Effective Qualification of Critical Utilities

Presented By Miguel Montalvo,

President, Expert Validation Consulting, Inc.
IVT Validation and cGMP Compliance Forum San Juan, P.R.
July 12th 14th, 2011

FDA 21st Century Initiative

Effects on Facility and Utilities
Qualifications

Aseptic Processing Concept Paper from 2002 Basis for 2004

Final Guidance
Goal build quality into products using science-based
facility, equipment and systems design.
Ensure reliable and robust product protection through
adequate design and control.
Advantages of Automation and Isolation Concepts - Innovation
Consistent with Agency efforts to harmonize with international
regulatory standards (ISO-14644 Classifications)
Agency intent to integrate quality systems and risk management
approaches into existing programs with the goal of encouraging
the adoption of modern and innovative manufacturing
technologies

April 23, 2013

ICH-Q7A - cGMPs for API

Manufacturing

HVAC Systems These systems

should be designed and
constructed to minimize risks of
contamination and crosscontamination
Qualification of Critical Equipment
and Ancillary Systems
Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
Periodical Review of Validated
Systems

Quality Systems Approach to

Pharmaceutical GMPs
Guidance from FDA (9/29/06)

The guidance describes a comprehensive quality systems (QS) model,

highlighting the model's consistency with the CGMP regulatory
requirements for manufacturing human and veterinary drugs, including
biological drug products. The guidance also explains how
manufacturers implementing such quality systems can be in full
compliance with parts 210 and 211.
Implementation of Quality Systems, when coupled with manufacturing
process and product knowledge, can handle changes without a need
for regulatory submissions - changes in facility, equipment or even
processes
Change Control managing change to prevent unintended
consequences
According to CGMP regulations, the QCU has the responsibility of
reviewing and approving all initial design criteria and procedures
pertaining to facilities and equipment and any subsequent changes
(see 211.22(c))
April 23, 2013

Quality Systems Approach to

Pharmaceutical GMPs
Guidance from FDA (9/06)

Quality by Design Concept:

Quality by design means designing and developing

manufacturing processes during the product development stage
to consistently ensure a predefined quality at the end of the
manufacturing process. A quality system provides a sound
framework for the transfer of process knowledge from
development to the commercial manufacturing processes and
for post-development changes and optimization
Quality should be built into the product, and testing alone
cannot be relied on to ensure product quality.
A quality system can provide the necessary framework for
implementing quality by design (building in quality from the
development phase and throughout a products life-cycle),
continuous improvement, and risk management in the drug
manufacturing process. This concept is being developed under
the ICH Q8 Pharmaceutical Development Expert Working
Group.
April 23, 2013

Effects on Equipment/Systems
Qualifications Quality Systems
Approach

Design Qualification/Review
Purchasing Controls

Vendor/Contractor Selection is Key to an Effective

Qualification/Project Implementation

Monitoring and Control Master Project Plan

It is the responsibility of the designer, construction manager

and plant engineer in charge of the project that all agreed
upon design requirements are met during:

During Construction
Start-Up and Commissioning

Qualification and Routine Monitoring

April 23, 2013

ISPE Efforts and Impact

Baseline Engineering Guides
Volume #5
Enhanced Design
Review Concepts

Structured Design
Review

System Impact and

Components Criticality
Levels and Applications

Scope of the ISPE

Commissioning
and Qualification Guide
Impact Assessment
Engineering Change Management

QA Change Control
Design

Development
Enhanced Design
Review

commissioning

PQ

Process
Validation

IQ & OQ

Design for Impact

Scope of Guide
GEP Contribution
Of Interest to the Regulatory
April 23, 2013

ISPE Impact Concepts and

Application

FDA cooperation with development of these concepts for new manufacturing

facilities and modifications to existing. It does not mean acceptance by FDA.
Guidelines still prevail Process Validation Guideline from 1987 which
includes qualification requirements.
Scope Facilities, Utilities, Equipment
Key Concepts:
Direct Impact Systems impact on product quality
Qualification required
Indirect Impact Systems not expected to have an impact on product
quality
Commissioning may be enough (Enhanced Commissioning
documentation)
No Impact Systems
Basis GEP application, Enhanced Design and Review and Commissioning
System Impact Assessment is key (Risk) rationales for decision are fully
understood, documented and endorsed by QA function
April 23, 2013

Validation Life Cycle

Qualification

Design

Discontinuation

Plan

Do

Act

Verify

Continued System Verification

10

Life-Cycle Phases

Design

User Requirements
Functional
Requirements
Detailed Design

Qualification

Continued System
Verification

Monitoring
Change Control
Deviations/OOS
Maintenance

Risk Management is applied

at every phase
11

Plan for Compliance

Application of GEPs during the Design and Construction Phases

Audits of vendors and suppliers

Proactive Review of Turn-Over Packages/Forms

Master Project Plan to include

Basis of Design Process/Product

User/Functional Specifications
Definition of Responsibilities
Scope of Installation
Cost/time considerations
Quality Plan to Include:
Design Review with pre-determined
acceptance criteria
FAT/SAT Requirements
Start-Up and Commissioning
Qualification Requirements
(may be in parallel to VMP)

12

Master Project Plan

Applicable to New Facilities or Major Modifications/

Projects
Project is awarded:
You may have User Requirements and Functional
Requirements Specifications
You may even have a Conceptual Design
document
Master Project Plan includes Quality Plan with
Design Review and Change Control processes

April 23, 2013

13

Project Phases

Process Support Systems or

Utilities Requirements Direct
Impact vs. Indirect Impact

Direct Impactraw material,

product contact or direct
impact on product quality
Water For Injection
HVAC System for Clean
Area
Clean Steam
Clean Compressed Air
IQ, OQ, and PQ required

Indirect Impactno
product contact but may
have indirect effect on
product quality
Vessel jacket heating/
cooling
Potable water for
washing/cleaning
not final rinse
Vacuum for drying/
coating
IQ and OQ required

April 23, 2013

15

Approval of Suppliers/Vendors

Approval is granted after all initial approval

requirements have been met and all
documentation has been gathered and reviewed
Purchasing must not be allowed to enter into a
contract or PO with a supplier/vendor that has not
been approved Approved Supplier List (for
Critical, Major and Minor class Suppliers)
Quality Agreement or Contract in place before
first order is issued for Critical or Major materials/
services
16

