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FDA Lifecycle Approach to Process Validation—What, Why, and How? ............................................................... 3
The Forgotten Origins of Quality by Design ....................................................................................................... 14
Understanding Physicochemical Properties for Pharmaceutical Product
Development and Manufacturing—Dissociation, Distribution/Partition, and Solubility ....................................... 19
Understanding Physicochemical Properties for Pharmaceutical Product Development
and Manufacturing II: Physical and Chemical Stability and Excipient Compatibility ........................................... 30
Patent Potential .............................................................................................................................................. 42
First Steps in Experimental Design—The Screening Experiment ........................................................................ 46
First Steps in Experimental Design II: More on Screening Experiments .............................................................. 54
A Further Step in Experimental Design (III): The Response Surface ................................................................... 63
Estimation: Knowledge Building with Probability Distributions .......................................................................... 71
Understanding Hypothesis Testing Using Probability Distributions .................................................................... 86
PQ=Confirmation ........................................................................................................................................... 102
PROCESS DESIGN
UNDERSTANDING THE PRODUCT
AND PROCESS
LIFECYCLE APPROACH TO PROCESS
VALIDATION – FDA STAGE 1
PROCESS VALIDATION – Process Design 3
Paul L. Pluta
[For more Author
information,
go to
gxpandjvt.com/bios
“PQ Forum” provides a mechanism for validation practitioners to share information about Stage 2 process qualification in the validation lifecycle. Information about supporting activities such as equipment and analytical validation is shared. The information provided should be helpful and practical so as to enable application in actual work situations.
Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Please contact column coordinator Paul Pluta at paul.pluta@comcast.net or managing editor Susan Haigney at shaigney@advanstar.com with comments, suggestions, or topics for discussion.
KEY POINTSThe following key points are discussed:
The US Food and Drug Administration issued
Process Validation: General Principles and Practices
in January 2011, which has given widespread
visibility to the lifecycle approach concept.
The process validation guidance integrates
strategy and approaches to provide a
comprehensive approach to validation. Three
stages in the lifecycle approach are identified.
The lifecycle concept links development,
validation performance, and product or process
maintenance in a state of control during routine
commercial production.
Understanding the sources of variation and
control of variation commensurate with risk is a
key component of the lifecycle approach.
FDA has provided recommendations for the
general lifecycle and stages 1, 2, and 3. Specific
expectations are discussed.
Stage 1—Process Design may be generally
described as “process understanding.” Stage
1 work is ultimately reflected in the master
production record and control records.
Stage 2—Process Qualification may be
described as “validation performance.” This
stage comprises demonstration of final process
performance by means of conformance lots.
Stage 2 confirms the development work of Stage
1 Process Design.
Stage 2 specific recommendations are provided
for design of a facility and qualification of
utilities and equipment, process performance
qualification (PPQ), PPQ protocol, and PPQ
protocol execution and report.
Stage 3—Continued Process Verification
may be simply described as “maintaining
validation.” This stage comprises the ongoing
commercial manufacturing of the product
under the same or equivalent conditions as
demonstrated in Stage 2 Process Qualification.
The integration of development work, process
conformance, and continuing verification
provides assurance the product or process will
consistently remain in control throughout the
entire product lifetime.
The lifecycle approach integrates various
strategies, approaches, and expectations that
had been mentioned in multiple previously
published documents, guidelines, and
presentations for many years.
ABOUT THE AUTHOR
Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive industrial development, manufacturing, and management experience. Dr. Pluta is also an adjunct associate professor at the University of Illinois-Chicago College of Pharmacy. Dr. Pluta may be contacted by e-mail at paul.pluta@comcast.net.
FDA Lifecycle Approach to Process Validation— What, Why, and How?Paul L. Pluta
4 PROCESS VALIDATION – Process Design
Paul L. Pluta
The concepts identified in the respective
stages of the FDA process validation
guidance—understanding, performance, and
maintenance—serve as a model for all areas of
validation and qualification.
The new guidance affects many areas of site
validation programs including organizational
aspects, validation performance specifics, risk
analysis, training, and documentation.
Senior and functional management support
is needed to transition organizations to the
lifecycle approach to validation. Risk analysis
is key to development and prioritization of a
suitable program that will be embraced and
supported.
INTRODUCTIONThe US Food and Drug Administration issued
Process Validation: General Principles and Practices
(1) in January 2011. This guidance has given
widespread visibility to the lifecycle approach
concept. Validation managers are now responding
to questions and comments about the guidance
from their colleagues. The following discusses
these and other areas of concern raised by
attendees at validation meetings in Montreal
(2010), Philadelphia (2010), and Amsterdam
(2011). These are relevant “hands-on” questions
from people that face validation problems every
day. Topics addressed in this discussion include
the following:
What is different about the lifecycle approach?
What is its emphasis compared to the 1987 FDA
process validation guidance (2)?
Why the lifecycle approach? Is it really a new
approach?
Should the lifecycle approach be applied to
other areas of validation and qualification?
What about using the lifecycle approach to
other processes and to equipment, HVAC,
computer systems, and other qualifications?
How does the guidance affect our current
validation programs? What areas need to
be modified to be compliant with the new
guidance?
THE LIFECYCLE APPROACHThe January 2011 process validation guidance
(1) has integrated information, strategy,
and approaches discussed in various US
and international documents to provide a
comprehensive approach to validation (i.e., the
lifecycle approach). The guidance provides specific
and detailed recommendations for each stage of the
lifecycle approach.
The definition of process validation stated in the
2011 guidance is as follows:
“Process validation is defined as the collection
and evaluation of data, from the process design
stage throughout production, which establishes
scientific evidence that a process is capable of
consistently delivering quality product. Process
validation involves a series of activities taking place
over the lifecycle of the product and process.”
The guidance describes process validation
activities in the following three stages:
“Stage 1—Process Design: The commercial
process is defined during this stage based on
knowledge gained through development and
scale-up activities.
Stage 2—Process Qualification: During this
state, the process design is confirmed as
being capable of reproducible commercial
manufacturing.
Stage 3—Continued Process Verification:
Ongoing assurance is gained during routine
production that the process remains in a state of
control.”
These sections of the 2011 guidance clearly
identify the key difference between the lifecycle
approach compared to validation in the 1987 FDA
guidance. The 2011 lifecycle approach to process
validation encompasses product and process
activities beginning in development and continuing
throughout the commercial life of the product. The
1987 definition and subsequent discussion in the
guidance placed major emphasis on the validation
protocol, testing, results, and documentation—what
is now considered to be Stage 2 in the lifecycle
approach. Development work and post-validation
monitoring were not emphasized in the 1987
guidance.
Approach to Process Validation–Stages 1, 2, and 3The approach to process validation stated in the
2011 guidance clearly emphasizes contemporary
concepts and expectations for pharmaceutical
manufacturing. The manufacturer should
have great confidence that the performance of
manufacturing will consistently produce active
pharmaceutical ingredients (APIs) and drug
products meeting expected attributes. This
confidence is obtained from objective information
and data from laboratory, pilot, and commercial-
scale studies (i.e., the work of Stage 1). After
completion of Stage 1 development, Stage 2
Process Qualification confirms the work of Stage
1. After successful Stage 2 performance, Stage
3 Continued Process Verification maintains the
validated state. The guidance states:
PROCESS VALIDATION – Process Design 5
Paul L. Pluta
“The lifecycle concept links product and process
development, qualification of the commercial
manufacturing process, and maintenance of
the process in a state of control during routine
commercial production. This guidance supports
process improvement and innovation through
sound science.”
