the risk, the actions

that need to be taken for different levels of risk,

and how to correct or prevent the problem from

recurring, depending on that risk assessment.”

Risk

Scope and depth of CAPA activities should

be commensurate with risk

Overly exhaustive investigation may unduly

delay correction

Well documented risk assessment and evaluation

may help support limiting investigation.

Consider defining endpoint for investigation

Risk

It may be necessary to take initial

corrections (e.g. containment, stop of

shipment/supply, issuance of advisory

notice) in order to address an immediate

risk or safety issue.

Initial action may be necessary prior to

completion of investigation

Consider risk assessments may need to be

reevaluated as new information comes to light

Risk

Do corrections introduce new risks?

Should be considered as part prior to making

corrections and confirmed during verification.

Consider CAPA findings should also feedback

to design risk analysis

Risk

Firm’s procedure states “As soon as

sufficient information is available to

establish the problem statement and scope,

the CAPA owner initiates the HHE”

At time of inspection firm had documented scope

and problem…but had not conducted HHE.

Resulted in no action by firm

Resulted in multiple avoidable recalls

Data Sources

Good data sources and inputs into CAPA

system are critical

Poor data sources fail to identify issues

Poor data sources fail to provide tools to

facilitate investigation and review

Poor data sources fail to support corrective

actions were effective.

Data Sources

Data should be analyzed against established

criteria.

Consider statistical and non-statistical

Level of analysis across data sources

Data Sources

Failure to establish and maintain procedures

for implementing corrective and preventive

actions for analyzing sources of quality data

…For example your quality procedures do

not contain sufficient instructions for the

analysis and monitoring of quality data using

appropriate statistical methodology to

identify potential sources of nonconforming

product.

Data Sources

“Multiple complaints involving serious injury

are attributed to user error; however, the

complaint information has not been

adequately analyzed to identify potential

quality problems with the device.”

59

Valuable References

http://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n18-2010-qms-guidance-on-corrective-preventative-action-101104.pdf

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/QualitySystemsRegulations/ucm230127.htm

FDA Medical Device Industry Coalition

Process Planning

Strategies for Effective

Monitoring and Control Cheryl Boyce, Principal,

Boyce Consulting, Inc.

Analyzing Metrics Required by

the CAPA Process 820.100 (a) (1)

Requires statistical analyses of quality metrics

Product, processes, service, returns, quality system

processes, quality records, work operations,

complaints, other……

Section 8 of ISO 13485:2016 requires

“monitoring, measurement, analysis and

improvement of processes” for product and the

quality system

Should your firm have a procedure for quality

system metrics?

Opportunities for Improvements

in this Area Yes, we need a Quality Metrics Procedure

Metrics must be determined that are meaningful

Every company won’t have the same metrics

Important Inclusions to the Procedure:

Metric Category, Specific Metric Name, Owner of

the Metric, Purpose of the Metric, Frequency of

Data Collection, Statistical Analysis Method,

Results and Conclusions.

Emphasis!!! This is a TEAM effort – all

departments and functional areas involved.

When Would these Metrics be

Used? During Working Monthly CAPA Meetings with Responsible

Departments.

Remember to have a procedure for these meetings requiring who shall

attend, what is required, and that analyses, conclusions, assigned tasks

& responsibilities shall be documented – opportunity for improvement.

What if there are no assigned tasks?

Inputs to Management Reviews

The primary foundation for a successful quality system is

management’s understanding of the status of the Quality System to

ensure….?

The quality system is appropriate for the specific medical devices

designed or manufactured, and that it meets the requirements of 820,

that the Quality Policy and Objectives are met, that there are

adequate resources. 820.5, 820.20

Why are Metrics Related to

Production Processes Important? To reveal the on-going process capability to

meet product conformance to

specifications;

To reveal costs of quality such as scrap and

rework; and,

To identify opportunities for investigations,

corrective actions and improvements.

So…What would be some Metrics Related to

Production Processes? Possibilities:

Normalized scrap data via a run chart on-going over 12

months.

Normalized rework data via a run chart on-going over

12 months.

Unscheduled Equipment Maintenance events per work

station, Pareto & Run Chart per month traveling 12

months.

# of NCRs (normalized) from manufacturing and

assembly areas, Pareto and Run Chart per month

traveling 12 months.

(Note: Your data must be customized to your needs.)

Production - Production Process Owner

Purpose of Metric Frequency Of

Reporting Statistical

Analysis Method Responsible

Department

Number of rejects sorted

by product failure codes

for each product#.

Measures the

effectiveness of the

manufacturing

operation

Monthly Pareto Chart &

Run Chart - per

month for the

current and

previous 12

months

Manufacturing

# of Scrap and rework

dispositions by product #

and work station/process

type

Measures the

effectiveness of the

manufacturing

operation

Monthly Pareto Chart

and Run Chart -

per month for

the current and

previous 12

months

Manufacturing

Unscheduled preventive

maintenance occurrences

by workstation/process

Measures the

effectiveness of the

PM program to

prevent unplanned

process shut-downs

Monthly Pareto and Run

Chart – per

month for the

current and

previous 12

months

Manufacturing

Revealing Metrics to Monitor Production Areas –

How might these be included in an SOP?

(Your data must be customized to your needs.)

Resource for Statistical

Production Monitoring

Utilization of Statistical Method for

Production Monitoring Technical Report No.

59, PDA

www.pda.org/bookstore

A Monthly CAPA meeting or

Management Review Meeting

Observed an increase in the number of

NCRs on the run chart for the heat

sealing packaging process over the last 3

months. (Were alert and action levels

established?)

The data was normalized.

Initiate Investigation and Remediation

Develop a Team

Develop an Investigation Plan including:

Defining the problem

Understanding the problem and its scope

Brainstorming its possible causes and analyzing causes and

effects and devising a solution to the problem.

Document all findings and results

Investigation reveals that the equipment qualification had been

over-looked as part of the validation.

There was no Manufacturing and Product Quality Plan as part of the Design

Transfer Phase which required the firm to plan including, but not limited to: all

equipment qualifications, test method validations, process validations,

equipment calibrations.

Is this actually the root cause?

Why Validate the Process &

Include Equipment Qualification?

Why would it require validation?

Each output quality characteristic cannot be

fully verified via inspection and testing

Why does that matter?

Instill quality into the process and product, cannot

inspect it in!!

Why Validate this Process..

Could result in inadequate packaging: Excerpt from a Hazards and

Harms Analysis for sterile product.

ID Hazard(s) Initiating Event Hazardous Situation Harm Severity

H6-

001A Bacteria and/or

viruses One or more components

are not sterile. Non-

sterile component

introduced or implanted

Patient acquires

infection Patient

hospitalized and

treated with

antibiotics (May

require revision)

3

H6-001B Bacteria and/or

viruses One or more components

are not sterile. Non-

sterile component

introduced or implanted

Patient acquires

infection

Patient Death 5

3 Severe

Injury requiring medical or surgical intervention to preclude

permanent impairment of a body function or permanent damage to a

body structure.

5 Catastrophic Patient Death

Why Validate the Process?

Costs of Quality

Rework, Scrap, Unscheduled Maintenance

The elements required to successfully validate

a process, such as Multi-Vari Analysis and DOE

techniques, reveal the key variables and

interaction of variables to instill consistency.

These become the variables you will monitor

along with the process parameters, which helps

with your production and process controls!.

Why Validate the Process?

A formal PFMEA- is part of a company’s quality system,

but will not achieve maximum benefits if used without

a compliant quality system such as a documented

design and development process, operating procedures,

training process and procedures, product

specifications, packaging specifications, etc.(Robin E.

