Risk Analysis & Mitigation Matrix
Risk Analysis & Mitigation Matrix
Risk Analysis & Mitigation Matrix
This article
presents a new
type of risk tool.
Risk Analysis
and Mitigation
Matrix
(RAMM) was
developed to be
incorporated into
a modern risk
management
system and align
with latest FDA
guidances.
isk analysis and management is the cornerstone of any science- and risk-based
approach1 for modern drug development
and manufacturing.2 In order to understand and document processes and products,
standard risk analysis tools have been adapted
from other industries and academia. These tools
include Ishikawa Diagrams,3 P-Diagrams, Preliminary Hazard Analysis (PHA), Failure Modes
and Effect Analysis (FMEA4), Failure Modes and
Effect Criticality Analysis (FMECA5), Hazard
Analysis of Critical Control Points (HACCP6),
and several more.
The Risk Analysis and Mitigation Matrix
(RAMM) was created to provide a pragmatic
compromise where other risk tools such as
Preliminary Hazard Analysis (PHA) or Failure
Mode Effects and Criticality Analysis (FMECA)
are maybe either too simple and lacking in detail, or they are maybe too complicated, making
it difficult to work consistently with limited
resource across all products.
The goal of the RAMM was also to align with
ICH and FDA guidances (Q8 to Q10 series7, 8,
9
and Process Validation10); especially around
tracking Critical Quality Attributes (CQAs)
and Critical Process Parameters (CPPs) in a
pragmatic manner. The tool was designed to
be at the heart of any modern quality system
with regular review in meetings and as a way
of tracking risks and any mitigation actions.
The tool had to be simple enough that everyone could use it and provide enough detail
that critical risks could be tracked, mitigated,
and be time savvy. If it were to take days to go
through the risk analysis every time a process
review occurred, it would never be as useable
as it should be.
This article will discuss how the tool works,
Risk Hierarchy
Risk tools are traditionally categorized as simple
or detailed. Simple tools are often used as a
precursor to using the detailed tools or early
in development where little is known about
processes, materials, and products. These simple
tools include:
Analytical Development
Manufacturing
Quality
Regulatory
Medical Professional
Facilitator
Ishikawa Diagrams
Preliminary Hazard Analysis (PHA)
Simple Prioritization Matrices
P-Diagrams
The list above is not exhaustive and the output of simple risk
tools are not particularly quantitative and are typically for
identification or hazards and/or risks only. These tools are
extremely simple to use and yield results quickly.
More detailed tools are used for comprehensive risk analysis
(and mitigation steps) and include a quantitative element.
Examples of these tools include:
Failure Modes and Effects Analysis (FMEA)
Failure Modes, Effects and Criticality Analysis (FMECA)
Hazard Analysis and Critical Control Points (HACCP)
The use of these tools typically leads to a comprehensive
analysis of risk. All of these risk tools, either simple or detailed, could be complimented by a middle level risk tool as
demonstrated in Figure 1. The Risk Analysis and Mitigation
Matrix (RAMM) was developed to be quantitative yet simple
to use.
The RAMM tool is potentially a useful compliment to the
other risk tools and can be used solely or in combination with
other risk tools. The potential to use something quantitative,
but not as complex as the detailed risk tools can potentially
serve as the useful keystone of a risk management system as
it is quantitative yet manageable. Each user should of course
make their own choice as to which tools serve them best, but
it is proposed that the RAMM is a useful addition to that tool
set.
It was felt that this team would give the best input to developing the process understanding and risk analysis, although
each organization and project is different and may include
different functions to those selected here. Though it was not
the case in this example, the right team may include people
who have not seen the actual process before, but who have
other experiences. It is important that these individuals get
an opportunity to walk the process so they get an understanding of what they are dealing with in terms of how the
process is run on a daily basis.
Mycoplasma
Viral Contamination
Identity
Acidic Variable Levels
Yield
Concentration Assay
Purity Assay
Visual Appearance
Osmolality
pH
Residual Host Cell Protein
Residual Host Cell DNA
Bioburden
Endotoxin
Viral Clearance
Vial Contamination
Identity
Yield
Concentration
(UV Assay)
Visual Appearance
Osmolaity
9
Viral Clearance
Endotoxin
Bioburden
Purity
pH
9
Mycoplasma
what was the justified total risk score at which action should
be taken based on their knowledge of the product, science,
patients, processes, and materials.
