Quality Risk Management (QRM) Considerations for Introduction of New Products 
 
Amarilys Benjamin Rodríguez 
Master in Manufacturing Competitiveness 
Edgar Torres, Ph.D. 
Industrial Engineering Department 
Polytechnic University of Puerto Rico 
Abstract   Quality Risk Management (QRM) is an systems has been recognized in the pharmaceutical 
optional tool to improve product effectiveness and industry and it is becoming evident that quality risk 
safety by assuring that the recognized risk is at a management is a valuable component of an effective 
desired level.  Also risk management tools provide a quality system [1]. Existing guidelines are not 
methodology to evaluate risk levels and prioritize on mandatory but it benefits both the patient and the 
risk mitigation and risk control strategies. For this developer which help identify, assess and mitigate 
design project an evaluation was performed to these risks. 
identify the factors and considerations that could be Quality Risk Management (QRM) is defined by 
adopted from the QRM methodology during the the guide ICH Q9 as a systematic process for the 
technology transfer process and new product assessment, control, communication and review of 
introductions. The technology transfer approach risks to the quality of the drug (medicinal) product 
was used to see possible risks and take on preventive across the product lifecycle. [1]. Therefore QRM 
actions to mitigate risk and avoid to inherit the risks could be a tool to be used since the discovery of a 
throughout product life cycle. ICH Q9 was used as a new product to its development and 
guide for risk assessment during a pilot program on commercialization to mitigate or minimize the 
whole to ICH Q10 Pharmaceutical Quality System. occurrence of any risk associated with the process 
An evaluation was conducted by determining risk during the life cycle of the product. 
prioritization numbers during the different new 
product introduction stages. It was noticed that as PROJECT DESCRIPTION 
the new product introduction process progressed 
This project will consist in the development and 
closer to commercial manufacturing, launch and 
interpretation of possible considerations for the 
distribution, the risk decreased which was a result of 
implementation of quality risk management to 
increased process detectability and reduced 
introducing new products to mitigate the risks 
occurrence. 
associated with product development using 
Key Terms FMEA, New Products, Quality 
technology transfer for maintaining control and 
Risk Management, RPN, Technology Transfer. 
quality during development. 
PROBLEM STATEMENT PROJECT OBJECTIVES 
In order to keep the industry in a competitive 
The project objective is to design and develop 
market the constant development of new products 
considerations for risk assessment methodology 
and processes are necessary. The industry is 
from the early stage of a product life cycle. Project 
regulated by various accrediting agencies to ensure 
Contribution 
the product safety, quality and efficacy. Currently 
Quality: maximize the contribution of QRM in 
there are some trends that are impacting the industry 
the process of introducing new products as part of 
to improve its performance. The quality system is 
the continuous and constant search for improvement 
one of them; industries not only focus on the 
the process of discovering and developing a new 
production of a product, but rather to comply with 
product, to ensure efficient and safe final product 
Good Manufacturing Practices (GMP) to prevent 
any risk to the consumer. The importance of quality 
that meets requirements and regulations from the transfers within or between manufacturing and 
accreditation agencies. testing sites for marketed products.  
 Commercial Manufacturing: Acquisition and 
LITERATURE REVIEW control of materials; provision of facilities, 
utilities, and equipment; production; quality 
   This section will summarize the most relevant 
control and quality assurance; release; storage; 
topics that will give us the key to understanding this 
distribution. 
article. 
 Product Discontinuation: Retention of 
Technology Transfer documentation; sample retention; continued 
The technology transfer (TT) is the documented product assessment and reporting.  [2]  
process for transferring a product developed from The goals of these approaches work together for 
research and development (R&D) through a continual improvement on quality through product 
manufacturing or within or between manufacturing lifecycle, as show Figure 2. The Technology 
and testing sites. This argument reinforces the Transfer (TT) goal is to transfer product and process 
importance to transfer all the information through knowledge between development and 
the development process.  The most transfers start manufacturing, and within or between 
after develop the product, as shown figure 1. manufacturing sites to achieve product realization.  
This knowledge forms the basis for the 
manufacturing process, control, strategy, process 
validation approach and ongoing continual 
improvement [2]. 
 
Figure 1 
Product Cycle Life and Tech Transfer 
Technology transfer is part of the technical 
activities for new and existing products explained in  
ICH Q10 guide.  The purpose of this guideline is Figure 2 
Diagram of the ICH Q10   
applied to product lifecycle activities [2]. 
