2. What is QbD?
1. QbD is a systematic , holistic and proactive
approach to Pharmaceutical Development.
2. Begins with predefined objectives.
3. Emphasizes product and process understanding
and process control.
4. Based on sound science and Quality Risk
Management.(ICHQ8R2)
5. A Quality by Design (QbD) principle can be simply
stated as follow…..
“Once a system has been tested to the extent that
the test results are predictable, further testing can
be replaced by establishing that the system is
operating within a defined design space”
2
3. Introduction of QbD?
ICH-concepts
1. Quality by Design
2. Design Space
3. Design of Experiments
4. Critical Quality Attributes (CQA)
5. Critical Process Parameters(CPP)
6. Control Strategy
Quality by Design (QbD) is a concept first
outlined by Juran
3
4. Quality by Design
1. Continuous improvement is hallmark of
quality by design
– G. Taguchi on Robust Design : design changes
during manufacture can result in the last product
produced being different from the first product.
2. In pharmaceutical manufacturing, we don’t
want this-patients and physicians must count
on each batch of drug working just like the
batches that come before .
4
5. Why QbD?
Generic industry business model: Regulator’s
perspective
File first, learn later
Major amendments during review process
-Exhibit batch stability failure, formulation
revision
Longer time for generic product approval
Approved product may not be marketed
Post approval changes-prior approval
supplements
5
6. How QbD will help improve?
Ensure higher level of assurance of product
quality for patient
Improved product and process design & understanding
Monitoring, tracking & trending of product & process.
More efficient regulatory oversight
Efficiency and cost saving for industry
Increase efficiency of manufacturing process
Minimize / eliminate potential compliance actions
6
7. INTRODUCTION OF PROCESS
VALIDATION
Regulators have the authority and responsibility to
inspect and evaluate process validation performed
by manufacturers.
cGMP regulations for validating pharmaceutical
manufacturer require that drug substances be
produced with high degree of assurance of meeting all
the attributes they are intended to possess.
In the Federal register of May,1987;FDA issued a
notice announcing the availability of a guidance entitled
“Guideline on General Principles of Process
Validation” (the 1987 guidance)
7
8. INTRODUCTION
Since then, regulators have obtained additional experience
that allowed to update recommendations to industries on this
topic.
A revised guidance published in Jan,2011; conveys FDA’s
current thinking on process validation and is consistent with
basic principles, first introduced in 1987 guidance.
A revised guidance also provides recommendations that
reflect some of goals of FDA’s initiative entitled
“Pharmaceutical cGMP for the 21st century; A Risk – Based
Approach”, particularly with regard to the use of
• Technological advances in pharmaceutical manufacturing
• Implementation of
Risk management
Quality system tools and management 8
9. GUIDELINES
A new approach of process validation is based on
following guidelines
• ICH Q7 GMP for APIs
• ICH Q8(R2) - Pharmaceutical Development
• ICH Q9 - Quality Risk Management
• ICH Q10 - Pharmaceutical Quality System
• ICH Q11 - Development and manufacture of drug
substances
and,
FDA Guidance for Industry - Process Validation:
General Principles and Practices.
9
10. WHY PROCESS VALIDATION IS REQUIRED?
It is a requirement by law.
Effective process validation contributes to assuring
drug quality.
The basic principle is that “A drug should be
manufactured that is fit for its intended purpose”.
• Quality, Safety and Efficacy should be designed or built in
to the product.
Quality can’t be adequately assured merely by in-process and finished
product inspection or testing.
• Each step of a manufacturing process should be controlled
to assure that the finished product meets all quality
attributes and specifications.
10
11. Traditional definition of process validation for
APIs (ICH Q7)
Process Validation (PV) is the documented
evidence that the process, operated within
established parameters, can perform effectively
and reproducibly to produce an intermediate or
API meeting its predetermined specification and
quality attributes.
11
12. TRADIT IONA L APPROA CH T O PROCESS VALIDA T ION
AND PROCESS DEVELOPMENT
The magic number is 3…
Three (3) successful consecutive validation batches = process
validation
In Process Development phase, final production process was
based on development through the clinical phases, usually with a
science or technical driven approach with a focus on-
• improving synthesis, often the synthetic strategy
• scale-up
• improving a unit operation/process step
• solving equipment related/technical issues
Chemometers (attributes and parameters related to chemistry)
was introduced as a tool during the 70s and 80s, mainly to
support the (above described) science/technical based approach
to process Validation.
12
13. New definition of process validation
13 /
GE /
The collection of data, from the process design stage through commercial
production, which establishes scientific evidence that a process is capable of
consistently delivering quality product.
Process validation involves a series of activities taking place over the lifecycle
of the product and process.
Process
Development
GLP Phase
I
Phase
II
Phase
III
Commerci
al
Process
Validatio
n
Life Cycle
Manageme
nt
Submissio
n
Process
Design ICHQ8
and Q9
Process
Performanc
e
Qualificatio
n
Continued
Process/
Quality
Verificatio
n
Process
Validation
14. New approach to process validation
The new approach of process validation activity is linked with a
“Product lifecycle concept” and with guidelines ICH Q8 to
Q11.
• The lifecycle concept links
• product and process development
• qualification of the commercial manufacturing process
• maintenance of the process in a state of control during routine
commercial production
• Thus, the new guidance on process validation supports
• process improvement, and
• innovation through sound science
14
15. FLOW DIAGRAM OF PROCESS VALIDATION
APPROACH
PDR
MBR
Process (synthesis and
purification) development,
analytical method
development
and validation
Synthesis,
purification,
analytical methods
for biological studies
Verify design
space
Synthesis route scouting,
purification method
testing,
and early analytical methods (PA
T?)
GL
P
Clinical Phase
Deviation
s
Changes
Final
PDR
Final
MBR
Factoria
l
design
Risk
management
Process design
Document
rationale
behind
choices
The key
Document:
Process
Developmen
t Report
15
16. GENERAL CONSIDERATION FOR PROCESS
VALIDATION
• Life cycle approach
• Good project management
• Good archiving
• An Integrated team approach
• Studies based on sound scientific principles
• Risk based decision making
• Evaluation of attributes (quality, product, component)
and parameters (process, operation and equipment) in
terms of their roles in the process and impact on the
product or in-process material.
• Exercise degree of control on attributes and parameters
commensurate with their risk to the process and process
output.
