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Risk-Based Approaches Facilitate Expedient Validations for Control of

Microorganisms During Equipment Cleaning and Hold
Edward C. Tidswell, BSc, Ph.D.
Eli Lilly & Company

Abstract

Risk management and formal risk assessment represents an efficient vehicle for achieving enhanced quality
assurance and regulatory compliance. One area of pharmaceutical manufacture which benefits especially from
risk-based strategy is validation. Moreover, expedient validation of the control of risks posed by extrinsic
microbial hazards to pharmaceutical manufacture may be achieved through formal risk assessment. For
decades, the food industry has recognized that the attendant uncertainty and variability associated with
microbial hazards is adequately accounted for in such risk assessments. Within routine pharmaceutical
manufacturing operations, the processes of equipment cleaning and hold (pre-clean and post-clean) are
chronically vulnerable to challenge from microbial hazards. Yet simultaneously they demonstrate great potential
for the incidental mitigation of risks realized from these hazards. Validation of the control of microbial hazards
during equipment cleaning and hold processes can be expedited via an orthodox application of formal
objective risk assessment; rationally identifying worst-case conditions. This review introduces these concepts
and the key microbiological and non-microbiological considerations within the risk hierarchy, risk components,
and contributing risk factors fundamental to a risk-based approach to cleaning validation.

Introduction

FDA recognizes that numerous potential sources of risk to the patient population exist in the administration of
drugs (Figure 1). Within this conceptual framework pharmaceutical manufacture is vulnerable to challenge from
a spectrum of hazards. These hazards, if not controlled, may realize a risk to product quality and may ultimately
adversely affect the recipient patient population. It is therefore not surprising that the practical application of risk
management has been formally recognized and actively encouraged by many pharmaceutical regulatory
agencies including FDA [1]. Risk management is now commonly regarded as the next phase in the continued
evolution of GMPs [2]. Effective risk management [3] represents a vehicle through which finite resources can
be directed to mitigate and reduce those risks with the greatest potential to detrimentally affect product quality.
Risk management incorporates a series of definitive activities: risk assessment, risk control, risk
communication, and risk review within an established process flow [3]. Adoption of a riskbased strategy in
pharmaceutical manufacture realizes a number of benefits; beside tangible cost reductions and enhanced
quality assurance risk-based strategy facilitates compliance to cGMPs. It should be stressed that a risk-based
strategy does not obviate the manufacturer from compliance to legal or regulatory guidance, but rather,
represents a means of efficiently achieving greater compliance and greater patient safety.

The concept of risk management and risk-based strategies is now well recognized within the pharmaceutical
industry with many publications providing contemporary commentary on this subject [4,5]. In contrast, there is a
lack of published guidance or case studies adequately illustrating how risk-based approaches can be applied to

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real-life scenarios. This may be attributable to the fact that translating the doctrine of orthodox risk assessment
into effective, applied risk assessment is significantly more difficult. The risk assessment activity of risk
management represents the ultimate decision tool; permitting the identification and prioritization of activities to
enhance quality assurance and patient safety. Risk-based strategies are especially valuable in the validation of
manufacturing processes. Welch et al. have recently described a succinct risk-based approach to validation;
here Design of Experiments (DoE) is dually incorporated, ensuring that the most appropriate and value-adding
validations are performed to benefit the patient [6]. This article seeks to describe how a riskbased approach is
applied from first principles, moreover how to rationalize worst-case conditions incorporated within a cleaning
validation program.

