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Risk Management For Aseptic Processing

El autor Ed White realiza una descricción general de los métodos de análisis de riesgo aplicadops a la Validación de Llenado Aséptico en la Industria Farmacéutica.

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424 views

Risk Management For Aseptic Processing

El autor Ed White realiza una descricción general de los métodos de análisis de riesgo aplicadops a la Validación de Llenado Aséptico en la Industria Farmacéutica.

Uploaded by

gbra80
Copyright
© © All Rights Reserved
Available Formats
Download as PDF, TXT or read online on Scribd
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Ed White

Risk Management for Aseptic


Processing
Ed White

Welcome to The Aseptic Core.


This column discusses scientific and regulatory
aspects of aseptic processing, with an emphasis on
aseptic formulation and filling. This column has been
developed with the intention of providing practical
advice to professionals involved in the qualification of
aseptic processes and the myriad support processes
involved. The primary objective for this column:
Useful information.
Aseptic processing is one of the most challenging
of all pharmaceutical manufacturing processes. It
is also one of the most difficult to qualify processes
because of the risk factors involved. Without aseptic
processing, however, many life-saving treatments
would not be possiblefrom vaccines against
childhood diseases to cancer therapies to treatments
for Hemophilia. Aseptic processing is a risky but
necessary process.
With that in mind, it is appropriate that the
first topic for this column is Risk Management
for Aseptic Processes. Future topics will include:
Aseptic process simulations, clean room certification,
environmental monitoring, aseptic gowning and
gowning qualification, lyophilization, container and
closure qualification, and sterile filtration.
Reader comments, questions, and suggestions
are needed to help us meet our objective for
this column. Please e-mail your suggestions to
[email protected].

For more Author


information,
go to
gxpandjvt.com/bios

22

KEY POINTS
The following key points are discussed in this article:
t"TFQUJDQSPDFTTJOHJTJOIFSFOUMZSJTLZ"OFGGFDUJWF
risk management program can help to reduce risk
while reducing wasted effort.
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components in a carefully controlled environment
using careful techniques to produce a sterile
product
t"TFQUJDQSPDFTTJOHQSFTFOUTBIJHISJTLCFDBVTFUIF
lack of post-processing sterilization increases the
risk of non-sterility, and because the severity of the
lack of sterility in a parenteral product is extremely
high
t5IFRVBMJUZSJTLNBOBHFNFOUQSPDFTTJTEFGJOFECZ
the International Conference on Harmonisations
(ICH) Q9. It can be divided into four steps: Risk
assessment, risk control, risk communication, and
risk review.
t3JTLBTTFTTNFOUTIPVMECFQFSGPSNFECZBUFBNPG
qualified experts
t4PNFPGUIFNPSFQPQVMBSNFUIPETPGSJTL
assessment include failure mode and effects
analysis (FMEA), fault tree analysis, and hazard
analysis and critical control points (HACCP)
t3JTLDPOUSPMDPOTJTUTPGSFEVDJOHSJTLPS
accepting risk. A formal risk control plan may
be the output of a risk control plan as part of risk
communication.

ABOUT THE AUTHOR


Ed White is a QA validation specialist at Baxter Healthcare Corporation. He can be reached by
e-mail at [email protected].

PROCESS VALIDATION Process Qualification

Ed White

t3JTLSFWJFXTIPVMECFQFSGPSNFEPOBQFSJPEJD
basis as part of the quality management process
t3JTLBTTFTTNFOUJTVTFEJOQSPDFTTJOHUP
determine project activities to reduce the risk
level. If reduction is not possible, there should be
additional in-process controls, additional testing,
and additional training to mitigate risk.
t3JTLBTTFTTNFOUJTVTFEJOWBMJEBUJPOUP
determine high-risk processes. There should
be proportionately increased sampling, testing,
or more rigorous acceptance criteria to provide
greater assurance of process acceptability.

INTRODUCTION
Aseptic processes are some of the most difficult
processes in the pharmaceutical industry. Because
of the nature of aseptic processes, sterile products
produced aseptically present a significantly higher
risk to the patient than terminally sterilized products.
Because of the high level of risk, an effective quality
risk management program is necessary to protect the
patient.
An effective risk management program aids in
the careful control of the process, reducing the risk
of contamination at the same time it reduces wasted
effort in controlling risks that are not significant. This
column discusses some of the common techniques
used to manage risks for aseptically processed
products.

