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Aseptic Transfer Risk Assessment: A Case Study

Tim Sandle

By May 6, 2015 11:00 pm EDT

Peer Reviewed: Case Study

ABSTRACT
This paper uses one example of a risk assessment approach to illustrate how risk assessment can be incorporated into good
manufacturing controls. The specific activity assessed involves transferring a set of sterilised stoppers from an autoclave to a
filling machine within a sterile manufacturing facility. The risk assessment approach adopted is a form of HACCP (Hazard
Analysis Critical Control Points). Approaches to risk assessments are discussed. Key activities are described.
Documentation is critical. There is no such thing as “zero risk.” A decision is thus required as to what is “acceptable risk. Key
components of HACCP including hazard analysis and critical control points. The “seven pillars” of HACCP are described.
Stepwise activities needed to accomplish the risk assessment are discussed. This case study described a low risk activity.
Rationale for the assessment is described. This discussion described a risk assessment approach using a relatively simple
case to illustrate its potential for other applications.

INTRODUCTION
Risk analysis and risk management are significant considerations in current pharmaceutical manufacturing practices. All
areas and functions in the pharmaceutical manufacturing plant assess level of risk to a process and then take steps to
eliminate that risk. This paper uses one example of a risk assessment approach to illustrate how risk assessment can be
incorporated into good manufacturing controls.

Risk assessment involves identifying risk scenarios either prospectively or retrospectively. The former involves determining
what can go wrong in the system and all the associated consequences and likelihoods; the latter this looks at what has gone
wrong. Risk assessment is then used to assess the process, product, or environmental risk and to aid in formulating the
appropriate actions to prevent the incident from re-occurring (1). The case examined here is a prospective risk assessment.

The case study involves transferring a set of sterilised stoppers from an autoclave to a filling machine within a sterile
manufacturing facility. The risk assessment approach adopted is a form of HACCP (Hazard Analysis Critical Control Points).

APPROACHES TO RISK ASSESSMENT

There are various approaches to risk assessment being used in the pharmaceutical industry. Each has their respective
merits. The use of risk assessment is commonly expected by regulatory authorities (2).

There are various tools that can be drawn upon for conducting risk assessments. Some common methods include FMEA
(Failure Mode and Effects Analysis), FTA (Fault Tree Analysis), and HACCP (Hazard Analysis Critical Control Points). Many
of these employ a scoring approach. No definitive method exists for all applications and different approaches are useful for
different situations (3).

The various approaches differ in their structure and with the degree of complexity involved. Nonetheless, there are some
broad similarities. The different analytical tools are similar in that they generally involve:

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.

Documenting risk assessments is important. When a risk assessment is presented to an auditor, it is likely that the reviewer
will be concerned with whether the risk assessment is traceable to a risk methodology and that the process is clear,
understandable, and that it has been performed consistently. In this sense, the reviewer will want to understand how the
decisions were made and that the risk (or problem) was defined upfront. With the question established, the reviewer will also
wish to see if the process performed actually answered the question in a meaningful way using scientific principles.

Important points to remember for any risk assessment are the following:

There is no such thing as “zero risk.” A decision is thus required as to what is “acceptable risk.”
Risk Assessment is not an exact science - different people will have different perspectives on the same hazard.

Risk assessments should always:

Be based on systematic identifications of possible risk factors

Take full account of current scientific knowledge
Be conducted by people with experience in the risk assessment process and the process being risk assessed
Use factual evidence supported by expert assessment to reach conclusions
Do not include any unjustified assumptions
Identify all reasonably expected risks-simply and clearly, along with a factual assessment and mitigation where required
Be documented to an appropriate level and controlled/approved
Ultimately be linked to the protection of the patient
Should contain objective risk mitigation plan.

Before embarking upon risk assessment it is important to establish and to define:

Develop and agree on the risk question. A clearly defining the risk question facilitates selection of the appropriate risk
assessment tool, identifies relevant data, information and assumptions; assists in the identification of resources,
responsibilities and accountabilities; and ensures that appropriate focus on the business objective is maintained.
Select the most appropriate risk assessment tool. The selected risk assessment method or tool will be used to
organise collected data, understand what steps can be taken to reduce or control risk, and to help make appropriate
decisions.

APPLICATIONS TO CLEANROOM ENVIRONMENTS AND PHARMACEUTICAL

PROCESSES
The primary risk assessment approaches can allow for a complete review of operations within the cleanroom ensuring those
facilities, operations and practices are also satisfactory. The approaches recognise a risk, rate the level of the risk, and then
develop a plan to minimise, control, and monitor the risk. For example, the monitoring of the risk will help to determine the
frequency, locations, and level for environmental monitoring (4).

This case study outlined in this paper uses a modification of the HACCP method, which is sometimes called the “Lifecycle
Approach”. The approach adopted has been used for similar assessments of pharmaceutical processes (5).

There are numerous risk factors to be considered when analysing aseptic processing. The HACCP approach can help to
identify these risk factors. The following factors shown in Figure 1 are useful to note when undertaking HACCP analysis in
pharmaceutical manufacturing.

FIGURE 1: ASEPTIC PROCESSING RISKS

HACCP
HACCP was developed during the 1960’s from collaboration between NASA, a food company (the Pillsbury Company), and
the US Army Natick Laboratories. The objective was to provide a zero-defect food supply for astronauts. HACCP was derived
from Failure Mode Analysis (6). There are two key components of HACCP:

Hazard Analysis: Determining what microbiological, physical, or chemical risks are associated with a process.
 Critical Control Point: A point, step, or procedure at which control can be applied.

HACCP generally involves an assessment of the following conditions – known as the “seven pillars.”

1. Conducting a hazard analysis. List all potential hazards associated with each step, conduct a hazard analysis, and
consider any measures to control identified hazards.
2. Determining the Critical Control Points (CCPs). Critical control points have to be defined as processing steps at which
necessary action can be applied to ensure and maintain compliance with specified conditions. Those points are
identified with appropriate measures that can be applied to control each hazard. If no such critical control points can
be established, product specific validation should eliminate potential risks of a certain process step.
3. Establishing critical limit(s). Establish critical limits for each CCP.
4. Establishing a system to monitor control of the CCP.
5. Establishing the corrective action to be taken when monitoring indicates that a particular CCP is not under control.
6. Establishing procedures for verification to confirm that the HACCP system is working effectively.
7. Establishing documentation and record keeping.

Aspects of these have been utilized in the case study.

In general, the advantages of the HACCP approach are that it allows for a systematic overview of the process for the
evaluation of each processing step, allows each step to be examined the possible risks, and allows for the specification of
measures required for controlling each risk. The primary disadvantage of HACCP is that, unlike FMEA, HACCP cannot be
used to rank or prioritize risks.

CASE STUDY
This case study describes a specific activity within the sterile area of a pharmaceutical manufacturing facility. An autoclave
that is connected to the filling room is unavailable due to a long-term malfunction. The autoclave is used to prepare the
stopper for a sterile injectable product and the need to process an important batch has arisen. The production management at
the facility has decided that stoppers will be sterilised using a different autoclave within the facility and that the sterilised
stoppers will be transported to the filling machine. The stopper swill be loaded by trained operators into a sterilised hopper
drum and wheeled through part of the facility. Putting aside any doubts to the suitability of this process, the quality personnel
have been asked to risk assess the proposed procedure.

DECONSTRUCTING THE PROCESS

Four stepwise activities are needed to accomplish the risk assessment:

A route map. The facility is drawn and the route indicated

Identification of hazards, which can be divided into biological; physical; equipment; transport and chemical. This will
allow an assessment of existing control measures
Process flow
Assessment of environmental monitoring. This will determine if the activity is safe to proceed (7).