Successful validation depends on knowledge
and understanding from product and process
development. Specific key areas mentioned in the
guidance include the following:
“Understanding the sources of variation
Detect the presence and degree of variation
Understanding the impact of variation on the
process and ultimately on product attributes
Control the variation in a manner
commensurate with the risk it represents to the
process and product.”
FDA RecommendationsThe 2011 guidance discusses several areas
and provides specific details. These include
recommendations for the general lifecycle and
stages 1, 2, and 3. The entire recommendations
section of the guidance is provided online at FDA.
gov.
General considerations. These considerations
are applicable to all stages in the lifecycle. For
example, an integrated team approach that includes
expertise from multiple disciplines and project
plans is recommended. The support of senior
management is termed “essential.” Other general
topics discussed include the initiation of studies
to further understand product and process during
the lifecycle, attribute evaluation, and the need for
higher levels of control for parameters associated
with higher risk.
Stage 1—process design. This stage may be
generally described as “process understanding.”
Studies are conducted during this stage to develop
and characterize product and process. The work of
Stage 1 should be commensurate with the identified
or expected risk for the product and process.
Stage 1 recommendations address development
activities that will ultimately be reflected in the
master production record and control records. The
guidance clearly states the goal of stage 1: “To
design a process suitable for routine commercial
manufacturing that can consistently deliver a
product that meets its quality attributes.” The
following two topics are discussed:
Building and capturing process knowledge
and understanding. This section discusses
the role of product development and uses
terminology common to the quality-by-design
(QbD) initiative—quality attributes, design of
experiments (DOE) studies, and so on.
Establishing a strategy for process control. This
section addresses reducing input variation,
adjustment for input variation during
processing, and related topics.
Stage 2—process qualification. This
stage may be simply described as “validation
performance.” This stage is most similar to
the traditional definition and performance
of validation. The testing of Stage 2 should be
commensurate with the risk identified for the
product and process.
Stage 2 comprises demonstration of commercial
process performance by means of conformance lots.
This stage confirms the development work of Stage
1. Successful stage 2 performance demonstrates
that the proposed manufacturing process is capable
of reproducible commercial manufacture. Process
performance qualification (PPQ) conformance
lot manufacturing includes increased testing
to demonstrate acceptability of the developed
formulation and process.
The 2011 validation guidance provides several
specific recommendations for the respective stages
of process validation. Validation managers must
become familiar with these requirements and
incorporate them into their site training programs.
The guidance discusses the following in Stage 2.
Facility, utilities, and equipment. The FDA 2011
guidance specifies the following regarding facility,
equipment, and utilities:
Utilities and equipment construction materials,
operating principles, and performance
characteristics must be appropriate for their
specific use.
Utilities systems and equipment must be
built and correctly installed, according to
manufacturer’s directions, and then properly
maintained and calibrated.
Utility system and equipment must be
qualified to operate in the ranges required in
processing. The equipment should have been
qualified under production-level loads and for
production-level durations. Testing should also
include interventions, stoppage, and start-up as
is expected during routine production.
The 2011 guidance provides specific expectations
for a plan to qualify facility, equipment, and
utilities, as follows:
The plan should include risk management to
prioritize activities and documentation
The plan should identify
(1) Studies or tests to use
(2) Criteria appropriate to assess outcomes
(3) Timing of qualification activities
6 PROCESS VALIDATION – Process Design
Paul L. Pluta
(4) Responsibilities
(5) The procedures for documenting and
approving the qualification
Change evaluation policy
Documentation of qualification activities
Quality assurance (QA) approval of the
qualification plan.
The above is a clear directive to the site
validation approval committee (VAC) as to
FDA’s expectations for facilities, equipment, and
utilities qualification.
Process performance qualification. The PPQ is
intended to confirm the process design and
development work and demonstrate that the
commercial manufacturing process performs as
expected. This stage is an important milestone in
the product lifecycle. The PPQ should be based on
sound science and experience. The PPQ should
have a higher level of testing and sampling. The
goal of the PPQ is to demonstrate that the process
is reproducible and will consistently deliver quality
products.
PPQ protocol. A written protocol is essential and
should discuss the following:
Manufacturing conditions, process parameters,
process limits, and raw material inputs
How data are to be collected and evaluated
Testing and acceptance criteria
Sampling plan including sampling points and
number of samples
Number of samples should demonstrate
statistical confidence
Confidence level based on risk analysis
Criteria for a rational conclusion of whether the
process is acceptable
Statistical methods used to analyze data
Provision to address deviations and
non-conformances
Design of facilities, qualification of equipment
and facilities
Personnel training and qualification
Verification of sources of materials and
containers and closures
Analytical method validation discussion
Approval by appropriate departments and the
quality unit.
PPQ protocol execution and report. Protocol
execution should not start until the protocol has
been approved. Changes to the approved protocol
must be made according to established procedures.
The routine manufacturing process and procedures
must be followed (i.e., usual conditions, personnel,
materials, environments, etc.). The PQ report
should do the following:
Discuss and cross-reference all aspects of the
protocol
Summarize and analyze data
Evaluate unexpected observations and
additional data not specified in the protocol
Discuss deviations and non-conformances
Describe corrective actions
State a clear conclusion whether the process
is validated or if not, what should be done to
validate the process
Be approved by appropriate departments and
the quality unit.
Stage 3—Continued process verification.
This stage may be simply described as “maintaining
validation,” or “maintaining the validated state.”
Maintenance activities of Stage 3 should be
commensurate with the risk identified for the
product and process.
Assuming good development of the process,
identification of potential variation, and control of
same, the manufacturer must maintain the process
under control over the product lifetime (i.e., the
work of Stage 3). This control must accommodate
expected changes in materials, equipment,
personnel, and other changes throughout the
commercial life of the product based on risk
analysis.
Stage 3 comprises the ongoing commercial
manufacturing of the product under the same
or equivalent conditions as demonstrated in
Stage 2. This phase continues throughout the
entire commercial life of the product or process.
Specific topics discussed in this section include the
following:
Ongoing program to collect and analyze process
data, including process trends, incoming
materials, in-process material, and finished
products
Statistical analysis of data by trained personnel
Procedures defining trending and calculations
Evaluation of inter-batch and intra-batch
variation
Evaluation of parameters and attributes at
PPQ levels until variability estimates can be
established
Adjustment of monitoring levels based on the
above
Timely assessment of defect complaints, out-of-
specification (OOS) findings, deviations, yield
variations, and other information
Periodic discussion with production and
quality staff on process performance
Process improvement changes
Facilities, utilities, and equipment must be
maintained to ensure process control.
PROCESS VALIDATION – Process Design 7
Paul L. Pluta
WHY THE LIFECYCLE APPROACH?For manufacturing processes to be truly validated,
each of the stages must be addressed and
integrated. This integration of development work,
process conformance, and continuing verification
provides assurance that the product or process
will consistently remain in control throughout the
entire product lifecycle. Process validation must
not be considered a one-time event or a focused
one-time task performed just prior to commercial
launch that emphasizes only the manufacture of
three conformance lots. Acceptable manufacture of
three conformance batches must not be interpreted
as completion of validation. These lots cannot
truly represent the future manufacturing process
with unexpected and unpredictable changes.
