Using QRM to Assure Lifecycle Process,

Equipment, and Facility Improvement |

IVT
By
Richard L. Friedman
Dec 21, 2015 8:00 am PST

Peer Reviewed: Risk

ABSTRACT
A pharmaceutical manufacturer is responsible for implementing robust daily operations that
consistently yield good quality drugs. This paper discusses how a mature quality system assures a
state of control throughout the product lifecycle by vigilantly managing manufacturing and quality
risks. If the system is working, process and facility vulnerabilities that lead to operational variation
and substandard pharmaceutical quality will be detected, understood, and addressed.
This paper also shares some practical considerations regarding a firms state of control and
application of Quality Risk Management (QRM) when making decisions regarding facilities,
equipment, processes, and raw materials.

INTRODUCTION
The ten year QRM journey travelled by industry and regulators since the 2006 publication of ICH Q9
Quality Risk Management (QRM) has been a fruitful one as many beneficial changes have been
implemented. Industry and regulators had begun discussing QRM even before 2006. Regulatory
efforts such as the FDAs 2002 Pharmaceutical Quality for the 21 Century initiative (1) encouraged
more holistic risk-based approaches to decision making in the area of pharmaceutical manufacturing.
The FDA initiative helped galvanize the still ongoing paradigm shift from reactive quality approaches
to performance and management-based quality. It was widely recognized that a harmonized, lifecycle
based framework was needed to promote large-scale change. This lifecycle approach was developed
in a trio of International Conference of Harmonization (ICH) guidelines (2,3,4) as follows:
st

ICH Q8 objective: Design processes and leverage innovations to improve process

understanding and pharmaceutical quality

ICH Q9 objective: Identify, understand and manage risks throughout the lifecycle through
objective, systematic, science-based decision making

ICH Q10 objective: Design and use an effective quality system to assure ongoing state of
control throughout the lifecycle (applies to both internal and outsourced operations).
A common thread in all of the guidelines was effective management of manufacturing and quality
risks throughout the lifecycle. The guidelines emphasized adaptation and continual improvement in
response to lifecycle learnings, and the value of using contemporary technologies to manufacture
more reliably. Below are a few relevant excerpts:

ICH Q8(R2): Throughout the product lifecycle, companies have opportunities to evaluate
innovative approaches to improve product quality (see ICH Q10).

ICH Q9: Quality risk management is a systematic process for the assessment, control,
communication, and review of risks to the quality of the drug product across the product lifecycle
Once a quality risk management process has been initiated, that process should continue to be
utilized for events that might impact the original quality risk management decision, whether these
events are planned (e.g., results of product review, inspections, audits, change control) or unplanned
(e.g., root cause from failure investigations, recall).

ICH Q10: Use of knowledge management and quality risk management will enable a company
to implement ICH Q10 effectively and successfully. This includes identifying and implementing
appropriate product quality improvements, process improvements, variability reduction, innovations,
and pharmaceutical quality system enhancements, thereby increasing the ability to fulfill a
pharmaceutical manufacturers own quality needs consistently.
Since the publications of these guidelines, there has been a growing understanding of the truly
integral role of QRM, and recognition that the true test of quality system effectiveness is its ability to
properly manage daily manufacturing and quality risks.

THE PATIENT: WHY LIFECYCLE MANUFACTURING CONSISTENCY MATTERS

Successful producers of goods manufacture products that consistently conform to specifications and
manufacturing standards. The pharmaceutical industry has an especially significant role in the world
of manufacturing. Its customer base is comprehensive and its products can have profound impact on
customers lives. We are all patients at some time, and many people including those with chronic
disease are daily customers.
Before a new product is approved, regulators seek confidence of its clinical performance in patients.
The scientific and legal framework is based on safety and efficacy. Given that clinical studies cannot
be done on every batch distributed to the public, suitable surrogates exist in the pharmaceutical
manufacturing world. Specifically, manufacturing practice standards and product specifications are
the quality surrogates that help a company gauge whether in vivo performance may change. In effect,
consistent manufacturing quality allows for the same clinical profile to be delivered for each batch
produced. Measuring adherence to these minimum standards provides crucial feedback throughout
the lifecycle. It determines if the product is fit for use. When a batch is produced that does not
meet these minimum standards, this flags the product as potentially drifting away from the product
proven to be safe and effective.
Of course, there is some uncertainty in identifying the exact point at which a quality problem impacts
safety or efficacy. Similarly, measurements of a products clinical performance also include some
ambiguity. Nonetheless, a failure to meet the minimum standards for pharmaceutical quality

provides a critical trigger in the quality system to evaluate potential consumer risk and take
appropriate steps to return the operation to a state of control.
Medical professionals expect predictable performance throughout a drugs shelf life. The system of
operational controls that are implemented in accord with CGMP (current good manufacturing
practice) are designed to assure that outcome. When systems break down, confidence of predictable
product performance is seriously undermined. QRM should always start and end with the objective of
minimizing risk to patients by employing lifecycle vigilance, and applying science in a practical way to
both detect and promptly solve emerging or existing manufacturing problems.

