You are on page 1of 10

Published on IVT Network (http://www.ivtnetwork.

com)

Quality Risk Management and Qualification—A Maturing Partnership with Real


Patient Benefits

By Aidan Harrington Dec 21, 2015 8:00 am PST

Peer Reviewed: Risk


ABSTRACT

Quality Risk Management (QRM) implementation has proven benefits in supporting the scope of qualification and validation
activities for projects and for on-going operations. A formal QRM approach in the site qualification program has multiple
benefits, beginning with capital program delivery efficiencies through operational excellence benefits throughout the product
lifecycle. A model for a best practice commissioning and qualification (C&Q) approach is presented. A cornerstone of this
model is the application of QRM in the early stages of system design, which is driven by the need to ensure that risks to
product quality and patient safety are identified and mitigated prior to system construction. The implementation of a robust
change management program and the application of Good Engineering Practices along with QRM principles are the primary
tools that underpin a successful C&Q program. However, the benefits of effective QRM implementation at this early stage go
far beyond the benefits to C&Q program efficiencies.

This paper describes an application of QRM principles to a C&Q case study and an assessment of the benefits of the
approach. The case study describes the implementation of isolator technology in an aseptic filling system. This technology
requires controls for critical aspects of the system. The lifecycle for identification of system critical aspects is described. The
risk assessment process for the system is described. A listing of potential failure causes related to isolator sterility failures
follows. Once the failure modes and causes were identified, likelihood and severity scores and determined the associated
level of risk. Determination of risk controls required to reduce the identified risks to an acceptable level followed. New
controls were a combination of design solutions and procedural controls. Some example risk controls are described. The
output of the risk assessment was incorporated into aspects of the equipment design. The outputs of the risk assessment
effort and the identification of risk controls provided the basis for a streamlined and focussed qualification effort in contrast to
the traditional C&Q program. The key benefit is that the qualification effort becomes focused on the critical aspects of the
system identified through the risk control process.

While the process described sets out with the objective of identifying critical aspects of a system to support the C&Q program,
other significant benefits included enhanced process understanding from concept design, an overall control strategy for
product, and general operational excellence. Projects performed using this model also accrued significant cost reductions
versus a traditional C&Q approach.

INTRODUCTION

“Risk has become the new lens which to view the world” as stated in a 2002 article on the attractions of risk-based Regulation
(1). Since the publication of ICH Q9 in 2005 (2), the lens through which we view all aspects of pharmaceutical operations has
evolved to varying degrees of maturity with risk management principles in mind. ICH Q9 set out to facilitate continual
improvement of process performance and product quality throughout the product lifecycle which was further developed with
the publication of ICH Q10 (3). The potential benefits of effective Quality Risk Management (QRM) implementation in the
pharmaceutical industry are well documented (4), though with known issues and challenges (5). In addition, there is also a
recognition that QRM implementation is not in all cases effective in the context of delivering safer medicines to the patient (6).

QRM implementation has proven benefits in supporting the scope of qualification and validation activities for projects and on-
going operations. The 2011 FDA Process Validation Guidance document brought together all the elements of Process
Validation in alignment with the principles of ICH Q8, 9, and 10 (7). For Stage 2 (Process Qualification), the plan “
should consider the requirements of use and can incorporate risk management to prioritise certain activities and to identify a
level of effort in both the performance and documentation of qualification activities.” The EU GMP’s require that a risk
assessment approach be used to determine the scope and extent of validation (8). The application of a formal QRM approach
to identify the scope of the qualification program has multiple benefits, beginning with capital program delivery efficiencies
through to operational excellence benefits throughout the product lifecycle.

This paper will discuss the application of QRM principles to a commissioning and qualification case study and an assessment
of the benefits of the approach.

CURRENT COMMISSIONING & QUALIFICATION (C&Q) BEST PRACTICES.

