Quality Risk Management For Pharmaceutical Industry

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The importance of quality systems has been recognized in pharmaceutical industry and the protection of the patient by managing the risk to quality is being given prime importance.

The manufacturing and use of a drug product has some degree of risk. It is important to understand that product quality should be maintained through out the product lifecycle.

Traditionally risk to quality have been assessed and managed in a variety of informal ways for example compilation of observations, trends and other information. These provide information that support topics like handling of complaints, quality defects, deviations etc. Now risk management can be performed with recognized management tools along with support of statistical tools in combination, which make easy for application of quality risk management principles. Risk Management is a process for identifying hazards associated with a product, estimating and evaluating the associated risks, controlling these risks, and monitoring the effectiveness of the control. An effective quality risk management ensures the high quality of drug product to the patient. Inaddition quality risk management improves decision making if a quality problem arises. It should include systemic processes designated to co-ordinate, facilitate and improve science-based decision-making with respect to risk.

Effective quality risk management facilitates better and more informed decisions and provide FDA regulators with greater assurance of a company’s ability to deal with potential risk.

Risk management principles are effectively utilized in many areas of business and development including finance, insurance, occupational safety, public health, pharmacovigilance and agencies regulating these industries. 1 It can be applied to different aspect of pharmaceutical quality including development, Manufacturing, Distribution, Inspection, submission and review processes through the life cycle of drug substances, drug product, biological and biotechnological product (including use of raw material,solvent,exciepient,packaging and labeling.)

Model for quality risk management is outlined in diagram below. 1

Model for quality risk management is outlined in diagram below

Decision-making nodes are not present in diagram because decision can occur at any point in process. Decision might be to return to previous step and seek further information, to adjust risk model or end the risk management process 1

Risk Assessment:

Risk assessment is identification of hazards and the analysis and evaluation of risk related to with exposure to those hazards. As an aid to clearly defining the risk for risk assessment few fundamental are often useful, such as what might go wrong? What is the probability and consequence of wrong occurrence? While doing effective risk assessment, the robustness of the data is important as it determines the quality of outcome. The risk assessment can be either quantitative or qualitative parameter. 1

Risk Management Methods and Tools:

Basic risk management facilitation methods:

The simple technique used to structure risk management by organizing data and facilitating decision-making are flow charts, check sheet, process mapping, cause and effect diagrams.

Failure Mode Effects Analysis (FMEA):

FMEA depends on product and process understanding. It methodically breaks down the analysis of complex processes into manageablesteps. It provides evaluation of potential failure modes for processes and their likely effect on product performance. 2 It can be applied to equipment and facilities and might be used to analyze a manufacturing operation and its effect on product or process. This tool is further advanced with studying criticality of the consequences and providing clear indication of situation. The purpose, terminology and other details can vary according to type ( e.g. Process FMEA, Design FMEA, Health FEMA etc.), the basic methodology is similar for all. 3

Benefits of FMEA

Some benefits of performing FMEA analysis include higher reliability, better quality, increased safety and its contribution towards cost saving includes decreased development time and reduced waste and non value added operations. 4

Cost benefits associated with FMEA are usually expected to come from the ability to identify failure modes earlier in the process, when they are less expensive to address. Financial benefits are also derived from the design improvements that FMEA is expected to facilitate, including reduced warranty costs, increased sales through enhanced customer satisfaction, etc. 4, 5

This Provides a learning tool for new engineers and meets customer requirement and/or to comply with Safety and Quality requirements, such as ISO 9001, QS 9000, ISO/TS 16949, Six Sigma, FDA Good Manufacturing Practices (GMPs), Process Safety Management Act (PSM) 4

Ideally, FMEA is best done in conjunction with or soon after PHA efforts. Results can be used to identify high-vulnerability elements and to guide resource deployment for best benefit. An FMEA can be done anytime in the system lifetime, from initial design onward.

The below given chart 1 describes the pattern of this tool in the maintenance applications and chart II serves as a typical example for problem cause during export of the finished products and its likely effect on the business.