Conformance lots are often inadvertently biased
(i.e., they may utilize well-characterized and
controlled API and excipients, be manufactured
under well-controlled conditions, be monitored
by expert individuals, and performed by most
experienced or well-trained personnel—all “best-
case” conditions). It is highly unrealistic to contend
that the manufacture of three conformance lots
under “best-case” conditions conclusively predicts
successful manufacturing over the product lifetime.
True process validation must be a process that is
never completed and is always ongoing.
Is This Really a New Approach?The lifecycle approach to process validation is not
really a new approach or a new concept (3). In an
interview with FDA investigator Kristen Evans
published in the Journal of Validation Technology in
February 2000, the investigator commented on the
failure of manufacturers to recognize a lifecycle
approach to validation (see Sidebar).
The three-stage lifecycle description of process
validation as discussed in the FDA process
validation guidance integrates various strategies,
approaches, and expectations that had been
mentioned in several published documents,
guidelines, and presentations. FDA representatives
have openly discussed the lifecycle approach to
process validation for several years (4,5,6). The
draft process validation guidance that formally
introduced the lifecycle approach for industry
comment was published in 2008 (7). The lifecycle
approach overcomes the “checklist” approach to
process validation, whereby, process validation is
considered to be a “one-time event.” Encouraging
comprehensive process understanding improves
root cause analysis when manufacturing problems
occur. Successfully manufacturing three validation
lots without sufficient process understanding does
not provide good assurance that the manufacturing
Excerpt from an interview with FDA investi-gator Kristen Evans published in the Journal of Validation Technology, Volume 6, No. 2, February 2000.
Q. What are some of the major process vali-dation problems you have seen during your inspections of manufacturing facilities in the United States?
A. I think, as a whole, the failure to recognize the lifecycle approach to validation. We see many firms, for whatever reason, thinking that once they complete their prospective three-batch validation, that’s the end and they’re on their way. I like to say that pro-spective validation is not the end. It’s not the beginning of the end; it is hopefully the end of the beginning. But, clearly, it’s an ongo-ing process. It requires a concerted effort to really maintain confidence in the process and to be able to demonstrate that at any given time. So, when we conduct our inspections, we want to know how the firm gives itself, and therefore us, the confidence that a given process on that day is under control. And you’re not simply saying, “Well, we validated it a few years ago,” or “We’re going to do our annual review in a couple of months, and that will show us,” but rather, systems are in place at any given time to show from a big picture that it’s validated. As opposed to general problems discussed in the previous paragraph, a more specific problem that we see is a lack of scientific rationale in the pro-tocols and acceptance criteria. At least there is a lack of documentation of such rationale, which is what we’re expecting to see. We want the process to be there, that you’ve come up with a scientific study, a protocol—this is what you’re attempting to show, and this is why, and this is how it’s going to be evaluated, and then just simply executing that. That’s documentation of the scientific rationale.
Note: The above comments are the per-sonal opinions of Mr. Evans and are not FDA policy.
8 PROCESS VALIDATION – Process Design
Paul L. Pluta
process will consistently yield an acceptable product
throughout the product commercial life.
The September 2006 FDA Quality Systems
Approach to Pharmaceutical CGMP Regulations (8)
clearly discusses expectations for maintenance of
the validated state. In discussing performance and
monitoring of operations, the regulations state,
“An important purpose of implementing a quality
systems approach is to enable a manufacturer to
more efficiently and effectively validate, perform,
and monitor operations and ensure that the
controls are scientifically sound and appropriate.”
Further, “Although initial commercial batches
can provide evidence to support the validity and
consistency of the process, the entire product
lifecycle should be addressed by the establishment
of continual improvement mechanisms in the
quality system. Thus, in accordance with the quality
systems approach, process validation is not a one-
time event, but an activity that continues through a
product’s life.” This document also discusses trend
analysis, corrective action and preventive action
(CAPA), change control, and other quality systems
programs.
The FDA Pharmaceutical cGMPs for the 21st
Century-a Risk-Based Approach (9), states the
following:
“We have begun updating our current thinking
on validation under a Cross-Agency Process
Validation workgroup led by CDER’s Office of
Compliance Coordinating Committee with
participation from CDER, CBER, ORA, and CVM.
In March of this year, FDA began this process
issuing a compliance policy guide (CPG) entitled
Process Validation Requirements for Drug Products
and Active Pharmaceutical Ingredients Subject to
Pre-Market Approval (CPG 7132c.08, Sec 490.100)
(10). The CPG stresses the importance of rational
experimental design and ongoing evaluation of
data. The document also notes that achieving and
maintaining a state of control for a process begins
at the process development phase and continues
throughout the commercial phase of a product’s
lifecycle. The CPG incorporates risk-based
approaches with respect to inspectional scrutiny;
use of advanced technologies, and by articulating
more clearly the role of conformance batches in
the product lifecycle. The document clearly signals
that a focus on three full-scale production batches
would fail to recognize the complete story on
validation.”
In the 2004 revision of FDA Compliance
Policy Guide Sec. 490.100, Process Validation
Requirements for Drug Products and Active
Pharmaceutical Ingredients Subject to Pre-
Market Approval (CPG 7132c.08), expectations
for validated processes are clearly stated. “Before
commercial distribution begins, a manufacturer
is expected to have accumulated enough data
and knowledge about the commercial production
process to support post-approval product
distribution. Normally, this is achieved after
satisfactory product and process development,
scale-up studies, equipment and system
qualification, and the successful completion of the
initial conformance batches. Conformance batches
(sometimes referred to as validation batches and
demonstration batches) are prepared to demonstrate
that, under normal conditions and defined ranges
of operating parameters, the commercial scale
process appears to make acceptable product. Prior
to the manufacture of the conformance batches
the manufacturer should have identified and
controlled all critical sources of variability.” FDA
has removed reference to manufacture of three lots
as a requirement for validation in this document.
The process validation guidance is consistent
with FDA QbD principles. The various QbD
presentations and publications strongly encourage
demonstrations of process understanding for both
API and drug product (11,12,13,14). In the 2006
FDA Perspective on the Implementation of Quality by
Design (QbD), a QbD system is defined as follows:
The API or drug product is designed to meet
patient needs and performance requirements
The process is designed to consistently meet
critical quality attributes
The impact of starting raw materials and
process parameters on quality is well
understood
The process is evaluated and updated to allow
for consistent quality over time
Critical sources of process variability are
identified and controlled
Appropriate control strategies are developed.
The various FDA guides to inspections (15,16,17),
all issued during the 1990s, emphasized the
development phase of the validated process
and associated documentation. This included
documented experiments, data, results, control
of the physical characteristics of the excipients,
particle size testing of multi-source excipients
and determination of critical process parameters.
Development data serves as the foundation for the
manufacturing procedures, and variables should be
identified in the development phase. Raw materials
were identified as a source of lot-to-lot variation,
as were equipment or processes that could impact
product effectiveness or product characteristics (i.e.,
the validated state must be maintained).
