Nancy H. Collins, PhD.

The University of Toledo Medical Center

Dept. of Medical Microbiology & Immunology

Deviation Management:From Discovery to Reporting

The Practical Side of What to Do

What are Deviations ?

Defined as unexpected or unplanned departures from regulations (cGMPs or cGTPs), SOPs, standards, or specifications that may affect product safety, quality, identity, potency, or purity

Many names: error, occurrence, accident, failures, variances, nonconformance, sentinel event, near miss, complaint, adverse event, discrepancies, or problems

Response to deviations described by CAPA (corrective and preventive actions)

CAPA accounts for large percentage of FDA 483 reports

Planned deviations share some elements, but usually simpler and may not warrant investigation

D e v i a t i o

n s a r e

s c a r y

Donor eligibility

Supplies& Reagents

PurityReview

Labeling

Mix-up

Complaint file

Equipment

Equipment

Testing

Storage

Reporting

How to handle a deviation:

The practical approach

Deviations will happen –both planned and unplanned. It is the role of the QM system to use them to improve lab practice.

QM is its own science, with its own vocabulary, evolutionary development

Can’t expect to keep pace with all those MBAs and Quality Specialists developing the science, so

Apply scientific thinking “Something has gone wrong. Let’s find out how why it happened

and prevent it from happening again, if we can.”

A logical approach will get you through!

Deviation Management:

an Integral Part of the QM Web

Quality Management Program is a web of interconnected threads connecting all parts of laboratory and clinical practice

When a deviation happens, it affects all of the web

Deviation Management (DM) informs all other systems (audit, process control, change control)

DM parameters can be drawn from standards & regulations

Doesn’t matter where you enter the system (deviation discovery, audit, reporting, root cause analysis, process improvement), you must deal with all the rest of the Quality elements

Deviation Management Building Blocks

Recognition & detection

Immediate correction?

Report (internal & external)

Analysis (track & trend)

Prevention of recurrence

(improve process)

Evaluation

Process improvement

Evaluation of DM operation

Lifecycle of an Planned Deviation (1)

Advance knowledge & approval

Physician or member of transplant

team reports potential deviation to responsible laboratory member before processing begins

Reason clearly stated in report

Develop strategy or plan (e.g., labeling, documentation)

Processing Facility Lab or Medical Director signs off on plan.

Immediate (or short term) corrective actions taken if necessary.

Deviation reported to internal team & regulators through specific documents.

Lifecycle of an Planned Deviation (2)

Relevant parts of DM procedure initiated: Quality Management notified in specified time frame (e.g.,

immediately or within one day).

QM evaluates deviation & assigns deviation classification & level as specified in QM plan

QM Manager assesses any potential impact to lab practice.

Long term preventive action needed?

Follow up: was preventive action successful?

Practical Tip #1:

Planned Deviations can be used

to train personnel in proper DM

Clear communication between lab, patient’s

physician, clinical team, quality team & other

responsible personnel

Preparative actions/education are taken.

Label & document appropriately!

Lifecycle of an Unplanned Deviation (1)

Any laboratory member, supervisor or designee detects deviation during or after processing Immediate (or short term) corrective actions are taken as

necessary. (“CA” from CAPA)

Short, unambiguous report initiated as soon as possible.

Deviation reported to patient’s physicians. Medical director authorizes release of product if warranted.

Clinical Program Director & Governmental regulators notified as necessary

DM procedure initiated: Quality Management notified in specified time frame (e.g.,

immediately or within one day).

QM evaluates deviation & assigns deviation classification & level

QM Manager assesses potential impact to lab practice.

Lifecycle of an Unplanned Deviation (2)

Investigation planned and executed. Level of investigation corresponds to level of deviation. Higher

level deviations lead to more intensive investigations.

Investigations should be timely (e.g., 30 days)

Deviation reporting does not correct problem.

Preventative action ( “PA” from CAPA) corrects problem. Thorough investigation into the root cause to prevent future

recurrences.