WHAT IS AN ASEPTIC PROCESS?


Aseptic processing involves manipulation of sterile
components in a carefully controlled environment
using careful techniques to produce a sterile product.
While aseptic processing usually involves filling of
final drug product, there are other types of aseptic
processes, including aseptic assembly of devices or
combination products, aseptic crystallization or aseptic
precipitation of drug product to produce a sterile bulk
drug substance, and aseptic formulation of final drug
product.
One thing all aseptic processes have in common is
their high level of risk. They require careful control
of the aseptic environment, of personnel practices
and procedures, sterilization of equipment and
components, extensive environmental monitoring,
and many other controls that will be covered in future
installments of this column. The number of controls
required and the severe consequences of control
failure make aseptic processing one of the highest risk
pharmaceutical processes. Quality risk management is
an essential tool in ensuring product quality.

QUALITY RISK MANAGEMENT


Although quality risk management (QRM) is a
relatively new concept to the pharmaceutical industry,

it has been used in other industries for many decades,


with some risk assessment tools dating back to the
World War II era. The pharmaceutical industry has
been slow to adopt many of these tools because of
the industry focus on regulatory compliance as the
driving force for quality. This traditional compliancebased approach had its drawbacks that became more
evident as the industry became more diverse and
sophisticated. A one-size-fits-all approach to quality
became increasingly unworkable, leading the US Food
and Drug Administration to develop a quality systems
approach to regulation.
The quality systems approach to the pharmaceutical
industry was launched on a large scale with the
FDA publication of Pharmaceutical cGMPs for the 21st
CenturyA Risk Based Approach in August 2002 (1).
This initiative had the ambitious goal of transforming
the FDA regulatory approach to the pharmaceutical
industry into a science-based and risk-based approach
with an integrated quality systems orientation.
In the time since the publication of the concept
paper, this initiative has been largely successful,
leading to publication of international guidance
documents such as ICH Q9, Quality Risk Management
(2) and Parenteral Drug Association (PDA)
5FDIOJDBM3FQPSU/P 2VBMJUZ3JTL.BOBHFNFOU
for Aseptic Processes (3). The publication of ICH
Q10, Pharmaceutical Quality System has further
enhanced the risk-based approach to pharmaceutical
manufacturing.
There are many potential uses for quality risk
management in the pharmaceutical industry,
including the following:
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of internal and external audits
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the potential quality impact of quality defects,
complaints, trends, and non-conformances
t1SPWJEJOHBGSBNFXPSLGPSFWBMVBUJPOPG
environmental monitoring data
t&WBMVBUJOHUIFJNQBDUPGDIBOHFTUPUIFGBDJMJUZ 
equipment, or process on product quality
t&TUBCMJTIJOHBQQSPQSJBUFTQFDJGJDBUJPOTBOE
identifying critical process parameters during
product and process development
t"TTJTUJOHGBDJMJUZEFTJHOEFUFSNJOJOHBQQSPQSJBUF
material, equipment, and personnel flows,
appropriate level of cleanliness for processing
areas, etc.
t%FUFSNJOJOHUIFTDPQFBOEFYUFOUPGRVBMJGJDBUJPO
of facilities, buildings, and production equipment
and/or laboratory instruments (including proper
calibration methods)
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t%FUFSNJOJOHSFWBMJEBUJPOGSFRVFODZ
t%FUFSNJOJOHUIFFYUFOUPGDPNQVUFSJ[FETZTUFN
validation
PROCESS VALIDATION Process Qualification

