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Risk Considerations for Installation of a New

Autoclave in a Pharmaceutical Manufacturing
Facility

Article June 2015

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Reference: Sandle, T. (2015): Risk Consideratons for Installaton of a New Autoclave in a
Pharmaceutcal Manufacturing Facility, Journal of Validation Technology, 21(1): 1-10
Online: http://www.ivtnetwork.com/artcle/risk-consideratons-installaton-new-autoclave-
pharmaceutical-manufacturing-facility

Risk Considerations for

Installation of a New Autoclave in
a Pharmaceutical Manufacturing
Facility | IVT
By
Tim Sandle, Ph.D.

May 6, 2015 11:00 pm PDT

ABSTRACT
This paper addresses some of the risk considerations that must be evaluated when
replacing a steam sterilizing autoclave within a pharmaceutical processing facility. It
demonstrates the application of Failure Modes and Effects Analysis (FMEA) for
assessment of risk as part of quality risk management. Formal risk approaches
normally share four basic concepts including risk assessment, risk control, risk
review, and risk communication. Risk management is fundamentally about
understanding what is most important for the control of equipment or design quality
and then focusing resources on managing and controlling these aspects. Before risks
can be managed, they need to be assessed. FMEA is a widely used risk assessment
tools. Steps to perform FMEA are identified; questions to be asked are listed.
Criteria for risk assessment must be defined. Either a numerical scoring system or
marker phrases such as high, medium, low may be utilized. Three areas are
evaluated: Severity of the hazard, likelihood of occurrence, and likelihood of
detection. Tables for classifying these aspects are provided. A team approach to risk
assessment is recommended. The risk assessment process is demonstrated using the
example of a steam sterilizing autoclave replacement.

INTRODUCTION
This paper addresses some of the risk considerations that must be evaluated when
replacing a steam sterilization autoclave within a pharmaceutical processing facility.
A cast study format is utilized. In outlining the key risk considerations, the paper
demonstrates a risk assessment approach Failure Modes and Effects Analysis
(FMEA).
 An autoclave is a pressure chamber used to sterilize equipment and supplies by
subjecting them to high pressure saturated steam (1). Autoclaves are used within
pharmaceutical facilities to eliminate microbial cells and spores from within a given
device. Autoclaves commonly use steam heated to 115134C (250 273F). To
achieve sterility, a holding time of at least 30 minutes at 115C, 15 minutes at 121C
(250F) or 3 minutes at 134C (273F) is required (2).

The validation and verification of the sterilization process is well monitored in the
pharmaceutical industry. Operators must ensure that autoclaves comply with
various regulatory guidances and regulations. Nonetheless, the purchase of a new
autoclave and the assessment requires evaluation. An additional dimension is added
when one autoclave is being used to replace another, as with the case study discussed
here. To make such an evaluation, a formal risk assessment is required under the
auspices of quality risk management.

Risk management and risk assessment principles should be applied as early as

possible during the design and construction of steam sterilization devices. The most
critical functions in a steam sterilization device are the steam sterilization of direct
and indirect the product contact parts. A second important aspect relates to air
removal. All of the trapped air must be removed from the autoclave before
activation. Trapped air is a very poor medium for achieving sterility during the
sterilization cycle.

Formal risk approaches normally share four basic concepts, which are listed below:

Risk assessment
Risk control
Risk review
Risk communication.

This paper considers the application of FMEA, failure modes and effects analysis, to
the replacement of a steam-sterilizing autoclave in a pharmaceutical manufacturing
facility.

FAILURE MODES AND EFFECTS ANALYSIS

(FMEA)
Risk management is fundamentally about understanding what is most important for
the control of equipment or design quality and then focusing resources on managing
and controlling these aspects to ensure that risks are reduced and contained. Risks
relate to a situation, event or scenario where a recognized hazard may result in
harm. Before risks can be managed, they need to be assessed (3).

Risk assessment involves identifying risk scenarios. In relation to cleanroom and

clean air design, this should ideally be a prospective exercise rather than in reaction
to a failure. This process involves determining what can go wrong in the system and
all the associated consequences and likelihoods. To achieve this, some kind of risk
assessment tool is required (4).
 Three key definitions are outlined in ICH Q9(5). These help to contextualize what is
meant by risks.

