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HOW TO PERFORM LABORATORY
OUT OF SPECIFICATION
INVESTIGATIONS THAT MEET FDA
REQUIREMENTS USING ROOT CAUSE
ANALYSIS.
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MODULE ONE
INTRODUCTION TO THE QUALITY
SYSTEM .
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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 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?
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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
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THE FIVE QUALITY SUBSYSTEMS
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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
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MODULE THREE
THE ROLE OF THE LABORATORY IN
THE QUALITY SYSTEM.
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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
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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
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MODULE FOUR
LABORATORY NON-CONFORMITIES
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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,µ)
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.
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REQUIREMENTS AND GUIDANCES
IMPLIED AND EXPLICIT.
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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
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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.
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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 lab’s 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.
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ROOT-CAUSE ANALYSIS
PHASE II INVESTIGATION
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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
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ROOT CAUSE ANALYSIS
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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.
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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
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THE FLOW. 1.DISCOVERY
2.CONTAINMENT
3. INVESTIGATION
4.IMPLEMENTATION
5.ASSESSMENT
ESCALATION
6.CLOSURE
END
START
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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
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MODULE ACTIVITY
CRITICAL THINKING
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MODULE SEVEN
ROOTCAUSE ANALYSIS TOOLS
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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.
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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
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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
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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
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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.”
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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
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1. ISHIKAWA
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2. PROBLEM MAPPING
LEFT TO RIGHT LINEAR
THINKING
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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.
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2.PROBLEM MAPPING.
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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
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3.FAULT TREE ANALYSIS
It is based on “OR”, and “AND” gates
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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
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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
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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
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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.
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5.THE “5 WHYs”
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5. THE “5WHYs”
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• 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.
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5.THE “5WHYs”
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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
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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
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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.
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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
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CLOSURE
DOCUMENTATION
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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
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REVIEW WARNING LETTERS.
MODULE ACTIVITY
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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
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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
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CONTACT
E-Mail:
Website: http://www.cgmpuniversity.com
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