ASTRAZENECA GLOBAL STANDARD OPERATING

PROCEDURE

3-P11-CV-MO: EQUIPMENT, UTILITY, FACILITY

QUALIFICATION

1 PURPOSE
This Standard Operating Procedure (SOP) describes how the minimum
requirements of the Equipment, Utility, Facility Qualification Standard (QCM 3-
S9-cv-M) are to be met for equipment, utility and facilities used for the
manufacture of medicinal products and medical devices.

2 AUDIENCE
This Quality SOP applies to all personnel inclusive of temporary staff,
consultants/contractors and outsourced service providers involved with
GMP/GDP activities.
This includes AstraZeneca Operations and Global Biologics Operations (GBO)
Sites.

3 SCOPE
The activities in this SOP support the development, manufacture, testing,
holding, or distribution of commercial drug products, including medical devices
and combination products for human use.
This SOP is applicable to all qualification activities and must be read and
applied in conjunction with its associated Standard (QCM 3-S9-cv-M), the
General Validation Standard (QCM 8-S5-cv-M) and other associated global
procedures and/or guidelines including 8-P135-cv-M
Legacy systems qualified under previous approaches are not impacted by this
procedure. Updates to legacy system qualification documentation are to be
handled at the discretion of each individual site.
4 PROCEDURE

4.1 General Requirements

System qualification demonstrates product quality understanding through
verification that critical product quality attributes can be achieved with each
given system, first at the design stage and then after installation.
Where equipment includes a computerised system element the automation will
be tested using this equipment Qualification process and the applicable parts of
the Computerized System Compliance Policy, LDMS_001_00158575.

4.2 Overview
Equipment, Utility, and Facility Qualification includes specific GMP/regulatory
documentation associated with engineering design, fabrication, and construction
deliverables.
Qualification strategy for equipment, utility and facilities begins with a definition
of critical quality/GMP requirements (URS); includes the verification that these
requirements are achieved on paper in the design (DQ); and concludes with the
verification that the finished installation achieves the user requirements and the
approved design through IQ/OQ/PQ. These three steps are required per
Equipment, Utility, Facility Qualification Standard, 3-S9-cv-M.

4.3 Procedure Steps

Installation,
User
System Impact Qualification Design Risk Operational &
Direct Impact Requirement
Assessment Plan Qualification Assessment Performance
System Specification
4.3.1 4.3.2 4.3.5 4.3.6 Qualification
4.3.3
4.3.7/4.3.8/4.3.9

Not Facility
Qualification
Direct Impact GMP Risk
Plan Report
System Assessment
4.3.10
4.3.4

Requalification/
Commissioning
Periodic Review
only
4.3.11
4.3.1 System Impact Assessment

Determine which systems require Qualification by performing a System Impact

Assessment (SIA). This risk assessment provides focus to systems which can
have a direct impact on product quality. Direct Impact systems require
qualification. All other systems are commissioned only.

For systems that clearly have no GMP impact (e.g. a restaurant facility) there is
no requirement for a SIA to be completed, or any further qualification activities
described in this procedure.

For each equipment system or utility an impact assessment is performed to

determine the potential role the system has relative to product quality. Each
system is to be assessed against the following statements. A designation of
Direct Impact is made if any of the attributes are answered “yes”:

1. The system contains components or performs functions that serve to meet

one or more process requirements including CPPs.
2. The system has direct contact with the product or process stream and such
contact has the potential to impact the final product quality or pose a risk to
the patient.
3. The system provides an excipient or produces an ingredient or solvent
(e.g., water for injection), and the quality (or lack thereof) of this substance
could impact the final product quality or pose a risk to the patient.
4. The system is used in cleaning, sanitizing, or sterilizing and malfunction of
the system could result in failure to adequately clean, sanitize, or sterilize
such that a risk to the patient would result.
5. The system controls a risk to the patient by establishing a proper
environment (e.g., nitrogen blanket, closed process, exposed filling zone air
quality, maintenance of temperature, humidity, when such parameter is part
of the product CPPs).
6. The system produces, processes, or stores data used to accept or reject
product, critical process parameters, or electronic records.
7. The system provides container closure or product protection, the failure of
which would pose a risk to the patient or degradation of product quality.
8. The system provides product identification information (e.g., lot number,
expiration date, counterfeit prevention features).