Chart I

Failure Mode And Effects Analysis (Fmea)

Subsystem/Name: DC motor                         Final Design:                          FMEA Date (Org.):

Model Year/Vehicle(s):                                  Prepared by:                           Reviewed by:

P = Probabilities of Occurrences S = Seriousness of Failure    D = Likelihood that the Defect will Reach the customer  R = Risk Priority Measure (P x S x D)   

1 = very low or none                2 = low or minor           3 = moderate or significant                    4 = high            5 = very high or catastrophic



Part Name

Part No.




Mechanism(s) & Causes(s) of Failure


Of Failure





Corrective Action(s)









Measures actual speed

Incorrect speed reading

Wear and tear

Extensive damage









Improve check procedures













Mode of failure

Cause of failure

Effect of failure

Frequency of occurrence


Degree of Severity


Chance f detection


Risk priority


(4) x(5)x(6)

Design action

Design validation

Drug product not delivered on time

Shipping delay from manufacturer

Customer loses time/$













Agent reviews timeline with supplier

Agent initials order form


Missing excipients

Customer loses time/$









Verify components needed for job

Initiate preliminary checklist for job

Assigned values for column 4-6

Column Value












(errors/100 customers











5.Severity for customer







Major time/$



Loss of customer

6.Probability of detection











Failure Mode, Effects and Criticality Analysis (FMECA):

It is the extension of earlier said FMEA tool. Extending FEMA to incorporate an investigation of the degree of severity of consequences, their probabilities of occurrence and their detectability is Failure mode, effects and criticality analysis. 2 In FMECA, each failure mode of the product is identified and then evaluated for criticality. This criticality is then translated into a risk, and if this level of risk is not acceptable, corrective action must be taken.  This can be utilized for failure and risk associated with manufacturing processes. The tool can also be used to establish and optimize maintenance plans for repairable systems and/or contribute to control plans and other quality assurance procedures. In addition, an FMEA or FMECA is often required to comply with safety and quality requirements, such as ISO 9001, QS 9000, ISO/TS 16949, Six Sigma, FDA Good Manufacturing Practices (GMPs), Process Safety Management Act (PSM), etc. 3

When we perform a FMECA, we are identifying all potential failure modes and their associated effects. To make this task more manageable, we must first decide what type of FMECA we want to perform - Design, Process, User, Software, Test, to name a few.

Severity classification    

This classification is assigned to provide a qualitative measure of the worst potential consequences resulting from design error or item failure. Classifications should be assigned to each identified failure mode and each item analyzed in accordance with the loss statements below. It may not be possible to identify an item or a failure mode according to the loss statements in the four categories below, but similar loss statements based on various inputs and outputs can be developed and included in the ground rules for the FMECA activity. Severity classification categories that are consistent with are defined as follows:

  • Category I–Catastrophic—A failure that may cause injury or death.
  • Category II–Critical—A failure which may cause severe injury, major property damage, or major system damage that will result in major downtime or production loss.
  • Category III–Marginal—A failure which may cause minor injury, minor property damage, or minor system damage which will result in delay or loss of system availability or degradation.
  • Category IV–Minor—A failure not serious enough to cause injury, property damage or system damage, but will result in unscheduled maintenance or repair. 13

FMECA's are similar to FTA's. The big difference is an FTA starts with one specific failure effec t and then identifies only those failure modes that can cause the particular effect, whereas a FMECA is trying to identifying all possible failure modes of a product and the effects of these failure modes.


Fault tree analysis (FTA):

This tool assumes failure of the functionality of a product or process. 6 The results are represented pictorially in the form of a tree of fault modes. This can be used to investigate complaints or deviation in order to fully understand their root cause and ensure that intended improvement will resolve the issues and not cause any other different problem. 1 A good example of this tool is provided in the picture below. 7

Fault Tree Analysis 7

Fault Tree Analysis

Hazard Analysis and critical control points (HACCP):

HACCP is a systematic, proactive and preventive tool for assuring quality, reliability and safety. 8 It involves hazard analysis, determining critical control point, establishing critical limit, establishing a system to monitor critical control point and establishing a record keeping system. 1 This might be used to identify and manage risk associated with physical, chemical and biological hazards. 1

Hazard operability Analysis (HAZOP):

HAZOP is a highly structured hazards identification tool. 9

This is based on assumption that events are caused by deviations from the design or operating intentions. 10 Guide words like for example no, more, other than are applied to relevant parameter (eg.contamination, temperature) to identify potential deviation from the design intentions. 1 For example, when the guide word "No" is combined with the parameter "flow" the deviation "no flow " results.