A model for a best practice C&Q approach is presented in Fig 1 below (9). This model represents current industry best
practice, and is grounded on the principles outlined in ASTM E2500 (10) and the ISPE Good Practice Guide on Applied Risk
Management for C&Q (11). A cornerstone of this model is the application of QRM in the early stages of system design, which
is driven by the need to ensure that risks to product quality and patient safety are identified and mitigated prior to system
construction. The implementation of a robust change management program and the application of Good Engineering
Practices are, along with QRM principles, the primary tools that underpin a successful C&Q program. However, the benefits of
effective QRM implementation at this early stage go far beyond the benefits to C&Q program efficiencies.
Image not found
file:///var/www/ivtnetwork.com/current/sites/default/files/u2255/Harrington-Fig-1_0.png

FIGURE 1. C&Q PROGRAM DELIVERY MODEL (9)

ASTM E2500-13 defines critical aspects of manufacturing systems as “… functions, features, abilities and performance or
characteristics necessary for the manufacturing process and systems to ensure product quality and patient safety. They
should be identified and documented based on scientific product and patient safety.” Through this definition, ASTM E2500-13
has provided the industry with what is now a globally used term that is well understood in the context C&Q program delivery,
and also the understanding that the application of QRM principles is the means by which these critical aspects are identified.

EU Annex 15 (8) states in that “The specification for equipment, facilities, utilities or systems should be defined in a URS
and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks
mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.” Critical aspects
of systems should be identified through a risk assessment process at a very early stage of the project in order to support the
development of User Requirements. However, this is challenged by the need to have the required level of process knowledge
and understanding as in their absence, outcomes may be significantly different (12). It is appropriately stated by the
Pharmaceutical Inspection Convention / Pharmaceutical Inspection C0-Operation Scheme (PIC/S) that “Common sense and
an understanding of pharmaceutical processing go a long way towards determining what aspects of an operation are critical”
(13). For novel and complex systems where new technology is being implemented, this challenge is even greater. While the
process depicted in Fig 1 implies a parallel risk assessment and URS development process, it is clear that where there is
limited process understanding (e.g., new technologies), such exercises may not add value if performed using a risk tool like
FMEA that presupposes a high level of process knowledge. The consequence of implementing such a tool can result in an
overly complicated C&Q effort, undermining the overall approach by the project team. Other risk tools, such as Preliminary
Hazard Analysis (PHA), are a better fit for use early in the process or system design where there is minimal data available.
PHA allows risks to be considered early in the lifecycle and is useful to define the scope of a complex system or process and
prioritising risk hazards (2). The PHA tool is however not without its limitations. For example, there is no formal requirement
to identify controls that are relevant to the risks or hazards in question. A “one size fits all” approach to risk tool selection is
not appropriate and the timing for the determination of critical aspects of systems needs to be considered as part of C&Q
planning.
CASE STUDY. RISK ASSESSMENT FOR ASEPTIC FILLING SYSTEMS INCORPORATING ISOLATOR TECHNOLOGY

The use of isolator technology is now widespread throughout the biopharmaceutical industry. Described for a number of years
now as advanced aseptic technology (14), it provides an enhanced sterility assurance over conventional filling processes.
From a technical perspective, isolator technology is now well understood and continues to evolve; for example, technologies
associated with vaporised hydrogen peroxide (VHP) decontamination allow for significantly shorter cycle times and therefore
greater operational efficiencies around manufacturing timelines (15). Closed (with no mousehole or exit where product is
discharged) isolated filling systems for nested tubs of vials, cartridges, and syringes are now available that are operated
without gloves and using robotic technology commonly used in other industries (16).

These developments are being driven by future market requirements for the aseptic filling of low volume, high value, and / or
cytotoxic products with greater flexibility in the manufacturing environment. It is clear that in the not too distant future, the
moniker of “conventional filling” will apply to what is now referred to advanced aseptic processing using isolator technology
due to the rapid advances in this area of aseptic manufacturing. In this case study, the identification of the critical aspects of
an isolator system are identified.

System Critical Aspects Risk Assessment and Design Lifecycle

The critical aspects risk assessment is the process used to identify the critical aspects of a system in order to ensure that
sufficient controls are in place to minimize the risk to the patient. Figure 2 illustrates the Critical Aspect lifecycle, which
reflects the C&Q model presented in Fig 1.

