‫صاحیت سنجی سیستم ا تج یزات‬

Qualification of Systems and Equipment

Based on PIC/S GMP, Annex 15 and

PI 006; Recommendations on VMP, IQ, OQ, PV & CV

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 1

Presentation Outline

 General principles
• GMP and Validation
• Validation and Qualification
• Approaches to Validation
• Selection Criteria
• V-Model
 Qualification of Systems and Equipment
• Stages of Qualification (DIOPQ)
• Alert/Action limits and Worst Case
• Change control
 Documentation of Qualification and Validation

June 2014 Qualification of Systems and Equipment 2

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Prerequisites for Guaranteed Medicinal Product Quality

Approved theoretical model

Reproduced with:

Suitable Qualified Validated Trained

Rooms Facilities Procedures Personnel

Based on:

Predetermined Written Defined Sufficient

Specifications Procedures Responsibilities Resources

June 2014 Qualification of Systems and Equipment 3

The Relationship Between Validation and GMP

 One of the GMP requirements is the constant production of quality

drugs that are fit for their intended use.

 It is by design and validation that a manufacturer can establish

confidence that the manufactured products will consistently meet
their product specifications.

 To maximize production consistency:

 critical steps must be validated,
 other steps must be under control.

 Validation is the medium with which compliance to these guidelines

is attained and presented in a systematic way.

June 2014 Qualification of Systems and Equipment 4

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 The Relationship Between Validation and GMP

 To show that a process can continuously produce what it purports to

do, validation was put into industry by pharmaceutical industry well
before the word “validation” first appeared in any governmental
regulations.

 The objective of all validation/qualification work is to establish

proof of the suitability of processes/procedures/systems for their
intended use within defined limits, namely the acceptance criteria.
(Fit for purpose)

June 2014 Qualification of Systems and Equipment 5

Semantic Niceties !

 One of the simplest and most easily understood definitions comes

from Fry (at the time a senior official of the FDA) at the PIC
conference in Dublin 1982:

To prove that a process works is, in a nutshell, what we mean by

the verb validation.

!!! ‫اثبات مستند صحت ادعا‬

)‫(شاهمیری‬

June 2014 Qualification of Systems and Equipment 6

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 The Relationship Between Validation and Qualification

 Validation and qualification are components of the same concept.

 Qualification is normally used for equipment, utilities and systems,
and validation for processes.
 In this sense, qualification is part of validation which should be
done before process validation.

June 2014 Qualification of Systems and Equipment 7

The Relationship Between Validation and Qualification

 Each piece of equipment must be qualified before it serves another

piece of equipment / system during validation of the latter.
 e.g. water purification system before steam generator; and
steam generator before autoclave; and only then
validation of sterilization process.

June 2014 Qualification of Systems and Equipment 8

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 The Relationship Between Validation and Qualification

Typical categories of system and equipment which require qualification:

 Systems:  Equipment:
• HVAC • Autoclave
• Compressed air • Depyrogenation tunnel
• Water purification system • Lyophilizer
• Pure steam generator • Continuous flow centrifuge
• WFI generator

June 2014 Qualification of Systems and Equipment 9

Approaches to Validation

 There are two basic approaches to validation:

• one based on evidence obtained through testing
(prospective and concurrent validation)
• one based on the analysis of historical data
(retrospective validation).

 Both prospective and concurrent validation, may include:

• extensive product testing,
• simulation process trials;
• challenge/worst case tests, which determine the robustness of
the process; and
• control of process parameters to obtain additional information
on the reliability of the process. )IPQC ≠ Validation(

June 2014 Qualification of Systems and Equipment 10

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 General Principles of Validation

 To perform validation tasks in a timely manner (specific program),

there should be an appropriate and sufficient system including:
• organizational structure
• documentation infrastructure
• sufficient personnel
• financial resources

 Qualified and experienced personnel should be responsible for

performing validation.

 They should represent different departments depending on the

validation work to be performed.

June 2014 Qualification of Systems and Equipment 11

When to Qualify and Validate?

 A risk assessment approach should be used to determine the scope

and extent of validation required

 Validation should be performed:

• for new premises, equipment, utilities and systems, and processes
and procedures
• at periodic intervals
• after major changes

 Validation should be done over a period of time to demonstrate

consistency.
(at least three consecutive full production scale batches!)

June 2014 Qualification of Systems and Equipment 12

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 When to Qualify and Validate?

 The concept of EQ is not a new one. (Commissioning!)