23

Ed White

t*EFOUJGZJOHUIFTDPQFBOEFYUFOUPGWFSJGJDBUJPO 
qualification, and validation activities
t%FUFSNJOJOHUIFDSJUJDBMBOEOPODSJUJDBMTUFQTJOB
process to assist in the design of process validation
t"OENBOZPUIFSVTFT
The uses for quality risk management tools are
nearly limitless. A few examples of the uses of these
tools in aseptic processing include the following:
tEquipment and facility design. QRM tools
such as 3-D risk assessment (4) can be used to
identify high-risk equipment and facilities,
as well as low-risk equipment and facilities;
this will allow risk control efforts to focus on
eliminating the highest risks. Design of highrisk equipment and facilities can be enhanced
using input from tools such as failure mode and
effects analysis (FMEA) and fault tree analysis
to identify potential failure modes. This input
allows the equipment designer to add preventive
measures to the equipment design to reduce
the occurrence of, or even eliminate, potential
failure modes.
tEquipment and facility qualification. QRM
tools can be used to identify the critical aspects of
the aseptic processing equipment or facility that
need to be intensively qualified, and the low-risk
aspects of the equipment or facility. QRM tools
can also be used to determine the extent and
frequency of requalification efforts.
tChange control. QRM tools can be used to
identify high-risk equipment and facilities that
need to be maintained under strict change control,
as well as the equipment and facilities that can
be placed under a simpler engineering change
management program.
tP rocess validation. QRM tools can be
used to identify the key inputs, key process
parameters, and key outputs that need to be
monitored and controlled. This allows for
focused process validation that ensures that
process parameters that are critical to product
quality are appropriately validated.

What Is Quality Risk Management?


Risk is the combination of the probability of harm and
the severity of harm. For the purposes of QRM, it is
the risk to the patient that is important, not the risk
to other stakeholders, such as government, industry,
medical practitioners, etc.
According to ICH Q9, quality risk management is
defined as a systematic process for the assessment,
control, communication, and review of risks to
the quality of the drug product across the product
lifecycle (2).

24

PROCESS VALIDATION Process Qualification

Some key concepts in this definition are that QRM is


a systematic process, and that it is designed to manage
the risks to product quality across the product lifecycle.
The introduction of a systematic process for managing
product quality is crucial to consistently providing a
high-quality product to the customer.
ICH Q9 defines the two primary principles of
quality risk management as follows:
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on scientific knowledge and ultimately link to the
protection of the patient
t5IFMFWFMPGFGGPSU GPSNBMJUZ BOEEPDVNFOUBUJPO
of the quality risk management process should be
commensurate with the level of risk.
These principles lead to a need for a formal risk
management program for manufacturers of parenteral
products. Because these products, which include most
biotechnology-derived drugs, bypass many of the
bodys defense systems, the level of risk to the patient
is significantly higher than in oral or topical products.

THE QUALITY RISK MANAGEMENT


PROCESS
ICH Q9 describes the quality risk management
process. Figure 1 illustrates the components of the
quality risk management process across the product
lifecycle.

Risk Assessment
Risk assessment is the first portion of the quality
risk management process. It consists of identifying
potential hazards, analyzing hazards, and risks
associated with exposure to those hazards. A few key
points about the risk assessment process include the
following:
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of qualified experts from disciplines such as
engineering, quality assurance, validation, and
manufacturing, preferably facilitated by someone
familiar with the risk assessment process. This
team should clearly define the risk question. A
poorly defined risk question can lead to lack of
focus in the risk assessment.
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in the risk assessment: What can go wrong, how
likely is it to go wrong, and how severe are the
consequences?
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assessment are given under Risk Assessment
Tools. These tools share some of the key
characteristics of a risk assessment process:

Ed White
Figure 1: Risk management process (from ICH Q9).
Initiate
Quality Risk Management Process

Risk Assessment
Risk Identication

The output of the risk assessment portion of the risk


management process is used in the risk control portion
of the risk management process.

Risk Analysis

Risk Control
Risk control consists of developing a plan to reduce and/
or accept risks. The purpose of risk control is to reduce
risk to an acceptable level. The formality and effort of
risk control should be appropriate for the level of risk.
The following questions should be asked during this
phase:
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t8IBUDBOXFEPUPSFEVDFPSFMJNJOBUFSJTLT
t8IBUJTUIFSJHIUCBMBODFCFUXFFOSJTLT CFOFGJUT 
and resources?
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A risk control plan may be the output of the risk
control process. This plan may be included in a project
plan or validation master plan, as part of the risk
communication process.

Risk Communication
Risk communication is simply thatcommunication
of risks between decision makers and other interested
parties, either within or outside the company. This
may be done formally or informally, as appropriate for
the risk level of the product and process.

Risk Review
Risk review is simply periodic review of risks as part of
the ongoing quality management process. Examples
of where formal or informal risk review might be
performed include periodic management review, as
part of a change control program or as part of annual
product reviews. However it is performed, risk review
should be integrated into the quality management
system.