McDermott, Raymond J. Mikulak, Michael R.

Beauregard, 1996)

An integral element of the process documentation

should be the design FMEA (DFMEA). It is extremely

difficult (if not impossible) to do a thorough PFMEA

without completion of a DFMEA (D.H. Stamatis, 1995)

Validate the Process

Process validation should be performed

along with your product design and

development.

Part of Design Transfer

Validation ensures a robust process and is

defined in 21 CFR 820.3.

establishing by objective evidence that a process

consistently produces a result or product

meeting its predetermined specifications.

Concept / Feasibility (Preliminary

Prototypes)

Design and Development

Design Verification

Pilot Production (= verification prototypes)

Production (=Actual Prod.

Units)

Distribution

Design Changes

Design Validation

Process Validatio

n

Design Control

Design

Transfer

Validation Resources

GHTF (now IMDRF)/SG3/N99-10:2004

(Edition 2) Quality Management Systems-

Process Validation Guidance;

Guidance for Industry Process Validation:

General Principles and Practices, U.S FDA,

CDER, CBER, CVM

CDRH not included in this, but is still a good

resource.

Investigation Results…

Based on the Investigation, a team shall

create and implement a corrective action to

fill the design transfer gap.

We won’t cover this today, but this is an

important point as previously discussed.

However we will discuss how to validate the process to

instill consistency to predetermined criteria utilizing

Multivari Analysis along with developing proper process

monitoring methods.

Develop the Proper Team

QA, Engineering, Manufacturing, Regulatory,

Purchasing….

Develop Validation Protocols per the

requirements of your Validation

Procedure(s) and your Protocol Development

and Maintenance Procedure

As part of your investigation, ensure that the

Validation Procedures are adequate.

Do you gain much benefit from monitoring a

process that is not in control?

Validation Elements, IQ

IQ (Installation Qualification) The primary purpose of the installation qualification is to ensure

that the actual physical equipment, raw materials, ancillary

equipment, and environmental requirements all meet the

engineering specifications.

Ensure that all of the equipment is properly installed according

to the company’s specs and that it operates according to

specifications.

Electrical and Air pressure requirements are met.

Ensure the environmental controls are in place and not

affected.

Should product and packaging specifications already be

established and verified?

Supplier Qualifications & Contracts for packaging?

Now is the Time To Ensure: Package Seal Strength has been specified

All equipment is calibrated and on schedule

All preventive maintenance is established

Test methods are validated

Personnel qualified

Test Method Validation Resources:

Concepts for R&R Studies, Larry Barrentine, ASQ

ASTM F1469

Want to ensure the repeatability and reproducibility of your test methods

so you know you are obtaining consistent results within each operator and

between operators within a certain confidence level during the OQ and

production process monitoring.

Your workmanship standards, including approved representative samples,

e.g., visual standard for seal integrity.

Software functional testing has been performed.

Validation Elements, OQ

The PRIMARY purpose of the operational

qualification is:

to determine the process variation;

to reduce the variability of the process within

some acceptable limits;

and to optimize the process so it is consistently

capable.

What is Process Variation..

Variation is the amount of change of a

quality characteristic. For example, the

amount of change in the package

tensile strength sampled at different

times over a specified time period.

First we are interested in the type of

variation the process has.

This helps to narrow the possible causes of

process variation to simplify the DOE

process and optimize your process

specifications.

What is Process Variation..

Using Multi-Vari Analysis one can understand the major

type of variation:

Time to time

Piece to piece, and

Within piece

Each type is associated with certain factors that cause

that variation, which can then be used in your DOE.

Performed via the selection and measurement of a

stratified sample of the product which usually consists

of several groups of consecutive pieces selected over a

period of several hours, shifts, or days.

Summary of Multi-Vari Analysis for

Heat Sealing Process

Capture worst-case or widest variation

conditions.

8 Cavities per die shot.

Took 2 sets of 8 samples after “steady state

obtained”, samples taken within 5 – 10 minutes

(Documented Machine time, temp., & pressure.)

Determined which 3 cavities had the widest

variation in tensile strength.

Summary of Multi-Vari Analysis for

Heat Sealing Process

Used those 3 cavities for rest of analysis

Took 3 samples from one die shot and then 3 samples immediately

from the next die shot. (Using the pre-identified “widest variation”

cavities.)

Waited 5 minutes and obtained another set of 6 samples.

Recorded the time and machine settings with each set of 3

samples.

Tested each sample on the side seal and the end seals.

Tested 3 samples immediately from each set of 6 and held the

other 3 for testing 24 hours later

Performed this 3 times during the shift, and one sampling was right

after lunch

Yielded 3 pairs of 6 samples where half of the sample were tested

right away and the other half were tested in 24 hours

Summary of Multi-Vari Analysis for Heat

Sealing Process

The side and end seals were treated as two different

data sets.

Determined the greatest variation was between the

outer and inner seals,

and between the Cavity that was located on the

outer-most location of the sealing machine vs. the

cavity that had both side seals in the inner locations

of the sealing machine.

Data showed the whole packaging machine was

weaker towards the middle – almost like how an old

mattress sags in the middle

Why Would that Be….

Performed some investigative work

We worked with the maintenance personnel

and the maintenance manual and discovered

that there were Teflon gaskets used to

support each cavity that had not been

replaced.

These were replaced.

What next?

Updated the PM Procedure and Log for the Heat Sealer.

Ensured Maintenance Personnel understood the importance of this

change through documented training session.

Did we find the root cause of variation in this heat sealing process?

Using the time, temp. and pressure specifications that had already

been established by the company, we randomly collected 50

samples each day for one work week. (company had 1 shift) using

the trained personnel and current operating procedures for a

Process Capability Study.

We ensured samples were collected right after lunch as well as

randomly throughout the day.

Process Capability

Sample size was based on a 95% Confidence level with

an Alpha Risk of .05 which required a Minimum Sample

Cpk of 1.598.

Cpk incorporates the centering of the process and its

dispersion.

Process was computer controlled and operators ensured

time, temp. and pressure were monitored to ensure the

process parameters were within the tolerances already

established.

However, no adjustments to the machine were made.

Tensile testing was performed. Calculated Cpks for

each day. (Had ensured test method was validated.)

Process Capability Results & Process

Monitoring

All Cpks were between 3.58 - 4.33,

Have Removed the Root Cause Variable.

So maintain the current time, temp, pressure

specifications. Monitoring them throughout the

production runs.

Software provides process parameter print out for

each run.

Ensured visual seal inspection workmanship

standard was available, and all personnel qualified.

Monitoring Methods, cont’d. Visual seal inspections are performed and documented evenly

spaced throughout each run.

Visual inspection monitoring includes:

Proper Seal Width

Lack of Wrinkles, fold-overs, cracks

Continuity (uninterrupted, no channels)

Cleanliness, i.e., lack of debris, any fluids

Pinholes

Tears

Oversealed areas, such as a transparent or translucent seal

areas

Any problem found, either with process specifications or

seal/package specifications, NCR documented, evaluation and

investigation performed commensurate to the risk.

Visual Standard for Seal Integrity

ASTM F1886 testing provides a qualitative (accept / reject) visual

inspection method for evaluating the appearance characteristics of

unopened, intact seals in order to determine the presence of

defects that may affect the integrity of the package. ASTM F1886

covers the determination of channels in the package seal down to

a width of 75 μm (0.003 in.) with a 60 – 100 % probability.

