HOW TO PERFORM LABORATORY OUT OF SPECIFICATION ... TO PERFORM LABORATORY OUT OF SPE · how to perform…

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  • HOW TO PERFORM LABORATORY

    OUT OF SPECIFICATION

    INVESTIGATIONS THAT MEET FDA

    REQUIREMENTS USING ROOT CAUSE

    ANALYSIS.

  • MODULE ONE

    INTRODUCTION TO THE QUALITY

    SYSTEM .

  • THE QUALITY SYSTEM

    UNDERSTANDING YOUR QUALITY SYSTEM

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  • QUALITY SYSTEM DEFINED.

    A Quality system is defined as:

    The organizational structure, processes, procedures, responsibilities and resources needed to implement quality management

    Source: ISO 8402:1994

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  • QUALITY SYSTEM DEFINED.

    Key words and phrases: Organizational structure

    Processes

    Procedures

    Resources

    Responsibilities

    Source: ISO 8402:1994

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  • 1.ORGANIZATIONAL STRUCTURE.

    ORGANIZATIONAL STRUCTURE Defined roles of management of the

    organization Example: CEO Quality Manager Quality Engineer Manufacturing Engineer Manufacturing Manager

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  • ORGANIZATIONAL

    STRUCTURE(Cont.)

    The organization of your laboratory is key to effective way of handling your laboratorys role and responsibility in the Quality system. How is your laboratory organized?

    What are its responsibilities?

    Are the roles for personnel defined? What are you paid for?

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  • 2.PROCESSES.

    A PROCESS

    Is defined as a set of steps that add value to inputs to produce an output, or outputs.

    Leading question:

    what is it you are trying to accomplish and how is success measured?

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  • PROCESSES (Cont.)

    F(X)

    PROCESS

    OUTPUT:

    PRE-DETERMINED

    SPECIFICATIONS

    (Y)

    INPUTS

    5M

    X1

    X2

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  • PROCESSES (Cont.)

    Inputs

    The 5Ms

    Machine----The equipment

    Material------Samples, and reagents

    Methods----work Instructions, test methods

    Man-----Analyst, lab manager, manufacturing operator

    Mother nature---The clean room, the contract lab, or your lab

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  • PROCESSES (Cont.)

    Out puts

    Defined specifications for

    Product

    Process

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  • PROCESSES (Cont.)

    EXAMPLE

    Process:

    Gas chromatography: GS analysis

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  • PROCESSES (Cont.)

    The Process:

    What: Analytical process for separating

    compounds based on their volatilities

    Measure of success:

    Retention times

    Peaks

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  • PROCESSES (Cont.)

    METHOD:

    Test procedure

    Work Instructions

    Laboratory SOPs

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  • PROCESSES (Cont.)

    MAN:

    The Analyst

    The laboratory manager

    The production operator

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  • PROCESSES (Cont.)

    MATERIAL:

    The samples

    The reagents

    Inert Career gas

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  • PROCESSES (Cont.)

    Machine: GS equipment

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  • PROCESSES (Cont.)

    Output:

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  • PROCESSES (Cont.)

    Defined spec:

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  • 3. DOCUMENTS

    LAYER

    1

    POLICY

    AND

    MANUA

    LL

    POLICY

    LAYER 2

    STANDARD

    OPERATING

    PROCEDURES

    WHO DOES

    WHAT

    LAYER 3

    WORK

    INSTRUCTIONS

    HOW TO PERFORM A

    TASK

    LAYER 4

    RECORDS

    PROOF THAT A TASK WAS PERFORMED

    LAYER 5

    JOB AIDS.

    FORMS,TEMPLATES,DRAWINGS.

    A DOCUMENTED QUALITY SYSTEM IS REQUIRED:

    A defined document hierarchy

    Policy

    Standard operating procedures

    Work Instruction

    Reports

    Forms

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  • DOCUMENTS (Cont.)

    What policies do you have in your laboratory about OOS Investigations?

    What SOPs do you have in your laboratory about who does what during OOS investigations?

    What work instructions do you have for performing OOS investigations in your laboratory?

    What records do you have for activities performed during OOS investigations in the laboratory?