RISK ASSESSMENT TOOLS


The following is a partial list of some of the risk
assessment tools used in the pharmaceutical industry.
This is hardly a comprehensive list. There are
numerous risk assessment tools available in different
industries and for different functions within the same
industry.

3-D Risk Assessment

Risk Communication

Risk Evaluation
Unacceptable
Risk Control
Risk Reduction

Risk Acceptance

Risk Management Tools

t Systematic identification of hazards referring to


the risk question (risk identification)
t Estimation of the risk associated with the
identified hazard (risk analysis)
t Comparison of the identified and analyzed risk
against pre-determined criteria (risk evaluation).

Output/Result of the
Quality Risk Management Process

Risk Review
Review Events

Three-dimensional (3-D) risk assessment (4) is a risk


assessment tool that takes into account a systems
distance from the process stream, its location along the
process stream (e.g., active pharmaceutical ingredient
[API] synthesis, and purification, bulk product
formulation, sterile filtration, filling and stoppering,
etc.), and the systems complexity. This tool is mainly
used to assign a risk level to an overall system. Where
appropriate, additional risk assessment tools may be
used to evaluate risks within a pharmaceutical system.
Figure 2 gives a visual representation of the 3-D
risk assessment process for a biotechnology-derived
product (4).

Failure Mode And Effects Analysis


Failure mode and effects analysis (FMEA) is one of the
most commonly used methods for pharmaceutical
risk assessment. It is a team-based structured risk
assessment method that can assign a numerical risk
priority number based on relative perceived risk. A
FMEA is dependent on the expertise of the team
members (see Table I).

Hazard Analysis And Critical Control Points


Hazard analysis and critical control points (HACCP)
is a tool mandated by FDAs Center for Food Safety
and Applied Nutrition for use in the seafood industry
and other food processing industries. Its use in the
pharmaceutical industry was described in detail by the

PROCESS VALIDATION Process Qualification

25

Ed White
Figure 2: 3-D risk assessment matrix (4).
1) Working cell bank thaw and inoculum cell culture
2) Bioreactor cell culture and harvest
3) Purication
1
4) Bulk formulation and sterile ltration
2

1
4
Distance along
product stream

5) Post sterile
ltration, lling,
lyophilization,
packaging,
patient information,
delivery to patient

Distance from
product stream

2
3
4

Area of
greatest risk

System complexity

World Health Organization (WHO) in 2003 (5). The


seven principles of HACCP include the following:
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t%FUFSNJOFUIFDSJUJDBMDPOUSPMQPJOUT $$1T

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t&TUBCMJTIBTZTUFNUPNPOJUPSDPOUSPMPGUIF$$1
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monitoring indicates that a particular CCP is not
under control
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that the HACCP system is working effectively
t&TUBCMJTIEPDVNFOUBUJPODPODFSOJOHBMMQSPDFEVSFT
and records appropriate to these principles and
their application.
Table II illustrates an HACCP worksheet for the
filling of product into vials for a hypothetical biotech
company.

Fault Tree Analysis


Fault tree analysis (FTA) is a risk assessment method
that begins with a failure event, and uses logic
diagrams to determine the sequence of events required
to cause the failure. FTA is frequently used as a design
tool for critical systems. FTA can be used with other
tools such as FMEA to ensure all failure modes are
included and to develop estimates of the frequency of
a particular failure mode.
This tool is excellent for equipment design
and commissioning, for determining procedural
controls needed to prevent a failure event, and for
determining qualification and control strategies. With
26

PROCESS VALIDATION Process Qualification

modification, it can also be used to assign probabilities


to each failure mode.
The limitation of this tool is that it requires a large
amount of time and effort to construct properly; it
can expand rapidly as more detail is added. It is more
suitable for large, complex systems than for simple
systems because of the time and effort required.
Fault tree analysis involves the following steps:
t%FGJOFUIFGBJMVSF VOEFTJSFEFWFOU
UPTUVEZ
t(BJOLOPXMFEHFPGUIFTZTUFNHBUIFSBUFBNPG
experts to analyze the system
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t&WBMVBUFUIFGBVMUUSFF
t%FWFMPQDPOUSPMTUSBUFHJFTGPSUIFJEFOUJGJFE
hazards.
Figure 3 shows a partial fault tree diagram for a
critical failurecross-contamination between two
products. The top event represents the failure. Each
subsequent level is connected by a logic gate (AND,
OR, etc.). As shown in this figure, a fault tree diagram
can grow rapidly and can become quite complex.