PROCESS VALIDATION – Process Design 9
Paul L. Pluta
Some of the key concepts in the 2011 process
validation guidance were originally mentioned in
the FDA 1987 guidance. For example, the 1987
guidance states, “...adequate product and process
design...quality, safety, and effectiveness must
be designed and built into the product...” and
“During the research and development (R&D)
phase, the desired product should be carefully
defined in terms of its characteristics, such as
physical, chemical, electrical, and performance
characteristics.” In addition to discussing actual
validation protocols, the document mentions
several post-validation considerations, as follows:
“...quality assurance system in place which requires
revalidation whenever there are changes in
packaging, formulation, equipment, or processes
which could impact product effectiveness or
product characteristics, and whenever there
are changes in product characteristics. The
quality assurance procedures should establish
the circumstances under which revalidation is
required.”
The 2011 process validation guidance clearly states
its consistency with International Conference on
Harmonisation (ICH) Q8, Q9, and Q10 documents
(18). These documents provide current global
thinking on various aspects of the product lifecycle
from development through commercialization. They
provide a comprehensive and integrated approach
to product development and manufacturing to be
conducted over the lifecycle of the product. ICH Q8
discusses information for regulatory submission
in the ICH M4 Common Technical Document
format (19). ICH Q8 describes a comprehensive
understanding of the product and manufacturing
process that is the basis for future commercial
manufacturing including QbD concepts. ICH Q9
provides a systematic approach to quality risk
management through various risk assessment tools.
ICH Q9 also suggests application of risk management
methods to specific functions and business processes
in the organization. ICH Q10 complements Q8 and
Q9, and discusses the application of the various
quality system elements during the product lifecycle.
Elements of the quality system include process
performance monitoring, CAPA, change control, and
management review. These quality system elements
are applied throughout the various phases of the
product lifecycle.
The 2000 ICH Q7 Good Manufacturing Practice
Guide for Active Pharmaceutical Ingredients (20)
discusses activities conducted prior to and post
validation. For example, ICH Q7 states that critical
parameters or attributes should be identified during
development, and these critical process parameters
should be controlled and monitored. Non-critical
parameters should not be included in validation.
Regarding post validation, there should be periodic
review of validated systems.
Medical Device Validation GuidanceAlthough the 2011 process validation guidance
does not apply to medical devices, medical device
documents espouse an equivalent comprehensive
approach to process validation. In the January
2004 Global Harmonization Task Force (GHTF)
Study Group 3, Quality Management Systems—Process
Validation Guidance (21), activities conducted during
product or process development to understand
the process are described. For example, “The use
of statistically valid techniques such as screening
experiments to establish key process parameters
and statistically designed experiments to optimize
the process can be used during this phase.” This
document also describes activities conducted post-
validation to maintain the product or process. For
example, “Maintaining a state of validation” by
monitoring and control including trend analysis,
changes in processes or product, and continued
state of control of potential input variation such as
raw materials. Tools including statistical methods,
process capability, control charts, design of
experiments, risk analysis, and other concepts are
described.
The 1997 FDA Medical Device Quality Systems
Manual (22) further emphasizes activities to be
conducted post validation. It states, “Process and
product data should be analyzed to determine what
the normal range of variation is for the process
output. Knowing what is the normal variation
of the output is crucial in determining whether
a process is operating in a state of control and is
capable of consistently producing the specified
output. Process and product data should also
be analyzed to identify any variation due to
controllable causes. Appropriate measures should
be taken to eliminate controllable causes of
variation...Whether the process is operating in a
state of control is determined by analyzing day-to-
day process control data and finished device test
data for conformance with specifications and for
variability.”
The 1997 Guide to Inspections of Medical Device
Manufacturers (23) states, “It is important to
remember that the manufacturer needs to maintain
a validated state. Any change to the process,
including changes in procedures, equipment,
personal, etc. needs to be evaluated to determine
the extent of revalidation necessary to assure
the manufacturer that they still have a validated
process.”
10 PROCESS VALIDATION – Process Design
Paul L. Pluta
APPLYING THE LIFECYCLE APPROACHThe concepts identified in the respective stages
of the FDA process validation guidance—process
design (understanding), process qualification
(performance), and continued process verification
(maintaining validation)—serve as a model for all
areas of validation and qualification. Although
not specifically mentioned in the FDA guidance,
the sequence of understanding, performance,
and maintaining the validated state is certainly
applicable and desirable for other processes in
pharmaceutical manufacturing including packaging,
cleaning, analytical, and so on. Further applying
this sequence to equipment qualification, HVAC,
computer systems, and other areas is also appropriate
and desirable. Presentations on these associated
topics at validation meetings have already been
structured according to this model. The installation
qualification-operational qualification-performance
qualification (IQ/OQ/PQ) model (24) and the
ASTM E2500 (25) model are consistent with
understanding, qualifying, and maintaining
qualification through calibration, preventive
maintenance, change control, and associated
activities. Applying the stages 1, 2, and 3 sequence of
activities to all validation and qualification unifies
the site approach to project management activities,
standardizes expectations, facilitates training, and
generally simplifies organizational thinking.
THE AFFECT ON CURRENT VALIDATION PROGRAMSA major concern of validation practitioners gets to
the “bottom line”—How does the 2011 guidance
affect current validation programs, and how can the
new guidance be implemented?
Organizational AspectsThe lifecycle approach to process validation
requires commitment from many areas in the
organization. The lifecycle approach must become
part of organizational strategy. This will require a
comprehensive and continuing view of validation
rather than focus on the performance of the usual
three conformance lots—and “job done.” Many
firms organize their operations in distinct silos
(e.g., R&D, manufacturing, and quality). The silos
create barriers to communication and cooperation.
The R&D organization develops the product. After
development is completed, the product is transferred
to manufacturing. Commercial operations
personnel “adjust” the process and make it ready for
validation and routine production. The validation
function coordinates process validation. After
the conformance lots are successfully completed,
the validation effort is finished. Manufacturing
then continues routine commercial production
with oversight by the quality unit or the qualified
person (QP). Often there is minimal ongoing
constructive interaction between R&D, validation,
manufacturing, and quality during the product
lifetime.
The lifecycle approach to validation is
clearly different than the above described
situation. Product R&D and technical support
should approach their work as supporting the
entire product lifecycle including commercial
manufacturing. They must be involved in
monitoring and maintenance of the validated
state. Their work should provide the technical
basis or justification for all aspects of
manufacturing including any changes and
necessary improvements. The validation group
should coordinate the process qualification stage
of manufacturing based on technical development
work, and should participate in determining
the ongoing control strategy. The validated state
must be maintained through process monitoring,
technical data evaluation, and change control.
Manufacturing “fixes” or “tweaks” should be
evaluated by technical people, and should ideally
be supported by data or sound technical judgment
whenever possible. R&D should be involved in
process improvements and provide the technical
justification for these improvements. Organizations
should foster development of a continuous
business process beginning in R&D and continuing
throughout the entire product lifecycle with
ongoing collaboration and communication among
all relevant organizational areas. The lifecycle
approach to process validation must become a
comprehensive organizational effort.
Validation Performance SpecificsThe 2011 guidance describes many specific details
and expectations for Stage 2 and Stage 3. Validation
and quality managers should evaluate their practices
and procedures regarding these specifics. FDA
recommendations for Stage 2 PPQ protocol-related
activities are substantial. FDA recommendations for
Stage 3 post-validation monitoring are significantly
different from a traditional “Annual Product Review”
approach. Deficiencies in site programs should be
identified and corrective actions or improvements
prioritized. Risk to the patient and to the
organization should be considered in prioritization.
