Quality Facilities HVAC and Water Systems

Qualify Facilities, HVAC and
Water Systems

Jerry Lanese
Ph.D.
The Lanese Group, Inc.

1

Credits
: GAMAL AMER, PH. D.
PRINCIPAL
PREMIER COMPLIANCE SERVICES, INC.

2

Critical Utilities Qualification
1. Overview
2. HVAC Qualification
3. Water System Qualification

Presented by: Gamal Amer, Ph. D.
Principal
Premier Compliance Services, Inc.

© All rights reserved. Do not copy without permission. 3

Process Validation:
General Principles and Practices
•  Guidance to industry issued by the FDA in
January 24, 2011.
•  Outlines the life cycle approach to validation.
•  Inline with the principles advanced in ICH Q8,
ICH Q9, ICH Q10 and in ASTM E2500.
•  Defines PROCESS VALIDATION as the
collection and evaluation of data, from the
process design stage throughout commercial
production, which establishes scientific evidence
that a process is capable of consistently
delivering quality products.

Three Times Is Not Even
The Beginning

Jerry Lanese

Journal of Validation Technology
Vol. 7, No. 2, February, 2001
Vol. 14, No 2, Winter 2008
5

VALIDATION
The accumulated, documented evidence
that a system performs as intended
VALIDATION
validation

The collection and evaluation of data, from
the process design stage throughout
commercial production, which establishes
scientific evidence that a process is capable
of consistently delivering quality products.

ICH Q10 Pharmaceutical Quality System
Pharmaceutical Technology Commercial Product
Development Transfer Manufacturing Discontinuance

Investigational
Products
GMP
Management Responsibilities
Process Performance and Product Quality Monitoring System
PQS Corrective Action/Preventive Action (CAPA) System
Elements Change Management System
Management Review

Knowledge Management
Enablers
Quality Risk Management 7
©2009 The Lanese Group

FDA Guidance:
Process Validation:
General Principles and Practices
•  Replaces the guidance issued in 1987
•  Quality of the product cannot be assured by
simply inspecting or testing in-process and
finished products. It must be built into the
product-process a-priori.
•  Focusing exclusively on the qualification effort
without understanding the process and ensuring
the process is maintained in a state of control
may not lead to adequate assurance of quality.

8
© 2012 The Lanese Group


FDA Guidance To Industry
January 2011
•  Three Stages of Process Validation
–  Process Design Stage (process is defined
based on development and scale-up)
–  Process Qualification Stage (Design is
confirmed as being capable of reproducible
production)
–  Continued Verification and improvement
(Continuously gaining assurance the process
remains in a state of control)
9

The Life Cycle Approach to
Process Validation

Planning &
Design (ICH Q8)
PAT
ICH Q9

Continuous Implementation
Verification & & Qualification
Improvement ICH Q9, CAPA, PAT &
Change Control

ICH Q10
The Quality System



The Design Stage
•  Understanding the science
•  Understanding the risk
•  Building Quality into the process
•  Establishing Control Strategy
•  Proper design of the facility and utility
serving the process.

11


Implementation and Process
Qualification
•  Qualification of utilities and equipment
(“… design of the facility and qualification of the
equipment and utilities”)
•  Performance qualification and PQ protocol
(… PQ combines the actual facility, utilities, equipment
(each now qualified), and the trained personnel with the
commercial manufacturing process, control procedures,
and components to produce commercial batches.)
•  Protocol execution and report
12


Continued Process Verification
•  Monitoring appropriate parameters to ensure
process in a state of control, including the
performance of the utilities (e.g. Environmental
monitoring for HVAC and water system
verification).
•  Use CAPA, PAT and Change control as well as
data collected in monitoring to continually
improve the process.
•  Proper maintenance of the facility, utilities, and
process equipment
13

Science and Risk Based Compliance:
An Overview

Gamal Amer, Ph. D.
Principal


Risk to What?
•  In GMP Compliance:
–  Risk to product quality
–  Risk to the patient's well being
•  In Manufacturing
–  Risk to personnel
–  Risk to the environment
•  In Business
–  Financial risk to the company


Focus for this workshop

•  Risk is always present
•  You need to know what it is and how it
manifests itself a-priori
•  We will focus on risk to product quality
during manufacturing and the patient’s
wellbeing
•  Thus we will focus on GMP issues


FDA Initiative August 2002

Pharmaceutical CGMP for the 21st Century:
A Risk-based Approach

A science and risk-based approach to product
quality regulation incorporating an integrated
quality system approach


FDA Guidance August 2002
•  Early adoption of new technology.
•  Adoption of modern quality management
techniques and implementation of the
quality system approach.
•  Focus on understanding the science &
technology associated with what you are
making.
•  Priority to mitigating the highest risk
elements of the manufacturing operation.

FDA Guidance August 2002
•  Take home:
–  You must understand what you are doing.
–  You must focus on critical areas (highest risk
to product quality) of your operation.
–  You should utilize automation and data
collection to reduce risk associated with the
operation and allow for continuous
improvement.
–  You must build the quality into your operation.
19

Mitigating Risk and Allowing
Continuous Improvement
FDA Progress Reports discusses QA
systems:
1. Quality by Design (QbD)
2. Process Analytical Technology (PAT)
3. Corrective and Preventive Action (CAPA)


Quality by Design


ICH Q8 – Pharmaceutical Development
•  Deals with product development and its manufacturing
process.
•  Defines the need for good Design Of Experiments (DOE).
•  Defines the need for prior knowledge.
•  Use data from product development studies to manage the
risk associated with the product (quality cannot be tested in
the product but rather built into it).
•  Managing quality through out the product life cycle from
initial development through discontinuation.
•  Defines continuous process verification as an alternative to
process validation.
•  Define the knowledge space, the design space and the
normal or control space.

