B I O P R O C E S S TECHNICAL
Risk Analysis and
Process Validation
A. Hamid Mollah
P
rocess validation is required manufacturing process will assist in
by the current good process validation. For the purpose of
manufacturing practice illustration, I’m applying risk analysis
(cGMP) regulations for to APIs; however, the concept can be
finished pharmaceuticals applied to other products as well.
(1). The FDA’s initiative in
pharmaceutical GMPs for the 21st DEFINITIONS
ILLUSTRATION BY C.A. SCOTT USING PHOTOS
Century is a science- and risk-based The FDA defines process validation FROM LORENZO COLLORETA AND AYAAZ RATTANSI
approach to product quality (PV) as establishing documented ([Link])
regulation incorporating an evidence to provide a high degree of
integration of quality systems. The assurance that a specific process will and operational controls. Those
risk-based approach should enhance consistently produce a product established to protect product
industry’s ability to focus on meeting predetermined specifications quality are critical control
identifying and controlling critical and quality characteristics (3). The parameters. Those monitored and
factors that affect process and ICH defines it as documented controlled during GMP production,
product quality. The International evidence that a process, operated but with no established evidence of
Conference on Harmonisation’s within established parameters, can product quality impact, are
(ICH’s) Q7A GMP guidance for perform reproducibly and effectively operational control parameters.
active pharmaceutical ingredients to produce an intermediate or API
(APIs) requires validation of critical meeting predetermined specifications PROCESS VALIDATION
processing steps determined to affect and quality attributes (2). The ICH FOR API MANUFACTURING
API quality and purity (2). To have a Q7A definition of critical refers to A series of qualification and/or
successful process validation, it is process steps, conditions, test validation activities take place after
imperative to determine critical requirements, or other relevant commissioning of a facility, its
processing steps and critical parameters or items that must be equipment and utilities. Routine
parameters. Risk analysis assists in controlled within predetermined qualification activities include design
identifying those steps along with the criteria to ensure that an API meets (DQ), installation (IQ),
critical factors and/or parameters its specification (2). qualification (OQ), and
that affect product quality. A Critical Control Parameters: Critical performance qualification (PQ).
documented risk analysis of a parameters and/or attributes are User requirements specifications
normally identified during (URS), functional specifications
PRODUCT FOCUS: ALL THERAPEUTICS development or from historical data (FS), and design specifications (DS)
— along with ranges necessary for documents are used in design
PROCESS FOCUS: THROUGHOUT reproducible operations. Critical qualification. Before PV begins, the
limits should not be confused with associated equipment, utilities, and
WHO SHOULD READ: VALIDATION, operational limits. In-process and control systems must be qualified.
QA/QC, REGULATORY AFFAIRS, release (end product) parameters are PV is the final step before declaring
PROCESS DEVELOPMENT, AND controlled and monitored during a manufacturing process to be
MANUFACTURING PERSONNEL production. Some noncritical validated. PV data are usually
KEYWORDS: FMEA, FTA, HACCP, process parameters are also presented to the regulatory agency
RISK ANALYSIS, PRODUCT LIFE CYCLE,
controlled and monitored to reduce during application submission.
PROCESS VALIDATION
variability and operator error in Therefore, they are critical to
GMP operations. All controlled regulatory approval. Regulatory
LEVEL: INTERMEDIATE process parameters can be divided input on PV along the way can
into two categories: critical controls speed up the approval process.
28 BioProcess International OCTOBER 2004
A Modular Approach: Because of the process using qualified equipment, and failure mode and effect analysis
complexity of the manufacturing facilities, utilities, and control systems. (FMEA) are both used in the
process, a modular approach is medical device industry (4). Hazard
routinely used in API manufacturing. RISK ANALYSIS TOOLS analysis and critical control points
The entire process is divided into The types of risks a pharmaceutical (HACCP) are used in the fisheries
several steps (modules) based on company must deal with include industry (5). The World Health
distinct process inputs and outputs. patient risk (safety and efficacy of Organization (WHO) published in
Figure 1 is a flow diagram of API the drug), operational risk an expert committee report an
manufacturing and process validation (operation safety, contaminations, or annex titled “Application of Hazard
modules. Output of any particular process variability), financial risk Analysis and Critical Control Point
module will provide the input (feed) (product loss, reputation, and legal (HACCP) Methodology to
of the subsequent module. Hence, costs), and regulatory risk (FDA Pharmaceuticals” (6).