Risk AnalysisRisk assessment has a critical role in all of the
activities described herein. All activities conducted
in the organization should be conducted with risk
in mind. ICH Q9 describes various risk assessment
PROCESS VALIDATION – Process Design 11
Paul L. Pluta
methods and potential applications of risk
assessment. There are numerous applications of risk
management used during the entire process validation
lifecycle. Examples cited in ICH Q9 relevant to process
validation include product and process development,
facilities and equipment design, hygiene aspects
in facilities, qualification of equipment, facility, or
utilities, cleaning of equipment and environmental
control, calibration and preventive maintenance,
computer systems and computer controlled
equipment, and so on. In brief, risk assessment helps
to identify the most important potential problems
in all three stages of process validation, and then
addresses these problems appropriately. There should
be consistency between the risk-based activities in all
three stages of process validation. Risk management
must become pervasive in the organization.
TrainingThe issuance of the 2011 FDA guidance requires
appropriate training for all involved in validation-
related activities. All involved in validation and
validation- or qualification-related activities must
be aware of the 2011 process validation guidance
and concepts therein. Personnel who previously
considered themselves to be apart or distant from
commercial product validation (e.g., development
scientists) must now be included in validation
training.
Especially important are personnel who
write validation plans, protocols, results, and
associated documents. These writers must think
comprehensively, incorporating pre-validation
development information as well as considerations for
post-validation maintenance of the validated state into
their validation documentation.
Also critically important for training are the site
VAC members. There must be a clear understanding
and agreement among VAC members and the
validation group as to their functions and
responsibilities. Clearly stating the responsibilities
of the VAC provides focus and expectations for the
VAC. Clearly stating the responsibilities of the VAC
provides clear expectations for those submitting
protocols, validation plans, and other documents
for VAC review and approval. VAC members must
maintain awareness and compliance with the 2011
process validation guidance. The VAC members
should consider themselves to be a surrogate FDA
(or other regulatory agency) auditor. The VAC should
assume responsibility for site preparedness for
future regulatory audits of the validation function.
Future audits will certainly include concepts and
recommendations stated in the 2011 process
validation guidance.
TerminologyThe terminology associated with the various
phases of validation has had minor variations over
the years. The 2011 process validation guidance
describes process design, process qualification, and
continued process verification stages in the validation
lifecycle. Stage 2 Process Qualification includes
PPQ manufacturing of commercial lots. The 1987
FDA validation guidance describes installation and
operational qualification, process performance
qualification, and product performance qualification.
Products lots manufactured in the process
qualification phase were termed “conformance lots.”
PPQ batches have also been named “demonstration
lots,” “qualification lots,” “PQ lots,” and “validation
lots,” in past years. Stage 2 process qualification
phase also includes equipment, facilities, and utilities
qualification.
While the variety of terminology used may
cause difficulties in communicating, the intent
of all validation programs is the same: Sequential
process understanding, validation performance,
and maintaining the validated state as described
herein comprise the validation lifecycle continuum.
Validation programs addressing these phases of
the product or process lifecycle, no matter what
specific terminology is used or how categorized
in documentation, will meet the expectations
robustness, repeatability, and reliability for validated
process. Regulatory investigators are knowledgeable
and able to interpret different organizational
terminology as long as the sequence of process
understanding, validation performance, and
maintaining the validated state are demonstrated.
DocumentationAll work associated with process validation in
all stages of the validation lifecycle must be
documented. This includes product and process
design, experimental and development studies for
process understanding, risk analysis in development,
designed experiments, process parameter
optimization, validation and qualification protocols,
and process monitoring to maintain the validated
state. Development scientists must understand that
their work is integral to the validation lifecycle.
Development reports may be requested in regulatory
audits. Summary documents are recommended,
especially when multiple documents must be
integrated by the reader. All work associated with
equipment, facilities, and utilities qualification and
analytical validation must also be documented.
Document quality is important; in many cases,
documents are reviewed literally years after they
are written and long after authors have moved on
to new careers inside or outside of the company. All
Validation Answers from GXP Experts ................................................................................................................ 3
Reduced Validation Effort—Approaches Used and Lessons Learned ................................................................... 9
Engineering Runs: An Insider’s Perspective ...................................................................................................... 16
Risk Management for Aseptic Processing ........................................................................................................ 22
Case Study #2—Questionable Equipment Qualification ..................................................................................... 31
Validation Report Conclusion–Is It Validated? .................................................................................................. 34
Responsibilities of the Validation Approval Committee...................................................................................... 38
Sampling Errors in Validation ........................................................................................................................... 43
Design and Execution of a Shipping Qualification for a Vaccine Drug Substance ................................................ 51
Improving Validation Through the Use of Confidence Statements Based on
Attributes Acceptance Sampling ...................................................................................................................... 58
PQ Documentation–Three Simple Rules ............................................................................................................ 65
Original Data Supporting PQ............................................................................................................................. 71
Sampling Pages .............................................................................................................................................. 79
Should Acceptable Product Yield be a Validation Requirement? Validation Case Study #6 ................................. 86
Statistical Tools for Process Qualification ........................................................................................................ 93
PROCESS QUALIFICATION
DEMONSTRATING PROCESS
ACCEPTABILITY
LIFECYCLE APPROACH TO PROCESS
VALIDATION – FDA STAGE 2
PROCESS VALIDATION – Process Qualification 3
Jerry Lanese and Alan SmithJerry Lanese and Alan Smith
Our sister journal, the Journal of GXP Compliance,
features the ongoing column, “GXP Talk,” a column
for discussion of issues identified by readers of
the journal and the current good practice for
resolution of those issues. Between 1993 and 2000,
the US Food and Drug Administration prepared a
series of communications from FDA headquarters
to field investigators in which headquarters
answered questions submitted by the field. These
communications were made available to the
Industry as a mechanism for communicating
current acceptable practice and interpretations
of the regulations. Based on these FDA “Good
Manufacturing Practice Notes,” editors Jerry Lanese
and Alan Smith began a forum where current
good manufacturing practices (CGMPs) could be
discussed by journal readers and experts.
Over the years, the editors of “GXP Talk” have
received reader questions on various validation
topics. Some of these questions and the editors’
responses are listed in the following sections.
For more information about the Journal of GXP
Compliance and “GXP Talk,” visit www.IVThome.
com/GXPTalk.
LIMS AND QUALITY ASSURANCE
Reader QuestionWe are entering instrumental data directly into
a validated laboratory information management
system (LIMS), that data is processed within the
LIMS using a validated macro; the results are
maintained in the LIMS and then reported on a
Certificate of Analysis to quality assurance. Is a
second review by the laboratory required? What
should be included in that review? What data or
records should be reviewed by quality assurance (1)?
Editors’ Response [1]Since we are clearly dealing with electronic
records and we are told that the LIMS is validated,
we assume in this response that the validation
considered the requirements for electronic records
and electronic signatures and the system is
compliant with 21 Code of Federal Regulations
(CFR) 211 (2). Therefore, we should consider the
requirements of the predicate rule, 21 CFR 211.
The “Laboratory Records” paragraph of “Subpart J,
Records and Reports” states:
“21 CFR 211.194(a) Laboratory records shall include
complete data derived from all tests necessary to assure
compliance with established specifications and standards,
including examinations and assays, as follows:
performs each test and the date(s) the tests were
performed.
showing that the original records have been reviewed
for accuracy, completeness, and compliance with
established standards.”
