Marilyn M. Marshall QAO

Office of the Vice-President for Research

Lindy Brigham

March 30, 2006

21 CFR Part 11

Rules for complying with the rules

The Rules

The rules and your lab The rules and your business The rules Your role in interpreting the rules

Rules and Research Labs

Good research requires good laboratory practices

Ho, experimental design, proceedures Equipment maintenance Employee training Data Collection Record keeping

Rules and Business

The same concepts apply to industry research PLUS Safety issues for consumers Efficacy expectations

But the time and money constraints are very different in industry

“From industry’s perspective, it is a big challenge to understand how it can combine compliance with improving business performance”

The Business of Compliance

How you bring new products to market, how you produce your existing product offerings and how you maintain your competitive advantage will all be impacted by the timeliness of your reaction to 21CFR11.

The drama will be played-out in both the medicine cabinets of consumers and in the boardrooms of Wall Street.

21CFR11 & Better Business Practices: Moving Beyond Compliance by Robert Yeager, President, Intellution Inc.

Intellution wants YOUR business

The FDA tells you that you MUST comply with 21CFR11

Intellution shows you why you’ll WANT TO comply

Compliance Requirements

Record keeping Submissions to the Regulatory

Agencies to show compliance The Government Paperwork

Elimination Act

The Government Paperwork Elimination Act

The focus of the GPEA is to promote the doing of business electronically, with the public and otherwise.

The GPEA (P.L. 105-277) took effect on October 21, 1998.

Under the GPEA persons required to submit information to the government, or maintain information, must be given the option to do so electronically when practicable.

21 CFR Part 11

21 CFR 11 defines the criteria under which the FDA will accept electronic records and electronic signatures as equivalent to paper-based records and handwritten signatures.

ERES – Everybody Run, Everybody Scream

Intent

The 21 CFR 11 criteria are designed to: prevent accidental alterations to

electronic records deter deliberate falsification and help detect such changes when they

do occur.

Subpart A – scope, implementation, definitions

Subpart B – electronic records Subpart C – electronic signatures

Scope

applies to records in electronic form that are created, modified, maintained, archived, retrieved, or

transmitted, . under any records requirements set forth in

agency regulations

Electronic Record

any combination of text, graphics, data, audio, pictorial, or other information in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system

Electronic Signature

a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature

Applicability of 21CFR11

Is the record or signature electronic? Is the record or signature required by

an existing FDA regulation (predicate rule), or by an SOP

Is the record or signature for submission to the Agency, or in support of that submission?

Predicate Rules

Any requirements set forth in the Act (Federal Food, Drug and Cosmetic Act), the PHS Act (Public Health Service Act), or any FDA regulation (GxP: GLP, GMP, GCP, etc.).

The predicate rules mandate what records must be maintained; the content of records; whether signatures are required; how long records must be maintained, etc.

If there is no FDA requirement that a particular record be created or retained, then 21 CFR Part 11 most likely does not apply to the record.

The term “Predicate Rule” is NOT

used in the 21 CFR Part 11 Final Rule.

The term “Predicate Rule” is used in

the Part 11 Guidance for Industry

document(s)

Your role in interpreting the rules

The FDA has acknowledged that a “one size fits all” interpretation of regulations, such as 21FCR11, is not feasible.

The onus of regulatory interpretation is on the organization being regulated

Organizations must now justify their course of action based on their interpretation of the regulations, as well as any risk associated with those actions

Are you in compliance?

Risk-Based Assessment

Definition of Risk (IEEE)

A measure of the probability and severity of undesired effects, often as the simple product of probability and consequence.

Definition of Risk Assessment

A systematic evaluation of the risk of a process by determining

what can go wrong (risk identification)

how likely is it to occur (risk estimation)

and what the consequences are.

Part 11 Scope and Application Guidance

“We (FDA) recommend that you base your approach

on a justified and documented risk assessment

and a determination of the potential of the system

to affect product quality, safety, & record integrity.”

Part 11 Scope and Application Guidance

“We (FDA) suggest that your decision

on how to maintain records be based on

predicate rule requirements and on a

justified and documented risk assessment and

a determination of value of the records over time.”

A risk-based approach is one way to

demonstrate that you have applied a

controlled methodology, to determine the

degree of assurance that a computerised

system is fit for it’s intended purpose.

Good Practices For Computerised Systems In Regulated “GXP” Environments

Consequences (Severity) of Risk

If a system should fail to be fit for its intended use,

what would be the impact:

Public Health and Safety – Death, Injury, Illness

Product Quality and Safety – Adulteration, Defective

Compliance – Warning Letter, 483, Study Non-compliance

Business Continuation – Out of Business, Loss of Business

Operation – Delay of project, Operator frustration

Risk Impacts

Critical/ Non-critical

Low/ Medium/ High

Defined and Quantifiable number (e.g. 1-3 or 1-10)

Examples of Systems

High Risk: Manufacturing Batch Records Patient Records Laboratory Test Results LIMS and QA systems

Low Risk: Environmental Monitoring Records (not affecting

product quality)

Training Records Master Schedule System

Methods of Determining Risk

High Level RiskFailure of the system

May cause harm to patients, and there is no correction possible Has significant impact on business operations for several days

Medium Level RiskFailure of the system

Can cause harm to patients, but the failure is likely to be able to be corrected Has potential impact on business operations for a few days

Low Level RiskFailure of the system

Will not cause harm to patients Will cause negligible impact to business operations