DAILY QUALITY ASSURANCE: THE IMPORTANCE OF MAINTAINING A STATE OF

CONTROL
The ICH Q10 Pharmaceutical Quality System guidance provides us with the definition of state of
control and the need to assure continued robust performance:
A condition in which the set of controls consistently provides assurance of continued process
performance and product quality (ICH, 2008).
This concept was further developed in the 2011 FDA process validation guidance that elaborated on
the challenge of maintaining a state of controlacross the lifecycle of the product, despite inevitable
variability arising with materials, methods, mother nature, machines, and man:
After establishing and confirming the process, manufacturers must maintain the process in a state
of control over the life of the process even as materials, equipment, production environment,
personnel, and manufacturing procedures change (5).
Dependable manufacturing and reliable quality will be assured on a daily basis if a company is
responsive to manufacturing variation and effectively adapts to maintain a state of control. This
assurance is gained when the set of controls appropriately adapt as commercial manufacturing quality
knowledge is gained.

PROCESS VALIDATION AND LIFECYCLE QUALITY RISK MANAGEMENT

The 2011 FDA PV guidance defines process validation as:
The collection and evaluation of data, from the process design stage through commercial
production, which establishes scientific evidence that a process is capable of consistently delivering
quality product (5).
Two important parts of the definition are capability and consistency. The ability of each unit
operation to meet required manufacturing standards and products to meet specifications can be
evaluated through sound daily batch measurements and periodic process capability assessments.
In effect, if a firms pharmaceutical quality system (PQS) closely monitors intra-batch and inter-batch
variability and takes prompt action to proactively resolve emerging issues, the firm is practicing good
risk management. But if a PQS only reacts to a manufacturing problem after recurring signals of
product quality risk, the system is an immature one that permits substandard practices to occur and
persist.

Regarding only reacting to manufacturing quality problems, W. Edwards Deming stated it best:
Putting out fires is not improvement of the process.
Notably and more than ever, management oversight of operations extends beyond the local site or
corporation and to the larger supply chain. This compels attentive management review and control of
outsourced activities (i.e., CMOs, contract laboratories) and purchased materials throughout the
lifecycle of those partnerships to identify risks to quality.
Knowledge Management Meets Risk Management: Connecting the Dots
Quality Risk Management (QRM) is considered one of the two enablers of an effective quality system.
The other enabler is Knowledge Management (KM). The two work together. Accordingly, the
remainder of this paper will focus on how QRM fundamentally relies on relevant current and
accumulated knowledge to make the right decisions.

INPUTS THAT TRIGGER RISK EVALUATIONS

Meeting the objective of daily quality assurance requires integration of the knowledge gained from
various sources and prompt action to address any meaningful risks. Adverse information -- whether
an individual major event or a potentially important trend -- may trigger a risk review or CAPA
(Corrective Action and Preventive Action). Major sources of relevant data on drug manufacturing
reliability include, but are not limited to (3,4,8,10,12,16):

Non-conformances, deviations, errors, and atypical events

Product quality failures, quality anomalies, and OOS (out-of-specification) results

Complaints

Returns

Recalls

Regulatory findings (local, or at another site in supply chain)

Internal and external audits

Record authenticity (integrity) questions

Stability testing results

Equipment suitability and performance

Facility suitability and performance

Process performance

Raw material variability

Routine review of these and other information sources within the PQS is critical to assure effective
oversight of manufacturing and quality risks. They should not be reviewed alone. Data from different
information sources should be reviewed together as part of a neural network in order to connect the
dots and determine prevalence. Industry has been working on improving these orthogonal
evaluations by developing informatics capabilities that help their expert staff to identify
interrelationships. Recognizing these links is critical as there are often multiple early signals that can
reveal a manufacturing and quality issue. Too often, these opportunities for early detection,
resolution, and hazard prevention are missed due to informatics limitations or other knowledge
management issues. In such cases, unnecessary and costly variation remains in the operation that
poses risks to both quality and supply dependability. Assuring good quality products without supply
shortages is also good business practice for a manufacturer. The quality-business synergy that derives
from vigilantly managing quality to produce medicines reliably and without supply shortfalls is often
discussed but is not well quantified (6,7,9).
In summary, lifecycle QRM means that a company turns various inputs into knowledge that informs
sound decision-making regarding drug manufacturing quality. The strength of an organizations PQS
is greatly based on how well they are connecting these dots.
Lets look more closely at four of the above items that may trigger risk review:
1.