    What templates do you have for collecting data during OOS investigations

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  • 4. RESPONSIBILITIES

    Your Quality system should have:

    Defined roles(who does what):

    An SOP for the following is required:

    The role of the Laboratory manager in OOS investigation

    The role of the Quality Engineer in OOS investigation

    The role of the Laboratory Technician, or Pharmacist in OOS investigations

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  • RESPONSIBILITIES (Cont.)

    Your Quality system should have:

    Defined responsibilities(Ownership):

    Job descriptions

    Defined tasks and ownership

    Understood ownership

    Question: What are you being paid for in

    your company?

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  • 5.RESORCES

    Your Quality system should have resources:

    Adequate facilities, or space for operation

    Commissioned facilities(Validated cleanroom)

    Labs Qualified for the intended use

    Validated environment for operation

    Correct infrastructure: IT solutions for what you are trying to do.(LIMS---part 11 requirements)

    Enough trained and Qualified personnel for the job.

    Adequate and Qualified equipment for operation

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  • TEST ON THE QUALITY SYSTEM

    MODULE ACTIVITY

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  • MODULE TWO

    THE PHARMACEUTICAL QUALITY

    SYSTEM

  • THE FIVE QUALITY SUBSYSTEMS

    PHARMACEUTICAL QUALITY SYSTEM MODEL 27 http://www.cgmpuniversity.com

  • THE FIVE SUB-SYSTEMS

    Your organizational structure, Processes,

    documents, responsibilities, and resources

    fit into five categories called subsystems:

    Facilities and equipment controls

    Laboratory controls

    Packaging and labeling controls

    Production controls

    Material controls

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  • THE FIVE QUALITY SUBSYSTEMS

    Each subsystem has processes that accomplish work

    The chemical analysis laboratory has several processes designed for analysis. Examples:

    1. HPLC analysis

    2. Gas Chromatography analysis

    3. Stability testing.

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  • THE FIVE SUB-SYSTEMS (Cont.)

    All the five subsystems have roles to play in the Quality system.

    The role of a Pharmaceutical laboratory are implied in three regulations:

    (1) 21CFR 211.160: Quality Assurance

    (2) 21CFR 211.165: Quality control

    (3) 21CFR 211.192: Investigation of Quality control test failures(OOS investigations)

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  • MODULE ACTIVITY

    CRITICAL THINKING

  • MODULE THREE

    THE ROLE OF THE LABORATORY IN

    THE QUALITY SYSTEM.

  • THE ROLE OF THE LABORATORY.

    The role of the laboratory in the Quality

    system is two fold:

    Quality Control

    Quality Assurance

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  • QUALITY CONTROL

    THE ROLE OF THE LABORATORY

    21CFR 211.165 ----Material

    Testing and release

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  • QUALITY CONTROL.

    21CFR211.165: Quality control

    (a) For each batch of drug product, there

    shall be appropriate laboratory

    determination of satisfactory conformance to

    final specifications for the drug product,

    including the identity and strength of each active ingredient, prior to release

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  • QUALITY CONTROL.

    21CFR211.165

    Key words and phrases:

    Determination of satisfactory conformance

    to final specifications

    The identity and strength of each active

    ingredient, prior to release of the product

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  • QUALITY CONTROL

    Testing each batch to determine

    conformance to specifications

    Where sterility testing is required batches

    may be released before test results are

    received.

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  • QUALITY CONTROL.

    Quality control : (Testing)

    The focus is on:

    In-process controls

    API, excipients

    Release of the finished products

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  • QUALITY CONTROL.

    (1)Quality Control

    The focus is:

    Incoming material testing

    Release of incoming material

    Testing of in-process material

    Release of in-process material

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  • QUALITY CONTROL.

    21CFR211.165

    (f) Drug products failing to meet established

    standards or specifications and any other

    relevant quality control criteria shall be

    rejected. Reprocessing may be performed.

    Prior to acceptance and use, reprocessed

    material must meet appropriate standards,

    specifications, and any other relevant

    criteria.