 Common sense and an understanding of pharmaceutical processing
determine the critical aspects.
 Critical systems, i.e. those whose consistent performance may have
an impact on the quality of the product should be qualified.
 The continued suitable performance of equipment is important for
batch-to-batch consistency.

June 2014 Qualification of Systems and Equipment 13

When to Qualify and Validate?

 Whether qualification is necessary or not, and if yes to what extent,

could be investigated by “Risk Analysis”. )Selection criteria!(
Field Effort

Commissioning
(GEP)

“No impact” System Complexity “Direct impact”

facility systems facility systems

June 2014 Qualification of Systems and Equipment 14

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 FMEA (Failure Mode and Effect Analysis)

 Risk is the combination of probability of harm and severity of harm.

 Parameters for Evaluating Risks:

Risk Priority Number (RPN) = P×S×D

Severity

Probability
June 2014 Qualification of Systems and Equipment 15

Stages of Qualification

 There’re different components of qualification, which is an

important part of validation.

 Different components of equipment qualification are:

• Design Qualification (DQ)
• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)

June 2014 Qualification of Systems and Equipment 16

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 Stages of Qualification

 There’re different components of qualification, which is an

important part of validation.
 Different components of equipment qualification are:

June 2014 Qualification of Systems and Equipment 17

Stages of Qualification

 Although these phases are described as separate activities they may

in some cases be appropriate to be performed in conjunction with
each other.

 i.e. activities such as worst case determinations, process simulation,

or …

 V-Model introduced by GAMP3 is a useful instrument to

demonstrate the qualification components and their relationship.

June 2014 Qualification of Systems and Equipment 18

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 GAMP3 / V-Model

Validation Protocol Validation Report

URS PQ
(User Requirements (Performance
Specifications) Qualification)

FRS OQ
(Functional Requirements (Operational
Specifications) Qualification)

DDS IQ
(Detailed Design (Installation
Specifications) Qualification)

Build System
(Software & Hardware)

June 2014 Qualification of Systems and Equipment 19

‫صاحیت سنجی سیستم ا تج یزات‬

Qualification of Systems and Equipment

Design Qualification (DQ)

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 20

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 Design Qualification

 The documented verification that the proposed design of facilities,

systems, and equipment is suitable for the intended purpose.
(PIC/S GMP, Annex 15)

 The design specifications should meet the GMP requirements.

 User requirements should be considered when deciding on the

specific design of a system or equipment. (URS!)

 DQ should provide documented evidence that design specifications

were met.

June 2014 Qualification of Systems and Equipment 21

Design Qualification

 DQ is most suitably performed by the instrument developer or the

manufacturer.

 A suitable supplier should be selected for the appropriate system or

equipment. (Vendor approval!)

 The instrument design is already in place for commercial off-the-

shelf (COTS) systems.

June 2014 Qualification of Systems and Equipment 22

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 ‫صاحیت سنجی سیستم ا تج یزات‬
Qualification of Systems and Equipment

Installation Qualification (IQ)

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 23

Installation Qualification

 The documented verification that facilities, systems, & equipment,

as installed or modified, comply with the approved design and the
manufacturer’s recommendations.
(PIC/S GMP, Annex 15)

 … is installed completely, correctly and satisfactorily.

 Systems and equipment should be correctly installed acc. to a

written and approved installation plan and IQ protocol.

June 2014 Qualification of Systems and Equipment 24

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 Installation Qualification

 IQ should include, but not be limited to the following:

• Identification and verification of the purchase specifications, all

system elements and components, drawings, manuals, spare parts
lists and vendor details,

• Verification of materials of construction,

• Installation of equipment, piping, services, and instrumentation

checked to current engineering drawings and specifications,

(P&IDs and PFS developed during the project planning phase)

June 2014 Qualification of Systems and Equipment 25

Installation Qualification

 IQ should include, but not be limited to the following: (cont.)

• Development of SOPs for cleaning, maintenance and operation,

• Calibration requirements for control and measuring devices.

(Traceable to national or international standards)

• Deviation report including any deviations, justification for

acceptance and impact on operation.

• IQ report including results and conclusions.

June 2014 Qualification of Systems and Equipment 26

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 ‫صاحیت سنجی سیستم ا تج یزات‬
Qualification of Systems and Equipment

Operational Qualification (OQ)

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 27

Operational Qualification

 The documented verification that facilities, systems, & equipment,

as installed or modified, perform as intended throughout the
anticipated operating range.
(PIC/S GMP, Annex 15)

 … operates as specified over normal operating range and worst

case conditions.

 The correct operation should be verified in accordance with a

written and approved OQ protocol.

June 2014 Qualification of Systems and Equipment 28

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 Operational Qualification

 OQ should include, but not be limited to the following:

• Based on specialist knowledge of the process and how the

equipment will work:
‒ Identification of critical operating parameters,
‒ Identification of the studies and the measuring equipment to
be used,
‒ Acceptance criteria to be met.

June 2014 Qualification of Systems and Equipment 29

Operational Qualification

 OQ should include, but not be limited to the following: (cont.)

• Tests based on knowledge of processes, systems and equipment

to show satisfactory operation over the normal operating range
as well as the limits of its operating conditions,
(including worst case conditions)

Action limit Action limit

Alert limit Alert limit

Design condition
Normal operating range
Operating range (Validated acceptance criteria)

June 2014 Qualification of Systems and Equipment 30

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 Operational Qualification

 OQ should include, but not be limited to the following: (cont.)

• Testing of operation controls, alarms, switches, displays, and

other operational conditions,

• Measurements made in accordance with a statistical approach,

• Finalization of SOPs for cleaning, maintenance, operation and

calibration,

• Documentation and finalization of operator training requirements,

June 2014 Qualification of Systems and Equipment 31

Operational Qualification

 OQ should include, but not be limited to the following: (cont.)

• Deviation report including any deviations, justification for

acceptance and impact on operation.

• OQ report including results and conclusions.

• A formal release of the facilities, systems, and equipment for

routine use only after all calibration, cleaning, maintenance,
training and related tests and results were found to be acceptable.

June 2014 Qualification of Systems and Equipment 32

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 Limits and Worst case

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 33

Limits and Worst Case

 Limits should be defined during the design stage.

 The manufacturer should define:
• design conditions,
• normal operating ranges,
• operating ranges, and
• alert and action limits.
Action limit Action limit
Alert limit Alert limit

Design condition
Normal operating range
Operating range (Validated acceptance criteria)

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 Limits and Worst Case

 Action levels are based on published standards, guidelines or

policies, e.g. standard or control limits.
 Alert levels are based on historical data and must be able to detect
trends or drifts from expected results.
 There should also be written and approved investigation program in
case alert/action levels are exceeded.
Action limit Action limit
Alert limit Alert limit

Design condition
Normal operating range
Operating range (Validated acceptance criteria)

June 2014 Qualification of Systems and Equipment 35

Limits and Worst Case

 Design condition and normal operating ranges should be identified

and set to realistically achievable parameters.
 All parameters should fall within the design condition range during
system OQ.
 Conditions may go out of the design condition range during normal
operating procedures but they should remain within operating range.
Action limit Action limit
Alert limit Alert limit

Design condition
Normal operating range
Operating range (Validated acceptance criteria)

June 2014 Qualification of Systems and Equipment 36

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 Limits and Worst Case

 Tests to include a condition or set of conditions encompassing upper

and lower operating limits and circumstances, which pose the
greatest chance of product or process failure when compared to ideal
conditions.
)sometimes referred to as “Worst Case” conditions(
 Out-of-limit results (e.g. action limit deviations) should be recorded
and form part of the batch manufacturing records.
Action limit Action limit
Alert limit Alert limit

Design condition
Normal operating range
Operating range (Validated acceptance criteria)

June 2014 Qualification of Systems and Equipment 37

‫صاحیت سنجی سیستم ا تج یزات‬

Qualification of Systems and Equipment

Performance Qualification (PQ)

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 38

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 Performance Qualification

 The documented verification that facilities, systems, & equipment,

as connected together, can perform effectively and reproducibly,
based on the approved process method and product specification.
(PIC/S GMP, Annex 15)

 … performs consistently over a suitable period of time and

under user’s environment conditions.

 The performance should be verified in acc. with a written and

approved PQ protocol.

June 2014 Qualification of Systems and Equipment 39

Performance Qualification

 PQ should include, but not be limited to the following:

• Tests, using placebos, that have been developed from knowledge

of processes, systems and equipment;

• Tests to include a condition or set of conditions encompassing

upper and lower operating limits.

 PQ may in some cases be performed in conjunction with OQ.

June 2014 Qualification of Systems and Equipment 40

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 Performance Qualification

 PQ should include, but not be limited to the following: (cont.)

• Test results should be collected over a suitable period of time,

e.g.:

‒ water purification systems: 3 phases over 14 month,

‒ HVAC: 20 consecutive working days for each of the 3 stages

as built, at rest and in operation

‒ Autoclave: 3 runs for various load configuration and cycles

using the worst case situation (largest load or mass).

June 2014 Qualification of Systems and Equipment 41

Performance Qualification

 PQ should include, but not be limited to the following: (cont.)

• Deviation report including any deviations, justification for

acceptance and impact on operation.

• PQ report including results and conclusions.

June 2014 Qualification of Systems and Equipment 42

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 Change Control

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 43

The Overall Concept of Qualification & Validation

V - Model
Vendor’s site Owner’s site
(FAT) (SAT)
Before After Before In
Purchase Purchase Use Operation
Equipment Qualification Performance
(Commissioning) Qualification
Design Installation Operational Process Maintenance,
Qualification Qualification Qualification Validation Revalidation

Change Control

June 2014 Qualification of Systems and Equipment 44

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 The Validity of Validation

 For any validation study, itself, to be valid it is essential that:

• The measuring devices and instruments used in study are

properly calibrated.
• Personnel performing the study are competent and trained to
undertake the work.

June 2014 Qualification of Systems and Equipment 45

The Validity of Validation

 Following the study, for the results to remain valid, it is necessary to:

• Maintain all equipment to the same standards as used in the study.

• Ensure that all measuring devices and process controlling
instruments remain in calibration.
• Ensure that operating staff remain properly competent to perform
the process in routine production.
• Implement a system of change control, which will guard against
unplanned process changes.

June 2014 Qualification of Systems and Equipment 46

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 Change Control

 Change control is a well known GMP concept that focuses on

managing change to prevent unintended consequences.

 Change control is an important element in any quality management

and quality assurance system.

 Commitment of the company to control change is essential to

ensure a continued validation status of the systems concerned.

 All changes should be formally requested, documented and

accepted by representatives of production, QC/QA, R&D,
engineering and regulatory affairs as appropriate.

June 2014 Qualification of Systems and Equipment 47

Change Control

 A formal system by which qualified representatives of appropriate

disciplines review proposed or actual changes that might affect the
validated status of facilities, systems, equipment or processes.
(PIC/S GMP, Annex 15)

 Significant amendments to the manufacturing process, including

any change in equipment or materials, which may affect product
quality and / or reproducibility of the process should be validated.
(PIC/S GMP, #5.23)

June 2014 Qualification of Systems and Equipment 48

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 Qualification of Established (in-use) Equipment

 While it is not possible to undertake the details of an IQ, OQ for the

in-use equipment,
 nevertheless there should be data available that support and verify
the operating parameters and
 limits for the critical variables of the operating equipment.

 Additionally, the calibration, cleaning, maintenance, operating

procedures, for the use of the equipment should be documented and
in use as SOPs.

June 2014 Qualification of Systems and Equipment 49

‫مستندات مستند سازی صاحیت سنجی اعتبارسنجی‬

Documentation of Qualification and Validation

Based on PIC/S GMP, Annex 15 and

PI 006; Recommendations on VMP, IQ, OQ, PV & CV

A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics
QC/QA Manager, Compliance Expert

[email protected]

June 2014 Qualification of Systems and Equipment 50

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 Validation Documentation

 PIC/S GMP annex 15 “ Qualification and Validation” contains only

the principles of qualification and validation.

 PIC/S document PI 006-3 “Recommendations on VMP, IQ & OQ,

Non-Sterile Process Validation, Cleaning Validation” is an aid to
interpretation and implementation.

 The most important relating documentations are:

• Validation Master Plan (VMP)
• Validation Protocol (VP)
• Validation Report (VR)

June 2014 Qualification of Systems and Equipment 51

Validation Documentation

 Of the many forms of the documentation, the following types may

be distinguished as of primary importance:
• Validation Master Plan (VMP), which summarizes the
company’s overall validation policies, plans, and also programs.
• Validation Protocol (VP), which defines a specific procedure.
• Validation Report (VR), which reports on the validation study.
• Supporting documentation presented with the report (SOPs,
flowcharts, diagrams, …(

June 2014 Qualification of Systems and Equipment 52

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 Validation Master Plan (VMP)

 In accordance with Annex 15, EU – PIC/S GMP Guideline (# 2):

“ All validation activities should be planned.
The key elements of a validation program should be clearly
defined and documented clearly in a validation master plan (VMP)
or equivalent documents.”

 In accordance with PIC/S PI 006-3 (# 4.3.1):

“ A validation master plan is a document that summarizes the
firm’s overall philosophy, intentions and approach to be used for
establishing performance adequacy.”