16
17. PROCESS VALIDATIN AND DRUG QUALITY
Effective process validation contributes significantly to
assuring drug quality.
The basic principle of quality assurance is that a drug
should be produced that is fit for its intended use.
This principle incorporates-
• Quality, Safety and Efficacy are designed or built in to the product.
• Quality can’t be adequately assured merely by in-process and
finished product inspection or testing.
• Each step of manufacturing process is controlled to assure that the
finished product meets all quality attributes including specifications.
17
18. APPROACH TO PROCESS VALIDATION
A new guidance of USFDA defines Process Validation as the
collection and evaluation of data, from the process design
through commercial production, which establishes scientific
evidence that a process is capable of consistently delivering
quality product.
Process validation involves a series of activities taking place
over the life cycle of the product and process.
This guidance describes process validation activities in three
stages.
Stage-1 : Process Design
Stage-2 : Process Qualification
Stage-3 : Continued Process Verification
18
19. APPROACH TO PROCESS VALIDATION(Contd..)
Stage-1 : Process Design
The commercial manufacturing process is defined during this
stage based on knowledge gained through development and
scale-up activities
Stage-2 : Process Qualification
During this stage, the process design is evaluated to
determine if the process is capable of reproducible
commercial manufacturing.
Stage-3 : Continued Process Verification
Ongoing assurance is gained during routine production that
the process remains in a state of control.
-- This guidance describes activities typical of each stage, but in
practice, some activities might occur in multiple stages.
19
20. GENERAL CONSIDERATION FOR PROCESS
VALIDATION
In all stages of product life cycle, good project management and good
archiving that captures scientific knowledge will make the process
validation program more effective and efficient.
The following programed practices should ensure uniform collection and
assessment of information about the process and enhance the
accessibility of such information later in the product life cycle.
1 FDA recommends an integrated team approach to process validation that
includes expertise from a variety of disciplines e.g.
• Process Engineering
• Industrial Pharmacy
• Analytical chemistry
• Microbiology
• Statistics
• Manufacturing
• Quality Assurance
20
21. GENERAL CONSIDERATION FOR PROCESS
VALIDATION (Contd…)
Through out the product lifecycle various studies can be initiated to
• Discover impacts of extended time cycle at various conditions and operations,
improvements in process.
• Observe impact of equipments design and inprocess tests and trends.
• Correlate process data with pilot batch, laboratory trials and commercial runs
with yield, quality and impurities.
• Confirm information with previous experience at pilot scale and commercial
batches, about the product and process.
All studies should be
‒ Planned
‒ Conducted
According to-
‒ Sound scientific principles
‒ With appropriate documentation
‒ Approve in accordance with established procedures appropriate for the
stage of the lifecycle.
21
22. GENERAL CONSIDERATION FOR PROCESS
VALIDATION (Contd…)
With a lifecycle approach to process validation that employs risk decision
making through out that lifecycle.
All attributes and parameters should be evaluated in terms of their roles in
the
‒ Process
‒ Impact on the product
‒ In process tests and materials
and re-evaluated as new information is available.
The degree of control over those attributes or parameters should be
commensurate with their risk to the process and process output. In other
words, a higher degree of control is appropriate for attributes or
parameters that pose a higher risk.
Many products are single-source or involve complicated manufacturing
processes. Validation offers assurance that a process is reasonably
protected against sources of variability that could affect production
output, cause supply problems and negatively affect public health.
22
23. STAGE -1: PROCESS DESIGN
Process design is the activity of defining the commercial manufacturing
process that will be reflected in planned master production and control
records.
The goal of this stage is to design a process suitable for routine
commercial manufacturing that can consistently deliver a product that
meets its quality attributes.
Building: Capturing Process Knowledge and understanding.
Generally, early process design experiments do not need to be
performed under cGMP conditions required for drugs intended for
commercial distribution that are manufactured during stage -2 ( Process
qualification ) and stage – 3 (continued process verification ).
Process design experiments should, however, be conducted in
accordance with sound scientific methods and principles including good
documentation practices (ICHQ10)
Decisions and justification of the controls should be sufficiently
documented and internally reviewed to verify and preserve their value for
use for adaption later in the lifecycle of the process and product. 23
24. STAGE -1: PROCESS DESIGN (Contd…)
Process design experiments are often performed at small – scale
laboratories, so, most viral inactivation and impurity clearance studies
cannot be considered at early stage.
Product development activities provide key inputs to the process
design stage, such as the
‒ Selection of the route ( scouting )
‒ Selection of raw materials, catalysts, solvents
‒ General manufacturing pathway
‒ Quality attributes
‒ Expected impurity profile
‒ Functionality and limitations of commercial manufacturing pathway
‒ Variability of environmental conditions.
‒ Expected measurement and monitoring system during commercial
manufacturing
‒ Requirement of specific quality of personnel to handle operations.
Designing of efficient process with an effective process control
approach is dependent on the process knowledge and understanding
obtained.
24
25. STAGE -1: PROCESS DESIGN (Contd…)
Design of experiments (DoE ) study can help develop process knowledge
by revealing.
• Relationships of variables to quality attributes.
• Multivariable impact on quality attributes
• In-process tests and limits
• Requirement of isolation of intermediates or in situ route
Risk analysis tools can be used to screen potential variables for DoE
studies to minimize the total number of experiments conducted to get
maximum knowledge regarding process.
The results of DoE studies can provide justification for establishing
• Ranges of incoming components quality
• Ranges of quantity of components
• Equipment parameters ( MoC, ancillary requirements )
• In process and intermediate materials quality attributes.
• FDA generally does not expect manufacturers to develop and test the
process until it fails.
25
26. STAGE -1: PROCESS DESIGN (Contd…)
Other activities, such as experiments and demonstrations at laboratory or
pilot scale to
‒ QA
‒ Process engineering
‒ Production
also assist in evaluation of certain conditions and predictions of
performance of the commercial process.
Such experiments or demonstrations also provide information to simulate
the commercial process.
It is essential that all informations collected during these experiment and
demonstrations be documented with review, conclusion and decisions.
For example, manufacturer should document the variables studied for
a unit operation and the rationale for these variables identified as significant.
All the information collected during this process can be related during
commercial manufacturing.
26
27. STAGE -1: PROCESS DESIGN (Contd…)
Establishing a Strategy for process control :
Process knowledge and understanding is the basis to establish an
approach to process control for each unit operation and the process
overall, for example.