Quality Agreements/Contracts

Defined Requirements specifications and other

needs
Communication changes
Giver versus Acceptor responsibilities
Testing/standards/regulations to be applied
Requirements for Qualification/Certification and impact
of deviations/non-conformances
Number of lots/batches and evaluation process
Documentation
Requirements for Sub-Contracting any step/process
Dispute Resolution
17

Quality Agreements/
Contracts

In the technical contract, both parties can agree upon a checklist,

in which the company contracting the services lays down all the
requirements for the supplier. A checklist with an extreme level of
detail is necessary, and should be an attachment to the technical
contract. For example, if there is a specific concern for cross
contamination, the list can put special emphasis on air handling
units, hygienic control, environmental monitoring, etc.
Process knowledge is also critical. Manufacturers must
characterize all processes, monitor process variables (in realtime if possible), and anticipate how product and process will
behave in this multivariate environment

18

Traceability Matrix Model

User Requirements
Spec
Functional Specs

Design
Specs

Performance
Qualification

Verifies

Operational
Qualification

Verifies
Verifies

Installation Qualification

Design Review
System Build
19

Specifications Purpose

User Requirements Describe clearly and precisely

what you need the system to do? It must be driven by
the business process needs.
Functional Requirements Specifications How the
system will achieve the User Requirements in terms of
functionality characteristics?
Design Specifications What are the specific (detailed)
attributes/characteristics for the system to be able to
meet the functions and user requirements?

April 23, 2013

20

Traceability Matrix Application/

Relation to Design Qual./Review

User Requirements Specifications basis for the

Functional Requirements Specifications basis
for the Design Specifications and Drawings
Design Qual./Review verifies the flow from one set
of specifications to the next has been effective/
complete and that all criteria/requirements are
met by the design

April 23, 2013

21

Design of a Process Support

System or Utility Plan for
Compliance

Clear Design Specifications: User Requirements and

Functional Requirements
Process Requirements determine what are the
requirements for your specific application (aseptic
conditions vs terminally sterilized products)
Risk analysis.
Facility Location environment conditions and seasonal
changes. Evaluate facility location in terms of
temperature/humidity worst case conditions
Feed (if applicable)

April 23, 2013

22

Design of a Process Support

System or Utility Plan for
Compliance (Cont.)

Initial Cost vs. Maintenance Costs evaluate the options in terms of

original investment vs. maintenance costs.

Other aspects to be considered reliability, future growth/flexibility

Average and Upper (peak) demand for utilities and environmental

conditions
Critical Parameters set-points, alert and action limits
Methods of Measurement, control, monitoring and documentation of
parameters
Automation Control Costs how much automation is desired
compared to operating and initial cost

April 23, 2013

23

Process Requirements and

Considerations

Potential for Contamination

Feed, Make-up air

Equipment/Personnel
Materials/Components
Room Finishes
Other Products

Effects of exposure to extreme

conditions - temperature,
humidity
Filtration requirements
Safety Considerations
Product requirements sterile,
particulate levels/
classifications

24

Design Qualification/Review
Application

New Facilities or Major Modifications to Existing

Facilities
Direct Impact Systems primary focus
Indirect Impact may select systems based on level
of impact
Typical Direct Impact Systems HVAC for Classified
Environments, Purified Water, Manufacturing
Equipment/Systems

April 23, 2013

25

What is Design Review?

Is it the same as Design
Qualification or Enhanced
Design Review?

ISPE Baseline Engineering

Guide #5 Section 7 on EDR

Enhanced Design Review (EDR) a documented review of the

design, at an appropriate stage in the project, for conformance to
operational and regulatory expectations.
It is in the interests of all to reveal design or specification
problems through a rigorous , structured and appropriate
review process early in the project, rather than discover them
laterwhere a remedy might involve significant delay and
expense.
Avoiding the use of the term DQ
EDR provides audit trail from conception of the project up to the
completion of the detailed design

April 23, 2013

27

ISPE Baseline Engineering

Guide #5 Section 7 on EDR

EDR aims to capture (organize) the design documents with

a formal index and a process for their archival
EDR should be described in the Validation Master Plan
(VMP) indicating intention, process to be followed,
responsibilities of persons involved, and position of EDR
with reference to GEP and Qualification Practices.
Master Project Plan with a Quality Plan Section instead
of the VMP
Impact and complexity of the design will influence the depth
of the review process.
April 23, 2013

28

EDR Rationale

To be included in Plan:
What will be reviewed
What method will be used supporting data
Who will be involved
When?
How will be documented?
Could be in a standard procedure

April 23, 2013

29

Steps in a Design Review

Define scope and objectives of the

review, the methods to be followed
and the outputs (SOP)
Who will be involved (SOP)
Identify and evaluate any potential
areas or items of noncompliance
(checklist)
Review the design documents and
drawings against the user/
functional specifications and other
requirements identified on the
checklist above
Ensure that designs are modified to
eliminate noncompliant features

April 23, 2013

Prepare a brief report that

summarizes the designreview process and
obtain appropriate
approvals, including
quality assurance.

30

When Should Change

Control Be Implemented?

Need a policy for Change Control Management which will

include applications at different points
Define application for new and/or modifications to facilities,
utilities, equipment and systems
Formal QA Change Control procedures MUST be implemented
upon completion of the Qualification / Validation
Implement change control for all Direct and Indirect Impact
systems level of detail/depth of impact determination will be
commensurate with the impact level of the system/process
Once the system / equipment is identified and specified
(approved documents), it falls under some level of change
control

April 23, 2013

31

Change Control Levels early in

Projects Impact Determinations and
Application of Risk

Direct Impact Systems more documentation required

and a formal risk assessment done for changes
Indirect Impact Systems basic procedure and form to
be completed. No need for formal risk assessment as
part of the change impact analysis.
Responsibilities must be defined for each project
phase
User functions to be involved Quality (at a defined
level)

April 23, 2013

32

Relationship between Design

Review and Change Control
Management during Design

Team for Design Review is normally same team

that will evaluate changes
Documentation of Design Review will serve to
document changes and their verification of
implementation.
The DQ process/meetings will provide the
opportunity to complete any Change Control
documentation required for the changes to Direct
Impact and Indirect Impact Systems.