Product Life Cycle
Verification and
Drug Discovery
Validation

Clinical Studies Product Development Manufacturing and
Operation

Decommissioning
Process Development

Operation Design & Product
Construction Discontinuation

23

Knowledge, Design, and Control Space

The concept
Knowledge space (KS) –
Science Based

Design Space (DS) – Based on
Design and technological
capability
Control/Operating Space
(CS)

24

ICH Q8 – Pharmaceutical Development

•  Benefits:
–  Improved knowledge
–  Manufacturing improvement within DS are not
changes
–  Operational robustness
–  Reduce post-approval submissions
–  Real time release and reduced product testing
–  Continuous process/product improvement


ICH Q8 (R1) – Pharmaceutical
Development (Revision 1)
•  Introduces the concept of Quality by Design
(QbD)
•  Emphasize use of design of experiments and
prior knowledge to define the design space.
•  Identifies Critical Quality Attributes (CQA) of the
product and Critical Processing Parameters
(CPP) that would affect it.
•  Defining a control strategy based on
CQA=f (CPP)


ICH Q8 (R1)
Quality by Design (QbD):

A systematic approach to development
that begins with predefined objectives and
emphasizes product and process
understanding and process control, based
on sound science and quality risk
management.


ICH Q8 (R1)
Critical Quality Attribute (CQA):
It is a physical, chemical, biological or
microbiological property or characteristic
that should be within appropriate limit,
range, or distribution to ensure the desired
product quality. CQAs are generally
associated with the drug substance,
excipient, intermediates, and drug
products.

28

ICH Q8 (R1)

Critical Processing Parameter (CPP):
A process parameter whose variability has
an impact on a Critical Quality Attribute
(CQA) and therefore should be monitored,
“alarmed”, and controlled to ensure the
process produces the desired quality.

29

ICH Q9
•  Outlines Quality Risk Management Principles for
Product Lifecycle.
•  Phases of QRM include risk assessment, risk
control, and risk review.
•  Defines Risk and How to Measure it.
•  Outlines the principle of focusing on the critical
aspects of the drug manufacturing based on the
level of risk.
•  Use of change management to reduce risk.


What Is Risk?

The combination of the probability of
occurrence of harm and the severity of
that harm.*

*ICH Consensus Guideline; Q9 Quality Risk Management; June 2006


Risk is Always Present:
•  Risk to the patient/public (Drug Side Effects,
Adulterated Drugs)
•  Risk to the product (Contamination)
•  Risk to the personnel (Potent Compounds)
•  Risk to the neighbors and environment
(Explosion, Release Objectionable to
Atmosphere)
•  Risk to the company (Regulatory Recalls)


Defining Level of Risk
Function of:
–  Severity
–  Frequency
–  Detectability

•  These three factors determine the numerical
Risk Priority Number (RPN)
•  Qualitative risk (low, medium, and high)


Mitigating Risk

The level and extent of actions to be taken
to eliminate or minimize actual or potential
risk must be appropriate to the magnitude
of the problem and commensurate with the
level of risk anticipated. (ICH Q9)


ICH Q10

•  Defines and discusses concepts such as:
–  Quality Manual
–  Management Responsibilities
–  Continual Improvement of Process & Product
–  Continual improvement of the quality system


ASTM E-2500 Consensus
Standard
Published in August 2007


ASTM Standard E2500
•  What is it?
–  A consensus standard developed with input from
industry and FDA
–  It is called “Standard Guide for Specification, Design,
and Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and
Equipment”
–  Applies to all elements of manufacturing systems of
biopharmaceutical products including facility
equipment, process equipment, utilities, controls, etc.


ASTM Standard E2500
•  What is its intent?
–  Describe a risk- and science-based approach to
design, specification and verification of the
manufacturing systems.
–  Satisfy international as well as US regulatory
expectations.
–  Follows the concepts introduced in August 2002 in
FDA Guidance “Pharmaceutical CGMP for the 21st
Century: A Risk-based Approach”


ASTM Standard E2500

•  Objective
–  Insure that manufacturing systems are fit for
the intended use and while reducing work
duplication and cost of the required validation.
–  Accomplish through building quality into the
design, specification and construction of such
systems.
–  Verify and certify suitability.


ASTM Standard E2500
•  Tools:
–  Use of User Requirements Specification (URS).
–  Use of Good Engineering Practice (GEP).
–  Use Scientific and Technical knowledge and enlist
Subject Matter Experts (SME).
–  Relating Critical Quality Attributes (CQA) to Critical
Processing Parameters (CPP).
–  Addresses Manufacturing System Lifecycle


Manufacturing Lifecycle
Construction
Installation
Design Verification
&
Validation

Certification
Specification &
Acceptance

Operation
Planning &
Maintenance
Decommissioning
41

Overall Approach to Verify
Manufacturing Systems
•  Define user requirements
•  Conduct risk- and science-based analysis
to define critical aspects of the operation
•  Ensure that quality was designed into the
operation a-priori
•  Ensure that Good Engineering Practices
were used in the design, specification and
construction of the operation.