Pharmaceutical Quality System Model 
 Pharmaceutical Development: Drug substance 
development; formulation development; Quality Risk Management 
manufacture of investigational products; Quality risk management is integral to an 
delivery system development; analytical effective pharmaceutical quality system.  It can 
method development, manufacturing process provide a proactive approach to identifying, 
development and scale up. scientifically evaluating and controlling potential 
 Technology Transfer: New product transfer risks to quality.  It facilitates continual improvement 
during development through manufacturing; 
of process performance and product quality Risk control purpose is to reduce the risk to an 
throughout the product lifecycle.  acceptable level.  The final decision might be 
It is important to understand that product quality obtained by the use of different processes, which 
should be maintained throughout the product includes benefit-cost analysis, for understanding the 
lifecycle such that the attributes that are important to optimal level of risk control.   
the quality of the product remain consistent with Risk reduction focuses on process for mitigation 
those used in the clinical studies.  ICH Q9 provides or avoidance of quality risk when it exceeds a 
principles and examples of tools for quality risk specified level.  It might include actions taken to 
management that can be applied to different aspects mitigate the severity and probability of harm.  
of pharmaceutical quality [1].  Process to improve the detectability of risks might 
Quality Risk Management (QRM) is defined by be used as part of the risk control strategy.  Risk 
ICH as a systematic process for the assessment, reduction implementation reduction measures could 
control, communication and review of risk to the introduce new risk into the system or increase the 
quality of the drug product through the product significance of existing risks. 
lifecycle.  Two primary principles are evaluation of 
the risk to quality should be based on scientific 
knowledge and ultimately link to the protection of 
the patient; and the level of effort, formality and 
documentation should be commensurate with the 
level of risk.  [1] 
Possible steps used to initiate and plan a QRM 
process might include the following [1]: 
 Define the problem and/or risk question.                        
 Assemble background information and/or data 
on potential hazard, harm or human health 
impact relevant to the risk assessment. 
 Identify a leader and critical resources. 
 Specify a timeline deliverables and appropriate 
level of decision making for the risk 
 
management process.  
Figure 3 
Risk assessment consists of the identification of Overview of a Typical QRM Process 
hazards and the analysis and evaluation of risks  Risk Acceptance is a decision to accept risk it is 
associated with the exposure to those hazards.  important to understand that for some types of harm, 
Risk identification is a systematic use of even the best QRM practices might not eliminate 
information to identify hazards referring to the risk risk entirely [1]. 
question or problem description.  Risk Communication is the sharing of 
Risk Analysis is the estimation of the risk information about risk and risk management 
associated with the identified hazards.  It is the between the decision makers and others.  
qualitative or quantitative process linking the  The pharmaceutical industry and regulators can 
likelihood of occurrence and severity of harms. assess and manage risk using recognized risk 
Risk Evaluation compared identified and management tools that could be uses are [1]. 
analyzed risk, against given risk criteria.  It considers  Basic risk management facilitation methods 
the strength of evidence for all three of the (flowcharts, check sheets etc.); 
fundamental questions.   Failure Mode Effects Analysis (FMEA); 
 Failure Mode, Effects and Criticality Analysis and facilities and to analyze a manufacturing process 
(FMECA); in order to identify high risk steps. 
 Fault Tree Analysis (FTA); 
 Hazard Analysis and Critical Control Points METHODOLOGY 
(HACCP); The Methodology used during this project was 
 Hazard Operability Analysis (HAZOP); a combination between DMAIC methodology and 
 Preliminary Hazard Analysis (PHA); Quality Risk Management tools as per referenced 
 Risk ranking and filtering; guidelines.  The DMAIC methodology consisted of 
 Supporting statistical tools. five (5) phases as previously discussed in the 
literature review. The phases consisted on the define 
DMAIC  
phase, the measure phase, the analyze phase, the 
Most of industries or companies implementing improve phase and the control phase.  
Six Sigma utilize the DMAIC methodology to keep During the define phase, a flowchart diagram 
continual improvement. This methodology can be was developed to focus on the product life cycle 
thought of as a roadmap for problem solving and process. The flowchart diagram helps to show the 
product/process improvement.  DMAIC is an actual state of QRM assessment on the process. This 
acronym for five interconnected phases; Define, visual is to help us have a high-level understanding 
Measure, Analyze, Improve, and Control. These 5 of the scope of the process and to give us the key of 
phases can be described as follows: the process. 
 Define the problem, improvement activity, During the measure phase the possible risks 
opportunity for improvement, the project goals, characterizations and its ranking system were 
and customer (internal and external) determined and used for the QRM of the product 
requirements; lifecycle. 
 Measure process performance; During the analyze phase 3 FMEAs were 
 Analyze the process to determine root causes of performed in order to analyze the most critical risks 
variation, poor performance (defects); and their impact through the process.  