The original record in the LIMS must be
signed and dated electronically by the individual
performing the test [211.194(a)(7)]. Although not
stated specifically, it is a regulatory expectation,
Validation Answers from GXP ExpertsJerry Lanese and Alan Smith
John (Jerry) Lanese, Ph.D., is an independent consultant in the areas of quality system and CGMP compliance. he can be contacted at jerry@lanesegroup.com. Alan J. Smith, Ph.D., is an independent consultant specializing in quality management and the application of CGMPs. He can be reached at ajsconsri@aol.com.
For more Author infor-
mation, go to ivthome.
com/bios[
4 PROCESS VALIDATION – Process Qualification
Jerry Lanese and Alan Smith
and also a reasonable scientific expectation, that
the signature of the individual performing the test
is acknowledgment that the test was performed
according to approved methods and procedures,
all defined acceptance criteria have been met, and
the reported data are accurate and complete. This
responsibility should be identified in an appropriate
laboratory procedure. This paragraph [(211.194(a)
(8)] also includes a clear requirement that a second
individual review the record(s) and verify that the
data is complete, accurate, and compliant with
internal procedures and regulatory requirements.
A second review by the laboratory is required! That
review should include all of the data entered into
the system. If any of the data is transcribed from a
notebook or worksheet, the review should verify the
accuracy of the transcription and the completeness
and compliance of the original notebook or
worksheet record.
It is reasonable to accept that the values
calculated within LIMS by the validated macro are
correct. However, 21 CFR “211.68(b) Automatic,
Mechanical, and Electronic Equipment” states:
“Appropriate controls shall be exercised over
computer or related systems to assure that
changes in master production and control
records or other records are instituted only
by authorized personnel. Input to and
output from the computer or related system
of formulas or other records or data shall
frequency of input/output verification shall be
based on the complexity and reliability of the
computer or related system.”
Although we may accept, on a day-to-day basis,
that the calculation within the LIMS is accurate,
there should be a systematic, periodic verification
that that macro is performing as intended. The
frequency of that verification should be defined in a
procedure and based on an evaluation of the science
and the risk associated with the calculation. This
includes a periodic evaluation of the accuracy of the
ultimate report, the certificate of analysis.
The question about what data or records should
be reviewed by quality assurance is not as clear.
“211.192 Production Record Review” states:
“All drug product production and control
records, including those for packaging and
labeling, shall be reviewed and approved
by the quality control unit to determine
compliance with all established, approved
written procedures before a batch is released
or distributed.”
Laboratory records are control records, and
companies differ in how they comply with the
requirement that laboratory records be reviewed
by the quality control unit. With most firms, it
is considered that the quality control laboratory
is part of the quality control unit, the second
review the laboratory meets the requirement for
the review and approval of the data and records
that up the certificate of analysis, and the quality
assurance department accepts the certificate of
analysis as an accurate report. In other firms,
quality assurance reviews all records, including the
quality control laboratory records before product
release. Either way meets the “letter of the law.”
Whatever way a firm chooses to operate, the process
must be defined in a procedure or procedures and
responsibilities clearly identified.
VALIDATION REPORTS
Reader QuestionIf you realize that a record such as a validation
report, calibration report, or environmental report
requested by a regulatory agency investigator, has
not been completed, what should you do? Should
you show the data or reports that have not been
reviewed or approved (3)?
Editors’ Response [1]When providing documents to an investigator or
auditor, it is accepted, good practice to review the
document prior to presenting it to the requester to
become familiar with it and, heaven forbid, find
problems that would need to be addressed.
If a document is incomplete or has not had the
required review and sign-offs, most importantly,
do not attempt a “quick fix” and add the missing
information or sign it; this could cause even more
problems.
Instead, begin an immediate investigation
according to your procedures. Once this
investigation has been started, present the
document and inform the investigator or auditor
that you have found something amiss and have
started an investigation. You will need to have some
information or closure to this issue by the end of
the inspection.
Generally speaking, if this is seen as a rare
occurrence, it should not be a problem (given of
course, what was missing). On the other hand, if
there are repeated problems with many documents,
it could point to a systemic issue.
PROCESS VALIDATION
Reader QuestionWith regard to process validation, at what point
during development or process transfer of the
drug product do you challenge the extremes of the
PROCESS VALIDATION – Process Qualification 5
Jerry Lanese and Alan Smith
process parameters, such as time, speed, pressure,
or temperature (4)?
Editors’ Response [1]There has been an evolution in thinking of
validation in the past ten years. More firms validate
on the philosophy that they want to demonstrate
that they have control of the process during
normal, anticipated operational conditions. This
is based on the capabilities of the equipment, the
normal variation of raw materials and components,
and what have been identified as critical and
operational parameters.
In FDA’s guidance document, Sterile Drug
Products Produced by Aseptic Processing
(September 2004), a list of factors is presented that
a firm should consider as they are developing the
product and designing the validation protocol.
Although this guidance is addressed to a specific
segment of the industry, the concepts apply to other
segments of the pharmaceutical industry as well
as the development and validation of processes in
other industries.
In addressing the factors, the firm needs to give
a rationale for what it decides to examine or not
examine. This is not to say that every possible
“what if” scenario needs to be examined during
development, but rather, as the guidance states,
“closely simulate aseptic manufacturing operations
incorporating, as appropriate, worst-case activities
and conditions that provide a challenge to aseptic
operations.” A risk analysis could be part of the
evaluation of what to challenge. The extremes of
the critical process parameters, such as time, speed,
pressure, or temperature should be examined and
established during development.
Validation is where you demonstrate that
you can consistently operate in control; process
development is where you want to generate an
understanding of where the “edges of failure” are
and where the optimal operational range is.
CHANGE CONTROL
Reader QuestionAre continuous improvements and process
improvements subject to change control (5)?
Editors’ Response [1]Any change that is not covered in a procedure
reviewed and approved by the quality unit should
be handled within the change control program.
This includes improvements to the processes.
Changes will require quality unit review and
approval consistent with the change control system
and probably some level of regulatory submission
or report, such as: Prior Approval Supplement,
Change Being Effected, or Annual Report.
FDA discusses an environment that promotes
continual improvements in its recent guidance on
the Quality System Approach to Pharmaceutical
Good Manufacturing Practices (GMPs) (6).
The concept is mentioned in the International
Conference on Harmonization (ICH) Q8 (7)
document. There is an interest on the part of both
the Agency and Industry that continuous process
improvements can be made with a minimal
requirement for regulatory submissions. In order
for this to happen, some or all of the following will
have to be in place:
a previous submission, that it understands
the process and the proposed improvement is
consistent with that information
identified in an approved submission (New
Drug Application [NDA], Amended New
Drug Application [ANDA], Biologics License
Application [BLA], or other market approval
submission)
submission and meets conditions, such as
protocol, comparability testing, and acceptance
criteria, defined in the approved submission.
VIRTUAL PHARMACEUTICAL COMPANIES
Reader QuestionWhat should virtual pharmaceutical companies
expect FDA to inspect during a routine
surveillance/compliance audit (8)?
Editors’ Response [1]First, we should give some background information
on this topic. As our society has become more
technologically advanced and specialized, it is
difficult for industry to do everything itself and
remain competitive. Because of this, companies are
relying on the expertise and capabilities in other
organizations. More companies are looking to
outsource services and functions and concentrate
on their core competencies, thus, the trend toward
companies “going virtual” is on the rise.