IMPLICATIONS OF RISK ASSESSMENT ON


PROCESSING
When a process step or other activity is determined
to be high risk, what should be done? These
determinations should cause initiation of project
activities to reduce the risk level. However, if
reduction is not possible, there should be additional
in-process controls, additional testing, additional
training, and so on. In summary, the organization
should expend additional effort to mitigate or control
the risk situation. At the same time, efforts on
processes or activities that are well controlled or do
not represent risk can be minimized. For example,
a new purified water (PW) supply was planned for
an aseptic processing facility. This PW supply was to
be used as feed water for a water-for-injection (WFI)
still, for initial rinse water for clean in place (CIP) of
formulation and filling equipment, and for make-up
of wash solutions for CIP of formulation and filling
equipment. WFI was used for the final rinse of this
equipment. Based on these parameters, a 3-D risk
assessment was performed on the PW system, giving
the results shown in Table III.
The overall score determined by this risk assessment
is 30, indicating the overall risk is low to medium.
This low overall score indicates that detailed formal
risk assessment methods such as FMEA are not
needed for this system. While the overall risk score
indicates few controls are needed, the distance along
product stream score indicates that some engineering
controls and in-process controls are justified. Based
on this analysis, the design engineer decides to add
an ultraviolet (UV) system for controlling bioburden,

Ed White

Table I: Sample FMEA for fill line change over.


System ID
Usage

Failure
Mode

Potential
Effects

Potential
Causes

Current
Controls

RPN Risk
Mitigation

Gaskets and
silicone tubing
changed
between products
to prevent crosscontamination

Gaskets
and
tubing not
changed
out
between
products

Residual
product could
remain in
tubing or
gaskets,
contaminating
next product

Operator error,
inadequate
instructions

None

125

Use documented
second operator
check to ensure
change over is
performed

CIP not
performed

Filler interlocked
to prevent use
without CIP/SIP

Current controls
are adequate

Excessive
temperature
on initial rinse
causes protein
denaturation

Over temperature
alarm and cycle
abort

Periodic testing
and calibration of
alarms

Automatic
chemical
addition fails

Conductivity
alarm to detect
failure to add
chemicals

30

Periodic testing
and calibration of
alarms

Filler is cleaned
in place to ensure
removal of
residual product

Filler not
cleaned
properly

Residual
product could
contaminate
next product

Table II: HACCP worksheet (adapted from FDA CFSAN website).


Firm Name

Anonymous Biotech

Firm Address

123 Elm Street, Anywhere, USA

Equipment Description

Multi-product filler

Product Description

Injectable biotech product

Processing Potential hazards


step

Are any
potential
hazards
significant?

Justification

Preventive measures

Is this step a CCP


(Yes/No)?

Fill product
into vials

Biological-microbial
contamination of
product

Yes

Non-sterile product
presents high patient
risk

Environmental controls
Personnel controls
Personnel and environmental monitoring

Yes

Physical-needle
strikes during filling

Yes

Needle strikes could


generate glass
particulate hazard

Setup tool
Automatic line stoppage
on needle strike

Yes

Chemical-protein
denaturation due to
foaming

Yes

Could cause loss of


product potency

Needle design
Bottom-up fill
Control fill pressure

Yes

as well as conductivity alarms to indicate system


problems. In addition, periodic monitoring and
trending of system bioburden is justified. A contrasting
example would be an aseptic filler intended for
multiproduct use. This filler is designed for high-speed
filling and stoppering of several different products
with rapid changeover. This filler is designed for
in-line check weighing, and for automated CIP and
sterilization in place (SIP). A 3-D risk assessment of
this equipment gave the results shown in Table IV.
The risk assessment clearly indicates the filler is a

high risk system. Based on this assessment, design and


process FMEAs were performed on the filler to identify
controls to mitigate high-risk items. Table V is a partial
example of a process FMEA used to identify design
controls for the new filler.
This example shows a small portion of a detailed
FMEA for the CIP process for a critical system (aseptic
filler). A FMEA such as this one could be used to put
additional controls into place during design of the
system, as well as to identify critical items that need to
be verified during validation.
PROCESS VALIDATION Process Qualification

27

Ed White
Figure 3: Fault tree analysis diagram.
Product A
contaminated with
Product B

AND

Equipment Not
Cleaned

Product A and
Product B Share
Equipment
Surfaces

OR

Cleaning
Procedure Not
Performed

Cleaning
Procedure
Inadequate

Cleaning
Procedure Wrong

Cleaning
Chemistry Wrong

Equipment Failure

Table III: 3-D risk assessment for purified water


system.
System

Distance
Distance
along prod- from
uct stream product
stream

System
complexity

Overall
score

Purified
water system

30

Table IV: 3-D risk assessment for aseptic filler.