Methods of Determining Risk

  Low Medium High

LowL L M

MediumL M H

HighM H H

ProbabilityIm

pac

t

Methods of Determining Risk

Failure Mode Effects Analysis (FMEA) Type Method

Severity 3 = High Impact 2 = Medium Impact 1 = Low Impact

Occurrence 3 = High Probability of Occurring 2 = Medium Probability of Occurring 1 = Low Probability of Occurring

Detection 3 = High Probability of Going Undetected 2 = Medium Probability of Going Undetected 1 = Low Probability of Going Undetected (Failure will be easily detected)

Methods of Determining Risk

Risk Value = Severity X Occurrence X Detection

e.g. High Severity X High Occurrence X Low Chance of Detection (High Risk)

Risk Value = 3 X 3 X 3 = 27

Med Severity X Med Occurrence X Low Chance of Detection (High Risk)

Risk Value = 2 X 2 X 3 = 12

Low Severity X Low Occurrence X High Chance of Detection (Low Risk)

Risk Value = 1 X 1 X 1 = 1

Med Severity X High Occurrence X High Chance of Detection (Low Risk)

Risk Value = 2 X 3 X 1 = 6

This Methods Makes It Easier To Prioritize &

Clearly Identifies The Higher Risk Systems!

Evaluating Risk Factors

Need for Validation: High Level Risk Assessment Major Functionalities of the System Identified Associated Risk

Extent of Validation: More Detailed Assessment Sub-functions and User Requirements Impact of Risk related to those Functions

Need and Extent of Audit Trail: Impact of Risk Resulting from Accidental or Intentional Adverse Events Traceability and Integrity of Records

Method of Record Retention: Impact from Loss of Record vs. Impact on Record Retrievability (by not using

electronic capabilities).

Examples of Justification of Risk Factors

Risk to Human Health & Safety = Low

<Company> is not involved in the analysis of final drug or

biological product, drug substance, active pharmaceutical

ingredients (APIs), or in the final testing of medical device

performance or combination products. The direct risk to human

health and safety therefore is determined to be minimal.

Part 11 Applicability = Low

<> has identified the hardcopy paper records as the primary raw

data. Only in cases where reprocessing is necessary will the

electronic raw data file be used. Electronic records maintained

in non-instrument related databases (e.g. sample tracking

system, sample labeling, training documentation) are entered

from original paper documentation which is maintained and

archived in secure facility files.

Examples of Justification of Risk Factors

Examples of Justification of Risk Factors

Risk of Data Corruption = Low

The risk and probability of unintentional corruption of electronic

records is considered to be low based on the level of education,

skill, and training of the staff. Computerized systems are

qualified and validated to assure proper performance of the

system for its intended use. In most cases, paper records are

available for the reconstruction of the data.

References

Guidance for Industry Part 11, Electronic Records; Electronic Signatures — Scope and Application, CDER, August 2003www.fda.gov/cder/guidance/5667fnl.pdf

Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations DRAFT, September 2004 www.fda.gov/cber/gdlns/qualsystem.pdf

Good Practices For Computerised Systems In Regulated “GXP” Environments PIC/S GUIDANCE PI 011-21 July 2004www.picscheme.org/BAK/docs/pdf/PI%20011-2%20Recommendation%20on%20Computerised%20Systems.pdf

FDA Glossary of Computerized System and Software Development Terminologywww.fda.gov/ora/inspect_ref/igs/gloss.html

The Impact of the Guidance for Industry Part 11 , Electronic Records, Electronic Signatures – Scope and Application White Paper, Robert J. Finamore CSSC, Inc Sept 4, 2003www.csscinc.net/company/Impact%20of%20New%20Part%2011%20Guidance.pdf

ISPE Risk-Based Approach to 21 CFR Part 11www.ispe.org/Template.cfm?Section=Search&CONTENTID=9020&TEMPLATE=/ContentManagement/ContentDisplay.cfm

References (con’t)

Guidance for Industry Part 11, Electronic Records; Electronic Signatures — Scope and Application, CDER, August 2003www.fda.gov/cder/guidance/5667fnl.pdf

Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations DRAFT, September 2004 www.fda.gov/cber/gdlns/qualsystem.pdf

Good Practices For Computerised Systems In Regulated “GXP” Environments PIC/S GUIDANCE PI 011-21 July 2004www.picscheme.org/BAK/docs/pdf/PI%20011-2%20Recommendation%20on%20Computerised%20Systems.pdf

FDA Glossary of Computerized System and Software Development Terminologywww.fda.gov/ora/inspect_ref/igs/gloss.html

The Impact of the Guidance for Industry Part 11 , Electronic Records, Electronic Signatures – Scope and Application White Paper, Robert J. Finamore CSSC, Inc Sept 4, 2003www.csscinc.net/company/Impact%20of%20New%20Part%2011%20Guidance.pdf

ISPE Risk-Based Approach to 21 CFR Part 11www.ispe.org/Template.cfm?Section=Search&CONTENTID=9020&TEMPLATE=/ContentManagement/ContentDisplay.cfm

Risk Management

Risk Assessment - Assess Potential Risks and Consequences

Risk Identification – Identify the Potential Risks

Risk Estimation – Determine the Likelihood that the Risk will Occur

Risk Impact – Determine the Potential Impact of the Risk

Risk Detection – Determine the Detectibility of the Risk

Risk Classification – Define & Quantify Risk Level

Risk Analysis – Determine Cost/Benefit Analysis

Risk Mitigation/Avoidance – Determine Risks which can be Lessened or Avoided

Risk Strategy - Determine and Document Strategies for Managing Risk

Risk Monitoring – Monitor Changes, New Risks, Risk Levels & Update Risk Plans