Image not found


file:///var/www/ivtnetwork.com/current/sites/default/files/u2255/Harrington-Fig-2.png

FIGURE 2. CRITICAL ASPECTS LIFECYCLE

The identification of the critical aspects of a system should be performed in parallel with URS development (8). In a cost and
schedule-driven capital project environment, this exercise requires planning, as there is a need to engage with vendors of long
lead time items at a very early stage and place orders as quickly as possible. Performing critical aspect assessments
presents a challenge purely from the perspective of having the resources in place at such an early stage of the project
program. As the objective of the critical aspects risk assessment is to ensure that prospective vendors will include these risk-
mitigating elements in their design, the earlier in the design lifecycle that it is performed, the more effective the exercise
becomes.

Risk Assessment Process

For the filling of parenteral products using isolator technology, the product CQAs are used as the basis for performing the risk
assessment. For each CQA, the identification of associated process failure modes and causes allows risk reduction measures
to be identified to eliminate, contain, reduce or control the potential failures (Fig 3). Clearly this method requires a deep level
of process understanding. In the absence of this, the potential for uncertainty to bias the risk assessment is likely, as stated in
ICH Q9 “Uncertainty is due to the combination of incomplete knowledge about a process and its expected or unexpected
variability” (2).
Image not found
file:///var/www/ivtnetwork.com/current/sites/default/files/u2255/Harrington-Fig-3.png

FIGURE 3. OVERVIEW OF RA PROCESS

For failure to preserve the aseptic environment, a list of potential failure causes is presented in Table 1 below that could apply
to any isolator system with a vaporised hydrogen peroxide (VHP) biodecontamination process. These causes were identified
by a multi-disciplinary team in a 2014 risk assessment prior to the procurement of a new integrated isolator filling line for a
lyophilized product.
Image not found
file:///var/www/ivtnetwork.com/current/sites/default/files/u2255/Harrington-Table-1.png

TABLE 1. LIST OF POTENTIAL FAILURE CAUSES RELATED TO ISOLATOR STERILITY FAILURE MODE

Once the failure modes and causes were identified, the team assigned likelihood and severity scores and determined the
associated level of risk. The determination of risk controls required to reduce the identified risks to an acceptable level was
the next step, bearing in mind that the amount of effort used for risk control should be proportional to the significance of the
risk. In doing so, as presented in ICH Q9, it is also about finding the appropriate balance among benefits, risks and resources
in addition to assessing that new risks are not introduced as a result of identified risks not being controlled. 0’Donnell et al.,
(17), highlight another aspect of risk control which is to ensure that risks are maintained to an acceptable level.

Based on the failure causes identified in Table 1, the team determined that the controls would be a combination of design
solutions and procedural controls, e.g. cleaning and sanitization procedures for Isolator set-up prior to load placement and
biodecontamination. With respect to the overall system lifecycle as presented in Fig 1 above, the output of the risk
assessment is a key step required to support URS development. This ensures that the proposed controls and design solutions
are incorporated into the design, and can be traced through a formal design review process at key design development
milestones. This process fulfils the associated requirements of EU Annex 15 (8) as highlighted in above.
Example of controls for some of the failure causes identified are presented in Table 2. As can be seen from the examples
provided, a pre-requisite for a successful outcome is a level of process understanding and knowledge of the system under
review. In a situation where this in not present or available, the determination of appropriate controls will possibly be
unsuitable or inappropriate. While the controls identified below are in some cases very specific, it may be that the vendor
provides alternative but equivalent controls, which is appropriate and takes in account the rapid advances being made with
respect to isolator technologies.

Image not found


file:///var/www/ivtnetwork.com/current/sites/default/files/u2255/Harrington-Table-2_0.png

TABLE 2 – EXAMPLE RISK CONTROLS

With respect to the overall system lifecycle as presented in Fig 1 above, the output of the brainstorming risk assessment
exercise is a key step required to support URS development. This will ensure that the proposed designed solutions are
incorporated into the design, and can be traced through the design review process at key design development milestones. The
process also provides a traceability tool from design through to testing. This process also fulfils the applicable requirements of
EU Annex 15 (8) as highlighted above.

Outputs of Risk Control Identification

The outputs of the risk assessment effort and the identification of risk controls provide the basis for a streamlined and
focussed qualification effort in contrast to the traditional C&Q program. The key benefit is that the qualification effort becomes
focused on the critical aspects of the system identified through the risk control process. In a paper by Dolign (18), the process
for critical aspect identification through risk assessment was presented as outlined in Fig 3. This paper also highlighted that
the specific type of assessment methodology is not as important as the identification of the risks and their associated control
strategies.

Image not found


file:///var/www/ivtnetwork.com/current/sites/default/files/u2255/Harrington-Fig-4.png

FIGURE 4. IDENTIFICATION OF CRITICAL ASPECTS THROUGH RISK ASSESSMENT

While the process described above sets out with the objective of identifying critical aspects of a system to support a best in
practice C&Q program (11), other significant benefits of this approach are as follows and are address in detail further below:

Enhanced Process Understanding from Concept Design


Is a basis of an overall Control Strategy for a product
Supporting Delivery of Operational Excellence

Enhanced Process Understanding. Oftentimes, the level of experience and understanding of a system will vary significant
amongst multi-disciplinary team members at the outset of the project program and risk assessment process. However,
following the analysis required to determine the critical aspects of the system that process understanding deepens. The
output of the brainstorming and risk assessment sessions will form the basis of the URS for the system. On receipt of design
documentation from the vendor (e.g. P&ID’s, Functional Design Specifications, Hardware and Software Design
Specifications), a design review process should be performed to assess if the risk controls identified are incorporated into the
design. This requirement is called out in EU Annex 15 as follows: “The requirements of the user requirements specification
should be verified during the design qualification” (8). Throughout these processes, the understanding of the system by the
overall group develops significantly in terms of how a complex system such as an isolator is designed and controlled,
specifically with respect to product quality and patient safety. This additional process understanding manifests itself throughout
the project and product lifecycle in many different ways, beginning with a more efficient and robust project start-up program. In
the European Medicines Agency 2014 Guideline (19) on Process Validation for Finished Products, it states that ‘the guideline
does not introduce new requirements on medicinal products already authorised and on the market, but clarifies how
companies can take advantage of the new possibilities given when applying enhanced process understanding coupled with
risk management tools under an efficient quality system as described in ICH Q8, Q9 and Q10. The output of a critical aspect
assessment significantly enhances understanding of the system, well before the system construction is completed and product
is actually produced.

Basis of an Overall Control Strategy for a Product. The guidance documents from both the FDA and EU on process
validation are very consistent in their expectations from industry; that organizations adopt a lifecycle approach whereby the PV
exercise is not seen a one-time event (20), and that the focus stays on maintaining a state of control. In order to achieve this,
organisations need to understand and assess what needs to be controlled. ICH Q10 (3) identifies the enablers of the ability to
establish and maintain a state of control as both Knowledge Management and Quality Risk Management. Consider the
process of identifying critical aspects of any system, the initial brainstorming, the identification of risks to the product critical
quality attributes and their associated controls, and the follow on design reviews to establish that the required controls are put
into place. While intended at the outset as a deliverable to support the C&Q program of a capital project, it is apparent that
perhaps the unintended benefits of this knowledge gathering process are perhaps more relevant. In terms of delivering a
lifecycle approach to PV, applying a QRM approach to critical aspect determination fulfils regulatory compliance objectives
very effectively.

Supporting Delivery of Operational Excellence. In a PDA commentary by Calnan et al. (21), the authors identify the
opportunities for applying the principles of operational excellence in every aspect of business. The attainment of excellence by
manufacturing organizations can be achieved through the application of ICH principles. More broadly, it is apparent that the
capability of an organization to deliver to FDA’s Quality Metrics initiative (22) will be enhanced by applying QRM principles to
establishing the scope of the qualification and validation effort as is an enabler of Operational Excellence delivery.

CONCLUSIONS

From a purely capital projects cost perspective, the benefits a implementing a QRM approach to identify the critical aspects of
systems to support a robust and efficient C&Q program using the model presented in Fig 1 above are evident. Where projects
were performed using this model, cost reductions of 20-50% versus a traditional approach have been reported (9). This is
delivered by a combination of an efficient use of the right resources to focus on critical aspects of systems for qualification and
a more efficient and robust engineering start-up program as a result of greater process knowledge and understanding by cross
functional teams within an organization. However it is arguable that the greatest benefits of this effort are beyond the capital
project delivery effort. The use of a lifecycle approach to pharmaceutical product quality is where the industry is striving
towards. Implicit in this is that organizations have a comprehensive understanding of their product and processes.
Qualification and Validation activities built on QRM process deliver this comprehensive understanding of product and
processes.

REFERENCES

1. B.M Hutter, “The Attractions of Risk Based Regulations: accounting for emergence of risk ideas in regulation.”
The London School of Economics and Political Science: Discussion Paper No 33: March 2005.
2. ICH, Q9 Quality Risk Management, Step 4 version (2005).
3. ICH, Q10 Pharmaceutical Quality System, Step 4 version (2008).
4. PDA, Technical Report No 54: Implementation of Quality Risk Management for Pharmaceutical and Biotechnology
Manufacturing Operations (Bethesda, 2012).
5. J. Brady, “Risk Assessment: Issues and Challenges”, Pharma. Eng. 35(1), 10-20, 2015.
6. K. O’Donnell, PCI/PDA/ISPE Meeting ‘Continuing the Innovation Journey Throughout the Lifecycle – Driving the
Industry Forward’ (Cork, Ireland, 2015).
7. FDA, Process Validation: General Principles and Practices (Rockville, MD, Jan. 2011).
8. EU, Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use: Annex 15:
Qualification and Validation (Brussels, Oct. 2015).
9. R. Brunell, ISPE Annual Meeting (Orlando, Fl, 2010).
10. ASTM, E2500-13 Standard Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment (Conshohocken, PA, Nov. 2013).
11. ISPE, Good Practice Guide: Applied Risk Management for Commissioning and Qualification (Tampa, FL, 2011).
12. H.G. Claycamp, “Probability Concepts in Quality Risk Management” PDA J. Pharm. Sci. and Tech. 66 (1), 78-89, 2012.
13. PIC/S, PI006-3 Recommendations on Validation Master Plan, Installation and Operational Qualification, Non Sterile
Process Validation, Cleaning Validation (September 2007).
14. E.A Isberg, “Advanced Aseptic Processing: RABS and Isolator Operations” Pharma. Eng. 27 (1), 2007.
15. V. Sigwarth and T. Huber, “Trends and Advances in Isolator Technology” Pharma. Eng. 31 (1), 2011.
16. G. Moelgaard, PDA Conference - The Universe of Pre-Filled Syringes and Injection Devices (Vienna, Nov 2015).
17. K. O’Donnell, A. Greene, M. Zwitkovits and N. Calnan, “Quality Risk Management: Putting GMP Controls First,” PDA J.
Pharm. Sci. and Tech. 66(3), 243-261, 2012
18. D. Dolgin, “Commissioning and Qualification (Verification) in the Pharmaceutical Product Process Lifecycle,” Pharma.
Eng. 33 (3), 2013.
19. European Medicines Agency, Guideline on process validation for finished products – information and data to be
provided in regulatory submissions (London, Feb. 2014)
20. G.E. McNally, FDA / PDA Joint Regulatory Conference (Washington D.C. Sept 2015)
21. N. Calnan, K. O’Donnell and A. Greene, “Enabling ICHQ10 Implementation – Part 1. Striving for Excellence by
Embracing ICH Q8 and ICH Q9” PDA J. Pharm. Sci. and Tech. 67(6), 581-600, 2013
22. FDA, Request for Quality Metrics – Draft Guidance for Industry (Rockville, MD, July, 2015).

Source URL: http://www.ivtnetwork.com/article/quality-risk-management-and-qualification%E2%80%94-


maturing-partnership-real-patient-benefits

You might also like