System

Distance
along
product
stream

Distance
from
product
stream

System
complexity

Overall
score

High-speed
aseptic filter

125

IMPLICATIONS OF RISK DETERMINATION


ON VALIDATION
What are the implications of high risk processes or
activities on validation? When validating high risk
processes or activities, there should be proportionately
28 PROCESS VALIDATION Process Qualification

increased sampling, testing, or more rigorous acceptance


criteria to provide greater assurance of process
acceptability. The 2008 FDA process validation draft
guidance (6) specifically incorporates the following risk
management principles:
ti3JTLBOBMZTJTUPPMTDBOCFVTFEUPTDSFFOQPUFOUJBM
variables for DOE studies to minimize the
total number of experiments conducted while
maximizing knowledge gained.
ti2VBMJGJDBUJPOPGVUJMJUJFTBOEFRVJQNFOUDBOCF
covered under individual plans or as part of an
overall project plan. The plan should consider
the requirements of use and can incorporate risk
management to prioritize certain activities and to
identify a level of effort in both the performance
and documentation of qualification activities.
The European Union Guide to Good Manufacturing
Practice, Annex 15 (7), also refers to the use of risk
management in validation and states, Significant
changes to the facilities, the equipment, and the
processes, which may affect the quality of the product,
should be validated. A risk assessment approach
should be used to determine the scope and extent of
validation.
How is risk management incorporated into
validation? Risk assessment tools are used to
determine the extent of validation and frequency
of validation. A few practical examples of how risk
management tools are used in validation may be
helpful.

Low Risk System


A chilled water system was used to cool a jacketed
tank during formulation of a product prior to sterile
filtration. This system contacts the tank jacket only.
The chilled water system was controlled by an off-theshelf temperature control system with a chart recorder.
A 3-D risk assessment of the chilled water system gave
the results shown in Table VI.
Because the system is low risk, no qualification
was necessary beyond engineering commissioning
of the system. Once commissioned, the system was
placed under a standard PM program, and the chart
recorder and temperature controller were calibrated
on an annual basis.

Medium Risk System


A bulk formulation tank was used to compound
a parenteral product before sterile filtration. This
tank was connected to a distributed control system
(DCS) that controls mixing speed and temperature
according to setpoints entered by the operator from
a local panel in the compounding area. Ingredients
other than WFI were added manually by the
operators. WFI was added from a WFI drop at the

Ed White

Table V: Process FMEA example (system=aseptic filler; process=clean-in-place).


Process
function

Failure mode

Potential
effects

Potential causes

Current
controls

RPN

Risk mitigation

Initial rinse
of fill lines

Inadequate flow Process


through filling
soil not
needles
removed

Inadequate flow
rate through
system

Monitor
and alarm
flows

15

N/A

Partially blocked
needle(s)

None

75

Verify needles are open


before CIP, use disposable
filling manifold

Needle design
does not allow
adequate flow
through filling
manifold

None

125

Design control, pulsed


rinse through manifold

Inadequate flow Process


through filling
soil not
manifold
removed

mixing tank, which was opened by the operator


from the DCS local panel. A level transmitter
connected to the tank indicates the volume of WFI
added to the tank. A 3-D risk assessment of the
formulation tank gave the results shown in Table
VII.
Based on the risk score of 60, the system was
designated as a medium risk system. Construction
and operation of the formulation tank were
verified under installation qualification (IQ) and
operational qualification (OQ) protocols. The
compounding process itself was verified under a
performance qualification (PQ) protocol. After
completing IQ, OQ, and PQ, the formulation
tank was placed under change control. No
periodic requalification was required, but periodic
assessment of the system was required to ensure it
maintained its validated state of control.

cake appearance and reconstitution, followed by


media fills and conformance lots for the protein
therapeutic. The lyophilizer was placed under
change control with periodic requalification,
including shelf mapping and requalification of the
CIP and SIP processes. Media fills were performed
using the lyophilizer on a quarterly basis.