– Reduce input variation
– Adjust input variation using inprocess tests during manufacturing.
– Intermediate tests and limits
– Equipment monitoring at significant processing points (RPM. Temperature ,
pressure, vacuum etc.)
FDA expects controls to include both –
• Examination of material quality
• Equipment monitoring
Special attention to control the process through operational limits and in-
process monitoring is essential in two possible scenarios –
• When product attribute is not readily measurable due to limitations of sampling
or detectability. ( e.g. viral clearance or microbial contamination ).
• When intermediates and products cannot be highly characterized and well-
defined quality attributes cannot be identified.
27
28. STAGE -1: PROCESS DESIGN (Contd…)
More advanced strategies, which may involve the use of Process Analytical
Technology (PAT ), can include timely analysis and control loops to adjust
the processing conditions so that the output remains constant.
Manufacturing system with PAT can provide a higher degree of process
control than non-PAT system.
28
29. Quality Target Product Profile-QTPP
What is QTPP?
1. A set of elements that defines the drug
product
2. The target or goal set in advance
3. A guide to Drug Product development
When to define QTPP?
1. At the start of development
2. Knowledge gained in development may
change some elements
29
30. Components of QTPP
Components related to safety, efficacy, identity,
purity and potency
Critical and non-critical components, e.g.
Critical: Assay, content uniformity, Impurity
Profile
Non-critical: Appearance
Fixed and variable components
Fixed elements must be present
e.g. Dosage Form, Strength
Variable elements may have a range of
acceptable values
e.g. Tablet weight, assay 30
31. Critical Quality Attributes- CQAs
CQAs are a subset of the QTPP
Quality Attributes that must be controlled within
predefined limits.
CQAs deliver assurance that Drug Product meets its
intended safety, efficiency, stability and performance
CQAs are monitored throughout the DP
development.
CQAs ensure that DP remains within safe and
effective levels.
31
32. Factor affecting CQAs (Critical
Quality Attributes)
CMAs
(Properties of input
materials)
Identify Critical
Material Attributes
-Particle Size
CPPs
(Critical Process
Parameter)
Identify Critical Process
Parameters
For drug substances:
-Temperature
-Time
-Pressure
-pH
-Moisture content or LOD
For drug Products:
-Dissolution
-Degradation Impurities
-Assay
etc
32
34. Critical Material Attributes(CMAs)
Risk Assessment of the drug substance
attributes
Solid state form and particle size of DS are CMAs
Drug Product
CQAs
Solid
State
Form
Hygroscopicit
y
Particle
Size
Residual
Solvents
Process
Impurities
Chemical
Stability
Physical
Attributes (size
and splitability)
LOW LOW LOW LOW LOW LOW
Assay LOW LOW LOW LOW LOW LOW
Content
Uniformity
LOW LOW LOW LOW LOW LOW
Drug Release HIGH LOW HIGH LOW LOW LOW
34
35. Control Strategy
“A planned set of controls, derived from current
product and process understanding that ensures
process performance and product quality….
ICH Q8 (R2) & Q10
Control Strategy includes following elements (but not
limited to):
Input material attributes(e.g. drug substance,
excipients, container closure)
Equipment operating conditions (process
parameters)
In-process controls
Finished product specifications
Controls for each unit operations
Methods and frequency of monitoring and control. 35
36. QTPP and Specifications
QTPP
• Desired target for
developmental work
• Components of QTPP
may or may not be in
specification
- Not in spec- Dosage
form, strength
- In spec- Assay,
impurities
• Does not include
acceptance criteria
Specification
• Includes all of the
CQAs
• Specification is a list of
- Tests
- References to analytical
procedures
- Acceptance criteria
• Establishes the set of
criteria to which DP
should conform to be
considered acceptable
for its intended use.
Defining a QTPP does not mean setting all acceptance criteria
or the product specifications before development work begins.36
37. Control Strategy
Developing Control Strategy
Formulation & Process
Design &
Understanding
Risk Assessment
CQA
CPP
CMA
Acceptance
Ranges
(CMA & CPP)
Limits for CQA
Control
Strategy
Ingredients
37
38. Control Strategy
Control Strategy Implementation Options
Enhanced Approach
Traditional Approach
Level 3
End product testing + tightly
constrained material attributes
and process parameters
Level 2
Reduced end product testing
+ Flexibility for critical
material attributes and
critical process parameters
within design space
Level 1
Real-time
automatic control
+Flexible process
parameters
38
39. QbD Tools - DoE
Design of experiments (DoE)
Useful for screening of variables with significant impact
on DP CQAs
Classical approach uses OFAT (One Factor At A Time)
Limited number of experiments gives limited information.
DoE helps study effects of interaction of multiple factor at
a time.
Used in optimization studies, enable creation of “design
space’’
“Design space” is proposed by the applicant and subject
to regulatory assessment and approval.
“Design space’’ developed at lab or pilot scale can be
proposed for commercial scale, but needs to be verified
at production for scale dependant parameters. 39
40. QbD Tools – Risk Assessment
Why risk assessment in product development?
To identify relative risk levels at the
beginning of product development.
To prioritize limited development resources
To document the decision making process
throughout development
To assess the needs of additional studies for
scale up and technology transfer
To identify appropriate specifications, critical
process parameters and manufacturing
controls
To decrease variability of critical quality
attributes .
40
41. Risk Assessment
Risk assessment for
Formulation-starting material properties,
levels of components
Manufacturing process
Step for risk assessment
List out all components / processes
Prepare the process flow chart
Identify all potential failure modes for each
item with risk query (what might go wrong?)
Risk analysis
Risk evaluation
41
42. Risk Assessment
Various formal methodologies available for risk
assessment
Failure Mode Effect Analysis & Failure Mode
Effects & Criticality Analysis
Hazard & Operability Analysis
Supporting statistical tools
It is neither always appropriate nor always
necessary to use a formal risk
management process…. The use of
informal risk assessment processes can
also be considered acceptable . – ICH Q9
A risk-based justification based on
experience and data is always necessary!
42
43. Quality Risk Management ICH Q9
QUALITY RISK MANAGEMENT
Quality risk management is a systematic process
for the assessment, control, communication and
review of risks to the quality of the medicinal
product. It can be applied both proactively and
retrospectively
The quality risk management system should
ensure that
- the evaluation of the risk to quality is based on
scientific knowledge, experience with the
process and ultimately links to the protection of
the patient.