 Improve process performance by addressing The improve and control phase will focus on 
and eliminating the root causes; technology transfer strategies to improve and control 
 Control the improved process and future process the risk through the cycle and will be to give us a 
performance [3]. relation between the product lifecycle process and 
the risk priority number. On this step a flowchart was 
Failure Mode Effects Analysis (FMEA) 
developed to show the “after” to use of QRM during 
FMEA provides for an evaluation of potential all product process lifecycle. 
failure modes for processes and their likely effect on 
outcomes and/or product performance.  Once failure RESULTS  
modes are established, risk reduction can be used to 
In this section results obtained will be explained 
eliminate, contain, reduce or control the potential 
and analyzed. 
failures.  FMEA relies on product and process 
understanding.  FMEA methodically breaks down Define Phase 
the analysis of complex processes into manageable 
A technology transfer is the documented 
steps. It is a powerful tool for summarizing the 
process for transferring a product developed through 
important modes of failure, factors causing these 
their lifecycle. This information could to give us a 
failures and the likely effects of these failures [1]. 
parameter to research the critical and priority risk 
FMEA can be used to prioritize risks, monitor 
through all the process or product lifecycle to an 
the effectiveness of risk control activities, equipment 
introductory product. The information will be our RPN = Severity X Occurrence X Detection   (1) 
source to see potential areas to high risk or critical 
Table 1, table 2, and table 3 refer to information 
parameters on the product lifecycle process. The 
about the characterization created to severity, 
product life cycle technology transfer is compound 
occurrence and detection respectively. Table 4 and 5 
to 3 phases; discovery, development and 
is the risk acceptability table that will determine the 
commercial. To help us to identify the areas develop 
risk is tolerated or not. 
process was created a flowchart, as shown the figure 
4.  Table 1 
Severity Classifications 
Ranking  Severity Description  
(Failure would not be noticeable 
1 None  
to the customer) 
(Failure could be noticed by the 
2 Minor  customer but is unlikely to be 
perceived as significant) 
(Failure causes a high degree of 
3 Moderate  
customer dissatisfaction) 
(Failure leads to customer 
perception of safety issue, cause 
4 High  
high degree of patient 
dissatisfaction) 
Extremely (Failure could lead to injury to 
5 
High  customer) 
Dangerously (Failure could lead to death or 
6 
high   permanent injury to customers) 
Table 2 
Occurrence Classifications 
Ranking Occurrence Description  
 
(Failure don’t have probability to 
Figure 4 1 Remote  
repeat, unlikely) 
Flowchart for New Product Lifecycle  
2 Low  (Failure happen infrequently) 
A flowchart is used to a better understand the (Failure happen in a low 
3 Moderate  
process and the relation between the TT, product frequency) 
4 High  (Failure happen frequency) 
lifecycle and the QRM. Actually, the pharmaceutical 
5 Very High  (Failure happen regularly) 
industry is limited to work QRM only with GPM 
regulations. The goal is to show how the QRM Table 3 
assessment could be applied to all the cycle and their  Detection Classification 
Ranking  Detectability Description  
direct relation with risk priority number. 
1 Almost (The defect is obvious, failure 
Measure Certain  can and will detected in all 
cases) 
Risk Assessment/Control Acceptability: 2 High  (Failure is detected by 
automatically inspected) 
Risk Assessment: Based on the QRM principles, 
3 Moderate  (Failure will normally be 
the risk should be based on scientific knowledge and detected with some statistical 
ultimately link to the protection of the patient in programs) 
order to achieve an effective and safe product.  4 Low  ( Failure is detected manually 
inspected in the process) 
Risk Control: The risk associated will be 
5 Remote  (Product is accepted based on no 
evaluated based on the FMEA assessment of defects in a sample) 
severity, occurrence and detectability. 6 Absolute (Failure is not detectable 
Risk Acceptability: Risk priority number (RPN) Uncertainly  because the product is not 
inspected) 
will be used to characterize risk. 