See ASTM.com for additional package testing methods.

Monitoring

What data might we collect from this

process for our monthly CAPA meetings

and/or Management Reviews?

# of NCRs (normalized) from manufacturing

and assembly areas, Pareto and Run Chart per

month traveling 12 months.

May want to consider the failure codes for each

type of seal problem.

DOE, Design of Experiments

If multi-vari analysis hadn’t been so powerful in

this case, then would have followed with DOEs

to determine the process operating limits to

optimize the process.

Would multi-vari analysis be a good

investigation tool?

Note: Most of the time, the interaction of time

and temperature will be the critical variables

to control for heat sealing.

DOEs would be analyzed with ANOVA

techniques.

PFMEA

Can conduct PFMEA more easily, since we

now more thoroughly understand the

potential cause(s) of failures.

The cause of potential process failures

should be the “root causes”

The likelihood of the failure occurrence(s)

will be lower with a Cpk equal to or greater

than 1.33.

Remember, if there is a high severity, must

still investigate the problem, regardless.

News to Consider……. http://www.packagingdigest.com/testing/inspecting-heat-seals-

form-fill-seal-line-151209

The Induction Integrity Verification System (I2VS) from DIR Technologies

(which stands for Dynamic Infra-Red Technologies) uses non-contact

infrared imaging for inspecting heat seals.

DIR Technologies has introduced the DIR Eye for monitoring and inspecting

the heat-sealing process on form-fill-seal machines, including those

commonly used for medical device packaging.

The technology can be used to detect and analyze the heat signature

generated from the sealing of Tyvek/poly seals of form-fill-seal packages.

“The DIR Eye monitors the uniformity of the heat seal—in each individual

package and in contrast to other packages in the same batch,” he says.

“The width of the sealing area is monitored. Inspection checks that the

seal is correctly aligned, continuous, and uninterrupted. The DIR Eye can

‘see’ whether the product or any debris (for example, errant pieces of the

Tyvek) has entered the sealing area.

News, Cont’d.

100% of the packages are inspected at the speed of the packaging

line.

We see what cannot be seen by the naked eye or a regular camera.

For example, clear cooling fluid that can drip from the sealing

press on to the sealing area of the package and interfere with the

ability for the package to be sealed. The Tyvek, for example, can

be too thick, making it impossible for the sterilizing gas to

penetrate the material. In some cases overheating can damage

the Tyvek in such a way that particles can enter the package and

contaminate it. None of these issues can be seen with a standard

visual test.”

Note: This is food for thought.

Bonus Material!

Extra reading from Cheryl Boyce

Read at your leisure – not discussed

here Improving Process Quality Through Variation

Research

MultiVari Analysis for Heat Sealing Process

MultiVari Analysis for Heat

Sealing

FDA Medical Device Industry Coalition

Break

10:30 – 10:45 am

FDA Medical Device Industry Coalition

Efficient Validation Strategies

and VMPs

Anne Holland Wilson

Agenda

History and Recent Trends

Why Validate

21 CFR 820.75 Process Validation

Standards and Guidance

Definitions and Terminology

Processes Requiring Validation

Validation Planning

Validation Sequence

Process Monitoring, Control and Revalidation

FDA Medical Device Industry Coalition

History and Recent Trends

What is a Process? ANSI/ISO/ASQ 9000

A process is defined as a set of interrelating or interacting

activities which transforms inputs to outputs

Process Validation History

In practice…

De facto validations in American Industry since 1950’s; Bell

Telephone, Aerospace Industry, Chemical and Paper Industry

For Medical Products…

1st documented Process Validation Studies were for sterilization

(steam, then EtO) in the pharmaceutical industry during the

1960’s.

2015 Trends

Process Validation, 21 CFR 820.75, moves to

5th Place in Warning Letters

Production and Process Controls, Subpart G,

moves to 2nd Place in Warning Letter

Deficiencies

From GMP News- Medical Device Warning Letter Statistics

FDA Medical Device Industry Coalition

Why Validate?

Why Validate?

Economic Reasons Customer Satisfaction: Non-conforming product

can lead to lost customers.

Product Liability: Product Specifications must be maintained.

Reduced Production Costs: PV leads to reduced inspections, testing, scrap, and rework. Shifts costs from production to prevention.

Why Validate? 1976 GMP, converted to law in 1979, was substantive (i.e.,

violation was a criminal act). Message was validate.

1987 Guideline on General Practices of Process Validation. “This guideline…states principles and practices of general applicability that are not legal requirements but are acceptable to the FDA.” Message was how to validate.

1999 (Edition 1)/ 2004 (Edition 2) Global Harmonization Task Force- Quality Management Systems- Process Validation Guidance. Message was to define process validation principles and methods such that the resulting product or service can be practically guaranteed.

FDA Medical Device Industry Coalition

21 CFR 820.75 Process

Validation

cGMP Requirements 21 CFR 820.75

Applies to processes where the results cannot

be fully verified by subsequent inspection and

test, the process shall be validated with a high

degree of assurance and approved according to

established procedures

Activities, Results & Equipment validated shall

be documented

Date and signature of individual approving the

validation shall be documented

cGMP Requirements 21 CFR 820.75 continued

Each manufacturer shall ensure that:

Written procedures are in place for monitoring and

control of process parameters for validated processes

Process validation is performed by qualified

individuals

Monitoring and control methods and data, the date

performed and the people associated are documented

When changes or process deviations occur, the

manufacturer shall review and evaluate the process

and perform revalidation where appropriate. These

activities shall be documented.

Automated Processes 820.70

Are computers or automated data processing

systems used as part of production or the

quality system?

Automated Processes 820.70

If yes… then the manufacturer shall validate the computer software for its intended use according to an established protocol.

All software changes shall be validated.

What May Happen if You Don’t

Validate or Do It Poorly?

REGULATORY IMPACT

483 Observation

Warning Letter

Worse

Warning Letter (June 12, 2015)

Your firm failed to adequately validate the

equipment:

Installation Qualification (IQ) not approved

No Operational Qualification (OQ) conducted

Performance Qualification (PQ) consisted of only (b)(4)

lot of production which is inadequate to demonstrate

the reproducibility of the production line and only

(b)(4) samples from the production lot. Further the PQ

documentation for the line verification was incomplete.

Warning Letter (August 12, 2015)

Failure to validate a process whose results cannot be

fully verified by subsequent inspection and test as

required by 21 CFR 820 .75(a). For example:

Your firm did not validate the complete range of process

parameters used for (b)(4) of the duodenoscope bending section

assembly…

Your firm did not document the statistical rationale for the sample

size used in the validation

…you did not segregate or determine the worst case materials

during EO/ECH residual testing as part of the sterilization

validation… to determine proper aeration time.

483 Common Themes

Missing SOP for Process Validation

Missing Statistical Rationale

Lack of Consecutive Runs

Not Following Protocol

Acceptance Criteria Not Met

They didn’t do what they said they would….

FDA Medical Device Industry Coalition

Standards and Guidance

Standards

Provide guidance to manufacturers to promote industry

consistency.

FDA: US Food and Drug Administration

ASTM: American Society for Testing and Materials

ISO: International Organization for Standards

AAMI: Association for Advancement of Medical Instrumentation

NOTE: If standards are not followed during process validation,

the rationale must be provided and approved prior to

validation.

Worldwide Validation Guidance

Title: Quality Management Systems – Process Validation Guidance

Authoring Group: SG3

Endorsed by: The Global Harmonization Task Force

(International Medical Device Regulators Forum 2011)

Date: Edition 2 - January 2004

FDA Medical Device Industry Coalition

Definitions and Terminology

Validation

FDA-Establishing documented evidence which

provides a high degree of assurance that a

specific process will consistently produce a

product meeting its pre-determined

specifications and quality characteristics.