- the level of effort, formality and documentation of
the quality risk management process is
commensurate with the level of risk. 43
44. Pharmaceutical Quality Systems Q10
1. Knowledge Management
2. Describes systems that facilitate
establishment and maintenance of a state of
control for process performance and product
quality.
3. Facilitates innovation and continual
improvement
4. Applies to drug substance and drug product
throughout product lifecycle
5. Control strategy
44
45. Pharmaceutical Quality System (PQS) ICH
Q10
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
Investigational
product Good Manufacturing Practice
Management Responsibilities
Process Performance & Product Quality Monitoring
System
Corrective Action / Preventative Action System
Change Management system
Management review
Knowledge Management
Quality Risk Management
PQS
elements
Enablers
45
46. Development and Manufacture of Drug
Substances- ICH Q11
Provides further clarification on the principles
and concepts described in ICH guidelines
on-
• Pharmaceutical Development (Q8),
• Quality Risk Management (Q9)
• Pharmaceutical Quality System (Q10)
As they pertain to the development and
manufacture of drug substance.
46
47. Development and Manufacture of Drug
Substances –ICH Q11
Traditional approach
- Set points & operating ranges
- Process reproducibility and testing to meet
acceptance criteria
Enhanced approach
- Risk management & science
- Process parameters and unit operations that
impact on CQA
- Further studies, design space & control
strategies over the lifecycle.
47
48. Development and Manufacture of Drug
Substances- ICH Q11
A company can choose to follow different
approaches in developing a drug substance.
For the purpose of this guideline, the terms
“traditional” and “enhanced” are used to
differentiate two possible approaches.
48
49. Process Analytical Technology
(PAT)
Timely measurements during processing
Critical quality and performance attributes
Raw and in-process materials
At-line, on-line or in-line measurements
Founded on “Process Understanding”
Opportunities for improvement
More reliable and consistent processes (&
product)
Less failures, less reworks, less recalls
Flexibility w.r.t. scale and equipment
Better / faster Quality Systems
Process Enhancement Opportunities
49
50. PAT in Tablet manufacturing
Stage Technique Measurement
Dispensing NIR /
Raman
Identification of raw
materials
Wet
Granulation
NIR Moisture distribution
Drying NIR Moisture content
Blending NIR Blend Uniformity
Compression Strain
gauges
Compression force
NIR Content Uniformity
50
53. STAGE -1: PROCESS DESIGN (Contd…)
PROCESS DEVELOPMENT / DESIGN :
Risk based approach to process development / design :
ISHIKAWA DIAGRAM :
Substance
Raw Materials Synthesis Purification
Equipments Work-up Analysis,
Stability
RM-1
RM-2
Purity Ratio
Reaction
Time
Temperature
Reactor InprocessDistillation
cfg.
36”
Solvent
48”
Washing
Location Limits
Instruments
GC HPLC
Choice of
solvent
Catalyst
Water
Quality Purity Ratio
RM Ratio
Catalyst
Solvent
Class 1 Class 2 Class 3
Recovery
Dissolution
Ratio
Solvent
Class 1 Class 2 Class 3
SS GLR
size
Stirrer
Column
Column
MOC Capacity
QTY
Ratio Temp.
cfg .
PH
Extraction
Final analysis
purity Impurity
Stability data
Long
term
Accelerated
Critical
quality
attributes
Target
Product
Profile
Rate
DRY
Temp
Temp.
53
54. STAGE-2 : PROCESS QUALIFICATION
During the process qualification (PQ), stage of process validation,
the process design is evaluated to determine if it
is capable of reproducible commercial manufacturing.
This stage has two elements-
• Design of the facility and qualification of equipments and utilities.
• Process performance qualification(PPQ)
During stage-2, cGMP compliant procedures must be followed.
Successful completion of stage-2 is necessary before commercial
distribution.
Product manufactured during this stage, if acceptable, can be
released for distribution. 54
55. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
Design of a Facility and Qualification of equipments and utilities :
Proper design of manufacturing facility is required under part 211,
subpart C, of the cGMP regulations on Building and Facility.
It is essential that activities performed to assure proper facility
design and commissioning precede PPQ.
Here, the term “QUALIFICATION”, refers to activities undertaken to
demonstrate that equipment and utilities are suitable for the
intended use and perform properly.
This activities necessarily precede manufacturing products at the
commercial scale.
55
56. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
Qualification of utilities and equipment generally includes the
following activities-
• selecting utilities’ and equipment’s construction material,
operating ranges, capacity and performance characteristics
based on whether they are appropriate for their specific uses.
• Verifying that utilities and equipment are built and installed in
compliance with design specifications (built as designed with
proper materials, capacity, functions and properly connected and
calibrated )
• URS
• DQ
o SAT
o FAT
• IQ
56
57. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
• Verifying that utility system and equipment operate in
accordance with the process requirements in all anticipated
operating ranges.
• This should include challenging the equipment or system.
Functions while under load comparable to that expected during
routine production.
• It should also include the performance of interventions, stoppage
and start-up as expected during routine production.
• Operating ranges should be shown capable of being held as
long as would be necessary during routine production.
• Qualification of utilities and equipment can be covered under
individual plans or part of an overall project plan.
• The plan should consider the requirements of use and can
incorporate risk management.
57
58. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
• The plan should identify the following aspects
• The studies or tests to use.
• The criteria appropriate to assess outcome.
• The timing of qualification activities
• The responsibilities of activities to be done by relevant departments
and the quality unit.
• The procedures for documenting and approving the qualification.
58
59. Qualification activity should be documented and summarized in the form of
protocol and report with conclusion.
Quality unit must review and approve the qualification plan and report.
Process performance Qualification:
The Process performance qualification (PPQ) is the second element to
stage-2 process qualification. The PPQ combines the actual
Facility
Utility
Equipment (each now qualified)
Monitoring and measuring tools (Calibrated)
Validated analytical methods
Commercial manufacturing process
Control procedures
Inputs and components
to produce commercial batches.
STAGE-2 : PROCESS QUALIFICATION (CONTD…)
59
60. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
A successful PPQ will confirm the process design and demonstrate that the
commercial manufacturing process performs as expected.
Success at this stage signals an important milestone in the product lifecycle.