April 23, 2013

33

Construction

Construction shall comply with

design drawings and
specifications
Changes shall be documented in
accordance to a change control
procedure (defined in Quality
Plan)
Cleaning procedures and criteria
for acceptance of the work must
be pre-defined
Security and access procedures
must be defined

34

Factory Acceptance
Testing (FATs)

FATs are standard tests that are

executed at the factory to verify
proper operations before the
system leaves the plant.

35

Start-Up and Commissioning

Adequate Installation/Construction Documentation - as per GEPs:

Design Concepts
Design Schematics
As Installed drawings
Instrumentation Calibrations
Test records
Operation and Maintenance Manuals
Statutory inspection Reports
Material Certificates, FATs
Duct Installation and Cleaning documentation
Changes are properly managed
and documented during construction
Training of personnel

36

Project Phases
Design
Purchasing
Construction
Installation
Start-up
Validation

V $
April 23, 2013

37

Commissioning Leads
to IQ/OQ for Indirect and
Direct Impact Systems

Documents created and collected during

Commissioning are incorporated into the
validation package
During construction, a review of current status
of installed equipment and walk through can
help ensure validation criteria are kept on target
avoid unnecessary delays
Start-up/field testing may address the needs of
IQ/OQ criteria

April 23, 2013

38

Key Question:
Is Commissioning going to be
considered part of Validation
Effort?

Yes!
Define Commissioning
process and documentation
in Project/Quality Plan and
in Master Validation Plan
and how they will relate to
further qualification of
systems

April 23, 2013

No

Complete
Commissioning
Will need to repeat
some tests for
Qualification
Still need to describe
Commissioning
requirements in
Plans

39

Commissioning as part of
Master Validation Plan

Advantages:

Pre-qualification determination if system is reliable/

operates according to specifications
Avoid redundancy

Requirements:

Pre-defined/documented test requirements

Training of personnel executing the tests
Adequate documentation practices
Quality review

April 23, 2013

40

Equipment Qualification Levels

Suggested applying Risk Assessment/

Analysis:

Historical:
Installation
Qualification
Operational
Qualification
Performance
Qualification

Direct Impact System:

Product Failure Hazard Level:

Level I Sterile/Biological/Critical Medical
Devices

Level II Oral Solid/Liquids

Installation adequate detail

Operational Qualification Basic Operational
Functions, Controls, Critical Alarms

In-direct Impact System:

Installation more detail

Operational Qualification basic operational
functions, controls, alarms, Challenge Parameter
Ranges and Worst Cases extremes

Installation not detailed

Basic Operational Functions - only those which could
impact the product quality

No Impact Enhanced Commissioning

Documentation

PQ no change. Only for critical direct

impact systems.
April 23, 2013

41

Questions to be Answered

Which sections of a system need to be qualified?

Which parameters to test and at what level Does
an OTC/Cosmetic system/equipment/facility
needs to test all systems at Worst case or the
extreme parameter limits?
How many runs/tests?
Decisions on criteria - equipment specifications
versus process needs?

April 23, 2013

42

Requirements for Installation

Qualification In-direct Impact
System

Main Components Verification critical components only

Base decision on risk assessment
Drawings Verification
Utilities Verification
Availability of Support Documentation Manuals, Specifications,
Design Review Documents, POs, Commissioning Documents
Procedures and corresponding training Operation, Maintenance,
Cleaning
Calibrations critical instruments
based on risk assessment
Hardware/Software Configuration and Set-up Information
Filter Verification (if applicable)
April 23, 2013

43

Requirements for Installation

Qualification Direct Impact
System (Level II Oral Solid/Liquids)

Main Components Verification as per design/drawings including controls/

instrumentation

Drawings Verification to be As-Built

Materials of Construction product contact only
Lubricant List
Utilities Verification Electrical, Water, Compressed Gases
Review Support Documentation Manuals, Specifications, FAT reports,
Design Review Documents, POs, Commissioning Documents
Procedures and corresponding training Operation, Maintenance,
Cleaning
Calibrations critical instruments

Base list of main components on risk assessment

Base list of instruments on risk assessment

Hardware/Software Configuration and Set-up Information

Input/Output Loop Verification
Filter Verification (if applicable)
April 23, 2013

44

Requirements for Installation

Qualification Direct Impact System
(Level I Sterile/Biological/
Critical Medical Devices)

Main Components Verification as per design/drawings including controls/

instrumentation
Base list of main components on risk assessment
Drawings Verification to be As-Built
Materials of Construction product contact only
Lubricant List and Spare Parts List
Utilities Verification Electrical, Water, Compressed Gases
Review Support Documentation Manuals, Specifications, FAT reports, Design
Review Documents, POs, Commissioning Documents
Procedures and corresponding training Operation, Maintenance, Cleaning
Calibrations critical instruments
Base list of instruments on risk assessment
Hardware/Software Configuration and Set-up Information applicable procedures
for back-up, restore
Input/Output Loop Verification
Construction completion documentation such as:

Piping pressure and leak testing

Pipe slope verification
Pipe insulation
Instrument loop checks

Filter Verification (if applicable)

April 23, 2013

45

Requirements for Operational

Qualification In-direct Impact
System

Verify the basic Operational Functions - only those

which could impact the product quality

Functional Tests critical parameters at nominal values

and verifying only critical responses or characteristics
Controls Verification
Motor verification
Sequence Verification (if applicable)

Select the parameters from risk assessment/analysis

select number of tests for each
Select the responses or resulting characteristics to be
verified from risk assessment/analysis

April 23, 2013

46

Requirements for Operational

Qualification Direct Impact
System (Level II Oral Solid/Liquids)

Verify the basic Operational Functions including critical

alarms

Functional Tests parameters at operational limits and

verifying critical responses or characteristics
Controls Verification
Motor verification
Sequence Verification (if applicable)
Critical Alarms verification and reporting

Select the parameters to be challenged from risk

assessment/analysis select number of tests for each
Select the responses or resulting characteristics to be
verified from risk assessment/analysis
April 23, 2013

47

Requirements for Operational

Qualification Direct Impact System
(Level I Sterile/Biological/
Critical Medical Devices)

Verify the operational functions and critical alarms.