GHTF- Establishing by objective evidence that a

process consistently produces a result or

product meeting its predetermined

requirements.

Worst Case Conditions

FDA: Worst Case- A set of conditions encompassing

upper and lower processing limits and circumstances,

including those within standard operating procedures,

which pose the greatest chance of process or product

failure when compared to ideal conditions.

Qualification

QUALIFICATION

OPERATING

CONDITIONS

FAULT

SEEDING

WORST CASE

CONDITIONS

Definition: To establish confidence that a process, process equipment, and ancillary equipment are capable of consistently operating within established limits and tolerances.

More narrowly focused than validation

FDA vs GHTF Terminology

Concept Relevant Questions FDA's 1987 Guidance GHTF 2004 Guidance

Is the equipment installed

correctly?

Does the equipment perform

as expected?

Are the process factors that

influence resulting product

quality understood?

Has "worst case" testing been

performed to establish

process control limits?

Is there consistent process

output under normal operating

conditions?

When operating under

controlled conditions, does the

process deliver product that

meets its specifications?

Equipment Capability

Process Characterization

Process Adequacy

Equipment Installation

Qualification

Installation Qualification

(IQ)

Preliminary

Considerations

Operational

Qualification (OQ)

Process Performance

Qualification / Product

Performance

Qualification

Performance

Qualification (PQ)

Comparison of Process Validation Terminology

FDA Medical Device Industry Coalition

Processes Requiring Validation

Which Processes Require

Validation? Processes whose outputs can NOT be fully verified by subsequent

inspection or test.

Processes whose routine end product testing may have

insufficient sensitivity to verify the safety and efficacy of

finished devices.

Processes for which validation might be more cost-effective than

verification.

Processes for which validation is performed due to the potential

impact on the product. Consider incorporating risk analysis into

decision-making.

Supplier processes for components and/or devices

Processes Requiring Validation

Process

Test methods Cleanrooms Air systems

Water systems Cleaning, sanitation, degreasing Calibration

Aseptic processing Unique filtration processes Filling operations

Plastic bonding Plastic injection

molding/extrusion

Wave/hand

soldering

Utilities Dipping plastic and rubber Mixing

Lyophilization Sterile packaging operations Sterilization

Formulation methods Software-controlled processes Shelf Life

Validation Decision Tree

Which Processes Do Not Require

Validation? Processes that can be fully verified by subsequent

inspection and/or testing.

Even though validation may not be required, the company may still decide to validate the process.

Examples:

Output of a machining process which contains a precision-bored hole. The hole can be fully verified by inspection.

Production-line test procedure for quality characteristic can be conducted 100% in an economical fashion.

FDA Medical Device Industry Coalition

Validation Planning

Validation Timing PROSPECTIVE VALIDATION (The Preferred Approach)

FDA: Prospective Validation-Validation conducted

prior to the distribution of either a new product,

or product made under a revised manufacturing

process, where the revisions may affect the

product’s characteristics.

Prospective validation involves proving that the

process does what it is supposed to do by

performing an experimental plan, otherwise

known as a validation protocol, before the

process is actually implemented.

Validation Planning

Form

validation

team

Select

methods &

tools for

validation

Document

rational for

not

validating

Establish

“Master

Validation

Plan”

Identify &

describe

processes

Plan

validation

approach

Apply GHTF

decision

approach to each

process

Establishing the Process Validation Program

AAMI Quality System Compendium, 2004

Validation Planning

Process Validation Master Plan

Top level document that defines the

approach to validation.

Roadmap for accomplishing related process

validations

Answers how much validation is enough?

Why?

Validation Master Plan- Example

Operation/

Process

Description SOP/WI Validation

Required?

Validation Category

& Reference

Comments

N/A Order Issuance WI-8.2-1 YES

Category B

PR-2016-XXX

ERP System is validated to assure

that when an order is received a

production schedule is created to

specific part numbers, lot numbers

and quantities to be produced.

A control plan and check sheets for

each lot number are generated. It is

reviewed, signed and dated prior to

issuance to production .

10 Machine WI-7.5-9

Yes A

Verifiable process controlled

through training and procedures.

Acceptability is based on

dimensional inspection.

IQ, OQ and PQ

VMP Example Cont’d Operation/

Process

Description SOP/WI Validation

Required?

Validation Category

& Reference

Comments

40 Wash

WI-7.5-XX

WI-7.5-XX

WI-7.5-XX

Yes A

PR-XXXX

IQ, OQ and PQ to demonstrate

cleanliness per ASTM F 2459-05

and ISO 10993-5.

45 DI Water

System

Service Agreement

with Supplier;

WI-7.5-XX

Yes A

PR-XXXX

IQ, OQ and PQ to demonstrate

process consistently meets cleaning

process and AAMI TIR34:2007

requirements.

Ongoing monitoring consists of

water sample collection performed

by trained personnel and analyzed

by an outside laboratory at defined

intervals.

70 Final Inspection SOP-8.2-X No N/A

Verifiable manual process controlled

through training and procedures.

Validation Process

Generally consists of (3) steps:

Installation Qualification

Operational Qualification

Performance Qualification

Elements of each qualification will vary-depending on

the process. Use standard templates for efficiency and

to minimize the possibility of omissions.

Note: Usually process validation coexists with, and

supplements in-process and end product testing.

Process Validation Flowchart

Individual Process Validation Steps

Create

Validation

Protocols

Determine

On-going

Process

Controls

Monitor &

Control

Process

Perform Process Validation

IQ OQ PQ

Process Validation Overview

Generate Installation

Qualification (IQ/OQ)

Protocol

Conduct IQ and OQ on

both the Killion and Wellex

Are Acceptance

Criteria Achieved?

Generate Performance Qualification

(OQ) Protocol

Determine Root Cause and

Develop Action Plan to Continue

Analyze Operational and QC Data

From Each Run

Are Acceptance

Criteria Achieved?

YES

NO

NO

Conduct the PQ (3 Runs at

Nominal Conditions) for Largest &

Smallest Diameters

Are Acceptance

Criteria Achieved?EndYES

NO

Conduct

Feasibility

Analysis

YES

Is Process

Capable?

YES

NO

Validation Documentation

Raw Data, Training Records, Referenced SOP’s

and Work Instructions

Data Analysis and Protocol Reports

Validation Protocols

PVMP

Validation Documentation Structure

What Should Be in the Protocol?

Purpose

Scope

Sample Size with statistical rationale for

selection

Reference Documents

Method

Acceptance Criteria

What This Means:

Process and product specification should be

determined before starting validation.

Validations must be in writing.

Confidence level should be based on

criticality.

For product performance qualification, at

least three (3) sequential groups of product

are evaluated.

Agree on Analysis Techniques Up

Front How good is your evaluation?

What test for distribution assumptions is appropriate?

Will you have access to the required number of samples?

What assumptions are being made about the process or the data?

Agree on process criticality and determine appropriate α value.

Will samples/material be “representative” of production?

Tools Used to Identify Key

Process Variables Based on Risk Fishbone Diagram

Process Flow Chart

Hazard Analysis

Fault Tree Analysis

Failure Modes, Effects and Critical Analysis

Screening Designs of Fractional Factorial

Experiments

FDA Medical Device Industry Coalition

Validation Sequence

IQ/OQ/PQ

Installation Qualification (IQ)

Definitions FDA

Establishing confidence that process equipment and ancillary

systems are capable of consistently operating within

established limits and tolerances.