A manufacturer must successfully complete PPQ before commencing
commercial distribution of the drug product.
The decision to begin commercial distribution should be supported by data
from commercial scale batches.
Data from laboratory and pilot studies can provide additional assurance that
the commercial manufacturing process performs as expected.
The approach of PPQ should be based on sound science and
manufacturer’s overall level of product and process understanding and
demonstrable controls.
The cumulative data from all relevant studies i.e.
– Designed experiment
– Laboratory batches
– Pilot batches
Should be used to establish the manufacturing conditions in the PPQ.
60
61. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
In most cases, PPQ will have a higher level of sampling, additional testing
and greater scrutiny of process performance than would be typical of
routine commercial production.
The level of monitoring and testing should be sufficient to confirm uniform
product quality throughout the batch.
The extent to which some materials such as
– Recycled solvents
– Column resins
– Molecular filtration media
can be reused without adversely affecting product quality can be
assessed in laboratory and /or pilot studies.
The usable life times of such materials should be confirmed by an ongoing
PPQ protocol during commercial manufacturing.
The goal of validating any manufacturing process will be to establish
scientific evidence that process is reproducible and will consistently deliver
quality products.
61
62. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
PPQ protocol :
A written protocol that specifies the manufacturing
• Equipments
• Conditions
• Controls
• Testing
• Expected outcomes
is essential for this stage of process validation.
FDA recommends that the protocol should discuss the following elements.
The manufacturing conditions, including operating parameters, processing
limits, raw materials or components inputs and equipment.
The data to be collected at different stages of operations and when and
how it will be evaluated, is to be addressed in protocol.
62
63. Tests to be performed.
– in process
– Intermediates
– Final product
release, characterization and acceptance criteria for each significant test.
Sampling should be precisely mentioned in protocol as-
– Sampling plan
– Sampling points
– Number of samples
– Frequency of sampling
– Acceptance criteria
The number of samples should be adequate to provide sufficient statistical
confidence of quality, both within a batch and between batches.
Sampling during validation stage should be more extensive than is typical
during routine production.
STAGE-2 : PROCESS QUALIFICATION (CONTD…)
63
64. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
Criteria and process performance indicators that allow for a science and risk
based decision about the ability of the process to consistently produce a
quality products. The criteria should include-
– A description of the statistical methods to be used in analyzing all collected
data (e.g. statistical metrics defining both intra and inter batch variability).
– Provision for addressing deviations from expected conditions and handling of
nonconforming data. Data should not be excluded from further consideration
in terms of PPQ without a documented, science based justification.(Any data
can be disregarded but cannot be deleted/OOS).
Design of facility; qualification of utilities and equipment; personal training;
qualification and verification of sources of materials if not previously
accomplished.
Status of the validation of analytical methods used in measuring the
process, inprocess materials and the product.
Review and approval of the protocol by appropriate departments and the
quality unit.
64
65. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
PPQ Protocol execution and report:
Execution of protocol should not begin until the protocol has been reviewed
and approved by all appropriate departments, including the quality unit.
Any departure from protocol must be made according to established
procedure or provision in the protocol.
Such departure must be justified and approved by all appropriate
departments and quality unit before implementation.
The commercial manufacturing process and routine procedures must be
followed during PPQ protocol execution.
The PPQ lots should be manufactured under normal conditions by the
personnel routinely expected to perform each step of each unit operation
in the process.
Normal operating conditions should include the utility ( including AHUs and
water system ), material, personnel, environment and manufacturing
procedures.
65
66. A report documenting and assessing adherence to the written PPQ
protocol should be prepared in a timely manner after the
completion of activity. This report should
− Discuss and cross – reference all aspects of the protocol
− Summarize data collected and analyze the data, as specified in
the protocol.
− Evaluate any unexpected observations and additional data not
specified in protocol.
− Summarize and discuss all manufacturing non conformances
such as deviations, aberrant test results or information that has
bearing on the validity of the process.
− Describe in sufficient detail , any corrective actions or changes
that should be made to existing procedures and controls
STAGE-2 : PROCESS QUALIFICATION (CONTD…)
66
67. STAGE-2 : PROCESS QUALIFICATION (CONTD…)
− State a clear conclusion whether the data indicates that the
process met the conditions established in the protocol and the
process is considered to be in a state of control.
− If not, the report should state what should be accomplished
before such a conclusion can be reached (CAPA and
recommendations )
− This conclusion should be based on a documented justification
for the approval of the process and release of lots produced by
it to the market in consideration of the entire compilation of
knowledge and information gained from the design stage
through the process qualification stage.
− Include all appropriate departments and quality unit for review
and approvals.
67
68. STAGE -3: CONTINUED PROCESS VERIFICATION
The goal of 3rd validation stage is continual assurance that the process
remains in a state of control ( the validated state ) during commercial
manufacturing.
A system for detecting unplanned departures from the process, is essential
to accomplish this goal.
Adherence to cGMP requirements, specifically, the collection and
evaluation of information and data about the performance of the process,
will allow detection of undesired process variability Evaluating the
performance of the process identifies the problem and determines whether
action must be taken to correct, anticipate and prevent problems so that the
process remains in control.
An ongoing program to collect and analyze product and process data that
relate to product quality must be established.
The data collected should include relevant process trends and quality of
incoming materials or components or in process materials or finished
product.
68
69. STAGE -3: CONTINUED PROCESS VERIFICATION
(Contd…)
The data should be statistically trended and reviewed by trained personnel.
The information collected should verify that the quality attributes are being
appropriately controlled thoughtout the process.
FDA recommends that the statistician or person with adequate training in
statistical process control techniques develop the data collection plan and
statistical methods and procedures used in measuring and evaluating
process stability and process capability.
Procedures should describe how trending and calculations are to be
performed and should guard against over reaction to individual events as
well as against failure to detect unintended process variability
The quality unit should review information.
If properly carried out, these efforts can identify variability in the process
and/ or signal potential process improvements.
69
70. STAGE -3: CONTINUED PROCESS VERIFICATION
(Contd…)
Good process design and development should anticipate
− Significant sources of variability and establish appropriate.
• Detection
• Control
• Mitigation strategy
• Appropriate alert and action limits.
Many tools and techniques, statistical and qualitative, can be used to detect
variation, characterize it, and determine the root cause.
FDA recommends that the manufacturer should use quantitative, qualitative
and statistical methods whenever appropriate and feasible.
