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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


QUALITY SYSTEM DEFINED.

Key words and phrases: • Organizational structure

• Processes

• Procedures

• Resources

• Responsibilities

Source: ISO 8402:1994


1.ORGANIZATIONAL STRUCTURE.

ORGANIZATIONAL STRUCTURE • Defined roles of management of the

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


ORGANIZATIONAL

STRUCTURE(Cont.)

The organization of your laboratory is key to effective way of handling your laboratory’s 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?


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?


PROCESSES (Cont.)

F(X)

PROCESS

OUTPUT:

PRE-DETERMINED

SPECIFICATIONS

(Y)

INPUTS

5M

X1

X2


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


PROCESSES (Cont.)

Out puts

Defined specifications for

• Product

• Process


PROCESSES (Cont.)

EXAMPLE

Process:

• Gas chromatography: GS analysis


PROCESSES (Cont.)

The Process:

What: Analytical process for separating

compounds based on their volatilities

Measure of success:

• Retention times

• Peaks


PROCESSES (Cont.)

METHOD:

• Test procedure

• Work Instructions

• Laboratory SOPs


PROCESSES (Cont.)

MAN:

• The Analyst

• The laboratory manager

• The production operator


PROCESSES (Cont.)

MATERIAL:

• The samples

• The reagents

• Inert Career gas


PROCESSES (Cont.)

Machine: GS equipment


PROCESSES (Cont.)

Output:


PROCESSES (Cont.)

Defined spec:


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


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


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


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?


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


TEST ON THE QUALITY SYSTEM

MODULE ACTIVITY


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


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.


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)


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


QUALITY CONTROL

THE ROLE OF THE LABORATORY

21CFR 211.165 ----Material

Testing and release


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


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


QUALITY CONTROL

• Testing each batch to determine

conformance to specifications

• Where sterility testing is required batches

may be released before test results are

received.


QUALITY CONTROL.

Quality control : (Testing)

The focus is on:

• In-process controls

• API, excipients

• Release of the finished products


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


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.


21 CFR211.160: Subpart I

QUALITY ASSURANCE


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.


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.


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.


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:


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


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.


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.


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


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:


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:


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:


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


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.


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


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


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


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


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,µ)

3. UCL-----Upper control Limit


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


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


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


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).


IDENTIFYING OOT RESULTS


IDENTIFYING OOT RESULTS


OOT TYPES FOR STABILITY

Three types of stability OOT results need to

be investigated:

• Analytical

• Process control

• Compliance


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:


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


OOT TYPE FOR STABILITY



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




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.


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


21CFR 211.192

1. THE REGULATION GOVERNING THE INVESTIGATION


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.”


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”


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.”


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


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


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.


2. THE GUIDANCE


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.


3.ICHQ10


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.


3. ICHQ10.

ICHQ10


ICHQ10

Requirements:

• Investigation of Product rejections

• Investigation of non-conformances

• Investigation of process performance

trends

• Investigation of Product Quality

monitoring trends


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:


4. CAPA REQUIREMENTS

(2) Investigating the cause of

nonconformities related to product,

processes, and the quality system

Note: Testing is a process


4.CAPA REQUIREMENT

NOTE:

CAPA is a universal continuous Quality

improvement subsystem

• It is independent of the product your

organization designs, manufactures, and

distributes.


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


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


INVESTIGATION


INVESTIGATION


INVESTIGATION


INVESTIGATION

USL

UCL

CL

LCL

LSL

Relationship between control limits and specified limits


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.


INVESTIGATION


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 lab’s SOP and recorded in the lab notebook

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


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


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


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


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)


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


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.


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?


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.


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).


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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


ROOT CAUSE ANALYSIS


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.


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


THE FLOW. 1.DISCOVERY

2.CONTAINMENT

3. INVESTIGATION

4.IMPLEMENTATION

5.ASSESSMENT

ESCALATION

6.CLOSURE

END

START


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


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.


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


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


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


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.


1. ISHIKAWA


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


1. ISHIKAWA


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.


2.PROBLEM MAPPING.


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


3. FAULT TREE ANALYSIS

TOP BOTTOM ANALYSIS

3.FAULT TREE ANALYSIS

It is based on “OR”, and “AND” gates



143

Characteristics:

• It is based on deductive reasoning

• It is system and process based

• Conditions are stipulated by “gates”

• Uses “and”, and “or” gates



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”





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


PROCESS FAILURE MODE

AND EFFECT ANALYSIS

4. PFMEA


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


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


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


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.


5.THE “5 WHYs”


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://pediaview.com/openpedia/Root_cause

http://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


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


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.


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


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


REVIEW WARNING LETTERS.

MODULE ACTIVITY


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


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:

[email protected]

Website: http://www.cgmpuniversity.com


mailto:[email protected]