Equipment Suitability and Performance

2.

Facility Suitability and Performance

3.

Process Performance

4.

Raw Material Variability.

Equipment Suitability and Performance

A sites manufacturing Infrastructure must be capable of meeting the processing needs of each
product. When equipment capability is insufficient to reproducibly deliver the quality level needed by
a process step, finished drug quality can be significantly impacted. Incapable equipment is a critical
manufacturing infrastructure issue. Industry managers should identify equipment that is unsuitable
for its intended use at pre-market stage based on process development work, or via scale-up and
qualification batch production. Nonetheless, in some cases, commercial experience has revealed poor
equipment capability to yield consistent output (i.e., delivering the required in-process
attributes). Maintenance data, production deviations, qualification data, and batch data are among
the key inputs for assessing equipment suitability. Notably, the equipment may have been suitable
for older products, but a new product may be introduced that has more demanding quality
requirements (e.g., a low potency tablet), and this more exacting process may demand more capable
equipment.
In other cases, the state of maintenance can be revealing and impactful. A detailed review of
maintenance history and shift logs for a piece of equipment or processing line can often provide very
important practical insights into the reliability of equipment.
In addition, commercial lifecycle experience can reveal excessive equipment vulnerability to manual
interactions. Such manufacturing problems are often attributed to human error. Companies later
found that the human-machine interface was flawed or equipment was frequently breaking down.
The true root cause was determined to be equipment suitability rather than operator incompetence.

This important concept is explained in the recently revised Chapter 1 of the EU GMPs (8),
entitled Pharmaceutical Quality Systems, section 1.4(A)(xiv):
Where human error is suspected or identified as the cause, this should be justified, having taken
care to ensure that process, procedural or system-based errors or problems have not been
overlooked, if present. Appropriate corrective actions and/or preventative actions (CAPAs) should
be identified and taken in response to investigations. The effectiveness of such actions should be
monitored and assessed, in line with Quality Risk Management principles (European Commission,
2013).
Throughout the lifecycle, it is valuable to consider the role of human factors in manufacturing process
variability. There are many opportunities to improve design (e.g., increased automation, closed
systems), work instructions, procedures, and policies. It is common for manufacturers to conduct
shopfloor feedback sessions to learn about difficult to accomplish process steps and obtain ideas on
how operator-equipment interfaces could be improved (13).
Facility Suitability and Performance
Facility suitability is also very influential to manufacturing quality. Examples of facility design and
control problems include lack of suitable materials of construction, architecture, layout (e.g., floor
space, volume, segregation to prevent cross-contamination or mix-ups), utilities (e.g., HVAC systems,
water systems), sanitary piping and instruments, and material / personnel flow.
State of maintenance and technological currency are critical factors in evaluating suitability. Delayed
upgrades or replacement of aging facilities and equipment have been major factors in quality and
supply problems (9,15).
Process Performance
Process performance should be evaluated, in part, through statistical tools. Some examples (3)
include:

Control charts

Histograms

Pareto charts

Process capability analysis

Design of experiments (DOE)

This monitoring of process performance is an integral input to quality assurance, and includes daily
reviews of each batch coupled with routine evaluation of longer-term batch trends. The FDA process
validation guidance discusses the importance of these ongoing evaluations of batch-to-batch variation
to determine state of control:
We recommend that the manufacturer use quantitative, statistical methods whenever appropriate
and feasible. Scrutiny of intra-batch as well as inter-batch variation is part of a comprehensive
continued process verification program.
The process validation guidance also notes that process monitoring should be adapted during the
lifecycle as areas of commercial process risk and variation become more clear: . Process variability