Challenge Parameter Ranges and Worst Cases extremes

Functional Tests parameters at operational extreme limits and

verifying critical responses or characteristics
Controls Verification more detailed
Motor verification
Sequence Verification (if applicable)
Critical Alarms verification and reporting

Select the parameters to be challenged from risk

assessment/analysis select number of tests for each
Select the responses or resulting characteristics to be
verified from risk assessment/analysis
April 23, 2013

48

Additional Areas to be covered

during the qualification

Process Parameters vs. Equipment Design Verify that the equipment is capable of
operating at the desired process parameters
independently of the equipment design
Flexibility, Reliability, Future Growth

April 23, 2013

49

How to determine qualification

requirements - Steps

Procedure/Policy to describe the evaluation process

and documentation requirements
Impact Assessment ISPE Baseline Engineering Guide
Volume #5 Commissioning and Qualification concepts
Hazard Level determination for Direct Impact systems
Risk Assessment on system parameters and
specifications
Protocol development including results from Risk
Assessment and rationale for decisions

April 23, 2013

50

Protocol Requirements
General Outline

Approvals
Objective/Purpose
Scope/Boundaries
System Description
Overview
Basis of Design
Flow Diagrams
Qualification Approach:
policies, procedures,
references
Responsibilities

Pre-Requisites
Definitions
Test requirements
Record of Signatures
Test Instruments
Calibrations
Qual. Tests
Acceptance Criteria
Documentation/ Handling
of deviations or exceptions
Attachments

April 23, 2013

51

Integrated PLC Qualification

Qualification should encompass all aspects

that could affect the operation of a system
Program code
Wiring
Labeling
Instrument enclosures
Transmitters
Recorders
Monitors
Final control elements

April 23, 2013

52

PLC IQ/OQ

Review of Program Code

Display/Graphics/Control
Panel Verification
Operator Interface
Challenges
Review of Software
Development procedures
and Test Protocols
Design review of all
peripheral equipment
Tests to verify that all wires
have been correctly
terminated
Reports Accuracy

April 23, 2013

Verification that the system

has been installed and
labeled in accordance with
the Process and
Instrumentation drawings
Review of security features
Fault tree analysis to
identify unwanted
operations activities
Review of all anticipated
operation activities and
maintenance activities
Control Software
Back-up/Recovery Test

53

BMS, DCS or SCADA

(Supervisory Control and Data
Acquisition)

Stand-Alone Systems that provide additional tools:

Recipe Manager (Specification, Stages, Alarms limits)

Reporting Tools
Screen Builders
Software Package Design Constraints
Data usually acquired without operator action
Data available for later retrieval, reporting, analysis, and
archiving
Communication with the PLC
Program timing

April 23, 2013

54

BMS, DCS and SCADA

Validation Issues

Field Device Calibration

Field Device Maintenance
Cabling Changes
PLC Maintenance (HW&SW)
Software and Hardware Upgrades

April 23, 2013

55

Legacy Systems Key

Questions

How much documentation is available from

original purchase/design/installation?
Change Control System How good is it?
Have changes to the system been
documented and tested properly?
How critical is my system to the operation?

April 23, 2013

56

Legacy Systems - IQ

Documentation Available:

Similar to new equipment in

terms of Specifications,
drawings, manuals, POs.
Verify history of changes
Inspect/Verify calibrations,
utilities installations, major
components, materials of
construction
Required SOPs and training
Software/Hardware
installation, configuration

Documentation not available:

April 23, 2013

Need to create specifications for

system as installed.
Verify drawings are created and/
or up-to-date.
Create/review operational and
maintenance procedures.
Document history of equipment
oper. and maintenance. Verify
training on those procedures.
Inspect/Verify calibrations,
utilities installations, major
components, materials of
construction
Software/Hardware installation,
configuration

57

Legacy Systems - OQ

Parameter Ranges in the absence of

specifications, use actual operational
parameters
Testing to be done similar to new system.
Retrospective is not a concept for
equipment qualification. Limitations and
risks are much higher for trying to defend
this position(History, Quality of Operational
and Maintenance Documentation, Change
Control)

April 23, 2013

58

Performance Qualification
(PQ) Direct Impact Systems

Test quality at use points for

a pre-determined period
Criteria as per specifications
Verify/document operational
data during the test period
Operational and PM SOPs
are effective and followed

59

Qualification Summary
Reports - Outline

Approvals
Objective
Data Summary
Analysis of Deviations or
Exceptions
Cause
Effect on Study
Conclusion
Approval By Quality
Function
Conclusions

60

Facilities
Requirements New

Electrical supply system

Terminationswalls,
ceilings, floors, drains
Access controls
Pest controls
Usually handled through a
facilities protocol

61

Design of an HVAC System

Plan for Compliance

Clear Design Specifications:

User Requirements
Functional Requirements

Process Requirements determine what are the

requirements for your specific application:

Potential for Contamination: Make-up air, Equipment/Personnel,

Materials/Components, Room Finishes, Other Products
Effects of exposure to extreme conditions - temperature,
humidity
Filtration requirements
Safety Considerations
Product requirements sterile, particulate levels/classifications

April 23, 2013

62

Design of an HVAC System

Plan for Compliance

Facility Location Evaluate in terms of

temp./humidity worst case conditions
Automation Control Costs how much
automation is desired compared to operating
and initial cost
Initial Cost vs. Maintenance Costs original
investment vs. maintenance costs.
Other aspects to be considered reliability,
future growth/flexibility
Average and Upper (peak) demand for
utilities and environmental conditions

April 23, 2013

63

Design Specifications

General Purpose of Areas, Operations to be Carried out,

Constraints, Specified Occupancy
Layout and configuration of the installation
Required Air Quality for each area
Critical Parameters set-points, alert and action limits. Worst case
conditions
Contamination Control Concept for each area/room/zone
Controls/Instrumentation/Automation Failure protection devices,
alarms for critical parameters, BMS, documentation of parameter
data
Dust Collection Systems (if applicable)
Material/Equipment/Personnel Flow to minimize possibilities of
contamination
April 23, 2013

64

Premises for Classified/

Clean Rooms

Surfaces must be smooth,

impervious and unbroken in
order to minimize the
shedding or accumulation of
particles or microorganisms
and to permit the repeated
application of cleaning
agentsNo uncleanable
recesses EU Annex 1
Sealed false ceilings
Walls/ceiling/floor
terminations seamless and
rounded corners

Utilities installations no
recesses, unsealed openings and
difficult to clean surfaces
Pressure differential warning
system
Changing rooms with physical
barrier between class levels
Air locks with interlocks
Layout of equipment consider
ergonomics and personnel
comfort and ease of movement
Flow of personnel limit entries
and exits and the amount of
personnel
Limit the activities/interventions
into the aseptic processing area
April 23, 2013

65

Decisions on Parameters
Parameter

Suggested Values/Limits from Reg.

