Stephen Fochios SOLABS User Group Meeting

September 24th, 2013 Montreal, QC

NonConformance Management

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What is a Nonconformance or “Deviation”?

The term “non-conformance” is synonymous with “Deviation”. An NC is defined as: An Unplanned event, unexplained discrepancy, or a departure from an approved instruction (i.e. procedure, batch record, test method, specification, protocol). Nonconformances can be discovered during audits, data review, investigation, trend review, routine operations which can impact product, facilities, equipment, data, systems, commercial or clinical trials.

Nonconformance Types

Method Manpower Machinery Materials Environment

Who is Responsible for Reporting an NC?

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EVERYONE!

If a nonconformance is observed, it is important to report the event to Management as soon as it is observed so the appropriate actions can be initiated

Not reporting, or a delay in reporting an NC can severely impact processes and result in an observation. If unsure, take the conservative approach and report it anyways!

What are the consequences of not reporting an NC?

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• A Quality Management System that covers all key areas: NCs, CAPA, internal/external quality audit findings, training, complaints, supplier quality, etc… • Trends -were they properly identified, handled, and addressed. • A Controlled Process that is in place and in use.

• Nonconformances are properly investigated and identify real Root Cause • Non-Conformances are closed within required timeframes • CAPA corrects Root Cause and is closed effectively

• SISPQ (Strength, Identity, Safety, Purity and Quality) of the product is properly assessed.

What Do Inspectors look for?

Can an Agency question me about an NC?

YES !!! That’s why it’s important to make sure a thorough compliant investigation is written!

Regulatory Agencies

Your signature is legally binding!

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Determining if it’s a Nonconformance - Example General Decision Tool

Question YES NO

1 Is the handling of the event covered by specific SOP ? Follow SOP instructions

Proceed to next Question

2 Do you immediately know there is no impact to : • Product • Material • Equipment • Area

Proceed to next Question

NC is Required

3 Can a further description clarify rather than correct the original documentation?

Can be a comment

NC is Required

4 For events at the time of performance: Is this a correction to a GMP document that can be made prior to the completion of the operation/process?

Can be a comment

NC is Required

5 For events found AFTER the time of performance: Can the required correction be verified from a GMP source? Corrections must reference GMP documentation that captures the same information.

Can be a comment

NC is Required

Suggestion: If it’s been determined that the event does not fit the criteria of an NC, the operator will document an agreed upon comment in the record where Management and QA will initial/date.

Comment • Clarifies the event- does not correct it • GMP source available to clarify • Easily explained, does not require investigation • Found at the time of performance and corrected the same day

Nonconformance • Deviation from procedure • Repeat or recurring event • Investigation required, immediate root cause or product impact is unknown • Error can not be immediately corrected

Classification

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Determining the Level of Classification

Minor Nonconformance

Major Nonconformance

Critical Nonconformance

• Low or No Risk of product impact to SISPQ (Safety, Identity, Strength, Purity, Quality • No product impact is immediately known or requires minimal evaluation • Probability of future detection is HIGH • Controls and testing in place to detect this event • No probability of impact to Quality of subsequent lots

• Moderate Risk of product impact to SISPQ (Safety, Identity, Strength, Purity, Quality • Product impact requires additional testing and is not immediately known • Probability of future detection is MODERATE - HIGH • Controls and testing in place to detect this event, however did not detect this event • Low - Medium probability of impact to Quality of subsequent lots

• High Risk of product impact to SISPQ (Safety, Identity, Strength, Purity, Quality • Product impact requires additional testing and is not immediately known • Probability of future detection is LOW • Controls and testing in place to detect this event, however did not detect this event • High probability of impact to Quality of subsequent lots

Classification – Examples

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• Failure of Critical Quality Systems • Evidence of contamination of a drug substance or drug product lot •Failure identified through periodic monitoring • Aseptic processing media fill failed acceptance criteria • Breach of aseptic operation conditions • Validation failure of sterilization or product impacting cleaning process that has been used in production lots

• Outside Validated Limits/conditions • Trends • Environmental Monitoring • Temperature Excursions • Testing Parameters exceeded • Label Content Errors • Post filter integrity test failure • Use of rejected or expired raw material •Calibration OOT for equipment used in the control or measurement of critical parameters

• Medias or solutions incorrectly prepared and discarded • Minor labeling issues identified during final product labeling/inspection. • Grammatical Errors that do not impact critical labeling information • Correct samples collected but documented on incorrect forms • Wrong form used, but form contains correct tests and acceptance criteria

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Ensure you are properly trained on the SOP before executing the task. DO NOT perform procedures from Memory SOPs MUST be open when performing tasks (**FDA Observation**) If you do not understand STOP and ask for clarification. If an error occurs, STOP and escalate immediately to supervisor or designee for guidance on how to proceed. Ensure that everything is documented at the time of performance! “Not Documented, Not Done!” Slow down, review your work for GDP before submitting for review. Focus on Right First Time! Be consistent with your work Quality is Key- it’s about Quality not Quantity of work.

Always Be Compliant!

cGMP Compliance

Be Proactive!

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Don’t Be Afraid To Speak Up If You Have A Concern!

• Provide constructive feedback to peers with regard to following procedures. • Suggest Process improvements or more efficient ways of operating. • Ensure the procedure is up to industry standards and is properly reflecting the task you are performing

Chances are if you don’t understand it, your peers won’t either! Catch problems BEFORE they occur!

Work Smarter not Harder!