Manufacturing Systems (cont.)
•  Utilize subject matter experts (SME) to plan and
define verification strategy.
•  SME to define acceptance criteria and selection
of appropriate test methods.
•  SME to execute the tests and review the results.
•  SME to review and accept the verification testing
and certify the system is “Fit For Intended Use”


Manufacturing Systems (cont.)
•  Utilize vendor documentation and testing
information to support the verification
effort.
–  Confirm acceptable vendor quality system and
technical capability

•  Avoid duplication of effort/testing by using
GEP commissioning data to support the
verification.
–  Confidence that info is accurate and suitable
44

The Process
Good Engineering Practices
Product
Knowledge

Specification &
Requirements

Acceptance &
Verification
Process
Knowledge
Operation &
Continuous

Release
Design
Improvement
Regulatory
Requirements

Company
Quality Req. Risk Management
Design Review
Change Management
45

The Verification Approach
Requirements Define Acceptance
defined Criteria and CQA

verification tests
Define
Science and risk Define Critical Systems/
based analysis done verification requirements

Quality is built Define Critical Process
into the design Parameters

Use vendor
GEP confirmed documentation Perform
test

Manufacturing Review and
Operation Certify
46

Qualify/Validate Verified System
•  Provide documented evidence that the
process will consistently produce product
which meets predetermined characteristics
and quality attributes. Ensure system
remains in a validated state.


In Summary
•  The facility and utilities are part and parcel of the
process and its operation.
•  You must understand how the utilities and facility
interact with the process.
•  Qualification of utilities is part of the process
qualification.
•  Monitoring and maintaining the utilities and
facility are part of the process validation. of the
facility
•  Focus on high risk components of the facility and
utilities.

Validation of Heating Ventilation
Air Conditioning (HVAC) System

Gamal Amer, Ph.D.
Principal


Heating Ventilation and Air
Conditioning System
•  HVAC or “aitch-vak” systems are mechanical
arrangement that treat outside air to produced
cleaned (from dust and microbes) and
conditioned air (temp. & Humidity) for use in
controlled and critical areas within the
Pharmaceutical manufacturing space.
•  The systems normally consist of filtration,
heating, cooling, dehumidification, and
humidification steps.
•  It is the technology of indoor environmental
control and/or comfort.

Heating Ventilation and Air
Conditioning
•  The most important utility in the manufacture of
drug products.
•  Controls the environmental conditions in the
manufacturing space, which may affect product
quality, safety, and Efficacy (temperature and
Humidity).
•  Control the cleanliness of the manufacturing
space (Room classification-particulate number
both viable and non viable).
•  Prevent cross contamination (relative
pressurization between spaces).


Regulatory Imperatives
•  Control Temperature, Humidity , Pressure, Dust
(Particulate), and Microbial load (21 CFR 211.46)
•  The need to filter the air coming into manufacturing
space (21 CFR 211.46)
•  Protect product from extraneous contamination by
microorganisms or their byproducts. Most intermediates
and materials used in the industry are excellent
promoters of microbial growth.
•  The need to ensure that the product is not cross
contaminated by other products being processed in
adjacent space.


You also must ensure the system is
validated and remains in a
validated state. The HVAC system
must perform to meet the product
requirements and ensure that the
conditions within the manufacturing
space are consistent.


Process Validation and HVAC
Systems
An HVAC system can be viewed as a process
using outside air as a raw material and
producing conditioned air. The conditioned air
comes into contact with the drug product and
hence has a direct impact on the quality of the
drug product.

Additionally, HVAC is a system that is a utility
and part of the facility in which production occurs
and as such must be qualified and maintained
as part of Stage2 of the proposed FDA guidance
on process validation.
54

HVAC System Consists of
1.  Air Handling Unit (AHU)
- Air filtration and conditioning.
- Pump and meter the air into the distribution system.

2.  Air Distribution System – Duct Work
- Distribute the air to the various areas.
- Temperature, humidity and smoke detection controls
- Final filtration and heating if necessary.
- Returning or exhausting the air.

3.  Use Areas
- Manufacturing spaces
- Support spaces

Typical HVAC System for a Biotech Facility (Schematic)

AHU
Meter Humidifier

Outside air
Cooling Coil Pre-heat

Filters
Recycle?

Reheat Coil

Terminal HEPA

Return Corridor
Buffer Prep Clean Corridor
Fermentation
Suite Class 100K

Hood


Schematic of Biotech Facility
(Air flow pattern for cleanliness and contamination control)

Air Flow

Soiled
Clean Storage Wash Storage

Return Corridor

Buffer &
Fermentation Isolation
Degown Media Prep

Purification
Clean Corridor
Gown

Packaging Finishing
Storage &
Staging


Schematic of Biotech Facility
(Air flow pattern for cleanliness and contamination control)

Typical Layout
Air Flow/Relative Pressure

Fill & Finish
Class 100 Cold Room
Packaging & Shipping
Class 10,000 Purification
Gown/Degown Class 100,000
RH 50% +/-10%

Gown &
Degown
Corridor Class 100,000

Air
Buffer & Media Prep Lock
Isolation
Wash room Class 100,000
Fermentation Class 100,000


Design Stage; Stage-1
•  User requirements
•  Risk issues and assessment
•  Functional specification
•  Design control strategy and how to control
conditions.