Long term corrective actions are taken. Note: AABB/ISCT session “Change control” workshop Technical Track

13, Wednesday 11 am, Liberty Ballroom B

Deviation records

Filed in patient records, or with batch report

Deviation information & CAPA activities Enter QM reporting system, audit report, complaint record, or

safety investigation report as appropriate.

DM Reporting System Regulations require that deviations are captured

so that all processes and systems are continuously improved.

Deviations must be Recognized

Categorized by system affected

Ranked or assigned level of seriousness

or impact

Investigated

DM reporting feeds into Corrective and Preventative Actions (CAPA)

Practical Tip #2:

Design all parts of QM reporting around

regulatory & standards requirements

Determine critical systems or parameters from regulations & standards which require reporting, auditing, tracking & trending

351 vs. 361 products, IND/IDE requirements, Core GTPs (Facilities, Environment, Equipment, Supplies & Reagents, Recovery, Process Controls, Labeling, Storage, Receipt & Distribution, Donor Eligibility Determinations), cell numbers, viability, mix-ups, microbial contamination, engraftment

Build reports to encompass these parameters

Maintain central file of deviations

classified by parameters

Make internal & external reporting

mechanisms as similar in language

& content as possible

Document, Document, Document!

Practical Tip #3: Design worksheets & reports to aid

detection & reporting

Simplify & standardize worksheets (e.g., all results & reviews in same place on page)

Standardize how results are expressed (Exponents!!!)

Clear expected results, ranges

Highlight points in process for review

Train personnel for consistency, to minimize individual interpretation (avoid over or under reporting)

“Is this a deviation?”

Clear instructions if out of range results occur (immediate correction, reporting)

Deviations as a measure of lab functioning

Deviation Report Form Elements

Planned Deviations

Anticipated specifics (date, time, personnel,

identifiers, responsible persons, reason, immediate corrective

action if necessary)

Root cause, if necessary

QA assessment & approval (system & ranking, target dates,

responsible person, closed date)

Medical and/or Laboratory Director approval (target date,

closed date, responsible persons)

Follow up or “APA” (target date, open & closed date,

personnel) if needed

Additional data (keywords)

Deviation Report Form Elements

Unplanned Deviations Specifics of event (date, time, personnel,

detection date, identifiers, responsible persons, immediate corrective action)

QA assessment & approval (system & ranking, target dates, responsible person, closed date)

Medical and/or Laboratory Director approval (target date, closed date, responsible persons)

Investigation with root cause

Follow up or “APA” (target date, open & closed date, personnel)

Additional data (keywords, case report, relevant documents)

Organized by category and by type

Describe deviation and Action taken at the time it occurred

Documentation of report to collection program

Follow-up correction actions

Requirement for additional follow-up

Final resolution

Confirmation of collection program investigation report

Review signatures

Note: Would include Medical Director when relevant

All reports discussed at laboratory meeting, if clinically relevant presented at program quality meeting

Deviation Log ElementsManual or Electronic

Report number & level

Date

Responsible person

System

Description

Corrective Action

Follow up

Re-training

Government report?

Review

Report # & Level

Date of

Report

Reported by

System Involved

Brief Description Corrective Action Follow Up Retraining NYS DOH FDA

Review

Practical Tip #4:

Use Classification & Levels

for Audit & Reporting

Classification of Deviation by systems:

Some deviations are unique to product

Identification of system affected (e.g., Core GTPs) can

help to focus on problem & may suggest improvement

Levels of Deviation (High risk to low risk):

Assignment to level based on the magnitude of event,

seriousness, or perceived risk

Introduces a metric that facilitates analysis

Simplifies reporting

DM Metrics Example 1 Level 1: Critical Deviation from standards and/or regulations

immediate and significant risk to product quality, patient safety or data integrity

combination/repetition of major deficiencies that indicate a critical failure of systems

Level 2: Serious Deviation from standards and/or regulations potentially significant risk product quality, patient safety or data

integrity

could potentially result in significant observations from a regulatory agency

combination/repetition of "other" deficiencies that indicate a failure of system(s).