Guidelines

Industry Suggestions
(PDA, Others)

Air Velocity
HEPA Filters

90ft/min is no longer required. It is suggested. FDA

statement is at a velocity sufficient to sweep particles
away from the filling/closing area and maintain
unidirectional airflow during operations. EU still
includes a range at working level of 0.36-0.54 m/s as a
guidance value.

No limit established - Optimum

air velocity is highly dependent
on the configuration of the HVAC
system and the production
facilities.

Air Exchange
Rates

FDA - 20 Room Air Changes for Class D (ISO #8) zones

would be typically acceptable. EU has no suggestions.

No specific number. Standard

practice NLT 50 for Class A/B
(ISO 5/6) and 20 for Class D (ISO
8)

Pressure
Differentials

FDA - at least 12.5 Pa (0.05 inches water gauge) should

be maintained between classified and un-classified
areas and between the aseptic processing room and
adjacent rooms.
EU - guidance values of 10-15 Pa between areas of
different classifications

PDA - Pressure Differentials

between 0.03-0.05 inches of
water are effective.

Temperature and
RH%
requirements

FDA and EU no suggestions (comfort)

66

Additional Tests to be Included

in Commissioning

Static tests installation of system

components
Dynamic tests verification of fan
volumes, checking heating/cooling coil
performance
System Balance and Testing
Including room pressure/air flow
verifications
Room Air Changes Calculations
HEPA filter certification tests
April 23, 2013

67

Qualification Requirements
for an HVAC System

Installation, Operational and Performance

Qualification of the HVAC System including Integrated
Control Systems (such as PLCs)
Separate protocols for Stand-Alone Systems such as a
BMS or other supervisory control systems
Basic Documents protocol, report for each segment
or combined if appropriate (IQ and OQ into one IOQ
protocol)

April 23, 2013

68

Requirements for Installation

Qualification of the System

Main Components Verification as per design/drawings

including controls/instrumentation
Drawings Verification to be As-Built
Materials of Construction
Utilities Verification Electrical, Chilled Water, Steam/Hot
Water
Review Support Documentation Manuals, specifications,
FAT reports, Design Review/Qual. Documents, POs, Duct
Cleaning Documents, Commissioning Documents
Procedures and corresponding training Operation,
Maintenance, Cleaning
Calibrations
Filter Verification

April 23, 2013

69

Requirements for Operational

Qualification of the System

Controls/Alarms Verification
Sequence of Operation
Interlocks testing
Reports
System Security/Data Retrieval
Temperature/Humidity Control Verification minimum of
five days for continuous monitoring. Longer for frequent
checks during the day.
Power Loss and Recovery Testing
Sterile Operations Air velocity, Pressure Differentials, Air
Flow/Laminar Flow Verification as per design. Pressure
Differentials for five days if continuous or longer for
frequent checks during the day.
April 23, 2013

70

Performance Qualification

System operating under normal

conditions (SOPs are effective
and monitoring is in place) This
includes cleaning and
sanitization procedures.
Particulate Counts three times
per location (twice per shift
beginning and end of operation)
during a week period for each
condition
Viable Counts air, surface.
Three results in a week for each
condition. Aseptic areas require
testing per shift.
Static vs. Dynamic Conditions
Challenge is for Environmental
Control System not only the
HVAC
71

Water System Design and

Specifications

72

Guide to Inspections of High

Purity
Water Systems, FDA 1993

System Design

Application based type of product. UF as an option for Biotech WFI

Loop Temperature (70-80C) versus sanitization cost vs risk
Quality level risk. Reliability of the system.

Microbial Limits sample of 100ml minimum for WFI

Specific contaminant versus counts

Biofilm

Water for Injection Systems

Pretreatment monitoring of feed water

Still, Heat Exchangers, Holding Tanks(Vent Filters), Pumps, Piping
(Steel vs PVDF), Reverse Osmosis
Proper Operation and Maintenance

Guide to Inspections of High

Purity
Water Systems, FDA 1993

Purified Water Systems

Process Water

Inspection Strategy

Data review micro

Investigation reports and actions

Maintenance records
System Drawing
System Validation

Description, Specifications, Documentation, Drawings

Procedures operation, cleaning, flushing, sanitization, sampling/testing

74

Variety of Pharmaceutical
Products

Potable Water: Manufacture of substances and initial

cleaning of equipment
Purified Water: For use onsite in manufacture of
ingredients of official preparations; not for parenterals
WFI: For use onsite in manufacture of parenterals
Internal Specification and Quality Requirements for
specific needs

What else does FDA expect?

Feed water must meet EPA Drinking Water Standards

May use WHO standards for international
applications
Microbial expectations
Purified Water NMT 100 cfu/ 100 mL
WFI NMT 10 cfu/100 mL
Sample size <100 mL is unacceptable
All microbial limits are considered action limits, not
pass/fail

Industry References

ISPE Baseline Engineering Guide Volume 4

PDA Technical Reports and additional references
ASTM Standards
ASME Standards Bioprocessing Equipment
Books:
Pharmaceutical Water: System Design, Operation
and Validation by William V. Collentro
Pharmaceutical Water Systems by Theodore A.
Meltzer

77

ISPE Baseline Engineering

Guide Volume 4 Water and
Steam Systems

Pre-Treatment Options
Final Treatment Options
Instrumentation
Storage/Distribution
Qualification/Validation
Appendix

78

Feed Characterization

Ground Water vs
Surface Water
Chemical and
Microbiological
Loads
Seasonal Variations
Volume and effects
of peak usage

Zero In On User Requirements

System Planning

Multi-Disciplinary
Team Approach
Define User Needs:
Water Quality
Use Points
Requirements
System Criteria

Water System Design

Water Quality Specifications - related to the type

of product to be manufactured
Clear Design Specifications: User Requirements
and Functional Requirements
Water Source Quality and Characteristics

Private Well, Public Well or City Potable Water

Seasonal variations
Location of Well (if applicable)

Quality and Performance Criteria for each

component of the system including capacity

Water System Design

System Operational and Maintenance Costs - Sanitization

Frequencies, Cleaning, Filter Replacement among others
Facility Location environment conditions and seasonal changes
Evaluate facility location in terms of temperature/humidity worst
case conditions
Industry Common Practices and Regulatory Input
Recirculation Loop Hot or Cold
Hot loop reduces sanitization requirements beware of heat
exchangers
Sanitization for cold loops daily?