Scrutiny of intra-batch as well as inter-batch variation is part of a
comprehensive continued process verification program.
FDA recommends continued monitoring and sampling of process
parameters and quality attributes during its life cycle to estimate the state
of control of process.
Process variability should be periodically assessed
70
71. STAGE -3: CONTINUED PROCESS VERIFICATION
(Contd…)
Variations can also be detected by the timely assessment of
‒ Defects/ complaints
‒ Out of specification
‒ Process deviation reports
‒ Process yield variations
‒ Batch records
‒ Incoming raw material records
‒ Adverse event report
Production line operations and quality unit staff should be encouraged to
provide feedback on process performance.
FDA recommends that quality unit meet periodically with production staff to
• Evaluate data
• Discuss possible trends
• Undesirable process variation.
and co-ordinate any correction or follow-up actions by production.
71
72. STAGE -3: CONTINUED PROCESS VERIFICATION
(Contd…)
Data gathered during this stage , might suggest ways to improve and or
optimize the process by altering some aspects of the process or product,
such as
• Operating conditions ( ranges or set points )
• Process control
• Components
• In process tests and /or material characteristics
Depending on how the proposed change might affect products quality,
additional process design and process qualification activities could be
warranted.
A description of the planned change, a well – justified rationale for the
change, an implementation plan and quality unit approval before
implementation must be documented.
Maintenance of the facility, utilities and equipment is another aspect of
ensuring that a process remains in control.
72
73. STAGE -3: CONTINUED PROCESS VERIFICATION
(Contd…)
Maintenance of the facility, utilities and equipment is another aspect of
ensuring that a process remains in control.
Once established, qualification status must be maintained through
‒ Routine monitoring
‒ Maintenance schedule
‒ Calibration procedures and schedules.
The equipment and facility qualification data should be assessed
periodically to determine whether re-qualification should be performed and
the extent of that requalification.
Maintenance and calibration frequency should be adjusted on feedback
from breakdown reports.
73
74. CONCURRENT RELEASE OF PPQ BATCHES
In most cases, the PPQ study needs to be completed successfully and a
high degree of assurance in the process achieved before commercial
distribution of a product.
In a special situation, the PPQ protocol can be designed to release a PPQ
batch for distribution before complete execution of the protocol steps and
activities i.e. concurrent release.
FDA expects that concurrent release will be used rarely.
Concurrent release might be appropriate for processes used infrequently
for various reasons such as
‒ Due to limited demand
‒ Rework processes
‒ Short retest period
‒ Minor use
‒ Manufactured in co-ordination with Agency to alleviate a short supply.
Circumstances and rationale for concurrent release should be fully
described in the PPQ protocol.
74
75. CONCURRENT RELEASE OF PPQ BATCHES (Contd…)
Even when process performance assessment based on the PPQ is still
outstanding, any lot released concurrently must comply with
‒ GMP
‒ Regulatory approval requirement
‒ PPQ protocol lot release criteria.
Lot released under PPQ protocol should be based upon meeting
confidence levels appropriate for each quality attribute of the drug.
When warranted and used, concurrent release should be accompanied by
a system for careful oversight of the distributed batch to facilitate rapid
customer feedback.
For example, customers complaint and defect reports should be rapidly
assessed to determine.
‒ Rootcause for defect or complaint
‒ Whether the process should be improved or changed
75
76. CONCURRENT RELEASE OF PPQ BATCHES (Contd…)
Concurrently released lots must be assessed in accordance with any
negative PPQ study finding or conclusions and appropriate corrective
action must be taken.
FDA recommends that each batch in concurrent release program be
evaluated for inclusion in the stability program.
It is important that the stability test data be promptly evaluated to ensure
rapid detection and correction of any problem.
Conclusion about a commercial manufacturing process can only be made a
after the PPQ protocol is fully executed and the data are fully evaluated.
If stage-2 qualification is not successful that is a process
• Does not demonstrate that as designed
• Does not capable to produce reproducible and consistent results at commercial
scale.
Then additional process design study and qualification may be necessary.
The new product and process understanding obtained from the unsuccessful
study can have negative implications if any lot was already distributed. Full
execution of stage-1 and 2 of process validation is intended to preclude that76
77. ANALYTICAL METHODOLOGY
Process knowledge depends on accurate and precise measuring
techniques used to test and examine the quality of
• Raw materials
• In process tests
• Intermediates
• Finished product
Validated analytical methods are not necessarily required during product
and process development stage or characterization studies but analytical
methods should be scientifically sound
• Specific
• Sensitive
• Accurate
and produce results that are reliable.
There should be assurance of proper equipment function for laboratory
instruments.
77
78. ANALYTICAL METHODOLOGY (Contd…)
Procedures for
‒ Analytical methods
‒ Instruments maintenance
‒ Calibrations
‒ Documentation practices
‒ Practices supporting process development efforts
(reviews, conclusion, recommendations )
Should be documented or described
New analytical technology and modifications to existing technology are
continually being developed and can be used to characterize the process
or product.
Use of this methods is particularly appropriate when they reduce risk by
providing greater understanding or control of product quality.
However, analytical methods supporting commercial release must follow
cGMP. 78
79. STATISTICAL ANALYSIS
FDA recommends that the manufacturers should use
quantitative, qualitative and statistical methods
whenever appropriate and feasible for assessment
and evaluation during stage -2 ( Process
Qualification) and stage -3
(continued process verification )
79
80. Pareto diagram is a technique of arranging data according to priority or
importance and using it in to a problem solving frame work.
This helps to find out the “Vital Few” from the “Useful Many” for problem
selection.
Mr. Vilfred Pareto was an Italian economist, has
developed this technique. Later, Mr. Lorenz the
US economist has presented this technique in a
theoretical curve. This curve is called Lorenz’s curve.
Example:
An annual review performed by quality assurance department has
revealed following data, which indicates reasons for unplanned
deviation v/s number of unplanned deviations occurred during calendar year.
PARETO DIAGRAM
80
81. Sr. No Reasons for occurrence of unplanned deviation No.
01
02
03
04
05
06
07
08
Environment control in confined area
Manufacturing process
Ambiguity in document /records instructions
Preventive Maintenance
Inadequate Training
Lack of Man power
Analytical error
Others
10
14
25
20
40
15
12
14
• In order to make a Pareto Diagram,
• A data available have to be arranged according to the descending order
in terms of numbers, in a next step.