GHTF

Establishing by objective evidence that all key aspects of the

process equipment and ancillary system installation adhere to

the manufacturer’s approved specification and that the

recommendation of the supplier of the equipment are suitably

considered

Items Generally Included in an IQ

Utility requirements

Safety features

Environmental conditions required

Equipment identity, serial numbers, location,

model numbers

Calibration

Preventative Maintenance

IQ- How to Perform

Verify equipment configuration and schematics exists

Verify any custom fixtures meet print(s)

Verify ancillary systems (air , water) are connected and operate as specified

Measure the equipment/systems to determine if they meet design specification tolerances.

Establish preventative maintenance procedures, and repair lists.

Develop and implement calibration methods and procedures, if required.

Document all results

Operational Qualification (OQ) Demonstrate it works over anticipated range and worst case conditions

In this phase, process parameters should be challenged to assure they will result in a product that meets requirements under all anticipated conditions of manufacturing. Also, action level(s) should be developed to monitor routine production.

OQ Considerations include: Should simulate actual production conditions and worst cases

Process control limits (time, temperature, pressure, setup conditions, etc.)

Software parameters

Raw material specs

Process operating procedures

Material handling requirements

Process change control

Training

Short term stability and capability of process (think process performance)

Potential failure modes, action levels (think FMEA, risk management)

Items Generally Included in an OQ

Process capability study

Design of Experiments

Gage R&R

Test method validation

Verification and testing of

circuit breakers and fuses

for proper operation.

Exercise of all moving

parts of the equipment to

assure that they perform

properly.

Exercise of any sensors or

control elements to make

certain they perform

properly.

Confirmation of the safety

shielding or other safety

devices to assure that

they perform properly and

that they prevent the

danger they are designed

to eliminate.

Verification and testing of

electrical connections for

possibility of power surge

or loss of power.

Measurement/Gage Qualification REPEATABILITY

Variation in measurements obtained with one gage when used several

times by one operator while measuring a characteristic on one part.

REPRODUCIBILITY Variation in the average of the measurements made by different

operators using the same gage when measuring a characteristic on one

part.

EXAMPLES GM

Chrysler

Ford

Barrentine

Sources of Variation

Statistical Process Control

(SPC)Terminology

USL/LSL – Upper/Lower Specification Limit.

Process Stability – Achieved when the measurable outputs of a

process have constant means and constant variance over time.

The process should not have any special (non-random) causes of

variation.

If Stable Then Assess Capability Process Capability – The ability to produce products/services that

meet specifications defined by the customer’s needs, or a

measure of the inherent uniformity of the process and the ability

to direct the process to a defined target.

An unstable process is unpredictable. Process stability must be

ensured before analyzing process capability.

Process Capability Performed

During OQ PROCESS CAPABILITY- The statistical measure of the

common cause variation of a process under controlled conditions (short term).

PROCESS CAPABILITY STUDY – A process capability study is a desirable element for validations involving measurable process outputs. It is a statistical method to determine the capability of a process is in a state of control. These studies can provide the basis for establishing evidence that a process is validated.

Process Capability Studies

Assumptions Statistical Stability

Normal Distribution

Specifications Based on Customer Requirements

Accept index/ration as “true” number

Many types of Indices (always look at >1) Cp and Pp-Process Variation Only

CPU, CPL, Cpk, Ppk-Process Variation & Centering

CR and PR-Process Variation Ratio Only

Goal: To align process with customer requirements Continually reduce variation and minimize loss

Graphical Interpretation of

Process Capability

Interpretation of Process

Capability Higher process capability index results in a more capable

process.

The following table lists expected defects for various

process capability indices:

Process Capability Index

(Cpk)

Estimated Defects per

Million

0.67 45,500

1.00 2,700

1.33 63

1.67 1

Performance Qualification (PQ) In this phase, the key objective is to demonstrate the qualified

process will consistently produce acceptable product under normal operating conditions.

PQ Considerations include: Actual product and process parameters, procedures established in OQ

Acceptability of product

Raw materials variation

Operator and shift variation

Assurance of process capability established in OQ

Process repeatability and long-term process stability

Challenges to process simulating conditions during actual production, including range of operating conditions established during OQ

Development of attributes for continuous monitoring and maintenance of process

FINAL REPORT At the conclusion of all validation activities,

prepare a final report.

Summarize and reference all protocols and

results.

Derive conclusions regarding the validation

status of the process.

Validation team should review and approve, as

well as appropriate management. Update the

VMP.

FDA Medical Device Industry Coalition

Process Monitoring, Control and

Revalidation

Validation Results Are not

Meaningful If… Measurement Systems are not appropriate

for the Job

Repeatable and reproducible

Process is not capable and stable

Maintenance is not established and deployed

Monitoring is not established to verify

process performs as validated

Changes are not revalidated as planned

Ongoing Controls

Attributes for monitoring process should be developed during

OQ/PQ.

Use SPC for routine monitoring of process output(s). Use tools

like:

Control charts, histograms, check sheets, Pareto charts, scatter diagrams, etc.

Sampling plans

Control plans

Also look at other Quality Management System trends, consider:

Nonconforming material trends

Customer feedback/complaint trends

Material Testing/Verification

When negative trends occur, investigate the cause and consider

corrective/preventive action to correct. If necessary, also

consider revalidation.

Revalidation Per the FDA, A system which requires revalidation with

a change to: Packaging

Formulation

Equipment

Sterilization

Process

Water System

which could impact product effectiveness or product

characteristics AND with a change to product

characteristics

Revalidation continued

Revalidate when…

Any significant change in product specifications,

process parameters, equipment type, function or

location, control system, raw materials,

manufacturing materials, major repairs to

process equipment, etc.

Scheduled, planned or otherwise anticipated

recurring validations to demonstrate continuing

compliance of validated process or operation to

meet its intended specifications (e.g.,

sterilization).

FDA Medical Device Industry Coalition

Take Away Message

Validation is the tool to meet high

product quality consistently…it’s your

reputation

FDA Medical Device Industry Coalition

Personnel Strategies:

Effective Training and

Selection Mona Elkhatib, TMAC

Session Topics

The training process stages

Determining needs

Design & Plan

Provide training

Evaluate training effectiveness

Share audit experience

Quote

“Recently I was asked if I was

going to fire an employee

who made a mistake that cost

the company $600,000.

No, I replied, I just spent

$600,000 training him!

Why would I want somebody

to hire his experience?

Thomas J. Watson

Chairman & CEO IBM

Does Training Need to be

Effective?

$1,229

$61.8 Billion

Why Train?

Ensures that employees can do current jobs

Improve employee performance

Bridge the gap between existing and

required:

Skills

Knowledge

Attitudes

Regulatory Requirement

Training Process ISO 10015

1. Define

Training

Needs

2. Design

& Plan

Training

3. Provide

Training

4. Evaluate

Training Monitor

Training Needs Analysis

Task Analysis:

Assessing New Employees’

Training Needs

Performance Analysis:

Assessing Current

Employees’ Training Needs

Detailed study of a job to

identify specific skills

required.

Task Analysis Record

Task list

When & how often performed

Quantity & quality of performance

Conditions under which performed

Skills or knowledge required

Where best learned

Training Needs Analysis

Task Analysis:

Assessing New Employees’

Training Needs

Performance Analysis:

Assessing Current

Employees’ Training Needs

Verify if there is a

performance deficiency

and determine if it can be

corrected thru training or

other means.

