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FMEA - Improving Quality Risk Manag During Qualific, Validation, and Change Control PDF
FMEA - Improving Quality Risk Manag During Qualific, Validation, and Change Control PDF
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Note: the views expressed in this paper are those of the authors, and should not be
taken to represent the views of the Irish Medicines Board.
INTRODUCTION
The September 18, 2006 European edition of Time Magazine1 carried three
interesting letters from readers on the subject of airline security and the related
governmental risk control measures. Under the heading “How Much Risk Can We
Take?” the letters showed, in very simple terms, how the perception of risk and risk
control measures can be widely subjective, and how there can be much perceived
uncertainty in the approaches used for managing risks.
In the above Time letters, one reader indicated a strong support for tightened
security measures at airports, and promoted “giving up some freedoms” in place of
accepting “a high risk of more attacks.” Another reader took a widely differing view of
the whole airline security issue, arguing that current risk control measures were
merely attempts by governments “to seize the opportunity to pass draconian
measures to control the population.” In the third letter, it was argued that the current
airline risk control strategies have actually “lost sight” of the real problem, which, in
that reader’s mind, lies in the cargo hold of the airplane being infiltrated with a small
bomb, and not through what passengers carry onto airplanes.
As different as each reader’s opinion is, there was an element common to each
letter. This was the level of uncertainty voiced by each reader, despite their stated
convictions, on the management of the risks concerned. The three readers’ letters
contained phrases indicative of uncertainty, such as “It seems that not much has
changed since then…,” “… we seem to have lost sight of the problem…,” and “what
they seem to have lost sight of is….”
Such problems of subjectivity and uncertainty are not confined to airline Risk
Management activities. In the Pharmaceutical Industry, the incorporation of Quality
Risk Managementa concepts and tools within Good Manufacturing Practice (GMP)
environments is an area that has been under considerable development in recent
years, and there are many references in the literature to the subjective and uncertain
nature of Risk Management for pharmaceutical applications and in other areas
also.2-9
The increase in the use of formalised Risk Management tools and approaches has
probably been accelerated by a number of developments, including the guidance
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Uncertainty
Problems of subjectivity and uncertainty during formal Quality Risk Management
activities are to be expected. Uncertainty is unavoidable, given the generally
accepted definition of risk,b which includes a probability factor for the occurrence of a
hazard or harm. ICH Q9 lists some typical sources of uncertainty during Quality Risk
Management, and these include gaps in knowledge, gaps in pharmaceutical science
and process understanding, and importantly for the discussion below, uncertainty in
sources of harm (e.g. failure modes of a process). In many cases, unless the source
of the hazard or harm is entirely eliminated, uncertainty cannot be avoided when one
tries to estimate and manage resulting risks.
Subjectivity
With respect to problems of subjectivity, this is acknowledged as an issue in many
publications,2, 5-8 including ICH Q9, which explains how “each stakeholder might
perceive different potential harms, place a different probability on each harm
occurring and attribute different severities to each harm.”
Despite these inherent problems, it should not be taken that the levels of uncertainty
and subjectivity cannot be reduced during Quality Risk Management activities. With
the use of formal, science-based and vigorous approaches, it is reasonable to
believe that uncertainty and subjectivity can be reduced and that an increased level
of confidence in the results and outputs of Quality Risk Management exercises may
be obtained. Within GMP environments, when such Quality Risk Management
methodologies are used as an aid to qualification, validation, and change control
activities, this should have two important outcomes:
Over the course of the past three years, the authors have been researching how
Quality Risk Management concepts and methodologies may be used within EU-
regulated GMP environments in the manufacture of medicinal products and active
pharmaceutical ingredients (APIs). The GMP areas of concern in this research were
those relating to qualification, validation, and change control activitiesc and a formal
and rigorous qualitative Quality Risk Management methodology19 was developed to
demonstrate a means by which compliance with the risk-related requirements of
Annex 15 (Qualification and Validation) to the EU Guide to GMP may be achieved.