Table 4 Table 6 
Risk Accessibility Table Product Lifecycle FMEA 
occurrence/probability severity/consequences Potential Potential 
Process Failures S O D RPN 
very unlikely to 
1 negligible 1 not impact cause 
unlikely happen Mode 
expected to Unknown Product 
unlikely 2 happen formulation 
cause a minor Developm
infrequently 2 Insufficient 6 4 6 144 
marginal impact in ent 
happen in 3 base of 
occasiona quality unstable 
3 low knowledge 
l 
frequency Specification 
happen cause Unsafe for are being 
moderate 4 1 4 6 24 
frequency 4 significant critical customer developed 
5 impact in R&D unknown 
happen quality 
frequent 5 Test Methods 
regularly severe impact 6 5 6 180 catastrophic 6 being 
in quality 
developed, 
Inefficient 
unknown 
product  
Table 5 damage to Total RPN: 348 
Risk Accessibility Table humans or 
environment 
Failure 
OCURRENCE synthesis and 
Very Moderat Frequen characterizatio
Unlikely Occasional Product 
unlikely e t n Chemically 
SEVERITY Developm
and fiscally 4 3 3 36 
Acceptabl Acceptabl Acceptabl
Negligible ent High High 
e e e unstable 
unstable 
Unknown 
Acceptabl Acceptabl Acceptabl
Marginal High High 
e e e pharmacokinet
Pre- ics (PD) 
Acceptabl Acceptabl
Critical High High High clinical Specifications 
e e 
Unsafe for and 
Catastrophi 3 4 4 48 Acceptabl
High High High High customer characterizatio
c e 
n in process 
Doses are not 
5 4 3 60 
Analyze defined Inefficient 
Pharmacokinet
product  
One (1) FMEA was conducted to characterize ics (PK) Total RPN: 144 
uncertain 
and evaluate the risk through product lifecycle Unknown 
Product process 
process. There are three (3) factors of risk that are 
Developm development 
3 2 2 12 
identified as priority for the process development; ent Problems with 
unstable reproducibility 
stability of product, customer safety and the product the product 
efficiency. To each parameter a ranking was Document do Unsafe for 
Clinical not have the 2 2 2 8 
allocated and assigned according to documentation customer IND approval 
obtained from the process. Dosing ranges 
are being 2 2 3 
The results of the FMEA’s performed are 12 Inefficient developed I 
showed on Table 6. product  and II 
On develop PK Total RPN: 32 
and PD 
Product 
Developm Product 
2 2 2 8 
ent Validated 
unstable 
Launch Safety and PK 
Unsafe for 
data 2 2 1 4 
customer 
satisfactory 
Inefficient Mfg. processes 1 2 1 2 
product  validated Total RPN: 14 
Improve and Control Recommendation 
 
The results demonstrated the direct relation 
Figure 5 
Graphic Result to FMEA between the RPN throughout the product lifecycle.  
As each phase is completed the RPN is reduced for CONCLUSION 
the potential fail mode.  The results are varied 
QRM helped us to understand risk and how 
because the use of technology transfer works to 
critical is the effect on compliance, effectiveness and 
minimize the risk throughout the process. The 
reliability of the product. Technological transfer is 
relation between RPN and all the process is shown 
helpful in order to obtain all the documentation to 
very parallel, where as you go through the process, 
keep the control, stability and quality of the product 
the RPN is reduced and improve the control of the 
during all processes. Also it gives us the necessary 
process and minimize risk.  
tools to prevent, minimize or eliminate the risks that 
affect the product process.   
Kevin & Arthur say on his article “GAMP 5 
Quality Risk Management Approach”: The 
companies need to focus skilled resources where the 
risks are highest, thus minimizing risk to patients 
while maximizing resource utilization and efficiency 
[4].  Definitely the utilization of QRM plays an 
 important role for the industry.  Regrettably the use 
Figure 6 
of this tool is not mandatory to the industry at this 
Flowchart for Technological Transfer to New Product   
time.  
The transfer of documentation on each station 
An evaluation was conducted by determining 
improves the next station to achieve a process 
risk prioritization numbers during the different new 
control, as shown next (figure 6).  The technology 
product introduction stages. It was noticed that as the 
transfer works as a facilitator to control the risk and 
new product introduction process progressed closer 
improve the process.  Using RPN as indicator of high 
to commercial manufacturing, launch and 
risk from the beginning of the cycle, we could obtain 
distribution, the risk decreased which was a result of 
a controlled process.  
increased process detectability and reduced 
Controlling the risk on all phases of the process 
occurrence. 
can reduce the hazards to customer and open a 
pathway to possible continual improvement, as REFERENCES 
shown in figure 7. 
[1] ICH. Quality Risk Management Q9, International Council of 
Harmonization, Step 4 Version, November 2005. 
[2] ICH. Pharmaceutical Quality System Q10, International 
Council of Harmonization, Step 4 Version, June 2008. 
[3] C. M. Borror. (2009). The Certified Quality Engineer 
Handbook (Third Edition) [Online]. Available: 
http://asq.org/learn-about-quality/six-sigma/overview/dmai 
c.html.  
[4] K. C. Martin and A. Pérez. (2008, May/June), GAMP 5 
Quality Risk Management Approach [Online]. Available:  
http://vialis.li/fileadmin/files/imgs/pdf/Newsletter/q1-09/08 
MJ-Martin.pdf. 
 
  
Figure 7 
Flowchart for New Product Lifecycle