Identifying Training Needs

Organizational or technological change

Data collected from past or current training

Performance evaluations

High turnover or seasonal temporary

employees

Internal or external certification needed to

perform specific tasks

Identifying Training Needs

Request from employees as opportunity for

personal development

Results of process reviews and corrective

actions, as a result of customer complaints

Observations

Tests

Regulations

Assessment

Review existing competence

Define the competence gaps

Identify solutions to close gaps

Define the specification for training needs

Training objectives

Expected outcomes of the training

Design & Plan Stage

Address the competence gaps identified

Include a criteria for evaluating the training

outcomes

Define Constraints

These might include:

Regulatory & policy requirements

Financial considerations

Timing and scheduling requirements

Availability and motivation of personnel to

be trained

Availability of in-house resources to provide

training

Training Methods Selection

The appropriate form of training will depend

on:

Resources

Constraints

Objectives

Training Methods Types

On-the-Job Training (OJT)

Courses and workshops (on or off site)

Audiovisual training

Simulated training

Self-training

Distance & on-line learning

Selection Criteria

Date & location

Facilities

Cost

Training objectives

Target group of trainees

Duration of training

Forms of assessment, evaluation &

certification

The Plan

Training objectives aligned with

organization’s objectives & goals

Trainees (target group)

Training method

Duration & resource requirements

Criteria and methods developed for

evaluation of training outcomes

Training Material

Make training material meaningful

Make skills transfer to job easy

Motivate the learner

Explain why the training is important and how it

will benefit the learner

Training Provider

Internal/External?

Do they have the necessary expertise and

competency to deliver the training as

specified by the plan?

“If the employee has not learned, then the

trainer has not taught!”

Provide Training Stage

Train the employees who need to learn the

skill

Structure the training to minimize fatigue

Evaluate Training Stage

Organizations should have evidence that the

training is effective and employee

performance improves as a result of the

training

Kirkpatrick Evaluation Model

Level 1

Level 2

Reaction

Learning

Level 3 Behavior

Level 4 Results

Reaction: Did They Like it?

Observe trainees

Get feedback in writing following session

Use uniform forms to tabulate results

Anonymous- honest reaction

Learning: Did They Learn?

Pre-and-post knowledge and/or skills testing

Use objective measurements to assess what

trainees learnt

Where practical, use a control group to

compare to trainees

Behavior: Are They Using Skill?

These must be met for behavior change:

Desire to change

Knowledge of what to do and how to do it

The right job climate

Help in applying what was learned during

training

Rewards for changing behavior

Behavior: Are They Using Skill?

Systematic appraisal before & after

Performance made by one or more:

Trainee, supervisor, peers, subordinates (if any)

Post training appraisal >3 months after

training

Control group used, where practical

Results: Did Performance Improve?

Monitoring

Ensure that the training process is

implemented

Ensure that the training process is effective

Recap

1. Define

Training

Needs

2. Design

& Plan

Training

3. Provide

Training

4. Evaluate

Training Monitor

Sharing Audit Experience

Adequacy of defining needs

Records of training

Evaluating training effectiveness

Planning for evaluation

Timing

Use of “Training” or “Re-Training” in the

CAPA process

FDA Medical Device Industry Coalition

Lunch

12:00 – 1:00

FDA Medical Device Industry Coalition

Managing Facility Expansions,

Equipment Modifications, &

Continued Growth

Failing to Plan is Planning to Fail

Presented by:

www.an-answer.com

Foundational Stuff

Interactive process…volunteer or be

victimized!

The need for an inquisitive nature

Why…

What…

How…

Who?

CFR 820 Part 21 & standards like ISO 13485

are intended to make organizations think in

terms of closed loop processes!

The Blended Triumvirate (also known as competence, definition, and control)

The Kaleidoscope Effect!

• Think in terms of a

kaleidoscope,

considering all

and applying each

as needed.

• It may be

different for each

process or activity,

so consider the

kaleidoscope

each time!

Managing Expansions & Modifications

Establish the big picture

Audit & analysis to verify the current

position

Gap analysis to understand differences &

improvements in relation to current

conditions & circumstances

Planning for Optimization, including

qualification/validation

The Big Picture What are we trying to accomplish?

What do we hope to gain from it?

How soon do we need to have it in place?

If we had to rely on existing methods and

controls, would we be able to meet regulations

and other requirements for the products and

processes involved?

Establish a preliminary plan for the

expansion/modification, including a risk analysis

Not resources…but resourcefulness!

Audits & Analysis of What’s Already There

Think in terms of performance-based auditing

How well do existing processes help us optimize?

How well do existing processes comply with

regulations and other requirements?

Analyze data related to process performance to

understand:

What the evidence says

What the evidence does not say

If what we observed is to be true, this must also be

true

If what we observed is to be true, this cannot be true

Gap Analysis Seeking first to understand…then to

undestand what needs to be updated or

adjusted

Start with an accurate picture (point of

reference) of what is already in place

Using the planned expansion/modification,

compare it with existing and note the gaps

Identify the risks associated with the transition,

including items impacted by the changes being

made

Report on the gaps

Planning For Optimization Establish a plan, considering:

Facility layout

Utility needs, including controls for sustainability

Equipment needs, including qualification/validation

Process controls, to reduce or eliminate risks

People, including required competence

Process instructions

Think in terms of optimization for

organizational benefit or they will struggle to

live it over time.

Coping With Continued Growth Plans and closed-loop process are only effective if they

help with brain cell management

Management’s review of the management systems is to

assess decisions already made, with actions taken intended

to make the organization more suitable (fits who the

organization is), adequate (covers everything the

organization has to live up to) , and effective (driving

behavior)

Changes to the organization, including those related to

facilities, equipment, and products need to be facilitated

by the management systems. Failing to do so affects the

organization’s ability to fulfill its purpose and can have

dire consequences!

FDA Medical Device Industry Coalition

Rework Strategies:

Effective Planning and

Execution Al Alonso

Alonso Quality System Consulting, LLC

NONCONFORMING PRODUCT

Nonconforming (NC) in-process or finished

product is expensive to discard/scrap

If the product can be reworked, what is

required from a product safety and regulatory

perspective?

PURPOSE

My purpose this afternoon is to provide a

path to successfully planning and executing

the rework of NC product into a product

that meets specification and is in regulatory

compliance.

21 CFR 820.90 NONCONFORMING

PRODUCT (a) Control of nonconforming (NC) product.

Each mfr. shall establish and maintain

procedures to control product that does not

conform to specified reqs. The procedures

shall address the identification,

documentation, evaluation, segregation,

and disposition of NC product. The

evaluation of NC shall include a notification

of the persons or organizations responsible

for the NC. The evaluation and any

investigation shall be documented.

21 CFR 820.90 NONCONFORMING

PRODUCT 820.90 (a) Control of NC Product

SOP for NC product

ID, document, evaluate, segregate,

and disposition NC

Evaluation of NC includes determining

need for investigation

And need for notification of the

persons/organization responsible for

the NC

21 CFR 820.90 NONCONFORMING

PRODUCT (b) Nonconformity Review and Disposition. (1)

Each mfr. shall establish and maintain

procedures that define the responsibility for

review and the authority for the disposition of

NC product. The procedures shall set forth the

review and disposition process. Disposition of

NC product shall be documented.

Documentation shall include the justification

for use of NC product and the signature of the

individual(s) authorizing the use.