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  • 21 CFR211.160: Subpart I

    QUALITY ASSURANCE

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  • QUALITY ASSURANCE

    Quality Assurance:

    Planned and systematic activities

    implemented in the Quality system so that

    Quality requirement for a product, or

    service can be fulfilled.

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  • QUALITY ASSURANCE.

    21CFR211-160: Quality Assurance

    (planned activities)

    (b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

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  • QUALITY ASSURANCE

    21CFR211.160: Quality Assurance

    (a) The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.

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  • QUALITY ASSURANCE

    Laboratory controls

    (b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include:

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  • QUALITY ASSURANCE

    Responsibilities for the Quality unit:

    Approvals of changes to specifications

    Approval of Test procedures

    Approval of sampling plans

    Approval and documentation of deviations

    Approval of developed specifications

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  • QUALITY ASSURANCE

    Laboratory controls

    (1) Determination of conformity to applicable written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products.

    The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.

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  • QUALITY ASSURANCE

    Laboratory controls

    (2) Determination of conformance to written

    specifications and a description of sampling

    and testing procedures for in-process

    materials. Such samples shall be

    representative and properly identified.

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  • QUALITY ASSURANCE

    Laboratory controls

    Description of sampling and testing procedures

    Sampling procedures for In-process materials.

    Samples have to be representative of the population/batch

    Samples should be labeled

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  • QUALITY ASSURANCE

    (3) Determination of conformance to written

    descriptions of sampling procedures and

    appropriate specifications for drug products.

    Such samples shall be representative and

    properly identified.

    Translation:

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  • QULITY ASSURANCE.

    (a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible. 51 http://www.cgmpuniversity.com

  • QUALITY ASSURANCE

    (c) Any sampling and testing plans shall be

    described in written procedures that shall

    include the method of sampling and the

    number of units per batch to be tested; such

    written procedure shall be followed.

    Translation:

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  • QUALITY ASSURANCE

    (d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels. Translation:

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  • QUALITY ASSURANCE

    (e) The accuracy, sensitivity, specificity, and

    reproducibility of test methods employed by

    the firm shall be established and

    documented. Such validation and

    documentation may be accomplished in

    accordance with 211.194(a)(2).

    Translation: Test method validation

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  • QUALITY ASSURANCE

    (f) Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.

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  • QUALITY ASSURANCE

    Rejection of drugs whose analysis is Out Of Specifications

    Drug reprocessing is allowed after failing specifications

    Reprocessed material and drugs must be re-tested

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  • QUALITY ASSURANCE

    SUMMARY:

    The regulation calls for the following:

    1.Established scientifically sound and specifications:

    Compedia-based, industry, or internal requirements

    2.Documented Standards

    3.Documented Sampling plans

    4.Documented Test procedures

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  • QUALITY ASSURANCE

    5.Validated test methods

    6.Documented processes and procedures

    7.Scientifically sound sample size

    8.Calibrated test equipment

    9.Trained and qualified laboratory personnel

    10.Defined roles and responsibilities

    11.Established standards

    12.Deviation control procedure

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  • MODULE ACTIVITY

    CRITICAL THINKING

    KNOW THE ENEMY----Tsansu

  • MODULE FOUR

    LABORATORY NON-CONFORMITIES

  • OUT OF SPEC TEST RESULTS

    There are three types of laboratory issues that must be investigated:

    1.Nonconformity:

    Out Of Specification(OOS) test results.

    Results that are outside Specified limits.

    2.Adverse trends:

    Out of Trend (OOT) test results

    Results that are out of established Control limits

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  • OUT OF SPECT TEST RESULTS

    3.Incidents

    Happenings with known and proven

    special causes

    All have to be investigated

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  • CONTROL LIMITS

    Are established through experiments:

    DOE, or during process design. They are:

    1. LCL----Low control limit

    2. CL-----Control Limit (the mean,)

    3. UCL-----Upper control Limit

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  • SPECIFIED LIMITS

    Specified Limits:

    1.Are specified from the compendium

    2.Are specified from given standards

    USL-----upper specified Limit

    SL--------Specified Limit

    LSL-----Low specified Limit

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  • OOS DEFINED

    Out of specification (OOS) results includes all suspect results that

    Fall outside the specifications in the drug master file(DMF)

    Fall outside acceptance criteria established in new drug applications

    Fall outside acceptance criteria from the official compendia

    Fall outside acceptance criteria by the manufacturer.