Water System Design

Initial Cost vs. Maintenance Costs evaluate the options in terms

of original investment vs. maintenance costs
Other aspects to be considered reliability, future growth/
flexibility
Average and Upper (peak) demand for utilities and environmental
conditions
Critical Parameters set-points, alert and action limits
Methods of Measurement, control, monitoring and documentation
of parameters
Automation Control Costs how much automation is desired
compared to operating and initial cost

Additional Requirements and

Considerations

Potential for Contamination

Remove higher level of
contamination first
Keep residual chlorine in as long as
possible how to eliminate when
necessary

Carbon filtration versus sodium

sulfite injection or UV

Dead legs and slope to drain

Keep distribution system simple

Filtration requirements

Safety Considerations

Water Systems

Entire water systems needs to be considered

Source (Feed) Water
Production method How much water will be used?
Sampling and Testing data to be collected
SOPs
Pre-treatment steps designed based on actual feed
water evaluation
Softener and carbon filter location will depend on
organic content of incoming water

Water System Design

Pre-Treatment
Multimedia Filter
Softener
Carbon Filter
Cartridge Filters
DI Columns
RO Units
UV Lamps
Storage and Distribution
Instrumentation
TOC On-Line
Resistivity/Conductivity Meters
pH

Pre-Treatment
Specifications

Required quantity and quality of treated water for the

final treatment process
Temperature and microbial control approach
Considerations for added substances chlorine,
sulfite, acid
Final treatment selected cost vs risk of failure
Quality of the feed water need to consider spikes and
seasonal variation (worst cases)
Operational, maintenance, safety, validation, location/
space, environmental and other requirements

Impact on Final Treatment

Caused by Impurities
Fouling particulates

Scaling
hardness and
minerals

Corrosion chlorides

Degradation chlorines

Large

Large

None

Large - Membrane
dependent

Other Membrane
Process

Large - Moderate

Large - Moderate

None

Large - Membrane
dependent

Single Effect Still

Moderate

Moderate

Moderate-Large

Large

Large - Moderate

Large - Moderate

Moderate-Large

Large

Moderate

Moderate

Small

Large

RO

Multi-Effect Still

Vapor
Compression Still

88

Micro Control in
Pre-Treatment

Micro Control Agent

Periodic sanitization (heat or chemical)
UV Lights
Avoiding dead legs and stagnation
Removal of control agent:
Chlorine simple (Carbon)
Chloramines much more complex (requires
several steps). Typically, RO is recommended before
Still with pH controls/adjustments and sulfite
injection to assure removal of chloramines and CO2

Final Treatment

Significant shift from Ion Exchange based

systems to membrane based systems for
PW production (90% systems are RO based
today) due to costs, ease of operation/
maintenance and quality of end product

90

Standard Conventional Purified Water

System Design

P-8

Carbon

Multi-Media

P-7

RO

Softener

CDI/EDI

Storage Tank

Heat Exchanger

Pump

Typical Options for Purified

Water

System A Pre-treatment followed by off-site regenerated IX (ion

exchange) separate beds or mixed beds(Cations and Anions) or
other configurations

System B Pre-treatment followed by RO (single or double pass)

and off-site regenerated IX for ionic polishing

RO means more pre-treatment

System C Similar to B with CEDI replacing IX (no chemical

regeneration)
System D pretreatment followed by distillation (meets WFI)

Feed Water analysis is key focus on meeting Conductivity/TOC levels

On-site handling of bulk regeneration chemicals not desired

Higher capital versus less downtime and maintenance (reliability)

Sanitization considerations (heat resistance) or additional steps

UV or microbial filtration
92

System C

93

Recommended HP" Purified Water System

Design
Multi Media

Carbon

Softener

RO

Nitrogen Blanket

Totalizing Flow Meter

Storage Tank

Pump

TOC
UV

Final filter

Virgin Ion Exchange

Mixed Beds

WFI Purified Water as a

feed to Still

Pre- treament for Still is critical

Will ease the operation/maintenance
Reduce the possibility of contaminations and
endotoxins in the product WFI
Typical high volume systems will have RO as part
of pre-treatment for Still

95

Still Design

Volume and temperature driven

Single Effect

Multi-Effect

VC

Capacity Range
(GPH)

1-100

25-3000

100-6000

WFI Temperature
Range (C)

80-100

37-100

- Ambient
-80-100
-Combination (hot/
cold loops)

Instrumentation and controls

Materials of construction
Vendor selection
96

Design Table Technology

Options for ME Still

For VC, RO or UF as Steps 5 and 6 is optional.

97

Key Factors for Storage

and Distribution

Designed to
maintain water
quality and
deliver to use
points at
temperature and
flow required
Capacity
Continuous flow/
movement
Minimize Cost
98

Materials of Construction

Non compendial:
Polyvinyl Chloride (PVC)
Polypropylene (PP)
Polyvinyldene flouride (PVDF)
Compendial water
316 stainless is preferred but PVDF is an option

Sanitary Fitting

Consistent diameter where possible

Orbital welding is preferred

Other Considerations

Points of Use Design application of

Zero Dead Leg Sanitary Valves
Sloped to drain
Maintained at positive pressure constant
Circulating Loop at 3 ft/second

Microbial Controls

Ozone periodically or continuously and UV to

remove it
Temperature Controls
UV Lights for Microbial control beware of issues
regarding UV such as cleaning/maintenance,
intensity monitoring, flow vs contact time and
typical flora/bacteria present
Filtration on Distribution System microfiltration
or ultrafiltration

101

Qualification Pre-Requisites

Well defined system and components specifications/

functional requirements and drawings

Well defined quality specifications

Well defined sampling/testing procedures

Training of personnel for water sampling/testing

Operational and maintenance procedures (Draft)