20-22
A major focus of this research has been on identifying strategies that might address
some of the uncertainty and subjectivity issues that arise during Quality Risk
Management activities.
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Selecting Risk Priority Number (RPN) cut-off values. This is a feature of some
applications of Failure Modes and Effects Analysis (FMEA) and Failure
Modes, Effects, and Criticality Analysis- (FMECA) based methodologies.4, 7,
23, 29, 32
During the testing of the formal Quality Risk Management methodology under
development here,19 a number of practical workshops were run to investigate the
application of this methodology as an aid to qualification, validation, and change
control activities. The workshops involved a large number of real-life, GMP-related
case studies, which spanned a wide range of areas relevant to GMP environments.
These included:
During the above workshops and case studies, some simple and easy-to-implement
strategies were developed which helped to reduce the level of guesswork,
subjectivity, and uncertainty associated with the Quality Risk Management exercises,
and which helped to increase confidence in the results obtained. Such strategies
served to facilitate more meaningful and value-adding Quality Risk Management
exercises for qualification, validation, and change control activities.
These strategies are science-based and qualitative in nature, and many are common
sense approaches. Often, however, they have been overlooked, or have not been
developed appropriately, by the current Quality Risk Management methodologies
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The resulting risks, which are estimated using these ratings, or the
resulting RPNs which are calculated, are likely to be prone to levels of
uncertainty and subjectivity which cannot easily be dismissed or dealt
with.
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During this case study, two workshops were run in which early versions of the
Quality Risk Management methodology under development were applied to the
above filter dryer change control proposal. In the first workshop, “low yield” of API
material following drying was identified and documented in a brainstorming session
as a potential failure mode. A number of potential causes were identified for this
failure mode, including, breakage of, or damage to, the stainless steel mesh screen
in the filter dryer. It was documented that this could result in a physical loss of
filtered, solid API material through the screen.
As this workshop progressed, it was evident that selecting such a high level potential
Failure Mode significantly limited the extent to which causative factors and their
mitigating controls were identified, and documenting the failure mode in this manner
impacted the outcome of the risk management exercise in quite a significant way.
For example:
The potential cause(s) of the actual breakage of, or damage to, the mesh
screen was not identified or discussed in any way. It is not unreasonable to
expect causative factors at this indenture level to have been identified, and
there was, for example, no discussion during the workshop on whether an
incorrectly rated screen (from a pressure perspective) could have been a
potential cause for the screen breakage.
2. Do a screen integrity check before first batch and after fifth batch.
3. Do a heavy metals test on the finished API in order to detect screen particles.
An analysis of the above five controls shows that 80% of the controls are detection-
related. The fifth control serves as a preventive measure that may reduce the
probability of screen damage or breakage, but to what extent this was unknown.
Thus, it is clear that the above controls were heavily skewed towards detection as
the primary means of addressing the risk posed by the failure mode in question. This
is likely a result of documenting the Failure Mode at such a high indenture level and
in a manner that rendered it effectively equivalent to its main end effects. When this
occurred, it meant that the causative factors identified were, by definition, quite high
level also, and it was found that preventive controls were not as readily determined
as with lower level causative events.
A second workshop was then run to investigate the impact on the results of the
above Quality Risk Management exercise when more care and vigor were applied to
the failure mode identification and documentation process. The strategies outlined
below were adopted during this repeat case study, and a simple Fault Tree Analysis
(FTA) approach was used during a brainstorming session to determine causative
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The intent here was that causative events could be identified via more vigorous, but
simple, procedures, and these could then be used to select potential failure modes
and the causes of such failure modes.f This approach ensured that the potential
failure modes that were identified and documented were adequately differentiated
from the high level faults that they related to, in this case the high level fault being
“Low Yield API Batches.” The approach also ensured that the causative events were
at a sufficiently low indenture level to facilitate meaningful and preventive risk
mitigation. Importantly, as a control between the two workshops, the high level fault
selected in Workshop Number Two was the same as the failure mode selected in the
first workshop on this Change Control case study.