Hazards and Risks

According to the World Health Organization (WHO), a hazard is, “any circumstance in the production, control
and distribution of a pharmaceutical which can cause an adverse health effect” [7]. Although this definition was
applied in the context of hazard analysis by hazard analysis and critical control points (HACCP; for
pharmaceuticals), this holds true for any pharmaceutical risk assessment technique. Despite the complexity of
pharmaceutical manufacturing operations, only a finite number of hazards truly have the potential to exact a risk
to product quality. However, the means or mechanisms of realizing risks to product quality are infinite. Hazards
can be distinguished into intrinsic or extrinsic hazards. Intrinsic hazards are those integral elements of the
process or systems which have the potential to affect product quality. Often, these are associated with failure of
plant, process, or systems and are discrete and singular events. Contaminants (chemical or biological) may
also be regarded as intrinsic hazards. An example of this might be the microbial load in the manufacture of a
low bioburden active pharmaceutical ingredient or terminally sterilized product. Extrinsic hazards are those
entities or events which are not an integral or pre-designed constituent of the process; generally originating
from outside the manufacturing process stream or operation. These hazards often pose a continual challenge
or risk to a process. Figure 2 summarizes a number of typical intrinsic and extrinsic hazards and their potential
means of exacting a risk to product quality during pharmaceutical manufacture. Recognition of the nature of a
hazard and its means of impacting (risk) product quality are the essential initial steps in conducting a risk
assessment. The outcome from these steps often assist or dictate the choice of the most appropriate risk
assessment technique (e.g., FMEA, FMECA, HACCP, etc).

Risk and The Risk Hierarchy

Risk is defined in the 1999 ISO/IEC Guide 51 as, “a combination of the probability of occurrence of harm and
the severity of harm.” A quantified risk is the arithmetic product of severity and probability; this numerical
quantification of risk (defined as a risk rating or risk score) can be defined by:

Where Rm is the overall risk rating, B is a risk factor value for severity and kP represents those risk factor
values for risk factors which contribute to the probability of the risk. Each risk factor interdependently

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contributes to the risk and hence, risk factor values are necessarily multiplied together. The existence of a
hazard will always represent a risk; risks are neither guaranteed absolute events nor events which will never
occur. A numerical value of a risk as calculated above will therefore exist along a continuum defined by values
of both severity and probability [8]. Each risk can however, be further divided into risk components that are
independent, unrelated but nevertheless integral contributors to the overall risk. Risk components contribute to
the overall risk independently of each other; their numerical values derived as described above are however
additive in the calculation of the overall risk rating or risk score. This hierarchical relationship between hazard,
risk, risk components, and risk factors is illustrated in Figure 3. Identification of the risk hierarchy for any risk
assessment permits clear simplification which aids accurate enumeration of risk. For non-critical situations it is
acceptable to adequately evaluate risk without the division of risk into risk components. However, for critical
manufacturing operations, this is a necessity. An example of the practical utilization of the risk hierarchy is
illustrated in Figure 4. Here, the risk of microbial ingress from a bioburden hazard to the fill and finish equipment
during manufacture of a parenteral product is structured to permit appropriate enumeration of the risk.

Risk Factor Values

There are two challenges faced when embarking upon an orthodox numerical quantification of risk:

1. Identification of appropriate risk factors whose incorporation in the risk equation permits an adequate
numeration of risk. This is only achieved through a thorough fundamental understanding of hazard and risk
posed.

2. Assignment of appropriate values for each risk factor. Risk factor values are necessarily representative of
the perceived magnitude of the risk factor. This is often achieved through empirical derivation or rather based
upon an informed choice of expert opinion. Where feasible risk factor scores should be based upon known
data, or related to specifications or accepted standards [9].

An important concept of the risk equation is that it can encompass both uncertainty and variability [10]. Where
“uncertainty” represents the lack of perfect knowledge of the parameter value, reducible by further
measurements and “variability” represents a true heterogeneity of the population that is a consequence of the
physical system and irreducible by additional measurements [11]. Failure to separate uncertainty and variability
in the analysis of risk may lead to erroneous assessments of risk [12].

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Cleaning Validation - Control of Microorganisms

Throughout the routine operational lifecycle, equipment items used in the manufacture of pharmaceuticals are
particularly prone to challenge from microorganisms. This microbial hazard may risk product quality by initially
accessing the equipment (ingress) and subsequently by proliferating and maintaining a physical presence upon
the equipment surface (retention). In counterpoint, the processes of equipment cleaning and hold (either dirty
or clean) exhibit inherent control over this microbial hazard. Figure 5 illustrates the typical equipment operational
lifecycle, highlighting the risks to equipment from microbial hazards and the inherent control points.
Fundamentally, the equipment cleaning process and clean hold process for equipment are critical for ensuring
equipment items are freed from bioburden and retained in a fit state for subsequent manufacturing operations.
It is at these points in the equipment lifecycle: 1) post-clean (pre-clean hold) and 2) clean hold time, that
validation data must be gathered demonstrating the effective and sustained control over bioburden.

Post-clean Validation

Validation exercises evidencing the control of bioburden after cleaning process must be designed to include
conditions supporting survival of the bioburden challenge. To this end, the following must be considered:

Dirty hold conditions

Cleaning processes

Equipment items

In each of the above, risk assessment assists in the choice of worst-case conditions.

Dirty Hold - Worst-case conditions must incorporate the soiling of equipment items with product and stationing
for a duration of time, which promotes the generation of bioburden in a physiological state most capable of
enduring subsequent cleaning steps. Risk assessment identifying which product supports the highest risk of
microbial retention permits the rationale selection of the worst-case product. The risk of microbial retention can
be separated into individual risk components defining risk of microbial growth, microbial adhesion to surfaces
and the survival of microorganisms. Each of these risk components is dependent upon risk factors
representative of environmental conditions influencing microorganisms and the likely type of microorganisms
present. It is essential to have an understanding of the physiology of microorganisms in the context of
equipment hold to identify the appropriate risk factors. Tidswell [13] has recently described in detail those
salient risk factors, and moreover, a formulaic orthodox means of assigning numerical values. Consideration of
multiple inter-related, influencing risk factors (the “Hurdle Concept” [14]) has long been used within the food
industry to identify and contrive conditions preventing microbial spoilage of food. This risk assessment
represents a similar form of “predictive microbiology” but rather appropriately applied to contrive conditions
sustaining microbial growth and survival. The risk hierarchy for the risk of microbial retention for worst-case
products is depicted in Figure 6.

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The time duration for the stationing of soiled equipment must be optimal for the survival of bioburden in a
physiological state to survive subsequent cleaning. As soiled equipment dries, the solute concentration
increases with attendant reduction in water activity. It is well established that with low environmental water activity
that microorganisms lose viability; during equipment drying the surface-borne bioburden will similarly lose
viability, such that upon complete loss of water there is an overall reduction in bioburden. Furthermore, the
surviving population of microorganisms will not be in the optimal physiological state to survive or advantage
subsequent cleaning processes. Worst-case dirty hold time is highly dependent upon the duration of
equipment drying.

Cleaning Cycle - Worst-case conditions must comprise of the most innocuous cleaning conditions; favoring
the survival and retention of microorganisms upon equipment surfaces. The risk of microbial survival and
retention during cleaning different cleaning cycles can be determined by evaluating the risk of microbial growth;
dependent upon environmental conditions influencing microorganisms. Again, understanding the physiology of
microorganisms; their ability to endure and proliferate, is essential to the choice of meaningful risk factors and
the designation of risk factor values. Consideration of these multiple influencing risk factors is directly
equivalent to the Hurdle Concept [14], which is applied to prevent the spoilage of food. The risk hierarchy for
the risk of microbial retention for worst-case cleaning cycle is depicted in Figure 7.

Equipment Items - Worst-case equipment items are those items which lend themselves to “protecting”
microorganisms, assisting in their survival, and physical retention upon surfaces. Choice of equipment item is
most appropriately achievable by risk assessment.

The risk of microbial retention on equipment items can be separated into individual risk components defining
risk of microbial adhesion and microbial retention during the cleaning process. Each of these risk components
is dependent upon risk factors representative of the physical nature of equipment items influencing microbial
adhesion and “cleanability” of equipment. The risk hierarchy for the risk of microbial retention for worst-case
equipment items is depicted in Figure 8.

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Clean Hold Time Validation

In contrast to the validation of control over microorganisms during cleaning, validating control during storage is
significantly less complex. Worst-case conditions for equipment storage should consider the duration of
storage and the storage environment. Cleaned and dry equipment does not support or promote the survival or
proliferation of microorganisms. The risk that equipment is contaminated with excess bioburden is therefore
related to the rate or risk of microbial ingress. For an effective means of risk assessment describing the
ingress of microorganisms the reader is directed to Whyte [15].

Conclusion

All risk assessments should include, as preliminary steps, the description of the hazards concerned, together
with the associated risk hierarchy. It is the generation of this framework that assists in the choice of the most
appropriate risk assessment tool and the identification of risk factors. Applying this approach within the risk
assessment of equipment, product, cleaning and hold processes facilitates the expedient validation of control
of microorganisms during the equipment operational lifecycle. The responsive and adaptive nature of
microorganisms introduces a dynamic never encountered during the validation of cleaning and hold processes
for chemical residues on equipment surfaces. It is the variability and attendant uncertainty associated with
microbial hazards that makes risk assessment an extremely effective tool in identifying those worst-case
conditions implicit to these validations.

References

1. Anon (2004) Pharmaceutical cGMPs for the 21st Century - A Risk- Based Approach. .

2. Anon. GMP movement to risk management seen. The Gold Sheet 2000; 34 (5): 1-19.

3. Anon (2005) ICH Q9 Quality risk management. EMEA/INS/GMP/157614/2005-ICH. .

4. Vesper, L.J. (2005) Assessing and managing risks in a GMP environment. BioPharm int. 18(3), 46-58.

5. Justicia-Palomares, H. (2003) Establishing a system-risk analysis for the production of parenterals. Eur.
J. Parent. Pharma. Sci., 8(3), 81-84.

6. Welch, K.A., Fung, C.A., Schmidt, S.R. (2004) Risk/science-based approach to validation: a win-win-win
for patients, regulators, and industry. PDA Journal of Pharama. Sci. Technol., 58 (1), 15-23.

7. Anon (2003) World Health Organization. WHO Technical Report Series, No. 908, 99-112.

8. Whyte, W, Eaton, T. (2004) Microbiological contamination models for use in risk assessment during
pharamaceutical production. Eur. J. Parenteral. Pharma. Sci., 9(1), 11-15.

9. Tidswell, E. C. (2004) Risk profiling pharmaceutical manufacturing processes. Eur. J. Par. Pharma Sci., 9
(2), 49-55.

10. Anderson, E. T., Hattis, D. (1999) Uncertainty and variability. Risk Analysis, 19, 47-49.

11. Nauta MJ. Modelling bacterial growth in quantitative microbiological risk assessment: is it possible ?

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Int. J. Food Microbiol. 2002; 73: 297-304.

12. Nauta, M. J. (2000) Separation of uncertainty and variability in quantitative microbial risk assessment
models. Int. J. Food Microbiol., 57, 9-18.

13. Tidswell, E. C. (2005) Bacterial adhesion: considerations within a risk-based approach to cleaning
validation. PDA Journal of Pharama. Sci. Technol., 59(1), 10-32.

14. Leistner, L. (1992) Food preservation by combined methods. Food Res. Int., 25, 151-158.

15. Whyte, W., (2002), “A cleanroom contamination control system,” Eur. J. Par. Pharma. Sci. 7 (2) 55.

Dr. Tidswell is the Sterility Assurance Leader for Eli Lilly and Company Parenteral operations in
Indianapolis. He has worked within bulk active pharmaceutical ingredient and Parenteral manufacturing
operations for human health and animal health products in both technical and validation roles. Specialist
areas of expertise include risk assessment, risk management, aseptic manufacture, cleanroom
management, bioburden control, and cleaning validation. As a microbial physiologist, Dr. Tidswell retains
an active interest in several areas of microbiology which include: bacterial adhesion, quorum sensing,
anaerobes, and microbial recovery from surfaces. Since 1994, he has served on the Editorial Boards of
Letters in Applied Microbiology and The Journal of Applied Microbiology.

To correspond with the author, please contact the editor at: nc@russpub.com

*This article was published in the Nov/Dec 2005 issue of APR, Volume 8, Issue 6, on pages 28-33.

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