CONCLUSION
Quality risk management is an essential tool for
qualification of aseptic processes. It is not just a
tool for CGMP compliance; it offers real benefits
to the validation process by identifying risks
and ensuring that critical risks are controlled.
By focusing managing risks to the patient,
pharmaceutical manufacturers can ensure that
the right resources are applied at the right place
at the right timeimproving patient safety while
eliminating unnecessary validation efforts.

High Risk System


An injectable protein therapeutic was not stable
in liquid form and requires lyophilization. The
lyophilizer was highly automated, with automated
CIP and SIP, automated moisture content and
product temperature monitoring using pressure rise
methodology, and a supervisory control and data
acquisition system containing the lyophilization
recipes for each dosage form of the product.
Product was loaded into the lyophilizer by an
auto-loading system. A 3-D risk assessment of the
lyophilizer gave the results shown in Table VIII.
Based on the risk score of 125, the lyophilizer was
designated a high-risk system. Extensive validation
efforts, including computerized system validation
(CSV), CIP, and SIP validation, IQ and OQ
including shelf mapping, condenser capacity and
sublimation rate, and other tests were performed
to characterize the performance of the lyophilizer.
PQ of the lyophilizer included surrogate lots
with site specific sampling for moisture content,
PROCESS VALIDATION Process Qualification

29

Ed White

Table VI: 3-D risk assessmentlow risk system.


System

Distance
along
product
stream

Distance
from product
stream

System
complexity

Overall
score

Chilled
water system

Table VII: 3-D risk assessmentmedium risk


system.
System

Distance
along
product
stream

Distance
from product
stream

System
complexity

Overall
score

Bulk formulation tank

60

Table VIII: 3-D risk assessmenthigh-risk


system.
System

Distance
along
product
stream

Distance
from product
stream

System
complexity

Overall
score

Automated
lyophilizer

125

REFERENCES

ARTICLE ACRONYM LISTING

1. FDA, Pharmaceutical CGMPs for the 21st CenturyA Risk


Based Appoach, August 2002.
2. ICH Q9, Quality Risk Management, November 9, 2005.
3. PDA, 5FDIOJDBM3FQPSU/P 2VBMJUZ3JTL.BOBHFNFOUGPS
"TFQUJD1SPDFTTFT 4VQQMFNFOU, Volume 62, No. S-1.
4. Oliver, James, A 3-D Risk Assessment Model, +PVSOBMPG
7BMJEBUJPO5FDIOPMPHZ, Vol. 14, No. 5, Autumn 2008.
5. WHO, Annex 7: Application of Hazard Analysis and Critical
Control Point (HACCP) Methodology to Pharmaceuticals.
World Health Organization, 8)0&YQFSU$PNNJUUFFPO
4QFDJGJDBUJPOTGPS1IBSNBDFVUJDBM1SFQBSBUJPOT 5IJSUZ4FWFOUI
Report, Geneva, Switzerland, 2003.
6. FDA, Draft Guidance: Guidance for IndustryProcess
7BMJEBUJPO(FOFSBM1SJODJQMFTBOE1SBDUJDFT, November 2008.
7. European Commission, Enter prise Directorate
General, Working Party on Control of Medicines and
Inspections, 'JOBM7FSTJPOPG"OOFYUPUIF&6(VJEFUP
(PPE.BOVGBDUVSJOH1SBDUJDF2VBMJGJDBUJPOBOE7BMJEBUJPO,
September 2001. JVT

API
CCPs
CIP
CSV
DCS
FMEA
FTA
HACCP
IQ
OQ
PDA
PQ
PW
QRM
SIP
UV
WFI
WHO

Active Pharmaceutical Ingredient


Critical Control Points
Clean in Place
Computerized System Validation
Distributed Control Systems
Failure Mode and Effects Analysis
Fault Tree Analysis
Hazard Analysis and Critical Control Points
Installation Qualification
Operational Qualification
Parenteral Drug Association
Performance Qualification
Purified Water
Quality Risk Management
Sterilization in Place
Ultraviolet
Water for Injection
World Health Organization

Originally published in the Spring 2009 issue of 5IF+PVSOBMPG7BMJEBUJPO5FDIOPMPHZ

30 PROCESS VALIDATION Process Qualification

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