• A % of numbers and cumulative % of total to be tabulated.
PARETO DIAGRAM (CONTD…)
81
82. Now, let
us make
a Pareto
Diagram
Draw a Vertical Axis on both sides.
Mark number on left Y axis and % on
right Y axis.
Draw horizontal X – X axis to devide in
reasons for unplanned deviations.
Draw a diagram
Draw a cumulative curve or Lorenz
curve.
PARETO DIAGRAM (CONTD…)
82
83. PARETO DIAGRAM (CONTD…)
Sr. No Reasons No. Cum. % Cum.%
1 Inadequate Training 40 40 27 27
2
Ambiguity in document /records
instructions
25 65 17 44
3 Preventive Maintenance 20 85 13 57
4 Lack of Man power 15 100 10 67
5 Manufacturing process 14 114 9 76
6 Analytical error 12 126 8 84
7 Environment control in confined area 10 136 7 91
8 Others 14 150 9 100
150 100%
83
85. TheUseof
ParetoDiagrams The Common use of pareto diagram is in prioritizing
and defining quality related issues. Any production
area faces numerous problems.
The pareto principle and pareto analysis lead the
quality members to focus on those few vital
problems that, when carefully addressed, will result
in the maximum benefit to the organization.
Pareto diagram can also be utilized to statistically
evaluated “Vital Few” from “Useful Many” reasons
for
• Complaints
• Training
• Process Failures
etc.
PARETO DIAGRAM (CONTD…)
85
86. What is fishbone diagram?
Any defect in a component can be due to one or more reasons or causes.
To find out the relationship between the causes and effect, a diagram is
drawn systematically by mapping out all the probable causes
influencing the effect. This is called a Cause and Effect Diagram.
Dr.Kaoru Ishikawa first developed this technique in 1953.
Because of its appearance and similarity with skeleton of a fish,
it is also termed as fish bone diagram.
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM
86
87. How to Draw a Cause and Effect Diagram?
First of all , in a center of a paper draw a thick horizontal arrow
about 75% of the length of paper.
Draw a square or rectangular box adjacent to the arrow head.
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
87
88. Draw 4 to 6 inclined arrows around 60⁰ angle with
the main Arrow.
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
88
89. Draw the sub-arrows (horizontal) meeting inclined arrows.
Balance sub arrows equally on both sides.
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
89
90. Name Main Causes with 4 M’s.
‒ Man
‒ Machine
‒ Material
‒ Method
We may add main reasons apart from 4M.Define the problem in
the box of effect.
Problem
(effect)
Man Machine Any Other
Material Method Any Other
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
90
91. Now start the brain storming session to find the causes
responsible for the existing problem.
As soon as cause is proclaimed, decide the main cause under
which it can be grouped and write it on the sub-arrow under that
main cause.
Continue this activity until the end of the brain storming session,
ensuring all the identified causes are entered under proper main
causes.
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
91
92. One Batch
During
Validation is
Failed
Machine Material Man
Method
Or
Process
Analysis Process
Design
Qualification
Calibration
reactors CFs Water
Balances
Vendors Training
Key RM Sampling
Sources Analysis
Recommended in
PDR New Process
Validation
Equipment
operation
Operational
Dryer AHU
Monitoring instruments
Analysis
Analysis
Cleaning
Impurity profile
RM-3RM-2RM-1
Verification of
Documents/records
Changes
Deviations
Critical parameters
Other operations
Qualification of instruments
Validation of analytical method
Comparison of specification
and methods with manual
Standards/reagents
Analytical data
RM In process intermediates
Verification of process
parameters
Comparison of RM ratio
Comparison of analytical
package
Summary Report
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
PDR
MOC
Vendor Certificates
Cleaning reports
92
93. Fishbone diagram can be used to investigate and
identify root cause during
FISH-BONE DIAGRAM OR CAUSE AND EFFECT
DIAGRAM OR ISHIKAWA DIAGRAM (CONTD…)
Use of
Fishbone
diagram
Complaint
Product
defect
System
failure
OOS
93
94. DESIGN OF EXPERIMENTS (DoE)
Design of experiments based on statistical
evaluations
Statistical data evaluation , results wide variation in
• Critical Parameters
• Impurity Profiles
• Quality Attributes
Factors or parameters influencing wide variations should be
identified and optimized to reduce variability in process and
prevent potential failures.
94
95. DESIGN OF EXPERIMENTS (DoE) (Contd…)
Example:
− A limit of individual
impurity A is <0.1%
in specification. Last
10 batch results are.
# Impurity A %
1 0.03
2 0.09
3 0.06
4 0.05
5 0.08
6 0.07
7 0.08
8 0.07
9 0.04
10 0.07
95
96. 0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0 1 2 3 4 5 6 7 8 9 10
Scatter Grapgh
Upper
Control
limit
Central
Control limit
Lower
Control
limit
The Scatter
of results
indicate
7 out of 10 results
are above central
control limit
(toward upper
limit)
Only 3 results are
either on central
control limit or
below.
There is a
potential for
failure
DESIGN OF EXPERIMENTS (DOE) (Contd…)
96
97. DESIGN OF EXPERIMENTS (DoE) (Contd…)
Action
to be
taken
To identify operational
parameters influencing
on impurity A generation
and plan DoE to control.
97
98. DESIGN OF EXPERIMENTS (DoE) (Contd…)
Uses of DoE
• This technique can be useful in R&D while designing of product.
• Retrospective evaluation of established parameters
• Systematically choosing certain variables and their individual effects.
• The results of DoE should be evaluated in the form of
Tables
Graphically
• DoE can be used to identify impact of deviations and to confirm root cause
for OOS.
98
99. SHEWART CONTROL CHARTS
Dr. W.A.Shewart, a physicist, from Bell laboratories, explained
that, even after extreme sophistication also , it will be
impossible to produce two batches identically same.
Various inputs which go in for an output have their inherent
variation, for example –
‒ Raw Materials
‒ Process Conditions
‒ Manual Operations
‒ Machine Condition
Under these circumstances, obviously output will have variation.
He defined the problem of managing quality as one of between
1. Acceptable variation
2. Unacceptable variation
Using mathematical formula he established boundaries of
variation for a given process. This technique is also called a
“Control Chart” .