21 CFR 820.90 NONCONFORMING

PRODUCT 820.90(b)(1) Nonconformity Review and

Disposition

SOP for review of and authority over the

disposition of NC product

Document disposition

Signature of individual(s) authorizing the use

21 CFR 820.90 NONCONFORMING

PRODUCT (2) Each mfr. shall establish and maintain

procedures for rework to include retesting and

reevaluation of the NC product after rework,

to ensure that the product meets its current

approved specifications. Rework and

reevaluation activities, including a

determination of any adverse effect from the

rework upon the product, shall be

documented in the DHR.

21 CFR 820.90 NONCONFORMING

PRODUCT 820.90(b)(2)

SOP for rework including testing and re-

evaluation

Ensure reworked product meets current

approved specs

Document rework and re-evaluation in DHR

Document any adverse effects from the

rework in DHR

DEFINITIONS

REWORK: Means action taken on a NC

product so that it will fulfill the specified

Device Master Record requirements before it

is released for distribution.

DEFINITIONS

REFURBISHING: The processing or

reprocessing to specified requirements of a

medical device which has been previously

released.

Note: Refurbishing applies also to

repackaging and/or re-sterilization of

medical devices, for example when a

container that maintains sterility has been

opened or damaged.

DEFINITIONS

REMANUFACTURER: Any person who

processes, conditions, renovates,

repackages, restores, or does any other act

to a finished device that significantly

changes the finished device’s performance

or safety specifications, or intended use.

Examples are endoscopes and cytoscopes;

also single use devices such as catheters

DEFINITIONS

REPROCESS: Validated processes used to

render a medical device, which has been

previously used or contaminated, fit for a

subsequent single use. These processes are

designed to remove soil and contaminants

by cleaning and to inactivate

microorganisms by disinfection or

sterilization. Examples are surgical

instruments

SOP REQS. FOR REVIEW &

DISPOSITION OF NC PRODUCT Defines the responsibility for review and

authority for disposition of NC product

The disposition shall be documented

Justification for the use of the NC product

Signature of the individual(s) authorizing the

use

SOP REQS. FOR THE REWORK OF

NC PRODUCT Process to define rework, retesting and re-

evaluation of the NC product to ensure that

it meets specs

Document in the DHR rework and re-

evaluation activities

Document in the DHR any determination of

any adverse effects of the rework

ROOT CAUSE ANALYSIS: KEY TO

ELIMINATING REWORK 1. Describe the problem

2. Gather data

3. Identify potential causes

4. Identify which you will remove or change

5. Identify solutions

6. Implement change

7. Monitor to ensure effectiveness

8. The use of your CAPA system is

appropriate

ROOT CAUSE ANALYSIS:

TECHNIQUES The Five Whys: Identify the problem and

continue to dig deeper for the root cause

Failure Modes and Effect Analysis: Aimed

to find various modes within a system. It

involves reviewing as many components as

possible to identify failure modes, and their

cause and effect. It is inductive reasoning

(forward logic) single point of failure

analysis.

ROOT CAUSE ANALYSIS:

TECHNIQUES Pareto Analysis: 20% of the work creates

80% of the results. Collect data and

determine which are the most prevalent

Fault Tree Analysis: At the Top of the Tree

is the problem and all potential causes tree

down from it. It is a Top Down deductive

failure analysis in which the undesired state

is analyzed logically.

ROOT CAUSE ANALYSIS:

TECHNIQUES FISHBONE = ISHIKAWA = CAUSE-and-

EFFECT DIAGRAMS: At the head of the fish

is the problem with the spine having 4 to 8

potential source categories attached to it.

Manpower, Methods, Machines, & Material

Measurements & Environment

REWORK PROCESS

CONSIDERATIONS A high rate of reworks is a strong indication

that the manufacturing process is not in a

state of control

If a non-validated process is used, then it

must be validated before the rework

Rework can effect other components

adversely. Ensure that is not the case.

Evaluate the product to ensure that it meets

the current approved specs

REWORK PROCESS

CONSIDERATIONS Ensure the SOP was followed

The CAPA system is a good tool for

addressing this process

Ensure that all the documentation was

completed and done correctly

Address any unforeseen anomalies with the

appropriate correction

REWORK FOLLOW-UP

BE PROACTIVE

Make management aware of the rework rate

via your monthly Quality report,

Management Review, etc.

As appropriate inform field personnel and

Customer Service

Inform QA and the Complaint Handling area

to alert for potential problems of Reworked

product

REWORK of NC PRODUCT

SUMMARY Understand what Rework means

Know the regulations, 21 CFR 820.90

Write SOPs to comply with the regulations

Follow your procedures

Perform robust and in-depth Root Cause

Analysis

Document

Follow-up for effectiveness

FDA Medical Device Industry Coalition

Effective CAPA: Determining

Appropriate Measures,

Intervals and Evidences

Raja Chatterjee

Director of Quality Assurance

Objectives

Recognize and address the common pitfalls

for the CAPA system.

Look at basic system requirements

Additional considerations

Who likes CAPA?

The process is too burdensome and does

not add value.

It is about blame not about improvement.

I do not know what is expected of me as a

CAPA owner.

Owning a CAPA is like checking into the

roach motel.

CAPA are not initiated using risk based

methods.

I would rather measure success than

failure.

CAPA

Management Leads

Auditors

Basic Steps Analyze quality

metrics to identify

impermissible issues

Stop the bleeding

(containment)

Investigate causes for

impermissible issues

Identify actions to correct

Verify and validate actions

Check effectiveness

• Assessment of issue (what happened)

• Risk Assessment (what is the impact)

• Determine need for CAPA (Corrective Action, Preventive

Action, Correction or No CAPA needed)

• Scope /Problem statement (Is/Is not)

• Containment

• Identification of immediate cause and systemic root-cause (for

Corrective Actions and Preventive Actions)

• Identify actions to address immediate cause and systemic root

cause

• Verify/Validate action (will it solve the problem statement? Will

it break something else?)

• Implement Actions

• Effectiveness check (did it solve the problem statement?)

Basics: Culture to nurture

improvement Avoid discussing fault in CAPA

Its about risk to health and safety of patients

Its about controlling waste and costs

Its about the benefit to the system to avoid

deviations which slow production

CAPA should discuss system improvement

and efficiency

Involve everyone in looking for areas of

weakness or for improvement

Basics: Locating Nonconformity Standard sources: where errors have already

been found Complaints, Nonconforming Product, Audit Findings (internal,

external, and supplier)

Hidden sources: Where potential errors hide Service records

Product returns (non-complaint)

Management Review

Internal Data sources (inspection, preventive maintenance ,etc.)

Employee observation

Filtering

Issues Non-tolerable

AND

Actionable Issues

Product related issues

Complaints and Product Non-Conformances

Evaluate based on risk to patient/user

Impact based filters - Severity versus Occurrence

scales

Can be done for every complaint / NCMR

Product related issues

Complaints and Product Non-Conformances

Evaluate based on risk to patient/user

Control based filters – control chart based

Create “buckets” based on product line as well

as defect types – ‘as reported’ and ‘as analyzed’

Periodic – at minimum quarterly

Quality System Issues

More difficult to monitor because the rules are

not as precise.

Need to build in significance factors (usually base

don potential impact on product) and

occurrence factors (multiple findings and

repeated findings indicate higher risk).

Tier risk using a defined scale like low, moderate

and high as an example.

Low Moderate High

Issue relates to

labeling but does

not affect

identity or usage

Issue affects

identity/usage of

a product but is

isolated.

Issue affects

identity/usage of

a product but is

not isolated.