Design Stage
•  User requirements:
–  Defines, temperature, humidity, cleanliness
requirements for the product as defined by the design
organization and others.
•  Risk assessment:
–  Identifies issues associated with maintaining the user
requirements such as required levels of cleanliness
and air flow parameters.
–  Relative importance of the various conditions and
whether or not there is a need to control all of them.


Design Stage
•  Functional specifications:
–  Identify how conditions can be reached using the
appropriate technology and technical knowledge.
•  Design specifications:
–  Defines the design specifications and the appropriate
design space that would allow reaching the required
conditions. Defines CQA and their relationship to the
CPP.
•  Control Strategy:
–  How will the conditions be controlled and how will the
CPP be manipulated to give the required CQA for the
resulting air.


Design Stage
•  Documents that would be needed to
support the qualification effort:
–  User requirements and design specifications
to define the conditions within the space and
the critical system components.
–  Control strategy to define what controllers are
used and where the monitoring takes place.
–  Mechanical and architectural drawings.


Implementation and Qualification
Stage; Stage-2
•  In this stage the systems are installed and the
installation as well as the operation of the
system is verified and its performance qualified
(PQ).
•  Process Performance Qualification (PPQ) of the
process (encompassing facility, utility, and
equipment) is conducted, through:
–  Protocol development and defining acceptance
criteria
–  Execution of the protocols and certification of the
process as being suitable for the intended use and
performs as expected.


What to Qualify?
•  The mechanical system
–  Its installation and operation
–  The controls
•  The air distribution system
–  Installation
–  Adequacy
–  Safety issues
•  The conditions prevailing in the room.
–  Temperature and humidity
–  Air Changes
–  Relative pressurization
–  Classification if applicable


Documents you need
•  Engineering specifications
•  Contractor’s submittals
•  O&M Manuals
•  Engineering drawings
–  Mechanical drawings (M series)
–  Architectural layout drawings (A series)
•  Test And Balance (TAB) Report

Qualification Plan For Utilities
(FDA guidance on Process validation)

•  Qualification of utilities and equipment can be covered
under individual plans or under an overall plan.
•  Plan should consider requirements of use and risk
management used to prioritize and define extent of
activities.
•  Plan should define:
–  Studies and tests to be conducted
–  The criteria to assess outcome of studies
–  Timing for qualification
–  Responsibilities for conducting the effort
–  Procedure for documenting and approving the qualification
•  Firm’s criteria for evaluating changes


Qualification of the HVAC System
•  First step is to confirm that the system has been
installed per the design and is capable of
operating within the required parameters.
•  Second is to verify that the system is capable of
providing the needed conditions within the space
and maintain them.
•  Finally a report summarizing the effort and
reaching the conclusion that the system is
acceptable for the intended use has to be
developed.


Installation & Operation
Verification Tests
and
Acceptance Criteria


IOQ or Verification Protocol
Normally the protocol will have the following sections:

•  Purpose
•  Scope
•  Responsibilities
•  System description
•  References
•  Procedures
•  Certification records
•  Attachments
•  Approvals

IOQ or Verification Protocol
Defining Acceptance Criteria
How to Define Acceptance Criteria
•  Manufacturer/Vendor Specifications
•  Engineering Design Specifications
•  Specific Requirements of System (e.g Temperature
homogeneity throughout the space)
•  Regulatory Application Requirements (NDA)
•  GMP and/or other Regulatory or Compendial
Requirements
•  Product/Intermediate Characteristics Requirements


Installation Verification
1.  List maker, local representative, and maintenance
contractor. Include addresses and phone numbers.
2.  Confirm completeness of components as per
specifications (Fans, Heaters, Humidifiers,
Condensers, etc.).
3.  Verify existence of Filters and compliance with design
specification (Pre-, Terminal, etc.).
4.  Document existence of Instrumentation at specified
locations (Thermostats, Humidistat, Sensors, Safety
devices, etc.) and indicate criticality and frequency of
calibration.
5.  Verify utilities and connections as per design (electric
service to unit, Steam for humidification, Natural gas
for heaters, etc.). 71

1.  Ensure control system is installed per the design and
verify its components.
2.  Confirm the existence of a spare parts list.
3.  Confirm that documentation and drawings for the
system exist and are accessible.
4.  Ensure maintenance, operation, calibration, and
training procedures are in place

72

Operation Verification
1.  Document that all instruments which will be
used in the qualification have valid calibration
certificates.
2.  Test controls, alarms, and interlocks to verify
their proper operation.
1.  Start and stop of system
2.  Heating and cooling response
3.  Humidification response
4.  Smoke alarm response
3.  Test, Adjust and Balance Report and Room
Air Changes Verification

Performance Qualification
and
PQ Acceptance Criteria


What will the PQ confirm
•  Ability of the system to maintain temperature and
humidity within the space for extended periods.
•  Ability of the system to properly function under normal
operating (load) condition of the facility
•  Ability of the system to maintain air flow and hence
relative pressure between the various spaces.
•  Ability of the system to maintain the particulate count
levels within the space
•  Ability of the system to maintain microbial count within
the space


Product Requirements are the
Driving Force
•  Temperature and Humidity in the space should
not negatively impact the product.
•  Temperature and humidity should meet the user
requirements.
•  If sterile space, room classification is 100 (M3.5; ISO
5 – Less than 100 particles of <0.5 micron/ft3)

•  If critical space, the air should flow from it to less
critical space.
•  If user requirements are not clear, use
engineering specifications, regulatory guidance,
standards, or compendial values.