FDA has not published guidance, or other
document, specifically on what quality systems
they expect virtual pharmaceutical companies
to employ and what they will look for during an
investigation of a virtual pharmaceutical company.
The response is based on some assumptions:
6 PROCESS VALIDATION – Process Qualification
Jerry Lanese and Alan Smith
applicable submission (Investigational New
Drug Application [IND], NDA, BLA, or other
appropriate registration document)
labels and labeling for the product
team that provides the leadership through the
product lifecycle (design, develop, transfer,
produce, package, distribute, monitor,
decommission).
Two efforts of FDA to encourage the
pharmaceutical industry to embrace contemporary
quality concepts and implement contemporary
quality systems are as follows:
The section of this guidance that is the most
relevant is MANAGEMENT RESPONSIBILITY.
Within this, the section, “Oversight of
Outsourced Materials,” stands out.
“A pharmaceutical company can outsource
activities at all stages of the product lifecycle.
the management responsibilities described
in this section, extends to the oversight and
review of outsourced activities. Normally,
under a contract, the contract giver should
be responsible for assessing the suitability and
competence of the contract acceptor to carry
out the work required. Responsibilities for
quality-related activities of the contract giver
and contract acceptor should be specified in a
written agreement.” (9)
Quality System Approach to Pharmaceutical
CGMP Regulations (10). The most pertinent
section in this guidance is also Management
Responsibilities. Management responsibilities
include:
1. Provide leadership:
plans
review
2. Structure the organization and identify
authorities and responsibilities to achieve
the goals through the product lifecycle
3. Build the Quality System to assure
compliance through the product lifecycle
4. Establish and implement appropriate
policies, procedures, objectives, and plans
5. Review the system.
In July 2007, the Center for Biologics Evaluation
and Research (CBER) issued a draft guidance
(11), Cooperative Manufacturing Arrangements
for Licensed Biologics, that is directly applicable
to virtual companies involved with licensed
biologics. The concepts apply to all pharmaceutical
firms through the product lifecycle. That guidance
states:
“Contract Manufacturing Arrangements.
For the purposes of this document, contract
manufacturing refers to a situation in which
a license manufacturer establishes a contract
with another entity(s) to perform some or all
of the manufacture of a product as a service to
the license manufacturer.
“Responsibilities of License Manufacturer.
A license manufacturer that establishes a
contract with another entity to perform some
or all of the manufacture is responsible for:
with the provisions of the BLA and the applicable
regulations, including, but not limited to, 21 CFR
standards.”
The virtual company is accountable for
everything that goes on during the product
lifecycle. FDA will look for the evidence of an
appropriate quality system that exhibits the
following criteria:
with the objectives, plan, product, and
processes
and quality through the various stages of the
lifecycle
ACCOUNTABILITY AND RESPONSIBILITY
Reader QuestionThe terms accountability and responsibility are
frequently used in quality standards and guidances,
but are not defined by any major document. It is
not clear whether these terms are synonyms with
no difference in meaning or whether there are
significant or subtle differences in meaning. How
are these terms to be interpreted or applied within
a standard or an internal policy or procedure (12)?
Editors’ Response [1]In addition to being used in quality standards, the
terms responsibility and accountability are used
often in both management and political circles.
Their definitions are, therefore, of wide concern.
PROCESS VALIDATION – Process Qualification 7
Jerry Lanese and Alan Smith
The problem is that their usage in both professional
and everyday language varies.
Dictionaries tend to regard the terms as
synonymous. However, we, the editors, are aware
that these words are sometimes used in different
contexts and can have graduated shades of meaning
as in the use of “directly responsible” versus
“indirectly responsible.” Accordingly, we surveyed
many of our colleagues for their opinions. They
provided a wide range of opinion with about half
considering the terms to be synonymous (i.e., “A
is responsible for performing X type actions” is the
same as “A is accountable for performing X type
actions”). The issue becomes more challenging
when the two words appear in the same sentence
(e.g., “A is accountable for the results of actions
performed within his/her areas of responsibility.”).
In the latter case, it is as though responsibilities
are action areas which have been assigned
(i.e., authorized) by a higher body and that
accountability is recognition by interested parties
as to who can be “officially held to account” for
performance within those areas.
We both hold the view that whenever a firm, or
any organization, communicates or documents its
practices, it should avoid ambiguity by defining
each term that it uses so that its meaning is
individually distinct. This would include making
sure each synonym used has a separate and distinct
meaning. We maintain that each organization
should do this and consider such definitions
to be internally published “as used in our
documentation.” We thus propose the following as
definitions for consideration:
action or duties being assumed by or formally
granted to an organizational unit.
identity of the persons, or organizational units,
who can be held to account for the adequacy of
performance of work done or to be done.
Under this arrangement, responsibility is
something which is assumed or assigned and
accountability concerns who should be identified
with the adequacy of performance. The definition
of accountability would allow not only those who
actually perform the work to be accountable but
also those to whom they report either directly or
less directly through the defined organization.
It is becoming a well-established principle that
the highest individual in the organization is
accountable. This was understood by President
Harry Truman by his display of the placard on his
desk in the Oval Office, which read: “The Buck
Stops Here.”
GMPS AND DEVELOPMENT ACTIVITIES
Reader QuestionHow much do GMPs apply to development
activities? What development data can FDA
investigators inspect during a site or pre-approval
inspection (13)?
Editors’ Response [1]Most people tend to regard GMPs as government
regulation for “product manufacturing” with which
firms must comply. However, it is more realistic
to regard the term as embracing practices that
industry uses to consistently produce a quality
product. Indeed, in keeping with this, FDA used
the term, CGMP, where “C” stood for the word
“current” when, in 21 CFR Sections 210 and 211, in
1978 and ever since, FDA adhered to the concept of
assessing the “up-to-dateness” of a firm’s practices
when performing inspections.
When Parts 210 and 211 were first issued,
they were intended to be the official regulations
governing the manufacture of batches intended
for commercial use. They were not intended
to apply to development activities with the
exception of clinical batch manufacture, which
was referred to in the preamble. However, since
the issuance of Parts 210 and 211, there has been
a veritable plethora of non-regulation documents
issued by FDA, and other organizations, that
have discussed the development work necessary
to produce a quality product. Paramount
among these has been the ICH Q series, which
identify “product knowledge” data that should
be included in the product submission (NDA,
ANDA), and are therefore, available before
marketing. FDA has provided members of the
expert work groups that developed the ICH
Guidelines. The ICH guidelines are thus officially
recognized as Guidance for Industry by FDA.
Because good development is a precursor to good
commercial production, FDA expects such good
development and looks for this feature when
performing pre-approval inspections. An even
greater emphasis is placed on good development
in the recent Quality Systems Guidance (6), ICH
Q8 (7) and ICH Q9 (14), and further emphasis is
expected in ICH Q10 (9).
