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...

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