my deviations and capa from the fda perspective

Deviations and CAPA from the FDA Perspective Gary Bird, Ph.D. PharmaConsult Global

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Outline of the Contents • Look at general deviation information • Compare regulatory requirements for

CAPA • Discuss best practices for CAPA

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By any other name, it’s still a “Deviation” • Incident • Non-conformance, nonconformity • Discrepancy • Atypical situation • Errors • Out-of-specification • Out-of-trend • Failures • Exceptions

Common “other” definitions (company specific)

• Departure from an approved instruction or established standard..

Deviation (ICHQ7)

• The nonfulfillment of a specified requirement. Nonconformity 21 CFR 820(q)

•Unexpected event with potential to adversely affect material or drug product quality, safety, efficacy, purity or stability. Includes unexpected malfunction(s) or issue(s) that may adversely impact reliability of equipment or processes to perform as expected.

Incident (Company)

Common Observations -2015

Citation Observation(s) % on 678

Inspections

Procedures

21 CFR 211.22(d) Not in writing or fully followed 23.6%

21 CFR 211.160(b) Scientifically unsound laboratory controls 19.2%

21 CFR 211.67(b) Written procedures not established/followed 7.82%

21 CFR 211.100(b) SOPs not followed / documented 7.67%

21 CFR 211.113(b) Sterile drug products 15.3%

21 CFR 211.100(a) Absence of Written Procedures 14.0%

21 CFR 211.198(a) Procedures: Complaint Handling Procedure 5.90%

21 CFR 211.160(a) Following/documenting laboratory controls 5.90%

21 CFR 211.192 Deviations: Investigations of discrepancies, failures 18.3%

Common Observations -2015

Citation Observation(s) % on 678

Inspections

21 CFR 211.42(c)(10)(iv) Environmental Monitoring System 12.2%

21 CFR 211.165(a) Testing and release for distribution 11.8%

21 CFR 211.110(a) Monitor and validate performance 10.2%

21 CFR 211.67(a) Cleaning / Sanitizing / Maintenance 10.0%

21 CFR 211.63 Equipment Design, Size and Location 8.26%

21 CFR 211.113(b) Validation lacking for sterile drug products 7.82%

21 CFR 211.25(a) Training--operations, GMPs, written procedures 7.37%

21 CFR 211.192 Written record of investigation incomplete 6.93%

21 CFR 211.194(a) Complete test data included in records 5.75%

21 CFR 211: References to Deviations • Components, drug product containers, and closures approved for use

shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.

Sec. 211.86 Use of approved components, drug product containers, and closures.

• (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

Subpart F--Production and Process Controls; Sec. 211.100

Written procedures; deviations.

• When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented.

Sec. 211.111 Time limitations on production.

• Written procedures shall be established, and followed, describing the distribution of drug products. They shall include:

• (a) A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.

Subpart H--Holding and Distribution; Sec. 211.150 Distribution procedures.

• (a) Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.

Subpart I--Laboratory Controls; Sec. 211.160 General

requirements.

Deviation Investigations/Resolution Process

Does It Function?

Did you try to fix

it???

Will you be in TROUBLE???

Don’t change it

You Idiot!!!

You’re in Deep E. coli

Then there’s no problem

Pretend you don’t know about it

Hide it

Can you blame someone else???

Yes No

Yes

Yes Yes

No

No

Yes

No No

Does anyone

else know about it?

Panic

The impact of deviations can be minimized if…

The events are Captured

The situation is

Investigated

The cause is

Corrected

The activities are Documented

The occurrence

is Reported

The potential impact is

Evaluated across product lots and

product lines

Use of Contractors • Manufacturers that use contract services

are ultimately responsible for ensuring that deviations and failures experienced by contractors are thoroughly investigated and resolved before the is batch released and distributed

The Reference Document – a Quality Agreement

• Any Deviations from the Process must be documented as described in Section X: Deviations and Out of Specification (OOS) Results and Approved by the Sponsor.