Risk: The combination of the probability of occurrence of harm and the severity of
that harm
Harm: Damage to health, including the damage that can occur from loss of product
quality or availability
Hazard: The potential source of harm.

For engineering systems, one of the most widely used tools for risk assessment is
Failure Modes and Effects Analysis (FMEA) (6).

FMEA is a highly structured approach and can be undertaken through the following
steps:

a) Setting the scope

b) Defining the problem

c) Setting scales for factors of severity, occurrence and detection (see below)

d) Process mapping

e) Defining failure modes

f) Listing the potential effects of each failure mode

g) Assigning severity ratings to each process step

h) Listing potential causes of each failure mode

i) Assigning and occurrence rating for each failure mode

j) Examining current controls

k) Examining mechanisms for detection

l) Calculating the risk

m) Examining outcomes and proposing actions to minimize risks.

STARTING THE RISK ASSESSMENT PROCESS

Before commencing a risk assessment, it is important to define the size and the scope
of the assessment while remaining focused on what is to be achieved, to select the
appropriate team (often an interdisciplinary team is best); selecting and reviewing
the appropriate risk management tool; deciding upon any numerical scale to be used,
and prioritizing the different problems to be addressed.

These steps can be broke down as follows:

 Gathering data through an audit and analysis
Constructing diagrams of work flows
Pin-pointing areas of greatest risk
Examining potential sources of contamination
Deciding on the most appropriate sample methods
Helping to establish alert and action levels
Taking into account changes to the work process / seasonal activities
Using some type of scoring system so that the risk can be ranked and the level of risk
determined.

In doing so the following questions should be asked:

What is the function of the equipment?

What are its performance requirements?
How can it fail to fulfill these functions?
What can cause each failure?
What happens when each failure occurs?
How much does each failure matter? What are its consequences?
What can be done to predict or prevent each failure?
What should be done if a suitable proactive task cannot be found?

These reflective questions help to structure the risk assessment activity.

RISK CRITERIA
It is important to establish the risk assessment criteria as part of the risk assessment
exercise. This is necessary in order to place risks in proportion to one another and
against a universal scale. Without this, it cannot be determined whether one risk is a
greater or lesser problem compared with another, or if a given risk could potentially
result in patient harm.

FMEA may utilitze either a numerical scoring system or marker phrases such as
high, medium, low for quantitation. Marker terms are used in the following
case study.

These terms are applied to three aspects. These are the severity of the hazard; how
likely the hazard is to occur; and whether there are any mechanisms in place to
detect the hazard should it occur. Here:

Severity is the consequence of a failure, should it occur

Occurrence is the likelihood of the failure happening based on past experience
Detection is based on the monitoring systems in place and on how likely a failure can
be detected. Sometimes, a good detection system is described as one that can detect
a failure before it occurs.

When these three are cross-compared, the overall risk can be established. The best
means to do this is through the use of risk filters. These are illustrated in Tables 1
and 2 below.
 Before looking at the risk filter tables, it is necessary to define each of the terms used
to establish the overall risk.

Severity of Impact
High = Patients safety will be impacted
Medium = Potential patient safety issues
Low = No impact on patient

Likelihood of Occurrence
High = 1 failure per year
Medium = 1 failure every 5 years
Low = 1 failure every 10 years

For documentation, the likelihood is as follows:

High = No Documentation
Medium = Incorrect Documentation
Low = Documentation present and correct

Probability of Detection
Low = Will not be detected by in-place systems
Medium = Only one mechanism for detection by existing systems
High = More than one mechanism for detection by existing systems

RISK CLASSIFICATION AND RISK FILTERING

Record the risk classification based upon the impact and likelihood from the table
(Table 1). This is established through the use of a filter (or matrix).

TABLE 1: CLASSIFICATION OF RISK

Risk Priority
Record the risk priority based upon the risk classification and probability of
detection from the table.
TABLE 2: RISK PRIORITY

Risk Process
In formulating the risk assessment a group was assembled consisting of engineering,
validation, microbiology, and the end-users. The process began by identifying the
key risk factors and potential failure modes. These were described as functional
details. Once these were defined, these primary categories were broken down into
sub-steps that are termed sub-functional details.