Qualification Documents

Installation Qual. Pre-Requisites

System description stating design intent
Schematic drawing of the system (P&ID)
Location and number of welds
Relative elevation
Slope of lines
Point(s) of drainage

System specifications
Performance criteria
Design parameters
System boundaries

Detailed design drawings

Qualification Documents

Installation Qual. Pre-Requisites

Vendor manuals and drawings
Field inspection and test reports

Cleaning procedures and records

Passivation procedures and records
Weld parameter documentation and inspection reports
Slope verification
Verification of absence of dead-legs

System commissioning test results

Reported as related to acceptance criteria

Verification of automated functions
Verification of temperature controls
Verification of distribution system velocity
Initial water quality determination

Installation Qualification
Documents

System/Components/Equipment Installation Qualification

Incoming components specifications and inspection
Installation verification
Utilities installation
Critical instrumentation calibration
Software Configuration
PM procedures
As installed system drawings
SOPs
Summary report and conclusion

Qualification Documents

Operational Qualification
Operational Verification
Sequences System/components cleaning/
sanitization/flushing/regeneration procedures
and frequency
Critical parameters data collection
Procedures may be in draft or operational

Qualification Documents

Operational Qualification
Sampling points
Source water
After each critical step in the purification process
Storage tank (temperature profile and water quality)
Circulation loop (temperature profile only)
At each POU (temperature profile and water quality)

Sampling procedures
Testing requirements
Testing methods
Acceptance criteria

Qualification Documents

Operational Qualification
Documentation
Summary report and conclusion

Qualification Documents

Performance Qualification

Critical instrumentation calibration

Operational Data Review System is operating under approved
SOPs
Sanitization/Cleaning/Regeneration/Flushing data review
Sampling plan
Sampling points

Source water initially, then weekly

After each critical step in the purification
Storage tank (temperature profile and water quality
Recirculation loop (temperature profile only)
At each POU (temperature profile and water quality)

Qualification Documents

Performance Qualification
Sampling procedures
Testing requirements
Testing methods
Acceptance criteria
Documentation
Summary report and conclusions

Sampling Plan

Phase 1 (OQ):
During the initial phase the operational parameters and cleaning/
sanitation procedures and frequencies will be developed.
Sampling should be daily after each step in the purification
process and at each point of use for two to four weeks. The
sampling procedures for point of use should reflect how they are
taken, e.g. use of hose, and time for flushing. At the end of the
two (2) to four (4) weeks of sampling, the firm should have
developed its SOPs for operation and maintenance of the water
system.
Develop operating ranges
Develop and finalize operating, cleaning, and maintenance
procedures
Demonstrate production and delivery of in-spec water

Sampling Program

Phase 2 (PQ Phase 1):

The second phase of the water system validation is to
demonstrate that the system will consistently produce the
desired water quality when operated in conformance with
SOPs. The sampling is performed as in the initial phase and
for the same period . At the end of this phase the data
should demonstrate that the system will consistently
produce the desired quality of water.
Demonstrate consistent operation within established
ranges
Demonstrate consistent production and delivery of
quality water

Sampling Program

Phase 3 (PQ Phase 2):

The third phase of validation is designed to demonstrate that
when the water system is operated, in accordance with the
SOPs, over a long period of time it will consistently produce
water of desired quality. Any variations in quality of the
feedwater, that could affect the operation and ultimately the
water quality, will be noticed during this phase of the
validation.
Demonstrate extended performance
Evaluate seasonal variation
For Water for Injection systems samples should be taken
daily from a minimum of one point of use, with all points
of use tested weekly.

Sampling Program

FDA Requirements:
The validation of the water system is completed
when the firm has collected data for a full year.
The FDA states that while the above validation
scheme is not the only way a system can be
validated, it contains the necessary elements for
validation of a water system.

Microbiological/
Chemical Limits
USP Limits
Tests

Potable
Water

Purified
Water

Water for Injection

pH
TOC
Conductivity

N/A
N/A
N/A

Bacteria
Endotoxins

500 cfu/mL
N/A

5.0 - 7.0
500 ppb C/liter
1.3 S/cm @ 25C
1.1 S/cm @ 20C
100 cfu/mL
Not Specified

5.0 - 7.0
500 ppb C/liter
1.3 S/cm @ 25C
1.1 S/cm @ 20C
10 cfu/100mL
0.25 EU/mL

cfu; = Colony Forming Units

Water Systems Critical

Quality Attributes (CQAs)

TOC

Conductivity

Temperature

Flow

Pressure

Rapid Microbiological Enumeration and ID off-line

On-Line Microbial rate of growth laser technology

On-line Endotoxin (Future)

Design and Qualification of

Other Utilities

Specific Requirements
Clean Steam

Design Aspects:

Stainless steel boiler

Deionized water feed
Sufficient blowdown level
Diaphragm valves not recommended

April 23, 2013

118

Specific Requirements
Clean Steam
(contd)

Clean steam:
IQ:
Control valves and
steam traps checked
Flushing, cleaning,
passivation logs/
records reviewed
OQ:
Temperature/pressure
PQ:
Pure steam condensate
= USP WFI

119

CLEAN STEAM
SPECIFICATIONS
Table: Microbiological/Chemical Limits
Tests
pH
TOC
Conductivity
Bacteria
Endotoxins

Clean Steam
5.0 - 7.0
500 ppb
USP 2? Specifications/
method
10 cfu/100mL
0.25 EU/mL

cfu; = Colony Forming Units

120

Specific Requirements
Compressed Gases

Compressed gas use as:

Oxygen supply for
bioreactors
Nitrogen purge to
remove oxygen
Clean air for aseptic
operations
Quality must meet product
specifications

121

Specific Requirements
Compressed Gases
(contd)

Product contact air:

Filtered at points of
use
Supplied by oil-free
compressor
Dried (to -40F)
Filter list
Air intake filter
(protect the
compressor)
Prefilter on desiccant
dryer

Filter list (contd)

After filter (for
retention of desiccant
particles)
Carbon bed
Point of use filter(s)
with integrity
certification
Controls and
instrumentation w/
calibration check
Pressure relief valve
Temperature and
pressure gauges

April 23, 2013

122

Specific Requirements
Compressed Gases
(contd)

OQ:
SOPs for operation and maintenance
Proper operation of controls and indicators
(compressor start or tankbank switching)
Alarms and interlocks
Line pressure (throughout distribution piping)
Air temperature

April 23, 2013

123

PQ: Process (Clean)

Compressed Air

Dew point
Hydrocarbons
Viable/non-viable
particulates

124

COMPRESS GAS SYSTEMS

TEST PROGRAM

Sample Site and Frequencies

Determination

For compress gas systems

samples should be taken daily from
a minimum of one point of use,
with all points of use tested weekly.