successful conformance runs require 483s, warning letters, product Fault Tree Analysis (FTA): FTA is a
meeting all acceptance criteria for recalls, seizures, even legal actions). deductive, top-down approach to
each module. Protocols must be Taking those risks into consideration failure mode analysis (7). First, a
developed and approved for all is an integral part of developing a system failure or safety hazard is
process validation activities. The manufacturing process. Risk analysis assumed. Then, the combination of
“Protocol Development” box lists in PV promises to minimize the conditions required for that event
considerations for a manufacturing process risk. Risk assessment tools (or failure) to occur is systematically
help in defining the process and defined, usually by identifying how
identifying critical areas and/or failure-related events at higher levels
PROTOCOL DEVELOPMENT steps in that process, areas of risk are caused by lower-level “primary
CHECK LIST and/or hazard, and critical control events” (failure of an individual
points. Performing risk assessment component) and “intermediate
Ensure that approved operating of scale-up and/or manufacturing events” (failure of a subsystem). The
procedures are in place. process is recommended as well. resulting information is organized in
Validate methods. Among the risk analysis tools the form of a “fault tree diagram,”
available, fault tree analysis (FTA) with the top event first. Events at
Train and/or qualify operating
personnel.
Complete process description and flow
diagram.
Identify product quality attributes, and
justify acceptance criteria. Review of
risk analysis, process development
runs, clinical manufacturing, and
license and in-house specifications for
an existing process will assist in
identifying product quality attributes
and their acceptance criteria.
Determine process variability. Various
methods used include statistics
(manufacturing and clinical data sets
are not significantly different);
historical trends (all data from
manufacturing scale runs are within
historic range of clinical
manufacturing data); and “mean ±
3SD” (data from manufacturing scale
runs are within mean ± 3 standard
deviations of the clinical data).
Perform at least three process
validation conformance runs.
Additional runs may be required for
verification of some critical
parameters.
For manufacturing processes, make
validation maintenance an ongoing
activity.
high-risk steps, and controlling or
Table 2: Hazard analysis for a bioreactor SIP and vial-thawing process
monitoring those steps to thereby
Potential Hazard Addressed Control ensure that the process will always
Step Hazard Justification in the Plan? Measure yield quality product (5). HACCP
Bioreactor Inadequate Bioburden growth Yes SIP process provides detail and documentation
steam-in-place microbial will contaminate proving that a company understands
(SIP) kill the bioreactor its product and process well enough
Working cell Thaw Thaw at warm No Operator to control or monitor parameters
bank (WCB) temperature temperature, not verification, SOP important to the manufacture of
vial thaw and time exceeding maximum to control thaw
temperature and time temperature and quality products.
specified time, and system HACCP involves the following
calibration steps or principles:
• Conduct a hazard analysis
different levels of the tree are functional team would prepare an (Principle 1).
connected by logic gates defined by FMEA to evaluate products and • Determine the critical control
Boolean logic (“and/or” gates, for manufacturing processes and ensure points (Principle 2).
example). The tree directly points to they are designed to meet customer • Establish critical limits
the root cause of an event (or expectations. Note that failure mode (Principle 3).
failure) along with other and effect criticality analysis • Establish monitoring
contributing events at all levels (FMECA) considers the importance procedures (Principle 4).
within the scope of the analysis. (criticality) of identified failure • Establish corrective actions
Sometimes certain events may modes with respect to safety, (Principle 5).
need to occur together for the top successful completion of a system’s • Establish verification
event to occur. In such cases, those mission, or other criteria. procedures (Principle 6).
events would be arranged under an The purpose of FMEA is to • Establish recordkeeping and
“and” gate, meaning that all the identify and possibly remove documentation procedures
basic events listed would need to probable failure modes during (Principle 7).
occur to trigger the top event. If the process and/or system design. Use
basic events alone would trigger the of FMEA typically begins in the HACCP IN DETAIL
top event, then they would be early stages of product and/or When applying the cGMP
grouped under an “or” gate. The system development. The FMEA regulations in pharmaceutical
entire system — as well as human progresses over time along with manufacturing, we in fact comply
interactions — would be analyzed changes in the product/system, with numerous HACCP principles
when performing FTA. Figure 2 design and accumulation of already. HACCP plan development
shows an analysis for microbial information about performance in includes identifying the members of
contamination in a fermentation preproduction testing, and filed an HACCP team, assigning
processes. experience. FMEA is a practical, responsibilities, creating a product
Failure Mode and Effect Analysis detailed tool for analyzing major description (distribution, intended
(FMEA) is a preventive, bottom-up areas identified by FTA. Table 1 use, consumers, and so on), and
approach to identifying all potential shows an FMEA process for developing a process flow diagram.