June 2014 Qualification of Systems and Equipment 53

Elements of VMP (PIC/S GMP; Annex 15)

 The VMP should contain data on at least the following:

a) Validation policy;
b) Organizational structure of validation activities;
c) Summary of facilities, systems, equipment and processes to be
validated;
d) Documentation format (for validation protocols and reports);
e) Planning and scheduling;
f) Change control;
g) References to existing documents.

June 2014 Qualification of Systems and Equipment 54

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 What’s a Protocol?

 A protocol is a written set of instructions broader in scope than a

SOP.

 A protocol describes the details of a comprehensive planned study

to investigate:
• the consistent operation of new system/equipment,
• a new procedure, or
• the acceptability of a new process before it is implemented.

June 2014 Qualification of Systems and Equipment 55

What’s a Protocol?

 Protocols include:
• significant background information,
• explain the rationale for and the objective of the study,
• give a full description of the procedures to be followed,
• set out the parameters to be measured,
• describe how the results will be analyzed, and
• provide pre-determined acceptance criteria for making
conclusions.

June 2014 Qualification of Systems and Equipment 56

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 What’s a Protocol?

 Examples of written protocols are:

• Qualification / Validation studies
• Stability studies
• Clinical studies
 Validation protocols are important in ensuring that documented
evidence is taken which demonstrates that an equipment, a system,
a process or a method consistently performs at a specified level.
 Each IQ, OQ and PQ protocols provide documents needed to
perform the qualification such as:
• Specific procedures to follow
• List of materials, equipment and documents
• Data to be recorded with the acceptance criteria
June 2014 Qualification of Systems and Equipment 57

Functions of VMP (PIC/S PI 006-3; # 4.2.2)

 A VMP helps management:

• To know what the validation program involves with respect to
time, people and money, and to
• Understand the necessity for the program.

 A VMP helps all members of the validation team:

• To know their tasks and responsibilities.

 A VMP helps GMP inspectors:

• To understand the firm’s approach to validation and the set up an
organization of all validation activities.

June 2014 Qualification of Systems and Equipment 58

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 Elements of VMP (PIC/S PI 006-3; # 4.5.2)

 A VMP should contain data on the following subjects:

• Firm’s validation policy.
• Personnel responsibilities.
• Company-specific definitions for validation approach & scope.
• Description of specific characteristics / requirements of the plant
/ process etc. (description of the validation project).
• List of the individual validation projects (in matrix format)
• General statement on key acceptance criteria.
• Documentation formats for validation protocols and reports.
• List of relevant SOPs.
• An estimate of resources.
• A statement of company’s commitment for change control.
June 2014 Qualification of Systems and Equipment 59

Contents of a Validation Protocol (PIC/S PI 006-3; # 6.3.3)

 The following items should be included in the validation protocol:

a) A description of the process,
b) A description of the experiment,
c) Details of equipment / facilities together with calibration status,
d) The variables to be monitored,
e) The sampling plan and the sampling procedure,
f) Product performance characteristics together with test methods,
g) The acceptance limits,
h) Time schedules,
i) Personnel responsibilities,
j) Details of methods for recording and evaluating results,
including statistical analysis.
June 2014 Qualification of Systems and Equipment 60

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Contents of a Validation Report (PIC/S PI 006-3; # 6.3.9)

 The following items should be included in the validation report:

a) Description of process, Batch/packaging document, including
details of critical steps.
b) Detailed summary of the results obtained from in-process and
final testing or references to the sources.
c) Formal explanation to any additional work or deviations.
d) A review and comparison of the results with those expected.
e) Formal acceptance / rejection of the work by the teams /
persons designated as being responsible for the validation, after
completion of any corrective action or repeated work.

June 2014 Qualification of Systems and Equipment 61

References
 “Qualification and Validation”
EU-PIC/S GMP; Annex 15, September 2009
 “Recommendations on Validation Master Plan, Installation and Operational
Qualification, Non-Sterile Process Validation, Cleaning Validation”
PIC/S document PI 006-3, September 2007
 “A WHO Guide to GMP Requirements, Part 2: Validation”
WHO, January 1997
 PDA TR No. 13; Fundamentals of an Environmental Monitoring Program
 GMP, Rational and Compliance
Chapter 15, Validation – General Principles, John Sharp, CRC Press
 GMP Manual
Chapter 7, Process Validation, Maas & Peither GMP Publishing
 Facility Validation; Theory, Practice, and Tools
Chapter 3, The Practice of Facility Validation, Graham C. Wrigley, CRC Press
 Pharmaceutical Validation Master Plan
Syed Imtiaz Haider, St. Luice Press
June 2014 Qualification of Systems and Equipment 62

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