In this second workshop, the first causative event identified under the high level fault
was “the stainless steel mesh screen in the filter breaks or is damaged.” The three
subsequent causative events were then identified at the next indenture level below
this one. These three subsequent causative events, each separated by “or” gates in
the Fault Tree, included:
The mesh screen in the dryer is not chemically resistant to the slurry material
(including the solvent) being filter-dried.
A wrong screen is installed in the filter dryer during set-up for this API
manufacturing campaign.
The first causative event documented in the Fault Tree under the high level fault was
selected as the potential failure mode, and in the indenture level below this in the
Fault Tree, the three causative factors mentioned above were taken to be the
potential causes of this particular failure mode. When the above failure mode,
together with the associated three potential causes, was input to the risk
management methodology under study here, substantially different and more useful
results were obtained compared to those from the first workshop, even though the
issue of concern was essentially the same – low yield API batches.
In the second workshop on the same case study, nine risk mitigating controls were
identified this time, for the same low yield problem described in the first workshop.
These were as follows:
1. Identify the correct pressure rating for the screen by determining (either via
developmental batches or engineering calculations) the pressures expected to
be exerted upon the screen when the dryer is in operation at maximum
agitation speed and at maximum load. Then, ensure that this screen is used in
the drying process.
2. Monitor the pressure across the screen in the dryer during operation. A
significant pressure drop may indicate a screen failure.
3. Have a second person verify that the correct screen was chosen during set up
of the dryer for this campaign.
4. Determine whether the screen material is inert with respect to the material
being screened, and ensure that an inert screen material is chosen for this
process.
5. Do a screen integrity check before drying the first batch in the campaign and
after every fifth batch in the campaign.
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7. Visually inspect the mother liquor for the presence of gross particulates.
9. Measure the yield of dried API for each batch. This may detect any gross
screen failure, as there will be physical loss of API to the mother liquor.
Secondly, in the repeat workshop, the risk mitigating controls that were identified
were based much more on prevention rather than on detection. Four of the nine
controls, numbered 1, 3, 4 and 8 above were preventive in nature, as opposed to
only one such control identified during the first workshop. Similar findings have been
observed with other case studies when this approach was used.
When these preventive controls are considered, the subjectivity and uncertainty
associated with assigning probability of occurrence values to the causes of the
failure mode are reduced, even with this qualitative methodology, because we are
not now merely guessing probability of occurrence values for the causes of failure
modes. Rather, there is now a more scientific rationale behind any probability of
occurrence values that are assigned.
In order to reduce the problems of subjectivity and uncertainty that were discussed
earlier in this paper, it is of prime importance that failure modes be identified and
documented in a scientific manner, using meaningful, consistent, and systematic
processes. This is because, with failure mode-based methodologies, the risks or
RPNs that are generated, and the overall results obtained from the Quality Risk
Management exercises, directly relate to, and are usually wholly dependent upon,
the failure modes that are identified and input to the methodology being used.
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often scant instruction provided in other publications and in company Quality Risk
Management procedures on how to actually identify and document failure modes,
beyond mainly conceptual steps.
From the practical case studies carried out as part of this research, it is evident that
there is a need for more rigorous and clear instruction or guidance in Quality Risk
Management methodologies in relation to the practicalities of identifying and
documenting failure modes, particularly during brainstorming sessions. In the
following sections of this paper, a number of simple and easy-to-implement
strategies are presented for use when identifying and documenting failure modes,
which the authors have found useful when developing and testing Quality Risk
Management concepts and approaches for GMP applications.
Ensure that documented and formal procedures are in place for carrying out
brainstorming. Define in advance the training requirements for those
participating in brainstorming activities.