Deviations and Out of

Specification (OOS) Results

• The Contractor shall conduct and record failure investigations to ensure root cause identification and document any Deviation(s) from the Approved Manufacturing, Packaging or analytical Process impacting the quality, strength, purity, safety and compliance of the Product.

• Unplanned Deviations will be Approved by The Sponsor prior to Release of impacted Lots.

• The Contractor shall notify The Sponsor of any Deviations that have an impact on the decision to Release the Product into the clinic.

Manufacturing Deviations

Elements of an Investigation: A Reasonable Deviation Investigation Template

• Product Name • Deviation Number • Date of Occurrence • Initiator • Executive Summary • Notebook / Master Batch Record

Reference or SOP Reference • Description of Deviation • Description of Immediate

Corrective Action, if any • Probable Root Cause • Impact Assessment: lot, line,

multiple lines, facility, worldwide • Classification

– Human Error – Instrument Failure – Processing Error

• Description of Deviation • Relevant Data • Impact of Deviation • Root Cause (potential, known,

unknown) • Corrective Action (reference to

other document if necessary) • Preventive Action (reference to

other document if necessary) • Confirm completion • Completion Date • Does a Method or Procedure

have to be updated • Sign-off (Initiator, Investigator,

Management) and dates

An example of a common deviation issue • Protocol MFP #4636 relates to the

validation of the lyophilizer used for freeze drying the final drug product in vials. The study was terminated after 2 of the 6 lots failed moisture acceptance criteria. These failures were not investigated, and the validation report concludes the lyophilization process is valid.

CAPA in the EU, US, and ICH

Different emphasis but

a high level of

consistency in that:

• Expected and required • Companies must investigate

discrepancies • The correction process must be a

routine process • The preventive program is “continuous

improvement” • Information must be assimilated and

acted on • Processes must be in place to address

issues with Management • The CAPA process is a lifecycle process,

continuing even when product is discontinued

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The Internationalization of CAPA: ICH Q10

System based • CAPA resulting from the investigation

of complaints, product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings, trends from process performance and product quality monitoring.

Structured approach • The level of effort, formality, and

documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9.

• CAPA methods should result in product and process improvements and enhanced product and process understanding.

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US: CFR 21 Part 211 • Sec. 211.192 Production record review.

– All drug product production and control records, … shall be reviewed and approved by the quality control unit …. Any unexplained discrepancy …. shall be thoroughly investigated, … The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up.

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We have a deviation, how do we “fix” it?

CAPA is a well-known CGMP regulatory concept that focuses on investigating, understanding, and correcting discrepancies while attempting to prevent their recurrence.

Quality system models discuss CAPA as three separate concepts, all of which are used in this guidance

Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem

Preventive action to avert recurrence of a similar potential problem

Remedial corrections of an identified problem

US FDA Quality Systems Approach to Pharmaceutical cGMP Regulations (Sept 2006)

Corrective action is a reactive tool for system improvement to ensure that significant problems do not recur.

SOP(s) to ensure the need for action is evaluated relevant to the possible results

The root cause of the problem is investigated,

Possible actions are determined,

Selected action is taken within a defined timeframe,

Effectiveness of the action taken is evaluated.

Document corrective actions taken

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Both quality systems and the cGMP (211.192) regulations emphasize corrective actions

Quality systems approaches call for :

FDA Guidance on CAPA continued

• Key sources of information: – Nonconformance reports and rejections – Returns – Complaints – Internal and external audits – Data and risk assessment related to

operations and quality system processes – Management review decisions

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Preventive Actions are the proactive component of an investigation and is an essential tool in quality systems management

•include succession planning, training, capturing institutional knowledge, and planning for personnel, policy, and process changes are preventive actions that will help ensure that potential problems and root causes are identified, possible consequences assessed, and appropriate actions considered.

“Soft” actions

•include modifications to systems, manufacturing processes, expectations for personnel, monitoring strategies, confirmation that systems are functioning correctly

“Hard” actions

•new problems can be identified by reviewing data and analyzing risks associated with operational and quality system processes, and by keeping abreast of changes in scientific developments and regulatory requirements.