should be periodically assessed and monitoring adjusted accordingly. For example, increased
monitoring at a vulnerable point in the process can lower risk by allowing earlier detection of the
problem.
There are many other inputs mentioned in this paper that provide feedback on process performance
including but not limited to deviations, defects, complaints, returns, and batch specification failures.
Regarding the latter, the FDAs guidance on Out-of-Specification results states:
OOS results may indicate a flaw in product or process design. For example, a lack of robustness in
product formulation, inadequate raw material characterization or control, substantial variation
introduced by one or more unit operations of the manufacturing process, or a combination of these
factors can be the cause of inconsistent product quality. In such cases, it is essential that redesign of
the product or process be undertaken to ensure reproducible product quality (11).
OOS investigations should be monitored by the PQS and trigger management review. From a QRM
perspective, top managers in quality and operations must focus on whether a high quality product is
being consistently delivered to the patient (or a test method is unreliable). When evaluating OOS
investigations, it is essential that these managers critically evaluate whether the appropriate cause(s)
was identified and if corrections were effectively made (14).
Raw Material Variability
Another area of continual learning and lifecycle QRM is raw materials. Raw materials (e.g.,
ingredients, containers, closures) have a substantial learning curve that continues from development
to scale-up to the commercial lifecycle. Raw material variability is a common cause of defects and
recalls. Both tested and untested attributes of raw materials can lead to problems. Regarding the
latter, some attributes of raw materials are not identified or their significance is underestimated, and
the supplier or the dosage form manufacturer does not test them. In some cases, firms have later
found that the unknown or poorly understood material property has led to drug quality failures.
Commercial experience can reveal influential variables not anticipated at the time of development
even when substantial process development studies were done. An effective Quality System will
therefore be sensitive to both direct and indirect changes that could indicate raw material quality
impact. This is accomplished through vendor audits and ongoing quality checks which may include
extra tests beyond those specified in the compendium and normal testing protocols.
The following questions (Table 1 and Table 2) can assist responsible managers in evaluating the state
of control of an operation, and whether improvements need to be made. This information also
provides insight into the continuous learning culture, QRM, and knowledge management mindset of
the facility.

SUMMARY: MANAGING RISK EVERYDAY THROUGHOUT THE LIFECYCLE

An effective quality system will integrate lifecycle QRM to:

Review original risk acceptance decisions as new knowledge is gained

Mitigate risk by designing and adapting operations to ensure they are reliable, and

Assure active engagement of senior management so that state of control of the equipment,
process and facility is maintained and reliable quality is consistently delivered to customers
(patients).
This vigilant and risk-based quality culture assures that every batch, every day, continues to be safe
and effective.
Industry technical organizations, regulatory agencies, and PIC/S (1,16) have made major progress in
promoting implementation of the quality risk management approaches discussed in this paper in both
industrial and regulatory realms. In the coming years, it is hoped that these QRM principles will be
even more widely implemented in industrial quality systems. Ultimately, daily risk management
decisions regarding various sources of variation will determine the quality of the drugs that are
shipped from a given facility.

REFERENCES
1.

Pharmaceutical CGMPs for the 21 Century Final Report 2004

2.

ICH Q8(R2) Pharmaceutical Development (2009)

3.

ICH Q9 Quality Risk Management (2006)

4.

ICH Q10 Pharmaceutical Quality Systems (2009)

5.

FDA. (2011). Guidance for Industry Process Validation: General Principles and

st

Practices

6.

Macher, Jeffrey and Raju, GK. The Business Case for Quality. EU/US/Japan
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International Society of Pharmaceutical Engineers (2011,
2012)http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM28
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7.

Dwyer, T.; Keresty, G.; Sherry, B. The cost of non-conformance: the linkage between
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8.

European Commission. (2013). Chapter 1: Pharmaceutical Quality System. EudraLex Volume 4 Good Manufacturing Practice (GMP) Guidelines, (January 2013), 18.

9.

Woodcock J and Wosinska M. Economic and technological drivers of generic sterile

injectable shortages. Clin Pharmacol Ther. 2013 Feb;93(2):170-6.

10.

FDA. (2006). Guidance for Industry on Quality Systems Approach to Pharmaceutical

CGMP Regulations.

11.

FDA. (2006) Investigating Out of Specification Results for Pharmaceutical Production.

12.

European Commission. (2013) Chapter 7 (Outsourced Activities) and Chapter 9 (Self-

Inspection)

13.

ODonnell, K. (2010). Human Error and Retraining An Interview with Kevin ODonnell,
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14.

Woodcock, J. Reliable drug quality: an unresolved problem, Journal of Pharm Sci

Technol 2012,66(3):270-272 Drug Association

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Friedman, R. Aseptic processing contamination case studies and the pharmaceutical

quality system. PDA J Pharm Sci Technnol 2005; 59(2):118-126

16.

PIC/S Aide Memoire (2012) - Assessment of Quality Risk Management Implementation

17.

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