    Suspect In-process laboratory tests

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  • SPECIFIED LIMITS.

    Originate from the compendia, standards, or

    industry research. They are:

    1.LSL-------Low Specified Limit

    2.SL---------Specified Limit

    3.USL------Upper Specified Limit

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  • OOT DEFINED

    Out of trend (OOT) results includes all suspect results that

    Fall outside the trend specifications

    Fall within acceptance criteria for the established new drug applications, official compendia, or by the manufacturer but out of historical trend.

    OOT stability data can be described as a result or sequence of results that are within specification limits but are unexpected, given the typical analytical and sampling variation and a measured characteristic's normal change over time (e.g., an increase in degradation product on stability).

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  • IDENTIFYING OOT RESULTS

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  • IDENTIFYING OOT RESULTS

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  • OOT TYPES FOR STABILITY

    Three types of stability OOT results need to

    be investigated:

    Analytical

    Process control

    Compliance

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  • OOT TYPES FOR STABILITY

    1. An analytical alert is observed when a

    single result is aberrant but within

    specification limits (i.e., outside normal

    analytical or sampling variation and normal

    change over time:

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  • STABILITY OOT RESULTS

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  • STABILITY OOT RESULTS

    2. A process control alert occurs when a

    succession of data points shows an atypical

    pattern that was possibly caused by

    changes to the laboratory or manufacturing

    process. These data points might originate

    from the same stability study (see Figure 2)

    or from multiple studies assayed within a

    reasonably close timeframe

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  • OOT TYPE FOR STABILITY

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  • STABILITY OOT RESULTS

    3. A compliance alert defines a case in

    which an OOT result suggests the potential

    or likelihood for OOS results to occur before

    the expiration date within the same stability

    study (or for other studies) on the same

    product

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  • STABILITY OOT RESULTS

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  • OOT RESULTS.

    Recommendation:

    The main focus for OOT identification and

    investigation should be annual, routine

    production stability studies rather than

    primary new drug application (NDA) batches

    because historical data are usually needed

    to determine appropriate OOT alert limits.

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  • MODULE FIVE

    REQUIREMENTS FOR INVESTIGATING

    LABORATORY NONCONFORMITIES.

  • REQUIREMENTS AND GUIDANCES

    IMPLIED AND EXPLICIT.

  • GUIDANCE AND REGULATIONS.

    The FDA approaches OOS and OOT investigations using FOUR sets of requirements:

    1. The code of Federal regulations: 21CFR211.192

    2. Guidance for Industry: Investigation of Out-Of-Specification(OOS) Test Results for Pharmaceutical production,(2006)

    3. ICHQ10:Pharmaceutical Quality system

    4. Part 21CFR820.100(J):Corrective Action and Preventive Action

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  • 21CFR 211.192

    1. THE REGULATION GOVERNING THE INVESTIGATION

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  • THE REGULATION

    21 CFR 211.192

    Any unexplained discrepancy of the failure of a batch or any of its contents to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.

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  • THE REGULATION.

    21 CFR 211.192

    Failure of a batch or any of its

    contents to meet any of its

    specifications shall be thoroughly

    investigated

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  • THE REGULATION

    21 CFR 211.192

    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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  • THE REGULATION

    Key phrases:

    1. Any unexplained discrepancies

    2. Failure of a batch or any of its

    contents to meet any of its

    specifications shall be thoroughly

    investigated

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  • THE REGULATION

    Key phrases:

    3. The investigation shall extend to

    other batches of the same drug

    4. A written record of the

    investigation shall be made

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  • THE REQULATION

    Summary of the regulation:

    All OOS and OOT must be investigated

    The investigation must be thorough

    There must be impact and risk

    assessment during the investigation

    Records of the investigation must be kept

    Results and follow up(effectiveness check)

    must be documented.