“Proactive”

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Comments and Cautions • Must have a qualified Quality lead • Is more important than generally acknowledged • May cause all product to be adulterated if not properly

resolved • Can not be dependent upon one person or a small group –

needs many perspectives • Can not be limited to one general direction, must be able to

evaluate multiple scenarios and results • Must be a living process • Multiple processes depending upon which group is

conducting the activity. • Should have the support of the Management team • Ultimately, Senior Management is responsible and will be

held accountable.

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Key Steps 1. Create the team 2. Identify the problem 3. Evaluate the issues 4. Investigate 5. Analyze the issues 6. Create action plans to address the findings 7. Implement 8. Verify effectiveness 9. Follow-up

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Create the CAPA Team • Should have a standing Data Integrity Team ready to

function • Never dismisses a potential major or critical issue without

formalized investigation. • The Data Integrity Team:

– Quality should always be chair – Teams should always be expert in the specifics – Avoid conflicts of interest (specific group or individuals should

not be involved in resolution) – Identify appropriate witnesses and knowledgeable personnel – Determine impact of potential data integrity or fraudulent

activities and know a priori what your course of action should be.

• Periodically activate the team to “keep them fresh” by conducting an in-depth review of a potentially “suspect” area.

Identify the problem

Confirm the source of the

information, e.g., deviations,

process changes, unscheduled maintenance,

audits, personnel observations, requests, data mining, third-party reviews, trend analyses

Focus on more than

just the issue at hand =

global

Explain all observations

in great detail but concisely.

Document that the

problem, as identified,

really exists.

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Evaluate the issues

Confirm likely impact(s) on the product

Is there any

product risk?

Are there any easily

identified, necessary remedial

actions, e.g., Is this a

“quick fix” or a permanent

solution.

Is the issue more far

reaching than a simple repair or solution

Where the remediation

is simple, this may be the end of the

investigation and the CAPA can be closed.

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Investigate

Should generally include a written plan to address the identified issue(s): • Objective • Team Members • Rationale • Strategy • Extent (boundaries) of

evaluation

Corroborate with experts

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Must follow the SOP for

investigations

Analyze the issues

Assimilate all results from the investigation and confirm each observation

All potential

causes are properly

identified

Necessary data is

available to drive

the analysis

Data is organized

and formatted for human evaluation

where necessary

Root Cause Analysis • Conduct a

root cause analysis to determine primary cause(s) of the problem.

• List all (but don’t be confused with symptoms)

• List all possible interactions of the potential root causes

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Create action plans to address the findings

Identify the best methods to correct

the existing issues, it recurrence, or

related activities

Document the action plan • Comprehensive • Interactive • Time lines • Personnel

Requirements and Responsibilities

• How much will it cost • All tasks required to

complete the action • Identify any related

products or processes that will also be impacted

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Create action plans to address the findings

Identify • Timing • Documents • SOPs • Physical equipment or system

changes • Processing changes • Computer system controls or

validation

Training Needs • Timing and requirements

related to identified changes • Must be comprehensive and

involve all affected personnel.

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Implement

Personnel • Technical experts own

each of the relevant sections

• A list of all activities is created and documented to support the changes.

Impact • System

interactions are confirmed during implementation

• No “unintended consequences”

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Plan • Action Plan is

broken into understandable pieces

• All tasks are properly identified and described

Follow-up

Verify • Results • Effectiveness of the CAPA • All objectives met • Changes completed and verified • No reoccurrences of the event

Confirm • Resolved root cause • Any resulting secondary

situations have been corrected • Effective controls in place • No unexpected consequences • Training updated?

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A Word About Software Based Solutions • Software programs are not CAPA, just a tool • All CAPA programs have something to offer • May be very expensive to install and validate • Should be adopted across the entire company for

them to be effective, often difficult to do • Requires an extremely well defined process • Requires an owner, generally a Quality function • Requires maintenance • Will not provide the “answer” regardless of how

hard it is pushed.

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