Defined CAPA Process

Stop the bleeding

Containment the problem does

not need to wait for completion

of root-cause analysis.

Revisit assessment often

Consider all sources product:

customer, in field locations, in-

stock, in-transit, supplier

inventory, demo, and in WIP

Don’t forget to assess risk

related to product that has

already been used

Investigate: Root-cause analysis Develop a clear (and short) problem

statement so a solution can be found.

Defining scope is critical

What product/systems are affected?

What is/is not the problem?

Structured problem solving

Macro tools to identify all problem sources

(Ishikawa, SIPOC or Affinity diagrams)

Micro tools to drill down to specifics

(HACCP, Fault Tree, 5 Why etc.)

A good root cause analysis will

define the plan

Plan your actions

After root cause is determined, reassess

scope and containment of the problem.

It is not uncommon to need both a short-

term and long-term plan

Define responsibilities and time-frames

carefully – the plan should be useful and

have milestones

Plan out how to verify/validate changes

Plan how to check effectiveness of actions

Implementation Should go through every step of the plan

Provide evidence of completion of each step

of the plan

Evidence should include things like Engineering

Change Orders, Completed Rework routers, new

forms or procedures, training records etc.

Make sure that the loop on any open

containment action is closed.

If validations are required, make sure they

are complete and adverse effects on

product will not occur.

Effectiveness check

Should ensure that there is evidence that

the problem has been resolved

Should consider the same set of

circumstances that manifested the

problem in the first place (real life usage)

Examples – complaint follow-ups for a

quarter, incoming inspection results for a

quarter, follow-up audits

Consider that the sample size/ duration

should be sufficient to address the original

occurrence rate

Review and Disclosure

Common pitfalls

Timeliness

Not covering the entire scope of the CAPA

Inadequate verification/validation

Late or no containment

Too many CAPAs for small issues

Unclear accountability for activities

Non-value added steps

Further Considerations

CAPA review board – a group of managers

that can take risk assessment decisions and

allocate resources

CAPA metrics should be a part of

departmental objectives (also for non-QA

groups)

The gateway threshold should be revised

periodically – consider both risk

acceptability and practical criteria such as

organizational bandwidth

FDA Medical Device Industry Coalition

Break

2:50 – 3:05 pm

FDA Medical Device Industry Coalition

Verification of Corrections

Lauren Skokan Priest

Compliance Officer

Denver, CO

CAPA - Review

Scope of CAPA

Immediately contain affected product

Hold distribution and consider options to correct

Determine timeframe of problem to ensure all

affected product is considered

Consider affected raw materials or packaging

shared with similar products

Consider other systems affected

CAPA – Review

Consider risk to the user and patient

Preamble requires consideration of risk

Corrective actions should be commensurate with

risk of the problem

Potential new problems introduced by the

correction must also be considered

Ensure data sources are comprehensive to

identify problems

CAPA Review

Effective CAPA: Determining Appropriate

Measures, Intervals and Evidence

Pointers on how firms can decide on the level of

documentation and appropriate measurement

tools to determine CAPA effectiveness

Approaches to assess risk, scope and measure

effectiveness

Keep documented evidence of every step!

How are corrections verified?

Verification – 820.3(aa)

“means confirmation by examination and

provision of objective evidence that device

specifications conform with user needs and

intended use(s).”

This definition identifies how firms must perform

verification actions

Preamble comment 43 addresses that the

definition was adopted from the ISO 8402:1994

definition

How are corrections verified?

FDA can verify a firm’s corrections during

inspections or during subsequent review by

Compliance or CDRH

During Inspections

Investigator will follow up on observations from

previous inspections

Verify by looking through actions that are

documented

If it isn’t documented, it didn’t happen

How are corrections verified?

During Inspections - Example

Previous inspection found the firm did not have

an adequate system in place for Purchasing

Controls

Next inspection will review corrections

Investigator can review new procedures, and

evaluate evidence of implementation (supplier

qualifications, supplier evaluations, SCARS, etc.)

How are corrections verified?

During Inspections – Use cross cutting approach to

verify records across multiple systems affected by

deficiency

Review receiving acceptance records to verify

raw materials are meeting defined specifications

Can review complaint investigations and CAPAs

for raw material and supplier issues

Review evidence of training to updated

procedures or recurring training

How are corrections verified?

After Inspections – Corrections verified by

Compliance or CDRH

After receiving a 483 during an inspection, a firm

has the option to send in written response(s) to

their local district office describing corrections

Firm may receive correspondence from district

compliance or CDRH describing deficiencies with

those responses which may include: general

letter requesting clarifications, Regulatory

Meeting Request, UTL, WL, etc.

How are corrections verified?

After Inspections – Corrections verified by

Compliance or Center

Firm will then work with the applicable

Compliance Officer in written correspondence to

provide documentation demonstrating

corrections

Firm should supply actual procedures and a

sample of records to demonstrate the new

procedure has been corrected and implemented

Deficiencies will also be assessed during a follow

up inspection

How are corrections verified?

After Inspections – Corrections verified by

Compliance - Example

Firm was cited for

Inadequate CAPA procedure– 820.100

Lack of complaint investigations – 820.198

Inadequate NCR procedures – 820.90

Incomplete Risk Analysis – 820.30

Case Study: What is missing?

After Inspections – Corrections verified by

Compliance - Example

Firm was cited for CAPA, complaints, NCR & RA

Firm sent several responses to the 483 in for

review by compliance to describe their

corrections but ultimately a warning letter was

issued

Some reasons the responses were found

deficient…

What could not be verified?

Response deficiencies Warning Letter

Not all complaints or NCRs were addressed from

the 483 and the firm did not include any

reasoning for why some were not reviewed in the

response

Firm did not conduct root cause investigations

and provide the results for relevant complaints

Firm referred to different CAPAs as justification

for not needing a new investigation, but those

CAPAs were missing necessary testing and data

What could not be verified?

Response deficiencies Warning Letter

Response did not address supplier issues related

to contaminated or otherwise unacceptable raw

materials

Response referred to new CAPAs to address some

concerns but did not include copies of these

CAPA records

Training records for the newly implemented

procedures were not included in response

What could not be verified?

Response deficiencies Warning Letter

NCR procedure was cited as being inadequate,

then firm supplied updated NCRs with

incomplete investigations to demonstrate

corrections

Firm referred to other NCR records to address

CAPAs, but did not include copies of these

records

What could not be verified?

Response deficiencies Warning Letter

Risk analysis did not include review of risks for

products regularly intended to be used with their

device

Response discussed that procedural changes will

occur but did not provide any description or

training to the new procedures

Firm did not commit to reassessing complaints

once changes had been made to assess

effectiveness of correction

Things to remember

FDA can only verify using the records

provided

Provide documentation including procedures

and a sample of records that demonstrate

implementation of the correction

Don’t forget training records!

Opening a CAPA isn’t sufficient if further

documented activities are not provided

Things to remember

Consider re-evaluating complaint rates

at a reasonable timeframe after

correction to assess adequacy

If actions are planned, provide

commitment dates

Perform your own review cross cutting

over various systems to determine how

effective correction was and provide

that information to FDA to show your

systemic correction

FDA Medical Device Industry Coalition

Panel Discussion: Making it

All Work

3:45 – 4:40

FDA Medical Device Industry Coalition

Inputs for 2018 “Big Event”

Future Needs and Desires

3:45 – 4:40

Wrap-Up

Complete and turn-in

Evaluation Form

Pick up thumb drive

Pick up Certificate of

Attendance

Have a safe trip home

Enjoy your weekend!

See you in 2018!