It concentrates on identifying both hazards as well as operability problems. While the HAZOP study is designed to identify hazards through a systematic approach, more than 80% of study recommendations are operability problems and are not, of themselves, hazards. Although hazard identification is the main focus, operability problems should be identified to the extent that they have the potential to lead to process hazards, result in an environmental violation or have a negative impact on profitability.

The purpose and scope of the study should be determined before a HAZOP Study objectives may be to check the safety of the design, decide whether and where to build, check operating and safety procedures, improve the safety of an existing and or modified facility, and verify that safety instrumentation is working optimally 11

HAZOP Methodology includes collection of document and drawing, breaking facility into manageable section, listing out parameters, create deviations, record cause and consequence for each cause, record controls to prevent the cause and list any future action that should be implemented. 9

It is imperative that accurate information associated with the project is sourced and included in the study.  Such information may include provisional layouts,material safety data sheets (MSDS),process flow diagrams, plant model, equipment arrangement drawings, provisional operating instructions,           heat and material balances layouts, logic diagrams, equipment datasheets, hazardous area layouts, and start-up and emergency shutdown procedures. 11

The operation of this tool is depicted

The operation of this tool is depicted in the above diagram. 7

Preliminary hazard Analysis (PHA):

This tool analysis is based on applying prior experience or knowledge of hazard to identify future hazards, hazardous situation. This can be used for product, process and facility design. This can be used in early development of a project where there is little information on detail is available. 1

Preliminary hazard analysis (PHA) is a semi-quantitative analysis that is performed to

 Identify all potential hazards and accidental events that may

lead to an accident, Rank the identified accidental events according to their

Severity and Identify required hazard controls and follow-up actions. 12

A typical PHA worksheet is shown below. 12

A typical PHA worksheet

Risk ranking and filtering:

This can be used to prioritize manufacturing sites for inspection. It is helpful in situation in which portfolio of risks and the underlying consequences to be managed are diverse and difficult to compare using a tool. 1

Statistical tool like histograms, control charts or Pareto charts can aid and facilitate in decision-making along with above-mentioned tools. 1


1.Guidance for industry “ Q9 Quality risk management” by US department of Health and Human Services, Food and drug Administration, Center for drug and evaluation research June 2006.

2. IEC 60812 Analysis techniques for system reliability—Procedure for failure mode and effects analysis (FMEA).

3. FMEA and FMECA An Overview of Basic Concepts and Directory of Other Resources by weibull.com

4.Reliasoft corporations’ xfmea applications and benefits

5.Failure mode effect analysis –Quality training and management by Geoff vorely 26 may 1999

6.IEC 61025 Fault tree analysis (FTA).

7.Risk Assessment: Use and Application in pharma and biotech manufacturing operations by Geoff pilmoor sims moelich associates

8. WHO Technical Report Series No. 908, 2003, Annex 7Application of Hazard Analysis and Critical Control Point (HACCP) methodology to pharmaceuticals

9.DYADEM – protecting people and profitability TM simplified risk analysis solutions

10. IEC 61882 - Hazard Operability Analysis (HAZOP).

11. CSIRO minerals OHS&E Intranet

12. Preliminary Hazard Analysis by Marvin Rausand System Reliability Theory (2nd ed), Wiley, 2004

13. The Complete Guide to the CREby Bryan Dodsonand Dennis Nolan, © 1996 by Quality Publishing

About Author


Mr.Kirupakar .B.R earned his master degree on Pharmaceutics in 2000 at the DR.MGR medical University ( India ) . He is working as senior research officer at Exela Pharmsci Pvt.Ltd., Bangalorewith more focus on Novel Drug Delivery Systems and have great interest in Nanotechnology.

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