Particulate Count
USP 23 and FDA Guidance on Sterile Drug Products, 2004

Room Classification Particles/ft3* cfu/ft3
100 (M3.5; ISO 5) 100 <0.1
10,000 (M5.5; ISO 7) 10,000 <0.5
100,000 (M6.5; ISO 8) 100,000 <2.5

* Less than the indicated number of particles of
diameter <0.5 micron/ft3


Air Changes
Based on: ISO Standard 14644 and IEST-RP-CC012.1

•  Room Classification •  Air Changes per hour
–  100 (M3.5) –  500-700
–  10,000 (M5.5) –  60-90
–  100,000 (M6.5) –  12-40

* Relative pressurization standard is 0.05” of water relative
to adjacent less clean areas.


Temperature
Based on USP; 8th supplement, dated May 15, 1998

* Room (Condition) Description Temperature Range
Freezer -25° C to -10° C
Cold 2° C to 8° C
Cool 8° C to 15° C
Controlled Room Temperature 20° C to 25° C (68-77 F)
Warm 30° C to 40° C
Excessive Heat over 40° C
Always insure that material is not in cold or hot spots.

* Relative Humidity 50% +/- 10% unless product requires
differently.

Example
PQ Acceptance Criteria for HVAC
•  Maintain temperature at 72°F ± 5° (design).
•  Maintain Relative Humidity at 50% ± 15%
(design).
•  Provide 12 (or 20) air changes per hour (design
standard).
•  Maintain a positive air pressure in the room with
respect to the hallway (GMP-prevent cross
contamination).
•  Maintain class 100,000 (GMP requirement,
Compendial requirement).


Instruments to Use
•  Data Loggers for temperature and humidity
monitoring (e.g. Hobo).
•  Particle counters for particulate monitoring (e.g.
Met One).
•  Smoke sticks or magnahelic gauges for airflow/
relative pressurization.
•  Active microbial sampling techniques
•  Possibly use data from BAS and its instruments
if calibrated and verified a-priori.


Example Procedure

•  Verify the directional airflow between
the production rooms and adjacent
areas by performing a smoke profile
around each door between the
spaces. When performing the smoke
test, verify that all other doors
adjacent to the spaces are closed.


Example Data Sheet
Attachment

Expected Airflow Actual Airflow Direction Pass Verified
(P) /Fail By / Date
Direction
(F)
Room 101 Air-Lock
⇒ Corridor
Room 102 Air-Lock
⇒ Corridor
Room 101 Air-Lock
⇒ Room 101
Room 102 Air-Lock
⇒ Room 102


Continued Verification Stage
Stage-3


•  Establish an environmental monitoring
program:
•  Collect data and ensure that no negative
trends are observed
•  Define alert and action levels (limits) a-
priori


What Do We Mean By Environment?

•  Defines the conditions which prevail within the
controlled space of interest (temperature,
humidity, particulate, pressure, and microbial).

•  Defines the influences and stresses prevailing
within the space of interest.

•  It is associated with a space, normally
controlled , where an activity of interest takes
place.

87

What Do We Mean By Environment?

•  Usually related to a sterile product or a drug
product that maybe affected by the
environmental conditions.

•  For non-sterile product it is important to be
aware of the environmental conditions within the
manufacturing space and their potential effect on
the drug product.

88

What is Environmental
Monitoring?
•  Documented program implemented through SOPs
describing method for monitoring temperature,
humidity, pressure, particulate, and microorganisms
in controlled environment. Such a program should
include definitions of:
» 1. Sampling (what and where)
» 2. Frequency of sampling
» 3.Investigative action
» 4.Corrective Action
» 5. Alert and action (levels) limits
» 6. Method for trend analysis

Why Monitor?
•  It is the law (21 CFR 211.42-10(iv))
•  Identify and correct potential environmental control
equipment problems
•  Complete the validation effort by collecting data which
takes into account the seasonal variations
•  Validate cleaning of environment / manufacturing area
•  Establish alert and action levels (by establishing
baseline conditions and identifying hot spots)
•  Insure that the manufacturing space is always in a
validate state and GMP compliant


Why Monitor? (continued):
•  Insure conditions within the
manufacturing space remain within the
appropriate ranges required by the
product
a.  No biological contamination for sterile space
b.  No cross contaminating particles from other
manufacturing operations or due to re-circulation of air.
c.  Appropriate temperature and humidity conditions.

•  Use information collected from the
monitoring program / system to control
the operation of the HVAC system
(BAS). © All rights reserved. Do not copy without permission. 91

Where to Monitor?
•  All Production Areas (including corridors and
airlocks)
•  Storage areas for product, intermediates, and
raw materials (especially if affected by
environmental conditions, especially in critical
areas near doors, ceilings, etc.)
•  Clean Rooms and Laminar Flow Hoods
•  Critical Surfaces
•  Environmentally Controlled Rooms/Chambers
•  Freezers, Refrigerators, Incubators

What You Should Monitor?
•  Temperature
•  Humidity
•  Pressure
•  Particulate
•  Microbial / Biological Load


Establishing Criteria &
Frequency?
•  Product requirements (temp sensitivity)
•  Regulatory requirements (Microbial
content for sterile areas)
•  Compendial, engineering, and federal
standard
•  Literature and industry experience


How to Monitor?
•  Temperature probes, thermocouples, chart recorders
•  Humidity probes, chart recorders
•  Temperature and humidity mapping devices and data
loggers
•  Magnahelic gauges
•  Building Automation Systems (BAS) when several
HVAC systems are used (T, RH, Pressure deferential)
•  Particle counters
•  Active microbial air sampling
•  Settling plates*
–  *Use appropriate media for organisms to be detected, e.g.
TSA for bacteria, SDA for mold and yeast


Data from routine monitoring should conform to a random pattern, and
should be within the action limits to indicate that the environment is
under control.