failures of a product, process, or microbial contamination, not HACCP Principle 1: Conduct a
system before use. It is also used to including ratings (risk numbers). hazard analysis. A hazard is defined as
assess the effects or consequences of HACCP is a systematic approach a biological, chemical, or physical
identified failure modes (8). A cross- to analyzing a process, determining agent that is reasonably likely to cause
Table 1: Failure mode and effect analysis (FMEA)
System Description: Microbial Contamination in a Bioreactor Date:
References:
Complied by: Reviewed by:
Potential Potential Potential Risk Priority
Item ID or Item’s Failure Effects Causes of Current Occurrence Severity Detection Number
Process Step Function Mode Next Level Failure Controls (1–5) (1–5) (1–5) (RPN)
Fermentation Aseptic Microbial Product Inadequate SIP
condition contam- discard Inoculation
ination Media feed
Sampling
Ineffective CIP
30 BioProcess International OCTOBER 2004
BENEFITS OF RISK ANALYSIS Figure 1: Process flow diagram and validation modules
IN PROCESS VALIDATION
Determines whether
process is robust
Can be presented to regulatory affairs
group or agency to resolve
issues/concerns
Meets regulatory requirements
Identifies critical parameters
for monitoring
Increases process understanding
Assists in process troubleshooting
Assists in focusing validation efforts
where they are required
illness or injury if not controlled. The
likelihood of a hazard should be
judged in the absence of controls.
For pharmaceutical application, the
definition of hazard should be
expanded to include the danger of a
product failing to meet its quality
attributes and thus being likely to
harm patients. Table 2 displays a
hazard analysis for a bioreactor steam-
in-place (SIP) and working cell bank
(WCB) vial-thawing process.
HACCP Principle 2: Determine the
critical control points (CCPs) at
which control can be applied and is
essential to prevent or eliminate
hazards or reduce them to
acceptable levels. Each step in a
manufacturing process comprises
individual actions or variables; not
every action within a step is a CCP.
The task here is to narrow those
down to the minimum number
required to control a process and
prevent hazards. The following
factors are considered in is crucial to validate a successful SIP critical control point are temperature
determining CCP: process in which saturated steam of (expressed in Fahrenheit or
• Controlling a subsequent a certain temperature is supplied in centigrade degrees), time, and steam
process step may be more effective the bioreactor for a certain amount quality (dry or moist).
for controlling a hazard, so it may of time. So bioreactor SIP qualifies HACCP Principle 4: Establish
be the preferred CCP. as a CCP. monitoring procedures to indicate a
• More than one step in a HACCP Principle 3: Establish state of control, and provide written
process can be involved in critical limits. Each CCP must have documentation for use in verification.
controlling a hazard. an assigned limit. Whenever that Continuous monitoring is preferred
• More than one hazard may be limit is exceeded, a corrective action whenever feasible. If monitoring
controlled by a single control (Principle 5) will be documented. indicates a trend toward loss of
measure. Usually, critical limits are different control, then action(s) can be taken
For example, any contamination from operational limits. Critical limits to bring the process back into
in a bioreactor will lead to must be attainable, accurate, robust, control before any deviation from the
nonaxenic operations. Therefore, it and scientifically based. For example, critical limits occurs. Among other
the critical limits for a bioreactor SIP factors, real-time monitoring includes
32 BioProcess International OCTOBER 2004
THE PDCA CYCLE Figure 2: Fault tree analysis (FTA)
PLAN:
Process risk analysis
Process development data
Clinical manufacturing data
Process equipment/facility/
utilities/system/computer qualification
Method validation
Approved operating procedures
and personnel qualification
DO:
Process validation
Conformance runs
Regulatory submission
CHECK:
Manufacturing operations
Trending manufacturing data Once hazards, CCPs, and limits means to ensure quality of that
Deviation history are known, asking and answering product.
the question, “What will be done if
Change-control history
this limit is exceeded?” (and BENEFITS OF RISK ANALYSIS
Stability analysis implementing that answer into a Use of a particular tool will depend
New regulation procedure) dramatically streamlines on a company’s in-house expertise.
the corrective action process. If a Any of the tools described herein
New industry standard critical limit is exceeded, the (FTA, FMEA and HACCP) can be
decision about what to do is already used alone or in combination. FTA
ACT: defined, and the disposition of the is a top-down approach to failure
Process risk analysis update
product is predetermined. The and safety analysis. A fault tree
Small-scale study and/or investigation can concentrate on shows a failure’s root cause. FMEA
plant trial runs how it happened. is a bottom-up approach to identify
Additional process validation HACCP Principle 6: Establish failures and their consequences. It
or revalidation verification procedures. Verification begins at the design stage and
is defined to include those activities, evolves with time. HACCP is a
Regulatory supplements other than monitoring, that proven system-based approach used
determine the validity of an HACCP in other industries and
visual observation and temperature, plan and that the system is operating recommended by WHO for
pH, and conductivity levels. according to that plan. One aspect is pharmaceutical manufacturers.