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  • 2. THE GUIDANCE

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  • 2. THE GUIDANCE

    Note the following:

    A guidance is exactly that: a guidance

    It is not legally binding

    A regulation is legally binding

    A guidance gives the current approach/thinking of the FDA

    The current thinking is that you should have an initial assessment using your lab SOP FOLLOWED by a full blown investigation by Quality : Phase I and Phase II.

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  • 3.ICHQ10

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  • 3.GUIDANCE

    Investigation of OOS and OOT as part of:

    Product Quality monitoring

    Process control

    Risk management

    Impact assessment

    CAPA.

    An activity that covers the entire product life cycle.

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  • 3. ICHQ10.

    ICHQ10

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  • ICHQ10

    Requirements:

    Investigation of Product rejections

    Investigation of non-conformances

    Investigation of process performance

    trends

    Investigation of Product Quality

    monitoring trends

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  • 21CFR820.100(J)

    CORRECTIVE ACTION AND PREVENTIVE ACTION

  • 4.CAPA REQUIREMENTS.

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

    The procedures shall include requirements for:

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  • 4. CAPA REQUIREMENTS

    (2) Investigating the cause of

    nonconformities related to product,

    processes, and the quality system

    Note: Testing is a process

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  • 4.CAPA REQUIREMENT

    NOTE:

    CAPA is a universal continuous Quality

    improvement subsystem

    It is independent of the product your

    organization designs, manufactures, and

    distributes.

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  • MODULE SIX

    INVESTIGATION.

  • INVESTIGATION

    REQUIREMENT:

    All un-explained discrepancies shall be investigated according to 21CFR211.192.

    They include:

    1.Incidents

    2.OOT (Adverse trends)

    3.OOS (Results not meeting specifications)

    4. Autlier data points

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  • INVESTIGATION

    We investigate special causes and the six assignable causes of variation: the 6Ms.

    The purpose is to:

    1.Understand the product, process, and Quality system 2.Improve the product, process, and Quality system

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  • INVESTIGATION

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  • INVESTIGATION

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  • INVESTIGATION

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  • INVESTIGATION

    USL

    UCL

    CL

    LCL

    LSL

    Relationship between control limits and specified limits

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  • INVESTIGATION

    (3) Outlier:

    observations that appears to deviate markedly

    from other members of the sample in which they

    occurs.

    They most extreme observations in an

    experiment.

    A data point that lies in an abnormal distance

    from other values in a random population sample.

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  • INVESTIGATION

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  • INVESTIGATION

    There are two phases of the investigation into laboratory test nonconformities:

    1.Phase I: Initial evaluation

    2.Phase II: Full blown investigation

    Phase one is done in the lab using the labs SOP and recorded in the lab notebook

    Phase two is handled in the CAPA system by the Quality unit.

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  • THE PROCESS FLOW

    108

    START INVESTIGATION

    PHASE I

    LABORATORY INVESTIGATION

    PHASE II

    FULL SCALE INVESTIGATION

    OOS/OOT

    FOUND

    1. ANALYST

    2. LAB

    SUPERVISOR

    OBVIOUS

    ERROR?

    NO.

    ASSINABLE CAUSE NOT KNOWN

    TEST HYPOTHESIS

    FOR ASSIGNABLE

    CAUSE

    PASS?

    DOCUMENT

    INVESTIGATION

    YES

    STOP RECURRENCE

    NO

    Report to Quality

    YES

    Analyst

    Inform supervisor

    QUALITY

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  • INITIAL EVALUATION

    PHASE ONE

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  • PHASE I:INITIAL ASSESSMENT

    Initial assessment is usually performed in

    the laboratory

    Initial assessment is lead by the analyst

    The assessment must be approved by lab

    manager

    Results are documented in the lab

    notebook

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  • PHASE I:INITIAL ASSESSMENT

    It covers two phases of CAPA:

    Initiation

    Containment

    Outputs:

    1.Problem statement

    2.Impact assessment

    3.Risk assessment

    4.CAR/PAR

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  • PHASE II: FULL BLOWN

    INVESTIGATION

    Initiated in the CAPA system

    Lead by the Quality unit

    Performed per the CAPA SOP

    Performed per CAPA process flow

    Performed per CAPA requirements in

    21CFR 820.100(J)

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  • INITIATION

    Step One: Draft a Problem statement for the

    test result

    A problem statement is a clear concise

    description of the issue(s) that need(s) to be

    solved.

    Use the 5 'W's - Who, What, Where, When,

    and What

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  • INITIATION

    Combine Who, What ,When ,Where and what

    Example: I tested six batches of a tablet

    product (pharmaceutical finished dosage form)

    on second shift in lab106B and got the

    following assay results of its active drug

    content: 91%,89%,75%,89%,90% and 92%.

    The Product specification is 89% to 95% of

    active drug content.

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  • INITIATION

    Step Two: Containment

    Re-test same batch if you must

    Perform impact assessment

    Perform risk assessment

    Leading Questions:

    What are the effects of these results?

    What is the risk to the end-user?

    Who should know about this?

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  • INITIATION

    Step 3 :Initiate a CAPA

    Complete a CAR/PAR

    Attach the problem statement to the CAR/PAR

    Obtain departmental signature

    Forward CAR/PAR to QA,or CAPA coordinator.

    Note: The CAR/PAR must be accompanied by

    initial risk assessment and impact assessment

    data.

    116 http://www.cgmpuniversity.com

  • ROOT-CAUSE ANALYSIS

    PHASE II INVESTIGATION

  • ROOTCAUSE ANALYSIS

    118

    What it is: Root- cause analysis (RCA): Refers to a problem-solving methodology that identifies and correct a problem's underlying cause (s). It assumes that the best way to solve problems is by eliminating their underlying causes. It also works under the belief that symptoms serves as indicators for underlying cause (s).

    http://www.cgmpuniversity.com

    http://www.thinkreliability.com/http://www.thinkreliability.com/http://www.thinkreliability.com/http://www.thinkreliability.com/

  • ROOT CAUSE ANALYSIS.

    It involves unearthing what is beneath the

    surface: (the root of the OOT, OOS, outlier,

    and errors)

    It takes place in CAPA(Phase II)

    It is systematic

    Methodical

    119 http://www.cgmpuniversity.com

  • ROOT CAUSE ANALYSIS

    120 http://www.cgmpuniversity.com

  • ROOT-CAUSE ANALYSIS

    Key:

    Get to:

    Special causes past assignable causes

    Root-cause

    Unearthing what lies beneath the surface of what is seen, or is the obvious

    Note: Pilot error is the assignable cause for a crush. The culture of the company maybe the root-cause.

    http://www.cgmpuniversity.com 121

  • ROOT CAUSE ANALYSIS.

    RCA takes place in in phase two of the CAPA life

    cycle:

    Investigation: Phase II

    Implementation: Phase II

    Effectiveness check/follow up: Phase II

    Closure: Phase II

    Note: Escalation can take place at any time

    122 http://www.cgmpuniversity.com

  • THE FLOW. 1.DISCOVERY

    2.CONTAINMENT

    3. INVESTIGATION

    4.IMPLEMENTATION

    5.ASSESSMENT

    ESCALATION

    6.CLOSURE

    END

    START

    123 http://www.cgmpuniversity.com

  • ROOT-CAUSE ANALYSIS

    There are five steps in performing RCA:

    STEP ONE

    Define the problem using a problem statement

    STEP TWO

    Come up with a hypothesis and define the criteria for success

    STEP THREE

    Select the right tool to test your hypothesis

    STEP FOUR

    Test your hypothesis

    STEP FIVE

    Validate/verify your solution

    STEP SIX

    Implement and monitor for success

    124 http://www.cgmpuniversity.com

  • MODULE ACTIVITY

    CRITICAL THINKING

  • MODULE SEVEN

    ROOTCAUSE ANALYSIS TOOLS

  • ROOT-CAUSE ANALYSIS

    There are several RCA tools. They all fall in

    two categories:

    Linear analysis

    Deductive reasoning

    1.Choose the right tool for the right job

    2.Some times you need a combination of

    tools to complete the investigation.