Input documentation (as applicable): Equipment and utility systems list

Output documentation: System Impact Assessment. This may be a

standalone document or included in the Qualification Plan (see 4.3.2)
4.3.2 Qualification Plan

Compile the results of the SIA into a qualification plan, protocol, or change
control which will document the qualification strategy and deliverables for the
direct impact systems. The Qualification Plan must include direct impact system
strategies (e.g. vendor deliverables, what will be leveraged, etc.) and may
include strategies for commission only systems. The Qualification Plan may be
a stand-alone document or described within a project Validation Master
Plan/Validation Plan or change control depending on the scale and complexity of
the project.

Input documentation (as applicable) : Project scope, systems list, System

Impact Assessment, procurement/contracting strategy, project organization,
design strategy, computer validation strategy, construction strategy.

Output documentation: Qualification plan including agreement to the approach

for commissioning and qualification.

4.3.3 User Requirement Specifications

Obtain the risk based critical process quality elements, such as Critical Quality
Attributes (CQA), Critical Process Parameters (CPP) and Computerised System
Validation Requirements, and develop a system User Requirement Specification
(URS) for each direct impact system.

While the URS is focused on product impacting quality requirements, it is

acceptable to include other non-GMP requirements, but the non-GMP elements
will not be subject to any qualification activities. The URS provides the targets
to achieve in the technical specifications and a point of reference through the
system lifecycle.

When the manufacturing process is not well defined, an FMEA style risk
assessment must be considered by manufacturing and process SMEs to
establish critical parameters, attributes, and allowable variability for proposed
raw materials and unit operations. Critical parameters and attributes are used
to establish adequate process controls. The extent and detail of requirements
must be commensurate with risk, previous experience or knowledge of a system
or process, and complexity.
Prepare a Facility URS which is a compilation of the GMP requirements for the
facility spaces, such as, classification of rooms.

Input documentation (as applicable): Process definition and process control

scheme with critical elements, such as CPPs and CQAs for process systems,
and facility GMP requirements and facility operating strategy.

Output documentation: URS for each direct impact system and a facility URS
4.3.4 Facility GMP Risk Assessment

Perform a facility risk assessment to confirm the preliminary facility design

adequately addresses GMP classification requirements, and flow of people,
materials, and waste. The assessment must include at least risk associated
with segregation and cross contamination.

Input documentation (as applicable): Preliminary facility design, facility URS

Output documentation: Facility risk assessment report

4.3.5 Design Qualification

Perform a Design Qualification (DQ) for each system/facility to confirm that the
design documents include features which will satisfy each URS element.
Design documentation used to satisfy DQ is to be appropriately controlled. In
cases where the design can’t achieve a URS element, a non-conformance is
documented. A risk evaluation is performed and where applicable a
remediation strategy must be applied. Remediation could include redesign to
address the deficiency, or justification to adjust the URS element; or procedural
requirements which provide for URS element control.

The scope of the DQ must include verification that the design, including
automation, will satisfy URS elements, and verification that the design meets
GMP expectations.

Input documentation (as applicable): System/facility URS and appropriate

system/facility design documents.

Output documentation: Design Qualification table/report for each

system/facility.

4.3.6 Risk Assessment

Perform a risk assessment to identify the elements which are to be included in

the Installation Qualification, and to identify tests which are to be included in the
Operational Qualification.
The level of effort, formality and documentation of the risk assessment must be
commensurate with the level of risk.
As a minimum, the actual design elements and functions which are to be
included in Installation Qualification and/or Operational Qualification must be
documented, and the rationale for elements and tests is to be included within
the assessment. Supporting documentation for the assessment include
highlighted design (P&ID and Technical Specification with System Boundaries
for example) documents.
 An additional structured risk assessment must be considered for systems that
fall under the following categories
 Bespoke or novel
 Significant GMP / high risk impact
 GMP impact is not known
Such structured assessments are described in 1-P57-cv-M, cGMP Quality and
Compliance Risk Management in Operations and Pharmaceutical Development
or in other industry standard approaches.
Input documentation (as applicable): URS, DQ, and approved design
documents with system boundaries.
Output documentation: Risk Assessment with installation and/or functional direct
impact components and functions identified.

4.3.7 Installation Qualification

Perform Installation Qualification for each direct impact system.