At this stage the RAMM could be sorted and filtered so
that process inputs can be assessed by their impact on a
specific response, by the interim process step, or for their
overall impact on the entire process. Likewise, the matrix
could be filtered to determine which process step or input
factor(s) had the greatest impact on a particular attribute.
The order of cross products for both the rows and columns
were gut-checked with the cross-functional team to ensure
the scoring agrees with their perceptions of the process. The
parameters receiving the highest cross product scores were
checked that they aligned with the cross functional teams
consensus of most important or highest risk parameters.
It can be seen above that for the process step highlighted
and the defined criticality flagging criteria that there were
several criticality points requiring further action. These included:
Step 6 Mitigation
The final point of discussion of the workshop was to assist
in defining which action would help mitigate risk for these
process parameters. The key action defined was around gaining improved process robustness. In order to improve this,
experiments were defined. Additionally, it was indicated that
some changes to the equipment would improve the equipment
setup weaknesses.
At this point, the team was adjourned, any documents
Figure 4. Process parameters with CQAs with risk scores detailed for just one process step (N-1 cell expansion).
Figure 5. Process parameters with CQAs with risk scores detailed for process step (N-1 cell expansion) (after one round of mitigation actions).
Figure 6. Impact of mitigation actions on total process and material risks. Mitigation actions change the risk flags from red to yellow or green.
Conclusion
The RAMM offers a risk analysis tool that may prove useful
to some as the cornerstone of a quality management system.
The authors have found RAMM extremely useful for risk
management for various reasons and these include:
The RAMM neatly handles CQA and CPP (including material attributes and others) parameters in one document
and is easily aligned with latest guidances.
The RAMM is fast; by presenting in a matrix that overlays
CQAs against CPPs (including material attributes and others), it is relatively straightforward to set up and rank.
The RAMM has speed, but is also relatively detailed allowing risk quantification or other risk flags to be identified
in detail.
The RAMM gives excellent overview an entire process can
be printed on just one to two sheets, allowing the overall
process to be very easily explained with detail.
The RAMM is very easy to incorporate into a quality system, follow up on, and make documented changes with.
The authors also have noted some disadvantages to the
RAMM:
The team using RAMM needs to be aligned and have
some knowledge of risk analysis; this is especially true of
scoring numbers as the individual risks are a combination
probability and impact.
If the process is not well understood, the team needs the
experience to realize that some pre-work identifying parameters (such as p-diagrams) are required.
All in all, all risk tools have their value in a risk management
system. It is expected that tools like RAMM will be especially
Notes
The RAMM template is available as free templates and downloadable examples. Please contact the creators Alex Brindle
and David Tiffany for details. The development and testing
of RAMM was greatly helped by the following individuals:
Line Lundsberg-Nielsen, Lene Bjerregaard, and George
Kizhakethil.
Acronyms
CMA
CPP
CQA
FDA
FMEA
FMECA
ICH
PHA
RAMM
References
1. FDA, A Risk Based Approach, Aug. 2002.
2. FDA, PAT Guidance for Industry, Sept. 2004.
3. FDA, Quality Systems Approach, Guidance for Industry,
(draft Sept. 2004).
4. FDA, Pharmaceutical cGMPs for the 21st Century A
Risk-Based Approach, Final Report, Sept. 2004.
5. AIAGs Potential Failure Mode and Effects Analysis
(FMEA) Reference Manual.
6. Ishikawa, K., (Translator: J. H. Loftus), Introduction
to Quality Control, 448 p, ISBN 4-906224-61-X OCLC
61341428, 1990.
7. National Aeronautics and Space Administration, Procedure for Failure Mode, Effects and Criticality Analysis
(FMECA), RA0060131A, 1966.
8. Food Safety Research Information Office, "A Focus on
Hazard Analysis and Critical Control Points," Created
June 2003, updated March 2008.
9. ICH, Pharmaceutical Development Q8(R2), August
2009.
10. ICH, Quality Risk Management Q9, September 2006.
11. ICH, Pharmaceutical Quality System Q10, June 2008.
12. FDA, Process Validation: General Principles and Practices, January 2011.