    127 http://www.cgmpuniversity.com

  • ROOT-CAUSE ANALYSIS

    128

    Here are the recommended RCA tools for OOS, and OOT investigations:

    Ishikawa: Fish bone

    Problem mapping

    The Affinity diagram

    Process Failure mode and Effect Analysis

    Fault tree analysis

    CTQ tree

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  • 1. ISHIKAWA

    FISHBONE ANALYSIS

  • 1. ISHIKAWA

    Ishikawa is a linear tool that focusses on:

    The five assignable causes of variation

    (the 5Ms):

    Man: The analyst

    Machine: Test equipment

    Material: Reagents, and samples

    Method: Test method/test procedure

    Mother nature: The lab/environment

    130 http://www.cgmpuniversity.com

  • 1.ISHIKAWA

    131

    This is an Engineering tool limited to Processes and system failure analysis

    The analysis is based on the belief that ALL effects in a process, or system are caused by the five (at times six including culture) assignable sources of variation

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  • 1. ISHIKAWA

    132

    Analysis is based on a cause-and-effect

    relationship.

    It is linear

    Used for process, product, and system

    failures.

    Note: Testing is a process.

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  • 1. ISHIKAWA

    133 http://www.cgmpuniversity.com

  • 1. ISHIKAWA

    HOW TO USE IT:

    134

    How to use cause-and-effect analysis

    to solve a problem:

    Start off by developing a

    hypothesis

    Example: It appears the new

    chemistry has an effect on the

    sensitivity of the test equipment.

    Work from right to left http://www.cgmpuniversity.com

  • 1.ISHIKAWA

    Firm your hypothesis into a problem statement

    Analyze your problem statement in term of 5M enablers

    Find enablers to support the 5M enablers

    Continue with enablers

    Look for the common themes

    Summarize themes into root causes

    135 http://www.cgmpuniversity.com

  • 1. ISHIKAWA

    136 http://www.cgmpuniversity.com

  • 2. PROBLEM MAPPING

    LEFT TO RIGHT LINEAR

    THINKING

  • 2. PROBLEM MAPPING

    The method:

    Works when the Effect is supported by one or several pieces of obvious evidence

    Go from left to right

    Start off with the problem

    Follow with the obvious evidence

    Attach the evidence to assumed causes

    Confirm the cause by elimination through validation, or verification.

    138 http://www.cgmpuniversity.com

  • 2.PROBLEM MAPPING.

    139 http://www.cgmpuniversity.com

  • 2.PROBLEM MAPPING

    140

    The problem or primary effect is shown on the

    left in red.

    The evidence boxes are shown in purple to

    distinguish them from the causes.

    You read this chart from left to right and add the

    words "was caused by" at each line.

    Eliminate suppositions based on available

    evidence

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  • 3. FAULT TREE ANALYSIS

    TOP BOTTOM ANALYSIS

  • 3.FAULT TREE ANALYSIS

    It is based on OR, and AND gates

    142 http://www.cgmpuniversity.com

  • 3. FAULT TREE ANALYSIS

    143

    Characteristics:

    It is based on deductive reasoning

    It is system and process based

    Conditions are stipulated by gates

    Uses and, and or gates

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  • 3. FAULT TREE ANALYSIS

    144

    FTA analysis involves five steps:

    Step 1:Define the undesired event to study

    One event per Fault tree analysis

    Step 2: Get an understanding of the test

    Number all causes of the event

    Develop your hypothesis

    Sequence all events in order of occurrence

    Step 3: Construct the fault tree

    Look for AND gates

    Look for OR gates

    The effect drives the GATES

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  • 3. FAULT TREE ANALYSIS

    145 http://www.cgmpuniversity.com

  • 3. FAULT TREE ANALYSIS

    146

    Step 4: Evaluate the fault tree

    Analyze the tree for FAILURE

    Propose solutions.