Formally review the potential effects of each proposed failure mode at the
time the failure mode is proposed, to ensure that failure modes are not
documented that are essentially the same as their effects. (The case study
presented above provides a detailed example in relation to this point.) In this
regard, it can be useful if the following questions are put to the Risk
Management team during brainstorming or other activities when Failure
Modes are being identified: What can go wrong? What are the effects or
consequences of this going wrong? Is the failure mode, as proposed, the
same as its effects? If the latter is the case, work to determine the true failure
mode relating to these effects.
Confusion between failure modes, their causes and effects can occur in
FMEA-based applications, because potential effects identified in one
indenture level of the system under study may become failure modes at
a higher level. Also, failure modes identified in one indenture level may
become failure mode causes at a higher indenture level.7, 23
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Ensure that any pertinent assumptions that are made relating to qualification
and validation issues, and which may be significant for specific failure modes,
are discussed and clearly documented during brainstorming sessions. For
example, assumptions relating to the qualification status of items of
equipment, or of maintenance activities for items of equipment to maintain
qualification or calibration status, can be important when equipment-related
failure modes are being identified, and these assumptions should be stated
up-front.
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Near miss incidents can provide valuable and real information on potential
failure modes and their frequencies, but they are often not formally
documented.
It is more useful, therefore, to ensure that the procedures in place for Quality Risk
Management exercises define in detail the data and documentation that should be
assembled on the item under study. If a process map or flowchart of the item under
study is to be used, it should be sufficiently detailed and descriptive if it is to be of
value. We have found it helpful to extend the scope of what is normally considered a
“Process Map,” so that more comprehensive information is assembled on the item
under study. This information can include:
A listing of the steps in the process or in the item under study in which human
intervention occurs, or is at its highest.
A list of equipment as well as all ancillary equipment relating to the item under
study. For example, if the item under study is a manufacturing process, and if
sampling occurs on that process, sampling equipment and facilities should be
included.
Copies of any ancillary SOPs or other documents which are required for the
item under study, such as SOPs for controlling room environments, for taking
samples from reactors, etc.
The known Critical Process Controls for the item under study, as well as the
in-process tests, the finished product tests, and their specifications or limits.
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Strategy 5:
Look for Strength of Evidence when Expert Judgment and Informed Opinions
Are Used
It is, of course, good practice to obtain informed opinion and expert judgement when
identifying potential failure modes, but it is important to always seek and assess the
strength of evidence for each opinion or suggestion proposed. This adds rigor to the
exercise, and it helps reduce the level of subjectivity and guesswork that can arise
during the failure mode identification process. In this regard, it is helpful to:
Seek the opinions of actual users and operators of the item under study. A
process operator may know very well what can go wrong with a process or
activity, and he or she may be in a position to advise as to its potential
frequency.
Seek the opinions of those employees or others who are knowledgeable in the
item under study. For example, during equipment-related Quality Risk
Management exercises, the vendor may have valuable knowledge about likely
problems and potential rates of failure of components, etc.
Where possible, take into account the concerns of stakeholder groups when
considering "what might go wrong" with an item under study. For example, if a
change control is proposed to roll out a new labelling and livery design for a
range of medicinal products, practicing pharmacists may usefully advise about
risks of dispensing or usage errors which may be introduced by the change,
even if the new labelling is fully compliant with Marketing Authorisation
labelling requirements.
CONCLUSIONS
In this paper, the problems of subjectivity and uncertainty that are associated with
formal Quality Risk Management methodologies are discussed. When such
methodologies are used as an aid to qualification, validation, and change control
activities within GMP environments, this research has found that an area that can
greatly influence the validity of the outcome of the exercise is the identification and
documentation of potential Failure Modes.
Following a review of the relevant literature, and based on the author's experiences
as a GMP inspector, it is evident that the identification and documentation of
potential Failure Modes is an activity that is often not adequately proceduralised
within failure mode-based Quality Risk Management methodologies and their
applications.