April 23, 2013

125

CLEAN AIR
SPECIFICATIONS
Table: Microbiological/Chemical Limits
Tests

Compress Gas

Dew Point
Hydrocarbon as Oil
Mist
Gas Content

< -10 oC
< 1 ppm

Bacteria
Non-Viable Particulate:

USP 23 Specifications/
method for Purity
< 0.1 CFU/ft3
Room Classification

cfu; = Colony Forming Units

126

Maintaining a Compliant System

127

Monitoring Program

Critical Parameter(s) Controls/Alarms

Reports verification and review (procedure)

Alert and Action Limits
Handling of Alarms
Process Deviations/Failure investigations

Laboratory testing:

Data handling
Analysis of Trends (Quarterly?)
Alert Limits and Action Limits
Outside Limit Conditions/Failure Investigations

Alarms

Critical parameters
temperature, RH%, Pressure
Differential, Velocities/Filter
Pressure Drop
Critical to Program
Adequate Alarm Limits and
Delays
Procedural Action Plan for
Alarm Conditions

129

Reports Verification and Review

(Procedure)

Operations must review the data

(recommendation weekly)

If system performs a review/trend and includes alarm

reports, this is simpler
If not, manual review is necessary

Procedure requirement for review, documentation

and archival (hard-copy or electronic)

April 23, 2013

130

Process Deviations/Failure
Investigations

If Action Limits are exceeded, need a Process

Deviation or similar form/documentation
Procedure must indicate form, process, review,
approvals and f/up.
Risk Based Interpretation/Possible Effects are the system controls working effectively?

April 23, 2013

131

Data Handling/Review/
Approval

Documentation: Forms, rules, review/approval in

a procedure
Critical for Bioburden-based sterilization cycles
Frequencies/samples need to be adjusted based
on actual results
Product Release Criteria for Aseptically Filled
Manufacturing

April 23, 2013

132

Training of Laboratory
Personnel

Sampling Techniques
Sample handling and testing
Incubation Controls
Media selection:
Incubation conditions
Growth promotion tests

April 23, 2013

133

Analysis of Trends

Statistical Analysis Control Charts with Alert

and Action Limits
Report to Responsible Management Operations
More critical for higher classifications

April 23, 2013

134

Alert and Action Limits

Not specifications
Alert potential drift from normal operational conditions

Based on historical information

Include a documented f/up investigation
May require corrective action and testing plan changes

Action Limits when exceeded, requires immediate f/up

and corrective action
Both levels should be re-examined at a defined frequency
References:

PDA Technical Report #13 (Revised) Fundamentals of an

Environmental Monitoring Program Sept./Oct 2002
ISO-13048-1, Aseptic Processing of Health Care Products
Part 1: General Requirements August, 1998

Alert and Action Levels should be derived from and consistent

with results obtained during the aseptic process validation.
Historical data from routine monitoring may also be
appropriate
April 23, 2013

135

Outside Alert/Action Limits

Conditions/Investigations

Include review of:

Area maintenance, Cleaning, Sanitization

Procedures/documentation
Operational Parameters
Training of personnel in area

Corrective Action may include:

Training enforcement
Additional testing/frequencies
Additional Sanitization
Additional product testing
ID of Microbial Contamination and possible source
Re-assess current procedures
Revalidation

April 23, 2013

136

Maintenance Requirements

Preventive Maintenance
procedures are being
followed:

Pumps, Filters,
Equipment
Frequency for
repassivation

Repairs equivalent
replacement parts
Changes following
Change Control procedure

Training Program for

Maintenance
and Operating Personnel

cGMPs
Documentation
Practices

Test Comprehension

Change Control is Key

Calibration of
Instrumentation

NIST Traceability
Calibration procedures per
type of instrument
Control software/hardware
maintained as per procedures

Change Control

Pre and Post Approval

of Change

Impact of Change
determined

Documentation of
results and modified
documents and
drawings included in
package
Quality review

Training is Key for

Effective Change Control
Typical Changes affecting
a Water System:

Operational Procedures
Sanitization/Cleaning
Procedures
Sampling/Testing
Procedures

Revalidation
Is it required?

DO NOT ESTABLISH TIME-BASED

REVALIDATION
Base decision to revalidate on change control and
monitoring procedures and controls (trending)

141

Auditing for Compliance

Internal Audits

Risk analysis for

audit observations
Remediation Plans
and Closure

Gap Analysis for

Legacy Systems

142

Exercise : Variance and

Deviations Investigations

Carbon tank, 2 mixed bed resin tank, single effect still. System
requirement is for Purified Water. Action limit is TOC does not
exceed 300 ppb. POU measurement is 1X/week. Successive weeks
look like this:
Week 1
100
Week 2

155

Week 3

95

Week 4

200

Week 5

290

Week 6

250

Week 7

275

Week 8

280

Week 9

270

Exercise : Variance and

Deviations Investigations

No specification have been exceeded.

What does this data tell you?

Is it time to investigate?

What questions should be asked?

Should any batches of product be

investigated?

Interactive Exercise:
Based on a critical utility system description
to be provided, the participants will list the
key protocol requirements and tests for the
OQ and PQ of these systems.

Conclusions

Facility and Utilities Design is dependent on

several factors including feeds and desired
specifications
Design must also consider costs, flexibility,
reliability. Options for system components are
numerous
Design Review for major systems is an FDA
expectation
Validation must be considered early in the
project
Sampling, routine monitoring and analysis of
the data to determine system consistency is key
Change Control is critical to maintain the
system integrity and documentation for the FDA
146

Questions?

147

THANK YOU!!!

Contact Info.:
Miguel Montalvo
Expert Validation Consulting, Inc.
Mobile Phone +1(407) 587-6540
Email: [email protected]
www.expertvalcon.com

148