Level 3: Standard Deviation less serious or isolated nature

not judged to critical or major

still require some correction or suggestions as how to improve systems or procedures

DM Metrics Example 2

Level I: Major Occurrence immediate harm to a patient, donor, or associate

may result in harm to a patient, donor, or associate if immediate medical

intervention does not take place.

Level II: Major Occurrence

potential harm to patient, donor, or associate.

Level III: Medium level occurrence

potential harm to a patient, donor or associate was obviated by

detection of an error.

Level IV: Low level occurrence

no harm to the patient, donor, or associate

Practical Tip #5:

Analysis determines extent of

investigation and preventative actions

Ask the following questions:

• Is this idiosyncratic to product?

• What is the extent of the deviation? Single batch? Previous batches?

• Have we seen this before? Is there a trend with similar cell types, products, supplies/regents, testing procedures, or other lab practices?

• What were the causes in similar occurrences? Should we re-evaluate?

• Is there any regulatory impact?

• How do we prevent this from happening again?

EVEN BIGGER

PROBLEMS

Practical Tip #6:If you believe

NO investigation or NO CAPA

is indicated,

then document

RESPONSIBLE PERSON & REASONING

Biological Product

Deviations 361 Products: Deviation (21 CFR 1271.3(dd) is unexpected or

unforeseeable event that may relate to transmission or potential transmission of a communicable disease or may lead to contamination OR that is an unexpected or unforeseeable event that may relate to the transmission or potential transmission of a communicable disease or may lead to HCT/P contamination.

351 products: Licensed manufacturers report unexpected or unforeseeable events or deviations from current good manufacturing practice (CGMP), applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potencyof a product (Title 21 Code of Federal Regulations (21 CFR 600.14).

Biological Product Deviation

For 361 and 351 products

For DISTRIBUTED HCT/Ps related to a MANUFACTURING step, must report any HCT/P deviation relating to the core GTPs (systems in report)

Reported on Form 3486 “Biological Product Deviation Report” within 45 days

Use General Instructions and Guidance on BPD available on FDA website or call FDA for guidance

Flow chart for reporting BPD

by Manufacturers of Licensed Products

Guidance for Industry:

Biological Product Deviation

Reporting for Licensed

Manufacturers of Biological

Products Other than Blood

and Blood Components

Practical Tip #7:

Put definitions in SOP Manual or training materials easily

available to personnel. Forms are easier to fill out if you

understand them.

Adverse reactions are deviations, and are always unplanned;

However, unplanned deviations are not always associated with

adverse events or reactions.

Adverse Reaction Reporting A noxious & unintended response to any HCT/P for which there is a

reasonable possibility that the HCT/P caused the response (21 CFR 1271.3(y)). Investigate any adverse reaction involving a communicable disease related to an

HCT/P made available for distribution

Must be reported if involving communicable disease if, fatal, or life-threatening, or resulting in permanent impairment of a body function, or damage to body structure; or necessitates medical or surgical intervention, including hospitalization

351: reporting requirements for drugs, medical devices, and/or biological products under the FFD&C Act and/or section 351 of the PHS Act Refer to links in Guidance for Industry: MedWatch Form FDA 3500A:

Mandatory Reporting of Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)

361 and 351: Adverse Reaction Reporting

361 :

Reported to FDA using Form 3500-A within 15 calendar days

Refer to “Guidance for Industry: MedWatch Form FDA

3500A: Mandatory Reporting of Adverse Reactions Related

to Human Cells, Tissues, and Cellular and Tissue-Based

Products (HCT/Ps)”

351:

Reported to FDA using Form 3500-A within 15 calendar days

Reporting requirements for drugs, medical devices, and/or

biological products under the FFD&C Act and/or section 351 of

the PHS Act

Links to reporting requirements in Guidance for Industry:

MedWatch Form FDA 3500A: Mandatory Reporting of Adverse

Reactions Related to Human Cells, Tissues, and Cellular and

Tissue-Based Products (HCT/Ps)