Bioburden testing and other delayed evaluating whether the facility’s The term hazard is used in food
results can be used for verification. HACCP system is functioning to signify safety concerns. To realize
HACCP Principle 5: Establish according to the plan. An effective the full benefit of HACCP, the
corrective actions. An important HACCP system requires little end- word can be used for both safety
purpose of corrective actions is to product testing because sufficient and quality concerns in the
prevent hazardous products from validated safeguards are built in the pharmaceutical industry, where
reaching consumers (9). Wherever a process early on. quality issues lead to
deviation from established critical HACCP Principle 7: Establish noncompliance, safety concerns, and
limits occurs, corrective actions are recordkeeping and documentation business risks. Clinical trial
necessary. Such actions should procedures. Any weakness in departments conduct product safety
include the following elements: recordkeeping indicates fundamental and efficacy studies. The
• Determine and correct the problems with the quality system. manufacturing department is
cause of noncompliance. Recordkeeping is the foundation for concerned with making a high-
• Determine the disposition of all regulatory requirements: “It was quality product that meets
noncompliant product. not done if it was not recorded.” predetermined quality attributes.
• Record the corrective actions For a manufacturing company, Business loss due to product
that have been taken. however, the documentation in itself rejection as a result of in-process
is not the product to be sold; it is a testing is not considered a hazard in
34 BioProcess International OCTOBER 2004
this context. Note that a process Washington, DC; [Link]/cfr/
The Most may be considered “out of control”
when there is a high rate of product
[Link].
2 ICH. Q7A: Good Manufacturing
Complete rejection (noncompliance), so
appropriate actions should be taken
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Ingredients (Guidance for Industry). Federal
Register 66(186) 25 September 2001:
Range of to minimize rejection rates. The
expected benefits of making risk
49028–49029; [Link].
3 Center for Drug Evaluation and
Rigid analysis (RA) part of process
validation are listed in the
Research. Guideline on General Principles of
Process Validation. US Food and Drug
Polymerics “Benefits” box.
Administration, May 1987; [Link]/
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4 MacKenzie D. Risk Assessment and
LIFE CYCLE APPROACH IN PV Hazard Analysis (training course). Noblitt
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continuously monitored through [Link].
in-process testing and release testing 5 National Advisory Committee on
of the end product. Trending data, Microbiological Criteria for Foods. Hazard
Analysis and Critical Control Point Principles
deviations, and change controls are and Application Guidelines. US Food and
reviewed by management in its Drug Administration and US Department of
annual product review. Process Agriculture, 14 August 1997;
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through prior approval supplements 6 WHO Expert Committee on
(PASs), changes being effected Specifications for Pharmaceutical
Preparations. 37th Report, WHO Technical
(CBE) documents, and annual Report Series 908. World Health
reports. A product–life-cycle Organization: Geneva, Switzerland, 2003.
approach in PV will organize and 7 Juran JM, Godfrey AB. Juran’s
verify major activities that occur Quality Handbook, Fifth Edition. McGraw
Complete Stability: during the life of a product. This Hill: Columbus, OH, 1999.
approach starts at PV planning and 8 Stamatis DH. Failure Mode and Effect
■ Strong acid/base ends with product discontinuation. Analysis: FMEA from Theory to Execution,
Second Edition. ASQ Quality Press,
■ 200oC+ The cycle is based on ISO 9001 Milwaukee, WI, 2003.
requirements: a plan–do–check–act 9 Aparicio D, Hallaway S. Focus on
■ 6000psi (PDCA) cycle (7). Activities that are Compliance: Achieving World-Class
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PV is a regulatory expectation.
interactions Applying risk analysis to PV will
meet regulatory expectations by A. Hamid Mollah, PhD, RAC, CQE, is
Exceptional identifying, controlling, and senior principal engineer in QA
documenting critical steps, actions, validation at Baxter BioScience, Rancho
Column Lifetimes
and parameters. The life-cycle Conejo Boulevard, Thousand Oaks, CA
approach to PV organizes and 91320; 1-805-480-2398;
verifies major activities that occur hamid_mollah@[Link]. The
throughout the life of a product. information provided reflects this
Using this approach can result in author’s view and is not intended to
numerous benefits such as creating represent the official position of Baxter
process expert teams, rapidly Healthcare Corporation. This paper was
Contact us today to discuss resolving process deviations, originally presented at the 2003 PDA
the solution you need. determining trends toward loss of Spring Conference. Actual processes
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☎ USA toll free 800 767 3963 requirements, assessing the impact
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Baxter Healthcare Corp. may differ from
or 413 253 9554 of process changes, and identifying those disclosed in this paper. The author
areas of process improvement. makes no representations or warranties
UK (+44) 01694 723581
Benelux (+31) 045 5414748 regarding these processes as may be
REFERENCES implemented by readers of this paper.
Germany (+49) 06151 860690 1 Food and Drug Administration.
France (+33) 04 91 17 64 00 Current Good Manufacturing Practice for
Finished Pharmaceuticals. Code of Federal
Regulations Part 211, Title 21, Vol. 4, Rev. 1
[Link]/hplc
April 2003. US Government Printing Office: