Risk Management for Aseptic Processing

Published on: November 1, 2009

Pharmaceutical Technology, Pharmaceutical Technology-11-01-2009, Volume 2009
Supplement, Issue 6

The author discusses the risks involved with aseptic processing, methods and tools
used to identify and control risk, and regulatory guidelines relevant to the risk-
management process.

This article is part of PharmTech's supplement "Injectable Drug Delivery."

Aseptic processes are some of the most difficult processes to conduct in the
pharmaceutical industry. Because of the nature of aseptic processes, sterile
products produced aseptically present a significantly higher risk to the patient
than terminally sterilized products. Because of the high level of risk, an
effective quality-risk-management program is necessary to protect the patient. An
effective risk-management program aids in the careful control of the process,
reducing the risk of contamination as well as wasted effort in controlling
insignificant risks.

What is an aseptic process?

Aseptic processing involves manipulation of sterile components in a carefully

controlled environment using careful techniques to produce a sterile product. While
aseptic processing usually involves filling of final drug product, there are other
types of aseptic processes, including aseptic assembly of devices or combination
products, aseptic crystallization or aseptic precipitation of drug product to
produce a sterile bulk-drug substance, and aseptic formulation of final drug
product.

One thing all aseptic processes have in common is their high level of risk. They
require careful control of the aseptic environment, of personnel practices and
procedures, sterilization of equipment and components, extensive environmental
monitoring, and many other controls. The number of controls required and the severe
consequences of control failure make aseptic processing one of the highest-risk
pharmaceutical processes. Quality risk management is an essential tool in ensuring
product quality.

Quality risk management

Although quality risk management (QRM) is a relatively new concept to the

pharmaceutical industry, it has been used in other industries for many decades,
with some risk-assessment tools dating back to the World-War-II era. The
pharmaceutical industry has been slow to adopt many of these tools because of the
industry focus on regulatory compliance as the driving force for quality. This
traditional compliance-based approach had its drawbacks that became more evident as
the industry became more diverse and sophisticated. A "one-size-fits-all" approach
to quality became increasingly unworkable, leading the US Food and Drug
Administration to develop a quality systems approach to regulation.

The quality systems approach to the pharmaceutical industry was launched on a large
scale with the FDA publication of Pharmaceutical CGMPs for the 21st Century—A Risk
Based Approach in August 2002 (1). This initiative had the ambitious goal of
transforming the FDA regulatory approach to the pharmaceutical industry into a
science-based and risk-based approach with an integrated quality systems
orientation.

In the time since the publication of the concept paper, this initiative has been
largely successful, leading to publication of international guidance documents such
as ICH Q9 Quality Risk Management, and the Parenteral Drug Association (PDA)
Technical Report No. 44 on Quality Risk Management for Aseptic Processes (2, 3).
The publication of ICH Q10 Pharmaceutical Quality System has further enhanced the
risk-based approach to pharmaceutical manufacturing.

There are many potential uses for quality risk management in the pharmaceutical
industry, including:

Determining the scope, complexity, and frequency of internal and external audits
Identifying, evaluating, and communicating the potential quality impact of quality
defects, complaints, trends, and non-conformances
Providing a framework for evaluation of environmental monitoring data
Evaluating the impact of changes to the facility, equipment, or process on product
quality
Establishing appropriate specifications and identifying critical process parameters
during product and process development
Assisting facility design (e.g., determining appropriate material, equipment, and
personnel flows, appropriate level of cleanliness for processing areas)
Determining the scope and extent of qualification of facilities, buildings, and
production equipment and/or laboratory instruments (including proper calibration
methods)
Determining acceptable cleaning validation limits
Determining revalidation frequency
Determining the extent of computerized system validation
Identifying the scope and extent of verification, qualification, and validation
activities
Determining the critical and noncritical steps in a process to assist in the design
of process validation.
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The uses for quality-risk-management tools are nearly limitless. A few examples of
the uses of these tools in aseptic processing include:

Equipment and facility design. QRM tools such as 3-D risk assessment can be used to
identify high-risk equipment and facilities, as well as low-risk equipment and
facilities; this will allow risk-control efforts to focus on eliminating the
highest risks (4). Design of high-risk equipment and facilities can be enhanced
using input from tools such as failure mode and effects analysis (FMEA) and fault
tree analysis to identify potential failure modes. This input allows the equipment
designer to add preventive measures to the equipment design to reduce the
occurrence of, or even eliminate, potential failure modes.
Equipment and facility qualification. QRM tools can be used to identify the
critical aspects of the aseptic processing equipment or facility that need to be
intensively qualified, and the low-risk aspects of the equipment or facility. QRM
tools can also be used to determine the extent and frequency of requalification
efforts.
Change control. QRM tools can be used to identify high-risk equipment and
facilities that need to be maintained under strict change control, as well as the
equipment and facilities that can be placed under a simpler engineering change
management program.
Process validation. QRM tools can be used to identify the key inputs, key process
parameters, and key outputs that need to be monitored and controlled. This allows
for focused process validation that ensures that process parameters that are
critical to product quality are appropriately validated.
What is quality risk management?

Risk is the combination of the probability of harm and the severity of harm. For
the purposes of QRM, it is the risk to the patient that is important, not the risk
to other stakeholders such as government, industry, medical practitioners, etc.

According to ICH Q9, quality risk management is defined as "a systematic process
for the assessment, control, communication, and review of risks to the quality of
the drug product across the product lifecycle" (2).

Some key concepts in this definition are that QRM is a systematic process, and that
it is designed to manage the risks to product quality across the product lifecycle.
The introduction of a systematic process for managing product quality is crucial to
consistently providing a high-quality product to the customer.

ICH Q9 defines the two primary principles of quality risk management as follows:

The evaluation of risk to quality should be based on scientific knowledge and

ultimately link to the protection of the patient
The level of effort, formality, and documentation of the quality-risk-management
process should be commensurate with the level of risk (2).
These principles lead to a need for a formal risk-management program for
manufacturers of parenteral products. Because these products, which include most
biotechnology-derived drugs, bypass many of the body's defense systems, the level
of risk to the patient is significantly higher than in oral or topical products.

The quality-risk-management process

ICH Q9 describes the quality risk-management process. Figure 1 illustrates the

components of the quality risk-management process across the product lifecycle.

figure image
Figure 1: Risk-management process (2). (FIGURE 1 IS COURTESY OF ICH)

Risk assessment. Risk assessment is the first portion of the quality-risk-

management process. It consists of identifying potential hazards, analyzing
hazards, and risks associated with exposure to those hazards. A few key points
about the risk assessment process include:

Risk assessments should be performed by a team of qualified experts from

disciplines such as engineering, quality assurance, validation, and manufacturing,
preferably facilitated by someone familiar with the risk assessment process. This
team should clearly define the risk question. A poorly defined risk question can
lead to lack of focus in the risk assessment.
Three fundamental questions should be answered in the risk assessment: What can go
wrong, how likely is it to go wrong, and how severe are the consequences?
A few of the more popular methods for risk assessment are given in the "Risk
assessment tools" section. These tools share some of the key characteristics of a
risk assessment process:
Systematic identification of hazards referring to the risk question (risk
identification)
Estimation of the risk associated with the identified hazard (risk analysis)
Comparison of the identified and analyzed risk against pre-determined criteria
(risk evaluation).
The output of the risk-assessment portion of the risk-management process is used in
the risk-control portion of the risk-management process.

Risk control. Risk control consists of developing a plan to reduce and/or accept
risks. The purpose of risk control is to reduce risk to an acceptable level. The
formality and effort of risk control should be appropriate for the level of risk.
The following questions should be asked during this phase:

Is the risk level acceptable?

What can we do to reduce or eliminate risks?
What is the right balance between risks, benefits, and resources?
Do the risk control efforts introduce new risks?
A risk control plan may be the output of the risk control process. This plan may be
included in a project plan or validation master plan, as part of the risk-
communication process.

Risk communication. Risk communication is simply that—the communication of risks

between decision makers and other interested parties, either within or outside the
company. This may be done formally or informally, as appropriate for the risk level
of the product and process.

Risk review. Risk review is simply periodic review of risks as part of the ongoing
quality management process. Examples of where formal or informal risk review might
be performed include periodic management review, as part of a change control
program or as part of annual product reviews. However it is performed, risk review
should be integrated into the quality-management system.

Risk-assessment tools

The following is a partial list of some of the risk-assessment tools used in the
pharmaceutical industry. This is hardly a comprehensive list. There are numerous
risk-assessment tools available in different industries and for different functions
within the same industry.

3-D risk assessment. Three-dimensional (3-D) risk assessment is a risk assessment

tool that takes into account a system's distance from the process stream, its
location along the process stream (e.g., active pharmaceutical ingredient [API]
synthesis, and purification, bulk product formulation, sterile filtration, filling
and stoppering, etc.), and the system's complexity (4). This tool is mainly used to
assign a risk level to an overall system. Where appropriate, additional risk
assessment tools may be used to evaluate risks within a pharmaceutical system.
Figure 2 gives a visual representation of the 3-D risk assessment process for a
biotechnology-derived product (4).

figure image
Figure 2: 3-D risk assessment matrix (4). (FIGURE 2 IS COURTESY OF THE AUTHOR)

Failure mode and effects analysis. Failure mode and effects analysis (FMEA) is one
of the most commonly used methods for pharmaceutical risk assessment. It is a team-
based structured risk assessment method that can assign a numerical risk priority
number based on relative perceived risk. A FMEA is dependent on the expertise of
the team members (see Table I).

figure image
Table I: Sample FMEA for fill line change over.

Hazard analysis and critical control points. Hazard analysis and critical control
points (HACCP) is a tool mandated by FDA's Center for Food Safety and Applied
Nutrition for use in the seafood industry and other food processing industries. Its
use in the pharmaceutical industry was described in detail by the World Health
Organization (WHO) in 2003 (5). The seven principles of HACCP include:

Conduct a hazard analysis

Determine the critical control points (CCPs)
Establish critical limits
Establish a system to monitor control of the CCP
Establish the corrective action to be taken when monitoring indicates that a
particular CCP is not under control
Establish procedures for verification to confirm that the HACCP system is working
effectively
Establish documentation concerning all procedures and records appropriate to these
principles and their application.
Table II illustrates an HACCP worksheet for the filling of product into vials for a
hypothetical biotech company.

figure image
Table II: HACCP worksheet (adapted from FDA CFSAN website).

Fault tree analysis. Fault tree analysis (FTA) is a risk-assessment method that
begins with a failure event, and uses logic diagrams to determine the sequence of
events required to cause the failure. FTA is frequently used as a design tool for
critical systems. FTA can be used with other tools such as FMEA to ensure all
failure modes are included and to develop estimates of the frequency of a
particular failure mode.

This tool is excellent for equipment design and commissioning, for determining
procedural controls needed to prevent a failure event, and for determining
qualification and control strategies. With modification, it can also be used to
assign probabilities to each failure mode.

The limitation of this tool is that it requires a large amount of time and effort
to construct properly; it can expand rapidly as more detail is added. It is more
suitable for large, complex systems than for simple systems because of the time and
effort required.

FTA involves the following steps:

Define the failure (undesired event) to study

Gain knowledge of the system—gather a team of experts to analyze the system
Construct the fault tree
Evaluate the fault tree
Develop control strategies for the identified hazards.
Figure 3 shows a partial fault tree diagram for a critical failure—cross-
contamination between two products. The top event represents the failure. Each
subsequent level is connected by a logic gate (AND, OR, etc.). As shown in this
figure, a fault tree diagram can grow rapidly and can become quite complex.

figure image
Figure 3: Fault tree analysis diagram. (FIGURE 3 IS COURTESY OF THE AUTHOR)

Implications of risk assessment on processing

When a process step or other activity is determined to be high risk, what should be
done? These determinations should cause initiation of project activities to reduce
the risk level. However, if reduction is not possible, there should be additional
in-process controls, additional testing, additional training, and so on. In
summary, the organization should expend additional effort to mitigate or control
the risk situation. At the same time, efforts on processes or activities that are
well controlled or do not represent risk can be minimized. For example, a new
purified water (PW) supply was planned for an aseptic processing facility. This PW
supply was to be used as feed water for a water-for-injection (WFI) still, for
initial rinse water for clean in place (CIP) of formulation and filling equipment,
and for make-up of wash solutions for CIP of formulation and filling equipment. WFI
was used for the final rinse of this equipment. Based on these parameters, a 3-D
risk assessment was performed on the PW system, giving the results shown in Table
III.
figure image
Table III: 3-D risk assessment for purified water system.

The overall score determined by this risk assessment is 30, indicating the overall
risk is low to medium. This low overall score indicates that detailed formal risk
assessment methods such as FMEA are not needed for this system. While the overall
risk score indicates few controls are needed, the distance along product stream
score indicates that some engineering controls and in-process controls are
justified. Based on this analysis, the design engineer decides to add an
ultraviolet (UV) system for controlling bioburden, as well as conductivity alarms
to indicate system problems. In addition, periodic monitoring and trending of
system bioburden is justified.

A contrasting example would be an aseptic filler intended for multiproduct use.

This filler is designed for high-speed filling and stoppering of several different
products with rapid changeover. This filler is designed for in-line check weighing,
and for automated CIP and sterilization in place (SIP). A 3-D risk assessment of
this equipment gave the results shown in Table IV.

figure image
Table IV: 3-D risk assessment for aseptic filler.

The risk assessment clearly indicates the filler is a high risk system. Based on
this assessment, design and process FMEAs were performed on the filler to identify
controls to mitigate high-risk items. Table V is a partial example of a process
FMEA used to identify design controls for the new filler.

figure image
Table V: Process FMEA example (system=aseptic filler; process=clean-in-place).

This example shows a small portion of a detailed FMEA for the CIP process for a
critical system (aseptic filler). A FMEA such as this one could be used to put
additional controls into place during design of the system, as well as to identify
critical items that need to be verified during validation.

Implications of risk determination on validation

What are the implications of high-risk processes or activities on validation? When

validating high-risk processes or activities, there should be proportionately
increased sampling, testing, or more rigorous acceptance criteria to provide
greater assurance of process acceptability. The 2008 FDA process validation draft
guidance specifically incorporates the following risk management principles:

"Risk analysis tools can be used to screen potential variables for DOE studies to
minimize the total number of experiments conducted while maximizing knowledge
gained.
"Qualification of utilities and equipment can be covered under individual plans or
as part of an overall project plan. The plan should consider the requirements of
use and can incorporate risk management to prioritize certain activities and to
identify a level of effort in both the performance and documentation of
qualification activities" (6).
The European Union's Guide to Good Manufacturing Practice, "Annex 15," also refers
to the use of risk management in validation and states, "Significant changes to the
facilities, the equipment, and the processes, which may affect the quality of the
product, should be validated. A risk assessment approach should be used to
determine the scope and extent of validation" (7).

How is risk management incorporated into validation? Risk-assessment tools are used
to determine the extent of validation and frequency of validation. A few practical
examples of how risk-management tools are used in validation may be helpful.

Low-risk system. A chilled water system was used to cool a jacketed tank during
formulation of a product prior to sterile filtration. This system contacts the tank
jacket only. The chilled water system was controlled by an off-the-shelf
temperature control system with a chart recorder. A 3-D risk assessment of the
chilled water system gave the results shown in Table VI.

figure image
Table VI: 3-D risk assessment-low risk system.

Because the system is low risk, no qualification was necessary beyond engineering
commissioning of the system. Once commissioned, the system was placed under a
standard PM program, and the chart recorder and temperature controller were
calibrated on an annual basis.

Medium-risk system. A bulk formulation tank was used to compound a parenteral

product before sterile filtration. This tank was connected to a distributed control
system (DCS) that controls mixing speed and temperature according to setpoints
entered by the operator from a local panel in the compounding area. Ingredients
other than WFI were added manually by the operators. WFI was added from a WFI drop
at the mixing tank, which was opened by the operator from the DCS local panel. A
level transmitter connected to the tank indicates the volume of WFI added to the
tank. A 3-D risk assessment of the formulation tank gave the results shown in Table
VII.

figure image
Table VII: 3-D risk assessment-medium risk system.

Based on the risk score of 60, the system was designated as a medium-risk system.
Construction and operation of the formulation tank were verified under installation
qualification (IQ) and operational qualification (OQ) protocols. The compounding
process itself was verified under a performance qualification (PQ) protocol. After
completing IQ, OQ, and PQ, the formulation tank was placed under change control. No
periodic requalification was required, but periodic assessment of the system was
required to ensure it maintained its validated state of control.

High-risk system. An injectable protein therapeutic was not stable in liquid form
and requires lyophilization. The lyophilizer was highly automated, with automated
CIP and SIP, automated moisture content and product temperature monitoring using
pressure rise methodology, and a supervisory control and data acquisition system
containing the lyophilization recipes for each dosage form of the product. Product
was loaded into the lyophilizer by an autoloading system. A 3-D risk assessment of
the lyophilizer gave the results shown in Table VIII.

figure image
Table VIII: 3-D risk assessment-high-risk system.

Based on the risk score of 125, the lyophilizer was designated a high-risk system.
Extensive validation efforts, including computerized system validation (CSV), CIP,
and SIP validation, IQ and OQ including shelf mapping, condenser capacity and
sublimation rate, and other tests were performed to characterize the performance of
the lyophilizer. PQ of the lyophilizer included surrogate lots with site-specific
sampling for moisture content, cake appearance and reconstitution, followed by
media fills and conformance lots for the protein therapeutic. The lyophilizer was
placed under change control with periodic requalification, including shelf mapping
and requalification of the CIP and SIP processes. Media fills were performed using
the lyophilizer on a quarterly basis.
Conclusion

Quality risk management is an essential tool for qualification of aseptic

processes. It is not just a tool for CGMP compliance; it offers real benefits to
the validation process by identifying risks and ensuring that critical risks are
controlled. By focusing managing risks to the patient, pharmaceutical manufacturers
can ensure that the right resources are applied at the right place at the right
time—improving patient safety while eliminating unnecessary validation efforts.

Ed White is a QA validation specialist at Baxter Healthcare Corporation, 1700

Rancho Conejo Blvd., Thousand Oaks, CA, 805.375.6779, ed_white@baxter.com. This
article was first published in The Journal of Validation Technology, Vol. 15, Num.
2, Spring 2009.

References

1. FDA, Pharmaceutical CGMPs for the 21st Century—A Risk Based Appoach (Rockville,
MD, Aug. 2002).

2. ICH Q9 Quality Risk Management, Nov. 9, 2005.

3. PDA, Technical Report No. 44, Quality Risk Management for Aseptic Processes,
2008 Supplement, Volume 62, No. S-1.

4. Oliver, James, J. of Valid. Technol., 14, (5), Autumn 2008.

5. WHO, Annex 7: Application of Hazard Analysis and Critical Control Point (HACCP)
Methodology to Pharmaceuticals, WHO Expert Committee on Specifications for
Pharmaceutical Preparations, Thirty-Seventh Report, Geneva, Switzerland, 2003.

6. FDA, Draft Guidance for Industry—Process Validation: General Principles and

Practices (Rockville, MD, Nov. 2008).

7. European Commission, Enterprise Directorate—General, Working Party on Control of

Medicines and Inspections, Final Version of Annex 15 to the EU Guide to Good
Manufacturing Practice: Qualification and Validation, Sept. 2001.

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