In pre-approval inspections, the main focus of
FDA is on the integrity of the development data
and the adequacy of the facilities, equipment,
people, and systems to perform as prescribed in the
submission. Anything described in the submission,
or suspected omissions, can be inspected and
this will include development work. In routine
inspections, FDA generally does not focus on
GMP Monitoring—What, Why, Where, and How .................................................................................................. 3
Rational Revalidation ........................................................................................................................................ 8
Dos and Don’ts of Control Charting—Part I ....................................................................................................... 17
The Dos and Don’ts of Control Charting—Part II ............................................................................................... 21
Understanding the Process Nonconformity Concept—The Scientific Reason for Process Validation ................... 27
Variation—Past, Present, and Future ............................................................................................................... 36
Having It All .................................................................................................................................................... 42
Substandard Data and Documentation Practices—Case Study #5 ..................................................................... 47
Using Probability Distributions to Make Decisions ............................................................................................ 54
Case Study #3—Process Validation Failure of a Liquid Product Batch
Size Increase—“Identical” Manufacturing Tanks ............................................................................................. 67
Like-For-Like Changes: Is Validation Testing Needed? Validation Case Study #7 ............................................... 73
Understanding and Reducing Analytical Error—Why Good Science Requires Operational Excellence ................. 78
Meeting Specifications is Not Good Enough—The Taguchi Loss Function .......................................................... 85
Process Modeling: A Powerful Weapon in the Fight to Reduce Variation—Part 1 .............................................. 90
White Spots on Tablets—Compliance Case Study #8........................................................................................ 97
Compliance Case Study #5—Secondary Packages With Defective Glue Joints ................................................ 102
CONTINUED PROCESS VERIFICATION
MONITORING AND MAINTAINING
THE VALIDATED STATE
LIFECYCLE APPROACH TO PROCESS
VALIDATION – FDA STAGE 3
PROCESS VALIDATION – Continued Process Verification 3
Gamal Amer
Welcome to “Maintaining Validation.”This column addresses topics associated with
maintaining the validated state of processes, equipment, facilities, utilities, and analytical methods (i.e., anything that has been validated or qualified and must be continually maintained in the validated state). We intend this column to be a useful resource for daily work applications.
This column was suggested by attendees at the 14th International Validation Week Meeting held in Philadelphia in October of 2008. The general topic of maintaining validation was a subject of great interest. An ongoing discussion addressing these questions and associated topics is warranted and will be useful to our readers.
Validation and compliance practitioners are well aware that the conformance lots of process validation, or the IQ/OQ/PQ of equipment, are at most “snapshots in time.” These events serve to document standard performance when completed. However, they do not guarantee continued good performance. It is through monitoring, data evaluation, statistical analysis, change control, and other programs that ongoing good performance is maintained. These topics, including relevant examples, are addressed in “Maintaining Validation.”
Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Case studies submitted by readers are most welcome. We need your help to make “Maintaining Validation” a useful resource. Please send your comments and suggestions to journal coordinating editor Susan Haigney at shaigney@advanstar.com.
KEY POINTS DISCUSSEDThe following key points are discussed in this
article:
considerations
draft guidance Process Validation: General
Principles and Practices (1) identifies continued
taken for excursions
other factors
ensure an ongoing state of control.
GMP Monitoring— What, Why, Where, and HowGamal Amer
[For more Author
information,
go to
gxpandjvt.com/bios
ABOUT THE AUTHOR
Gamal Amer, Ph.D., is principal at Premier Compliance Services, Inc., management consultants for compliance and manufacturing operations performance in the life sciences industry. He holds a Ph.D. in chemical engineering and has over 27 years of experience in the pharmaceutical and related industries. He can be reached by e-mail at vpainc@aol.com or amerg@premierc.net.
4 PROCESS VALIDATION – Continued Process Verification
Gamal Amer
INTRODUCTION: WHAT IS MONITORING?
current state
initiated.
Process Validation:
General Principles and Practices (1) identifies three
WHY MONITOR?
The following is a partial list of such regulatory and
21 CFR 211.42-10(iv).
conditions.
211.110 (a).
211.122 (h).
21 CFR 820.70 (a).
820.70 (2).
820.75 (b).
820.75 (b2).
ICH Q7, Good manufacturing Practice Guide
for Active Pharmaceutical Ingredients (9). This
PROCESS VALIDATION – Continued Process Verification 5
Gamal Amer
ICH Q8 Pharmaceutical Development
point) to ensure that the product is of the desired
ICH Q9 Quality Risk Management
in that collection and analysis of operating data
WHAT TO MONITOR IN A GMP ENVIRONMENT
surrounding the process
supplied
operation and should collect appropriate data and
operating experience.
WHERE TO MONITOR
and at the end of any critical steps are also logical
conditions at the point where the product is at
steps in the process and at the critical use points.
particulate data are collected at surfaces where
6 PROCESS VALIDATION – Continued Process Verification
Gamal Amer
HOW TO MONITOR
recording data
taken
issues or trends are identified.
actions:
conducted if issues arise
ESTABLISHING THE PARAMETERS TO MONITOR
one can plainly see that the resulting product would
process yield or the yield of certain critical steps
products
and suggests how to deal with trends and issues
as they arise.
SUMMARY
to ensure the process is in a state of control. The
Table: Environmental sampling frequencies for aseptic manufacturing facilities.
Area Classification Sampling Frequency
Class 100 Each shift*
Support to Class 100 (Class 10,000) Each shift*
Other support areas (Class
100,000) Twice/week
Potential product/container con-
tact Twice/week
Non-product contact are
(Class 100,000 or less)
Once/week
*FDA guidance on sterile processing suggests daily monitoring (13).
PROCESS VALIDATION – Continued Process Verification 7
Gamal Amer
The Journal of Validation Technology
REFERENCESProcess Validation: General
Principles and Practices, Draft Guidance
Q7, Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients
Q8, Pharmaceutical Development
Q9, Quality Risk Management
Pharmacopeia Forum
Sterile Drug Products
Produced by Aseptic Processing JVT
ARTICLE ACRONYM LISTINGCAPA Corrective Action and Preventive ActionCPP Critical Process ParametersCQA Critical Quality AttributesGMP Good Manufacturing PracticesFDA US Food and Drug AdministrationFMEA Failure Mode Effects AnalysisFMECA Failure Mode, Effects, and Criticality AnalysisHACCP Hazard Analysis and Critical Control PointsHAZOP Hazard Operability AnalysisUSP United States Pharmacopeia
8 PROCESS VALIDATION – Continued Process Verification
Hosam Aleem, Tim McCarthy, and Rodger Edwards
[For more Author
information,
go to
gxpandjvt.com/bios
ABSTRACT
This discussion addresses the need for
considered.
INTRODUCTION
Q9
Rational RevalidationHosam Aleem, Tim McCarthy, and Rodger Edwards
ABOUT THE AUTHORSHosam Aleem has spent several years in the pharmaceutical industry as a validation and cali-bration engineer at both IPR owners and contract manufacturers. He may be reached by email at hosam.aleem@manchester.ac.uk. Dr. Tim McCarthy is a professor of engineering design at the University of Wollongong, NSW Australia. Dr. Rodger Edwards is a senior lecturer at the School of Mechanical, Aerospace and Civil Engineering at the University of Manchester Institute of Science & Technology and University of Manchester.
PROCESS VALIDATION – Continued Process Verification 9
Hosam Aleem, Tim McCarthy, and Rodger Edwards
litigations).
procedure to follow in executing it. This discussion
WHY REVALIDATE?
Supplementary Guidelines on
Good Manufacturing Practices: Validation
countries.
Other regulations introduced in the past such
in focus of regulatory inspections. This is also
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