During the course of this research, using a wide range of real-life GMP-related case
studies and workshops, it was observed that, in the absence of clear and rigorous
procedures, failure modes are sometimes poorly identified and documented. This
can have a significant impact on the results of the Quality Risk Management exercise
in question. The outputs and conclusions of such exercises may be questionable,
lacking in scientific evidence, and there may be a lack of confidence in the results
generated. This problem especially arises when failure modes are selected for
assessment which are identified at too high an indenture level in the system under
consideration, or when the failure mode is documented in a way that renders it
essentially the same as, or very similar to, the potential effects of that failure mode.
A detailed case study is presented which demonstrates the above, and a number of
simple strategies are proposed which can be adopted to improve how failure modes
are identified and documented. This work has found that when such strategies are
used, a greater level of confidence can be placed in the output from such Quality
Risk Management exercises, and subjectivity and uncertainty issues can be reduced.
REFERENCES
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ACKNOWLEDGEMENTS
Kevin O'Donnell would like to thank the Irish Medicines Board for supporting and
funding this research. The views expressed in this paper are those of the authors,
and should not be taken to represent the views of the Irish Medicines Board.
Thanks to Noel Whelan, whose research on ICH Q9 as part of his Master's Degree in
2006 was helpful for this work, and to Akiko Nanjo and Kenneth Martin for assistance
in sourcing several helpful papers from the literature. Thanks also to Mitsuko Oseto,
for valuable discussions and for accepting the ultimate risk!
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###
EC European Community
EU European Union
QA Quality Assurance
QS Quality System
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FOOTNOTES:
a. The term Quality Risk Management is being used in this paper to denote Risk
Management activities relating to the quality and availability of pharmaceutical
products.
c. These areas were chosen because, in the EU, there are specific and explicit
obligations placed on manufacturers of medicinal products to employ risk-based
qualification, validation and change control programmes,20-22 but to date, there has
been a lack of detailed guidance on how these requirements may be implemented in
practice.
d. It is recognized that often, there may be limited historical data available on failures
that occur with processes or in equipment, or on the rates of such failures. This can
especially be the case during prospective Quality Risk Management exercises and
change control proposals, for which experience and historical data may be limited.
e. As noted above, the author has also observed this confusion between failure
modes and their potential effects during GMP inspections; for example, failure
modes such as “out-of-specification batches” may be documented, with their effects
listed as “non-compliant product.” This problem has also occurred in other
workshops using different case studies.
f. FTA is useful when Failure Modes need to be identified during FMEA and FMECA-
based Quality Risk Management exercises. When using FTA methodology, there
can be many causative events identified at the same or at different indenture levels
in the fault tree and these may contribute to the high level fault. All of these causative
events could potentially be considered to be failure modes, and this presents a
practical difficulty when FTA approaches are used to identify failure modes, as it can
sometimes be difficult to determine where in the fault tree the failure mode(s) should
be selected. We have found it useful to first select the causes of the failure mode,
before identifying the corresponding failure mode from the fault tree. (The latter will
normally be one level above on the fault tree.) The causes of the failure mode can be
chosen from the fault tree by examining which causative factors in the tree are most
readily suitable for assigning meaningful and practical preventive, detection or other
controls to. This is a simple approach, but it has been found by the authors to be
useable and effective.
g. During 2005 and 2006, the author asked senior QA personnel within six
multinational pharmaceutical manufacturing companies which used formal risk
management methodologies as part of internal Quality Assurance activities, whether
their procedures allowed for brainstorming as a means of identifying failure modes,
faults, or hazards, and if so, whether there were documented and detailed
instructions in place for how such brainstorming was required to be carried out. In all
cases, brainstorming could be used as a means of identifying failure modes, faults,
or hazards, and in all cases, there were no documented instructions in place for how
such brainstorming was to be carried out.
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