Installation Qualification assures that equipment or utility, as installed, meets

specifications and that critical installation requirements have been verified. IQ
will include direct impact components only as identified in the risk assessment.
IQ must include, but is not limited to the following as applicable:

1. Verification that installation of equipment, pipework (where applicable),

services and instrumentation matches as built approved engineering drawings
and specifications.
2. Collection and collation of supplier operating and working instructions and
maintenance requirements.
3. Verification that critical instruments are calibrated.
4. Verification of materials of construction for product contact parts.
Input documentation (as applicable): DQ, risk assessment, appropriate
system verification documents, approved system verification drawing, calibration
records
Output documentation: Completed IQ protocol with IQ report and supporting
documentation
4.3.8 Operational Qualification

Perform Operational Qualification for each direct impact system.

Operational Qualification assures, through documented testing, that all critical

functions identified through risk assessment are capable of operating within
established limits and tolerances. OQ will include direct impact functions only
and must include as applicable:

1. Tests designed to challenge critical operating requirements such as speed,

pressure, temperature, flow rate as determined from system specifications.
2. Tests to confirm upper and lower operating limits, and/or worst case
conditions.

Input documentation (as applicable): DQ, risk assessment, appropriate

system functional specifications

Output documentation: Completed OQ protocol with report and supporting

documentation.

4.3.9 Performance Qualification

Perform Performance Qualification (PQ) to confirm that the system can achieve
URS elements and parameters identified through risk assessment, and can
perform effectively and reproducibly to achieve the product specifications as
applicable using the approved process methods (SOP).

In some cases PQ elements may be included within OQ or process validation

(Examples include: controlled temperature units, worst case/empty mapping
approach, and analytical instrument qualification).

For a Direct Impact utility PQ the period and extent of qualification must consider
the impact of any seasonal variations, if applicable, and the intended use of the
utility.
PQ must include, but is not limited to the following:
1. Tests to include a condition or set of conditions encompassing the full
operating range of the intended process, unless documented evidence
from the development phases confirming ranges is available.

2. Tests using production materials, qualified substitutes or simulated

product proven to have equivalent behaviour under normal operating
conditions with worst case batch sizes.

Input documentation (as applicable): URS, DQ, Risk Assessment, approved

SOPs.
 Output documentation: Completed PQ protocol with report and supporting
documentation.

4.3.10 Qualification Plan Report

The Qualification activities described in the Qualification Plan will be

summarized in a Qualification Plan Report. The Qualification Plan Report may
be a stand-alone document or described within a Project Validation Master
Report/Validation Plan Report or change control consistent with the Qualification
Planning approach.

Input documentation (as applicable): Appropriate Qualification plan and

completed DQ, IQ, OQ and/or PQ

Output documentation: Qualification Plan Report

4.3.11 Requalification/Periodic Review

When a direct impact system is changed, requalification must be considered as

part of the change control process. In addition, all direct impact systems must
have a periodic review completed at an appropriate frequency to confirm that
they remain in a continued state of control. The periodic review may be fulfilled
through the product quality review process.
The frequency of the review must be based on quality risk management
principles, and it may be different for different systems and it may change over
time.
The periodic review must include the following factors,
 Routine (planned) maintenance
 Corrective / reactive maintenance (breakdowns)
 Deviations
 Change controls (these must be considered individually but also the
combined and/or cumulative effect of multiple changes, including small
changes)
 Calibrations (Critical Instruments)
The periodic review must also draw a conclusion based on the information
collated and presented that the system has remained in a “state of control” and
is likely to over the next time period until the next review.
Where a system or a group of systems have been identified as high risk*, the
need for re-qualification on an ongoing basis must be considered. Where this is
the case, the frequency must be justified and the criteria for evaluation defined
in local procedures.
 * High risk may be where adverse trends or critical issues have been identified;
or where there is high risk of failure to the product/patient and the additional
assurance of repeat qualification is necessary to confirm appropriate
functionality and thus reduce the risk to the product/patient. This could be
determined by an approach such as Risk Priority Number calculation.
Certain high risk systems are required by regulations to have routine
requalification performed at a pre-determined time period. Independent of the
outcome of the above periodic reviews, these minimum requirements must
always be met.
The approach to re-qualification for each system, including the periodic review
frequency and if required the requalification frequency, must be detailed in the
site Validation Master Plan or equivalent document – see 8-S5 and 8-P135 for
further information.