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GDP Requirements

Handwritten entries are in indelible ink (Black or Blue) Pencil, gel ink, markers & RED pen are not accepted

Empty spaces are "N/A” initial and dated “Ditto marks” or arrows are not acceptable The use of white out is strictly prohibited Entries must be clear, legible and made at the time of performance Correction to original documentation is one strike through and must provide justification

Military time format (24-hour clock) is preferred however regular time format is accepted Acceptable date formats are properly documented Backdating is strictly prohibited

When attaching a label to a GMP record, initial and date ensuring the entry is overlapping both the label and document Do not record raw data on sticky notes, or loose paper as it is considered original documentation

Always check your work for GDP before submitting it!

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Nonconformance Expectations

• Check your work for errors and accuracy • Be consistent with writing and reviewing • If you don’t understand a reviewer’s comment, don’t be afraid to ask! • Address ALL comments • Meet with approvers to ensure you understand their expectations • Keep your NC team informed and involved…..Communicate! • Write to the unknown audience (Think FDA Inspectors) • Be direct and to the point • Keep it factual (No Opinions) • Include only relevant information • Project Manage your time and deadlines

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Example Nonconformance Process Overview

• Recognizes potential NC and informs Management and QA • Performs immediate corrective actions with QA and Management where possible • Initiates NC

• Makes final determination of classification

• Ensures lot tagging is appropriately assessed

• Reviews NC for compliance and accuracy

• Trending of NC

• Approves closure of NC

• Provides technical support for root cause and product impact if required

• Provides supporting memos and reports if required

• Assigns NC owner

• Provides resources and ensures deadlines are met

• Participates in NC Team Process

• Reviews NC for technical accuracy

• Assumes responsibility for timely completion of the NC • Provides status updates

• Identifies root cause and suggests CAPAs

• Approves the NC as author

• Identify lots associated

Initiator Owner Area Management QA SME

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Investigation • Details of all investigations and conclusions and WHY it occurred •Identify individuals involved by Title and Department (minimum) • Interviews-

• what day it was conducted? • who you interviewed? • what did they indicate?

• Background information • Key decisions made • Scope of investigation • Review of historical data to identify related events •All NonConformances should be investigated for determination of root cause and product impact •Major and Critical NCs require a more in depth investigation

Scope: (example)

Scope: The scope of this event is limited to lot……. as this was the only lot processed after the event which occurred on (date). Subsequent batches are not affected as a result of this discrepancy as… (explain why they are not affected)

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Root Cause Analysis Identifying the Real Root Cause! Multiple Root Causes may exist!

STEP 1: Collect and Analyze Data Minimum requirements • Who? • What ? • Where? • When? • How Much/Many/Often?

STEP 2: Identify Potential Risk Factors • Manpower • Machine • Materials • Environment Each needs to be justified why it was “Ruled In” or “Ruled Out”

STEP 3: Analyze Confirmed Potential Factors: Perform 5 Why analysis for each factor identified

STEP 4: Determine if RC is Satisfactory: Root cause is FACT based and corrective actions will likely prevent this from reoccurring

• Goal is to determine the true root cause(s) • Ask for the opinion of those involved: what do they think happened? • Be open minded and non-judgmental • Ask open ended questions when possible and don’t guide their answers • Ask what went right AND wrong • Don’t overlook the obvious • Be a good listener • Ask them to re-enact the event • Ask technical questions • Use a friendly approach when interviewing • Try to think of potential factors that may have contributed to the event • Ask how they think it can be improved?

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Interview Tips and Techniques

Do NOT Place Blame

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Interview Questions What Questions do I ask?

• What do you think could have contributed to this deviation? • Why did you (overlook the error)? • Were you distracted? • What were you doing at the time of the event? • Who did you contact? • What did you immediately do to stop the problem?

• Do you recall any unusual circumstances at the time of the event? • Were you following the SOP? • Do you find the SOP confusing? If so, what can we do to improve it? • Have you performed this procedure before and do you feel comfortable performing it? • In your opinion, what do you think we can do to improve the process to prevent this from happening again?

Examples Examples

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Corrective and Preventative Actions - CAPA

• CAPAs are created to correct the problem identified as the Root Cause • CAPAs should not continue the investigation • Ensure your CAPA always aligns with your Root Cause • Consult with QA to determine if a CAPA is already open before initiating • QA assigns the CAPA number once the NC is approved • Assign Due Dates that are Realistic and Achievable • When assigning the tasks, ensure the owner is aware and can take on the responsibility • If no CAPA is necessary, justification is required

Identifying the Correct Root Cause will eliminate reoccurrence!

Key Points to Consider

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Attachments What Do I need to Attach?

• Anything directly referenced that can NOT be easily retrievable from a published GMP system :

• GMP Systems: SOP or Report) • GMP Systems but not retrievable: QC test results, Chart Recorder or CMS results, Calibration Certs, CoA, completed batch record pages • Memos originating to support NC must be attached to show approval of memo thru NC approval • Attachments must include NC number, attachment number, page numbers and initials and date.

Examples of Attaching Proof 1) Endotoxin testing results indicated they were within

specification (attach test results) 2) Product was quarantined (attach Inventory Control

sheet) 3) Unit was in alarm for 8 hours (attach alarm report)

Providing Proof!

No Emails!

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When is Regulatory Affairs Approval Required?

Approvals

• Missing Product • Potential theft or adulterated product

• broken seals • incorrect packaging • boxes that appear compromised

• Impacted Product that has been released or is out of a company’s control • If it’s been identified as a possible reportable event

QA will help determine if Approval is Required.

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Status Update Example

“Where is my NC? Who has it?” NC Board- What is it? •Tracks status of NC • Dates routed for comments • Dates comments were provided • How many days it was with each approver

NC Meeting • Status Updates • Roadblocks/ New Developments • Any New NC Events • Attendees- Management,Initiator,Owner,QA • Discuss classification

Standard Deviation Process

Standard Non-Conformance Process

Questions?

Stephen Fochios Eliassen Group Life Sciences Consulting sfochios@eliassen.com 1 (917) 297-9976