Route Map

The first step was to outline a route map. This focused on transporting the stoppers by the shortest and safest route possible
as illustrated in figure 2.
FIGURE 2: ROUTE MAP. Arrows indicate stopper transfer route from autoclaves to filling room

Identification of Hazards

The second step was to understand the hazards and the process. The primary hazards with an aseptic process are biological,
physical, and equipment related (8) as displayed in Table 1.
TABLE 1a: IDENTIFICATION OF HAZARDS
TABLE 1b: IDENTIFICATION OF HAZARDS

Process flow

The third step was to outline the process flow as shown in Figure 3.
Figure 3a: Process flow with CCPs (critical control points) marked. Process flow identifies hazards.
Figure 3b: Process flow with CCPs (critical control points) marked. Process flow identifies hazards.

Environmental monitoring

The fourth step involved assessing dynamic state viable microbiological environmental monitoring and particle counts. If data
have been satisfactory and there are no indications of adverse trends, the proposal can be advanced. If there is a level of risk,
this must be addressed first using appropriate corrective and preventative action. Undertaking an unusual event in a high-risk
situation will compound the problem.

RISK ASSESSMENT – PERFORM A SIMULATION

Before undertaking the activity, a simulation should be performed so that any previously unforeseen problems can be noted
and further preventative measures taken. If any variability is expected, the simulation should be repeated.

The simulation should be timed and the number of staff required noted. The focus should remain on the ease of transit. In
this case study, the duration of the activity is five minutes and the number of staff involved is two.
CONCLUSION
From three possible options -- high risk, medium risk or low risk -- the conclusion of this risk analysis was that the risk level
was low. This evaluation is based on the successful identification of the hazards and control points. The strongest evidence
for this came from the following:

The process being performed by trained clean room personnel operating in an aseptic manner
The autoclaved stoppers being contained within a sealed box. The seal remains intact throughout the transfer
The outlet at the bottom of the box has an integrity tested vent filter
An additional vent filter is placed on the top of the box
The stoppers are wheeled on a trolley which minimises human intervention
The microbiological environmental monitoring for the rooms is satisfactory.

It is important to note the impact of change and to review any risk assessments on a regular basis in developing any risk
assessment.

This case study may or may not be typical. It may or may not be wise for an organisation to undertake such an activity. The
purpose of this discussion was to demonstrate an example of the risk assessment approach using a relatively simple case so
that the wider application can be appreciated.

REFERENCES
1. Sandle, T. (2011): Risk Management in Pharmaceutical Microbiology. In Saghee, M.R., Sandle, T. and Tidswell, E.C.
(Eds.) Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices, New Delhi: Business Horizons,
pp553-588
2. Sandle, T. and Lamba, S. S. Effectively Incorporating Quality Risk Management into Quality Systems. In Saghee, M.R.
(2012) Achieving Quality and Compliance Excellence in Pharmaceuticals: A Master Class GMP Guide, New Delhi:
Business Horizons, pp89-128
3. Sandle, T. (2013). Contamination Control Risk Assessment. In Masden, R.E. and Moldenhauer, J. (Eds.)
Contamination Control in Healthcare Product Manufacturing, Volume 1, DHI Publishing, River Grove: USA, pp423-474
4. 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
5. Munro, M. J., Millar, B. W. and Radley. A. S. (2003): A Risk Assessment of the Preparation of Parenteral Medicines in
Clinical Areas, Hospital Pharmacist, Vol. 10, pp303-305
6. Gavin, A., and Weddig, L.M. (Eds.). (1995): Canned Foods: Principles of Thermal Process Control, Acidification and
Container Closure Evaluation, Food Processors Institute, Washington, D.C., pp5-10
7. Sandle, T. (2006) Environmental Monitoring Risk Assessment, Journal of GXP Compliance, 10(2): 54-73
8. Whyte, W. and Eaton, T. (2004): Assessing microbial risk to patients from aseptically manufactured pharmaceuticals,
European Journal of Parenteral and Pharmaceutical Sciences, 9 (3): 71-79
9. Whyte, W. and Eaton, T. (2004): Microbiological contamination models for use in risk assessment during
pharmaceutical production, European Journal of Parenteral and Pharmaceutical Sciences, 9 (1): 11-15
10. Sandle, T. (2004): General Considerations for the Risk Assessment of Isolators used for Aseptic Processes,
Pharmaceutical Manufacturing and Packaging Sourcer, Samedan Ltd, Winter 2004, pp43-47
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