Action Level
*
Function Alert Level
* *
* * * *
Being * * *
* * * * **
* * * *
Monitored Alert Level
Action Level

Time

Defining Alert & Action Limits
•  Use historical data for variable to calculate
Standard Deviation
•  One way is to use 3 Standard Deviations around
the mean as Action Level and 2 Standard
Deviations as Alert Level
•  Usually Alert level is based on where you expect
to operate and action levels are based on
design/process capability values.
•  Make certain the limits you chose do not
adversely affect the product when reached
•  Be mindful of any pattern or trends in your
historical data

What to Look for?
•  Data trends towards deviations; Do not
overreact to individual events -FDA Guidance on
Process Validation January 2011

•  Repeat occurrences, which may indicate a
certain problematic event
•  Patterns in the data
•  Any changes/differences from what you
have been observing in the past


Validation of Pharmaceutical
Water Systems

Gamal Amer, Ph.D.
Principal


Pharmaceutical Water System
•  Water in the pharmaceutical industry must be
treated prior to use. Treating the water ensures
that it would have consistent quality and be free
of contaminants that may negatively impact
product quality, safety and/or efficacy.
•  Water systems normally consist of filtration,
deionization, microbial removal/reduction,
conditioning of water, and distribution to use
points.


Water In The Pharmaceutical
Industry
•  One of the most important if not the most
important utility in the manufacture of drug
products.
•  Water systems control the quality of the
water, which may affect product quality,
safety, and efficacy (chemical content,
solids content, microbial content, etc.).


Where is water used?

•  In manufacture.
•  In formulation.
•  In cleaning of equipment
•  In cleaning of the facility.


Problems with untreated water
•  Chemical content
•  Dissolved Gases and odor
•  Microbial and endotoxin content
•  Inconsistent quality
•  Seasonal variation


•  The introduction of undesirable chemicals
or other contaminants through the use of
water in the manufacture of drugs would
result in adulterated product.
•  Water should be supplied in a fashion that
would not contribute to contamination of
drug(ICH Q7a)

104

•  Potable water (this should apply to any
water supply) shall be supplied under
continuous positive pressure in a plumbing
system free of defects that could
contribute contamination to any drug
product. (21 CFR 211.48 (a))
•  Where water used in the process is
treated by the manufacturer to achieve a
defined quality, the treatment process
should be validated and monitored with
appropriate action limits. (ICH Q7a)
105

You also must ensure the system is
validated and remains in a validated state.
The water system must perform to meet the
product requirements and ensure that the
quality of the water used in the production of
drug products is consistent.


Water Systems Consist of
1.  Water Conditioning
- Water Filtration and removal of inorganic.
- Microbial control.
2.  Water Treatment
- Deionization.
- Distillation
- Microbial Control.
3.  Water Distribution
- Storage of treated water
- Pump and meter to use points
- Condition water at use point
- Microbial control
- Recycle the water


Types of Water
Increased Quality,
complexity and
compliance issues

•  Potable Water
•  Deionized Water
•  USP purified water (DI-RO)
•  Water for Injection (WFI)


Water Properties
•  Water Properties:
–  Organic chemical content (TOC)
–  Inorganic chemical content (Conductivity)
–  Microbial and endotoxin content
–  Dissolved gases
•  Water System Variables
–  Flow rate
–  Pressure


Schematic diagram for purified water production in Biotech
Facility (possible example)

To WFI Production/Distribution Return
Purified Distribution loop

Water
Ozone inject Storage
RO/Final For distribution
Filter (0.45 & in facility
0.2 µ) UV Ozone
destruct
UV Sterilizer

Municipal Water
Ion Exchange
Beds
Meter
Resin Trap UV Sterilizer Carbon Filter Pre-filter

Conditioning


Water For Injection (WFI)
Schematic of WFI Production in a Biotech Facility
Distribution

USP Water Still(s) Hot Cold
Storage Storage Cold WFI Loop
Or UF Tank
Tank

Hot WFI Loop
HE

Filter

Use Points Use Points


Design Stage; Stage-1
•  Risk issues and assessment
•  Functional specification
•  Design control strategy and how to control
conditions.