99
100. SHEWART CONTROL CHARTS (CONTD…)
Example:
– A result of Assay
value of 25 batches
are graphically
presented against
upper limit and lower
limit.
– Specification of
Assay; 98.0 to 100%
– Batch wise Results.
# Assay %
1 98.3
2 99.6
3 98.5
4 98.6
5 98.9
6 99.2
7 98.4
8 98.3
9 99.2
10 98.4
11 99.9
12 98.1
13 99.7
14 98.2
15 99.1
16 98.6
17 98.6
18 98.4
19 98.3
20 98.6
21 98.6
22 98.3
23 99.6
24 99.3
25 98.4
100
102. Uses of control charts :
• To demonstrate statistical control of process parameters
and quality attributes.
• Further to this, alert limits and actions limits can be
defined to propagate continual improvement in product
quality during its cycle.
• To identify potential problems.
• To monitor critical parameters.
• Provides information to determine.
• Process capability
• Variability
• control
SHEWART CONTROL CHARTS (CONTD…)
102
103. RADAR CHART
103
Radar chart is gating popularity in statistical evaluation techniques.
28.20 Example:
28.21 Quality assurance department has compared “Review of defects” for
consecutive 2 years i.e. 2012-13 and 2013-14 for manufacturing of product A.
Following data revealed in comparison study.
Sr. No Cause for defect Number of defects Column1
2012-13 2013-14
1 Moisture content 3 1
2 Impurity profile (orgainc) 3 4
3 Assay 3 3
4 Description 2 1
5 Solubility 2 1
6 Black particals 4 2
7 Lump formation 1 0
8 Partical Size 2 1
9 Heavy metals 1 0
10 Residual solvent 1 0
104. RADAR CHART(CONTD…)
28.22 Now draw a Radar Chart as follows –
1. Draw a Circle and divide it in 8 part (equal parts
360⁰
8
=
450)
104
1
2
4
3
58
7 6
105. Title the vertical line with 10 causes.
-10
0
Assay
Description
Solubility
Black particals
Lump formation
Partical Size
Heavy metals
Residual solvent
Moisture content
Impurity profile (orgainc)
RADAR CHART
105
106. 28.22 Calibrate 0 to 10 with 0 at center and 10 at outer circle.
28.25 Conclusion:
• Radar chart indicates quantities increase in number of defects due to impurity profile in
organic impurity.
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Assay
Description
Solubility
Black particals
Lump formation
Partical Size
Heavy metals
Resideal solvent
Moisture content
Impurity profile (orgainc)
2012-13
2013-14
RADAR CHART
106
107. SPREAD SHEET
Following spread sheet can be studied a set of data to plan for
the actions-
• Trend analysis of quality attributes
• Data of critical process parameters
• Trends of yield
• Trend of in process results
• Trend of equipment performance against breakdown.
Further to this, mean and standard deviation can be derived to
study variation of results and identifying border cases and
potential problems.
107
108. 1. Scatter diagram is a
graphical presentation of
relationship between two
variables.
2. It will be between causes
and effect or between
two causes.
3. The direction and
“tightness” of the scatter
gives a clue that there a
relationship between
both the variables.
108
Variable-2
Variable-1
SCATTER GRAPHS
109. Patterns of scatter diagrams
Positive
Relationship
Negative
Relationship
No Relationship
SCATTER GRAPHS (CONTD…)
109
111. 68
70
72
74
76
78
80
82
84
86
88
90
92
94
96
98
100
0 1 2 3 4 5 6
Assay % Value
Batchwise
Maintaining hours
Series1
Series2
Series3
Series4
Series5
Linear (Series1)
Linear (Series2)
Linear (Series3)
Linear (Series4)
Linear (Series5)
Uses
To correlate two variables
To correlate one variable with effect.
SCATTER GRAPHS
111
112. Fault Tree Diagram
1. Fault Tree Analysis is a technique for reliability and
safety analysis.
2. Bell Telephone Laboratories developed this concept
in 1982 for the US Air Force.
3. It was later adopted by the Boeing Company.
4. Fault Tree Analysis is one of the many symbolic
“analytical logic technique” found in operations
research and in system reliability.
113. What is Fault Tree Diagram? (FTD)
1. Fault Tree Diagram is a logic block diagram that
displays the state of a system (top event) in terms of
the states of its components (basic events).
2. FTD uses a graphic model of the pathways with in a
system.
3. The pathway connect contributory events and
conditions, using standard logic symbols (AND, OR
etc.).
4. The basic constructs in a FTD are Gates and Events.
115. FTA
1. It is a systematic method of system analysis
2. Examines system Top Down
3. Provides graphical symbols for easy of
understanding
4. Incorporates mathematical tools to focus on critical
areas.
116. FTA used to
Investigate potential faults
It is modes and Causes
And to quantify their contribution to system
unreliability in the course of product design.
119. Thought Process in FTA
FTA is backward looking
The end result is the analysis starting point
(Failure).
The end result is then traced back one step
at a time its immediate causes.
The relationships of the causes or events
are shown with logic symbols.
This backward tracing process continues
until the basic causes are identified.
120. Basic Fault Tree Structure
Top Undesired
Event
Logic
Gates
Intermed
iate
Event
Basic
Event
121. FTA Process
Launch Plan
Analyze for root causes
Draw the fault tree diagram
Add actual or potential causes
Add inputs or faults
Define top level failure
122. FTA Examples
1. Investigation of Laboratory Failure
OOS
Resu
lt
o
r
Production
Lab. error
Others
o
r
Others
Systematic
Random
o
r
Calibration
Interface
Others
123. FTA Examples (Count…)
2. FTA for Cleaning process.
Cleaning Change of
Product
Product
Manufactured
previously
Product to be
Manufactured
afterwards
Characteristics
of equipment
used
Characteristics
of cleaning
process
Solubility in
Solvent used
Solubility
Batch Size
Time of
Cleaning
Batch Size
Residual
Contaminants
Stickyness
Type of surface
of equipment
Area
Design
Worst area for
cleaning
Type of
automisation
Time to be taken
for cleaning
Temperature
Time remaining
for dirty
124. FTA Examples (Count…)
2. Complaint Entry. Complaint
Entry
QA Review
Investigation
required
Report
Assessment
ReportibilityInvestigation
CAPA
Assessment
Follow-up
Reportibility
ClosureActions
US
or
EU Canad
a