5 REPSONSIBILITES
Approval of all qualification documentation described in this SOP, must be in
accordance with the requirements detailed in 8-P135, i.e. the documents must
have a Management/Technical approver and Quality Assurance Approval.
Different documentation may require different level of approvers, dependant on
the scope and scale of the document. Due to organisational differences across
the Company (structure, role titles etc.), the appropriate approvers for all
qualification/validation documentation must be detailed within Site Procedures
or the site VMP.
An integrated team approach to qualification that includes expertise from a
variety of disciplines (e.g., process engineering, manufacturing, IT compliance,
qualification/validation, engineering and quality assurance) is key for success,
and is applicable from system design & development, through to system testing
and reporting.
Each site/function must comply with the requirements detailed in this SOP.

6 GLOSSARY
All terms employed throughout this document are used in accordance with
the definitions given in the AstraZeneca Glossary. Glossary terms that are key
to the understanding of this document are listed below.

Terms Definition

The process of verification that new or modified assets can

meet their design intent, while bringing them from a
*Commissioning constructed state into beneficial operation, as defined by
the acceptance criteria and agreed with the Project
Sponsor.
Terms Definition

A Critical Quality Attribute (CQA) is a physical, chemical,

biological, or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution
*Critical Quality
to ensure the desired product quality. CQAs are generally
Attribute (CQA)
associated with the drug substance, excipients,
intermediates (in-process materials) and drug product.(ICH
Q8).

A process parameter whose variability has an impact on a

*Critical Process critical quality attribute and therefore should be monitored
Parameter (CPP) or controlled to ensure the process produces the desired
quality. (ICH Q8 R2)

An engineering system which may have a direct impact on

*Direct Impact product quality. These systems shall be validated and are
System likely to contain critical devices. These systems will depend
on indirect impact systems for effective operation.

Individuals with specific expertise in a particular area or

Subject Matter field. Subject Matter Experts should take a leadership role
Expert (SME) to represent their function within initiative constraints to
influence good decision making and positive outcomes.

A system delivers a unit process step which is a physical

System and/or chemical change to material which will be some or
all of the final product.

System Parts of a system, a system is made up of components

Component

The process of evaluating the impact of the operating,

System Impact
controlling, alarming and failure conditions of a system on
Assessment (SIA)
the quality of a product.

User Requirement Describes what the equipment or system is supposed to do,

Specification thus containing at least a set of criteria or conditions that
(URS) have to be met.

* These are AZ Glossary definitions and were correct are time of publishing.
For latest versions please check the AZ Glossary.
7 REFERENCES
1. 3-S9-cv-M, Quality System Standard for Equipment, Utility, Facility
Qualification
2. 8-S5-cv-M, General Qualification and Validation
3. 8-P135-cv-M, Quality System General Qualification and Validation
Procedure
4. LDMS 001 00158575, Computerised System Compliance Policy
5. 1-P57-cv-M, cGMP Quality and Compliance Risk Management in
Operations and Pharmaceutical Development
The following documents are not directly referenced in this SOP, but were used
for the document’s preparation.
1. EU Guidelines for Good Manufacturing Practice and Medicinal Productss
for Human and Veterinary Use, Volume 4, Annex 15: Qualification and
Validation
2. EU Guidelines for Good Manufacturing Practice and Medicinal Products
for Human and Veterinary Use, Volume 4, Annex 11: Computerised
Systems
3. FDA CFR Title 21, Chapter I, Subchapter H, Part 820 Medical Devices
4. FDA CFR Title 21, Chapter I, Subchapter A, Part 11 Electronic Records;
Electronic Signatures
5. Guidance for Industry, FDA Process Validation: General Principles and
Practices, January 2011
6. ISPE Baseline Guide for New and Renovated Facilities, Volume 5,
Commissioning and Qualification Volume 5, March 2001
7. PICS GMP Guide PART II: BASIC REQUIREMENTS FOR ACTIVE
PHARMACEUTICAL INGREDIENTS – Effective 1 March 2014
8. PICS GMP Guide Annex 15 – Effective 1 Oct 2015
9. Standard Guide for Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical Manufacturing Systems and
Equipment, ASTM E2500-07

8 REVISION HISTORY
Version Description of Change

1.0 First Version

9 APPENDICES
Not Required.