Design Stage
•  User requirements:
–  Defines water quality and type of water requirements
for the product as defined by the user.
–  Defines quantities needed and where within the
process.
•  Risk assessment:
–  Identifies issues associated with maintaining the user
requirements such as required quality and its potential
effect on the quality of the product.
–  Where to use the various types of water within the
process.
–  Relative importance of the various requirements/
needs and whether or not there is a need to control all
of them. © All rights reserved. Do not copy without permission. 113

Design Stage
•  Functional specifications:
–  Identify how properties and quantities can be
achieved using the appropriate technology and
technical knowledge.
•  Design specifications:
–  Defines the design specifications and the appropriate
design space that would allow reaching the required
conditions. Defines CQA and their relationship to the
CPP.
–  Takes into consideration eventual cleaning and
sanitization issues
•  Control Strategy:
–  How will the conditions be controlled and how will the
CPP be manipulated to give the required CQA for the
resulting water. reserved. Do not copy without permission.
© All rights 114

Design Stage
•  Documents that would be needed to
support the qualification effort:
–  User requirements and design specifications
to define the conditions within the space and
the critical system components.
–  Control strategy to define what controllers are
used and where the monitoring takes place.
–  Mechanical, piping, and architectural
drawings.

Water System Design Issues
•  Sanitary piping, valves and fittings requirements (design)
•  Materials of construction and passivation requirements
(design-SS vs. PVDF, PVC)

•  Dead legs and loop design considerations (design)
•  Regular cleaning and sanitization (Maintenance - design)
•  Hot vs. Cold System (Energy Considerations, material of construction-
Design)

•  Purification methods to be used (design; DI-RO, DI only, etc.)
•  Control of microbes and endotoxin (include UV, ozone generators, etc.)
•  Operating procedure of the system (design and initial testing)

Implementation and Qualification
Stage; Stage-2
•  In this stage the systems are installed and
the installation as well as the operation of
the system is verified.
•  Performance qualification of the system is
conducted, through:
–  Protocol development and defining
acceptance criteria
–  Execution of the protocols and certification of
the system as being suitable for the intended
use.

What to Qualify?
•  The Treatment system
–  Its installation and operation
–  The controls
•  The water distribution system
–  Installation and operation of use points
–  Adequacy
–  Cleaning and sanitization issues
•  Water quality at the use points
–  Flow rate
–  pH
–  Chemical content
–  Conductivity/Resistivety

Documents you need
•  Engineering specifications
•  Contractor’s submittals
•  O&M Manuals
•  Engineering drawings and Documentation
–  System Description
–  Mechanical drawings showing mechanical
components (M Series)
–  Plumbing drawings showing sampling points (P
series)
–  Architectural layout drawings (A series)


Qualification Plan
(FDA guidance on Process validation)

•  Qualification of utilities and equipment can be covered
under individual plans or under an overall plan.
•  Plan should consider requirements of use and risk
management used to prioritize and define extent of
activities.
•  Plan should define:
–  Studies and tests to be conducted
–  The criteria to assess outcome of studies
–  Timing for qualification
–  Responsibilities for conducting the effort
–  Procedure for documenting and approving the qualification
•  Firm’s criteria for evaluating changes


Qualification of the Water System
•  First step is to confirm that the system has been
installed per the design and is capable of
operating within the required parameters.
•  Second is to verify that the system is capable of
producing water meeting the quality
requirements and effectively distributing it to use
points, when proper operating procedure used.
•  Finally a report summarizing the effort and
reaching the conclusion that the system is
acceptable for the intended use has to be
developed.

IOQ Verification Tests
and
Acceptance Criteria


1.  List maker, local representative, and maintenance contractor.
Include addresses and phone numbers for all system
components.
2.  Confirm completeness of components as per specifications
(Deionization Beds, UV Light Generators, Tanks, Pumps, etc.).
3.  Verify existence of Filters and compliance with design
specification (Pre-, Secondary, carbon, 0.2 µ, etc.).
4.  Document existence of Instrumentation at specified locations
(Flow meters, temperature, pressure, conductivity meters, etc.)
and indicate criticality and frequency of calibration.
5.  Verify utilities and connections as per design (Feed water,
Steam for evaporators, Steam for sanitization, electric service to
pumps, etc.).
6.  Verify correct material of construction for piping and other water
contact surfaces. Document correct installation of piping per
design.

Installation Verification (cont.)
7.  Ensure control system is installed per the design
and verify its components.
8.  Document the existence of use points and their
location.
9.  Confirm the existence of a spare parts list.
10.  Confirm that documentation and drawings for the
system exist and are accessible. Make sure all
sampling points are shown on drawings.
11.  Confirm the existence of certifications such as weld
logs, leak tests, passivation certification, etc.
12.  Ensure operation, maintenance, calibration, and
training procedures are in place.
13.  Confirm training Documentation.

Operation Verification
1.  Document that all instruments which will be
used in the qualification have valid calibration
certificates.
2.  Test controls, alarms, and interlocks to verify
their proper operation. e.g.
1.  Start and stop of system components.
2.  RO interlock with de-chlorination system.
3.  Alarms for UV and Ozone generator failure.
4.  Additional system specific interlocks and alarms
3.  Leak testing through out the system
(pressurize and observe leaks)
4.  Flow testing at use points

Performance Qualification
and


What will the PQ confirm
1.  Document that all instruments which will be used in the
qualification have valid calibration certificates.
2.  Ability of the system to maintain water quality at the
various intermediate and use points.
–  Conductivity (based on compendial requirements)
–  pH
–  Chemical content
3.  Ability of the system to maintain water flow at the use
points.
4.  Ability of the system to maintain the temperature (if
applicable) at the use points.
5.  Ability of the system to maintain required conditions and
water property at use and intermediate points over time.