Once these were selected and agreed, the steps were grouped together. The group
then proceeded to assess the risk for each step, using the FMEA schema outlined
above. This consisted of:

a) Considering the relevance of each sub-functional detail. For example, whether it

could potentially impact upon product quality
b) The possible risk scenarios were considered
c) The severity of impact was then assessed as either high, medium or low,
using the definitions outlined above
d) The likelihood of impact was then assessed, using the same descriptors
e) With the severity and likelihood assessed, the risk class was determined using
Table 1 above.
f) The probability of detection was assessed next
g) Knowing the probability of detection allowed the overall risk priority to be
determined using Table 2 above.
h) The penultimate step was to consider whether any controls or risk mitigation
factors were in place
i) The final step was to reach a conclusion in relation to risk management.

The risk assessment process is outlined in Appendix I using the example of a steam
sterilizing autoclave replacement.

Equipment preparation
The defined loading of the autoclave with equipment to be sterilized in an important
sub-functional detail is in autoclave operation. The relevance of loading an autoclave
incorrectly significantly impacts product quality. Here the risk scenario is an
incorrect sterilization of the load. In this case:
 a) The severity of impact would be high;
b) The likelihood of impact could be medium.

This produces, according to Table 1, a high risk class.

The probability of detection would be low, because the activity is operator dependent
and there are no system aspects that prevent an incorrect load from being prepared.
Therefore, using Table 2, the risk priority is high.

However, in terms of risk mitigation and risk management, a clear SOP can be put in
place and operators can be trained in order to lower the possibility of an incorrect
load being prepared. In addition:

Photos of the loads can be prepared during the Operational Qualification

Schematics may be included in the SOP
Worst-case loads can be verified during both the Operational Qualification and
Performance Qualification.

This example is included in Appendix I. Other sub-functional steps were derived

using similar processes.

RISK EXAMPLE
Appendix I contains an example of risk assessment for a replacement steam-
sterilizing autoclave. The table is arranged in a fashion to facilitate the risk
assessment steps described above where functional and sub-functional steps are
outlined. The case study was designed around a particular device and should be
regarded as illustrative. Users embarking on a similar process may take note of the
items covered. However, they should construct their own risk schematic and reach
conclusions that are relevant to their own particular circumstances.

CONCLUSION

The final assessment of the FMEA risk exercise was that the new autoclave can be
fitted and that the risks are adequately controlled. It was noted that although the
new autoclave has newer control systems technology, the steam sterilization
principles together with the load/ test cycles remain in line with the autoclave that is
being replaced.

The FMEA risk assessment methodology was appropriate to the task. An alternative
approach could have been to use a numerical risk assessment. However, the use of
descriptor words like high, medium, and low proved adequate in relation to the
activity.
 REFERENCES

1. Sandle, T. (2013). Sterility, Sterilisation and Sterility Assurance for

Pharmaceuticals: Technology, Validation and Current Regulations, Woodhead
Publishing Ltd.: Cambridge, UK, pp93-110
2. Hugo WB (1991). A brief history of heat and chemical preservation and
disinfection. J. Appl. Bacteriol. 71 (1): 918
3. Sandle, T. (2011): Risk Management in Pharmaceutical Microbiology. In Saghee,
M.R., Sandle, T. and Tidswell, E.C. (Eds.) (2011): Microbiology and Sterility
Assurance in Pharmaceuticals and Medical Devices, New Delhi: Business Horizons,
pp553-588
4. Sandle, T. and Lamba, S. S. (2012) Effectively Incorporating Quality Risk
Management into Quality Systems. In Saghee, M.R. Achieving Quality and
Compliance Excellence in Pharmaceuticals: A Master Class GMP Guide, New Delhi:
Business Horizons, pp89-128
5. ICH Q9: Quality risk management. International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for Human Use ICH,
Geneva (November 2005)
6. Sandle, T. (2003). The use of a risk assessment in the pharmaceutical industry the
application of FMEA to a sterility testing isolator: a case study, European Journal of
Parenteral and Pharmaceutical Sciences; 8(2): 43-49

FMEA KEY

BI - Biological Indicator

IQ - Installation Qualification

O&M - Operation and Maintenance

OQ - Operational Qualification

PQ - Performance Qualification

PC - Personal Computer

SOP - Standard Operating Procedure

SAT - Site Acceptance Test

UPS - Uninterruptable Power Supply

APPENDIX 1
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