    Step 5: Test your proposed solutions

    Step 6: Validate/verify solutions

    Step 7:Implement solution

    Step8: Monitor for effectiveness check

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  • PROCESS FAILURE MODE

    AND EFFECT ANALYSIS

    4. PFMEA

    147 http://www.cgmpuniversity.com

  • 4.PFMEA

    148

    PFMEA is : (1) A risk assessment tool used to: Anticipate process failures Mitigate process failures Reduce the likely-hood of process failure

    occurrence Improve detection methods Improve detection of failure at Critical

    Control Points (CCPs) in a process. (2) Brain storming tool for cumulative variation analysis

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  • 4.PFMEA

    149

    PFMEA (process failure mode and Effect Analysis)

    is based on three factors:

    Occurrence of the failure

    Severity of the failure

    Detection of the failure

    The mode: Manifestation of the failure

    RPN: The magnitude of the effect

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  • 4.PFMEA

    150

    Failure Mode:

    The manner in which the failure is observed, or

    manifests itself

    Effect:

    The consequences of the failure

    Detection:

    Method for catching the failure

    Occurrence

    Frequency during normal use

    Severity

    Consequence when failure manifests itself

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  • 4. PFMEA

    USE OF THE TOOL:

    Anticipate and mitigate

    Analyze and fix

    NOTE:

    It is both a reactive and proactive tool

    Assumption:

    The effect(OOS) is the results of existing failure modes.

    151 http://www.cgmpuniversity.com

  • 5.THE 5 WHYs

    152 http://www.cgmpuniversity.com

  • 5. THE 5WHYs

    153

    The 5 Whys is a questions-asking method

    used to explore the cause/effect

    relationships underlying a particular

    problem.

    Ultimately, the goal of applying the 5 Whys

    method is to determine a root cause of

    a defect or problem.

    http://www.cgmpuniversity.com

    http://pediaview.com/openpedia/Root_causehttp://pediaview.com/openpedia/Defect

  • 5.THE 5WHYs

    154

    How to use It:

    Step1: Define the problem in a problem statement

    Step 2:Find the reasons why the problem

    occurs

    Step 3: Define the enablers of the reason/s

    Step 4: Define enablers of enablers

    Step 5: Continue to the 5th why

    Step 6: Drill down to the root of the problem

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  • IMPLEMENTATION

    VALIDATION /VERIFICATION OF

    SOLUTIONS AND PLAN

  • IMPLEMENTATION

    Define the solution to the root-cause

    Define tasks to be performed

    Assign timelines

    Validate the proposed solution to the root-cause

    Define the measure of success

    Note: The MSA is required

    Implement the proposed solution

    The implementation plan

    156 http://www.cgmpuniversity.com

  • EFFECTIVENESS CHECK.

    Follow up: Monitor the data for proof of

    success.

    Use the chosen MSA to proof success

    Request for closure

    Escalate if you have to

    Ask for an extension if you need more

    time.

    157 http://www.cgmpuniversity.com

  • MSA:MEASUREMENT SYSTEM ANALYSIS

    Common MSA statistic tools:

    Measure of repeatability and reproducibility:

    Cpk (variable data): Analysit,shift,lab

    Kappa agreement (attribute data):Operator

    to operator

    ANOVA

    158 http://www.cgmpuniversity.com

  • CLOSURE

    DOCUMENTATION

  • RECORD

    Investigation record should cover the entire CAPA life cycle and should include:

    Problem statement

    Raw data

    Impact assessment/risk assessment

    CAPA implementation plan

    Investigation report

    Methodology for RCA

    Post implementation(follow up/effectiveness check) data

    160 http://www.cgmpuniversity.com

  • REVIEW WARNING LETTERS.

    MODULE ACTIVITY

    161 http://www.cgmpuniversity.com

  • LECTURE SUMMARY

    What you must know

    Regulatory requirements governing and OOS/OOT

    Your role as a Quality professional

    Acceptable practices

    Practices that are not acceptable

    How your lab will be inspected by the FDA

    How to prepare for the inspection

    162 http://www.cgmpuniversity.com

  • THANK YOU!

    I also teach:

    How to design a Quality system for a pharmaceutical company

    How to perform Process validation

    How to write SOPs and WIs

    Principles of Corrective Action/Preventive Action(CAPA)

    On-site and off site

  • CONTACT

    E-Mail:

    david@cgmpuniversity.com

    Website: http://www.cgmpuniversity.com

    164 http://www.cgmpuniversity.com

    mailto:david@cgmpuniversity.com