Product Requirements are the
Driving Force
•  Water characteristics should not negatively impact the
product.
•  Chemical and microbial content of the water should meet the
user requirements.
•  If WFI then microbial content should be <0.1 CFU/ml and 0.25
USP Endotoxin unit per ml (action level/limits-no pass fail
limits).
•  DI Water should meet USP 23 criteria for conductivity for
either stage 1, 2 or 3.
•  DI water should meet USP 23 criteria for TOC (limit 500 ppb).
•  Sample for two to four weeks to demonstrate consistency.
•  If user requirements are not clear, use engineering
specifications, regulatory guidance, standards, or compendial
values.

Sampling Requirements
•  Sample daily after each step in the
process
•  Continue sampling for a minimum of 2 to 4
weeks
•  Samples at use points should reflect how
the use point will be used (e.g. if hose to
be used sample with hose in place)


Example
Acceptance Criteria for Purified
Water System
•  Maintain Flow Rate at 7 GPM within the loop.
(design).
•  Confirm water conductivity at use point is ≤1.3
µS/cm at 25ºC. (Compendial).
•  Maintain a total bacterial count of ≤100 cfu/mL
(Compendial).
•  Repeat testing over 28 days (may use 14 or anything in
between) with all tests meeting the specified
acceptance criteria. (FDA Guidance)

Instruments to Use
•  Mass flow meters.
•  Stop watches and graduated containers.
•  Pressure meters.
•  Temperature probes, pH meters,
conductivity meters, etc.
•  TOC Analyzers.
•  Proper water sampling techniques and
proper aseptic technique training.

Example Procedure

•  For all use points obtain a sample of
water and verify the conductivity of
water at use point at 25ºC±1ºC is
greater than 2.1 µS/cm (USP Stage 2
criteria).


Example Data Sheet
Attachment
STAGE 2: Measured conductivity not to be greater than 2.1 µS/cm.

Use Point Location: __________ Use Point ID: _______
Time: ______ AM/PM Date: _____________

Item Result
Temperature of Sample @ 25° C ± 1 C° ? 0 YES 0 NO
Conductivity of Sample
Acceptance Criteria Met 0 YES 0 NO


Continued Verification Stage
Stage-3


Stage-3 Components

•  Update documentation (Update as-built drawings
regularly)

•  Maintenance of the system and equipment
logs (no leaks which could lead to contamination, filter replacement)
•  Regular sanitization of the system
•  Quality system components (CAPA, Change Control,
OOS Investigations, etc.)

•  System monitoring



•  Establish a water monitoring program.
•  Collect appropriate data and ensure that
no negative trends are observed
•  Define alert and action levels (limits) a-
priori
•  Ensure maintenance and regular
sanitization.


Where to Monitor?
•  Incoming feed water
•  Water quality at all use points.
•  Critical processing parameters (CPP) within
the system (e.g. Temperature of the still, UV
Intensity, etc.).
•  Storage Tanks (e.g. temperature, microbial
content, etc.).
•  Filter integrity.
•  Water quality at critical processing/purification
points within the system.

What You Should Monitor?
•  Chemical content (TOC, pH, Conductivity, etc.).
•  Microbial / Biological Load.
•  Endotoxin content.
•  Flow.
•  Dissolved gases (Chlorine- for RO protection).
•  Solids, color, odor.
•  CPP (temp, pressure, Ozone concentration, etc.)
•  Other (e.g. failures, Deviations, Maintenance
issues, OOS, etc.)


Establishing Criteria &
Frequency?
•  Product requirements (chemical content, microbial, etc.)
•  Regulatory requirements and guidance
(Microbial content for sterile production- Daily for WFI one use points with
all points tested weekly )

•  Compendial, engineering, and federal
standard
•  Literature and industry experience


How to Monitor?
•  TOC analyzers (on-line and in the laboratory)
•  Conductivity meters (Laboratory and on-line )
•  pH Meters and mass flow meters
•  Turbidity meters
•  Temperature sensors and indicators
•  In-line pressure and flow meters
•  Sampling for microbial (plating) and endotoxin
(LAL) content


Defining Alert & Action Limits
Again,
•  Use historical data for variable to calculate Standard
Deviation
•  One way is to use 3 Standard Deviations around the
mean as Action Level and 2 Standard Deviations as
Alert Level
•  Usually Alert level is based on where you expect to
operate and action levels are based on design/process
capability values.
•  Make certain the limits you chose do not adversely affect
the product when reached
•  Be mindful of any pattern or trends in your historical data


What to Look for?
Again,
•  Data trends towards deviations; Do not
overreact to individual events -FDA Guidance on
Process Validation January 2011

•  Repeat occurrences, which may indicate a
certain problematic event
•  Patterns in the data
•  Any changes/differences from what you
have been observing in the past


Summary
•  HVAC and water systems are the most important
utilities in health product manufacturing
operations.
•  HVAC and water systems are critical and
represents increased risk as the complexity and
cleanliness of the operation increases.
•  Qualification/validation of HVAC and water
systems is necessary
•  HVAC and water systems must be properly
designed for the intended application, qualified,
and their operation monitored continuously to
complete their validation.

Quality Facilities HVAC and Water Systems

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to Quality Facilities HVAC and Water Systems

Similar to Quality Facilities HVAC and Water Systems (20)

More from Institute of Validation Technology

More from Institute of Validation Technology (20)

Recently uploaded

Recently uploaded (20)

Quality Facilities HVAC and Water Systems