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INTEGRATING RISK BASE MODELING IN MANUFACTURING

TO DRIVE QUALITY DECISIONS

A Project

Presented

to the Faculty of

California State University, Dominguez Hills

In Partial Fulfillment

of the Requirements for the Degree

Master o f Science

in

Quality Assurance

by

Ivette Larralde-Valdes

Fall 2015
ProQuest Number: 10017817

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IVETTE LARRALDE-VALDES

2015

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This work is dedicated to my family, especially to my husband Frank and my son

Alexander, for their support and love.

iv
ACKNOWLEDGMENTS

This project is dedicated to the memory of Peter Amanatides who sponsored this project

and mentored me through most of my work. His commitment to quality inspired me to

grow as a quality professional.

v
TABLE OF CONTENTS

PAGE

TITLE PAGE............................................................................................................................... i

COPYRIGHT PAGE.................................................................................................................. ii

APPROVAL PAGE...................................................................................................................iii

DEDICATION........................................................................................................................... iv

ACKNOWLEDGMENTS.........................................................................................................v

TABLE OF CONTENTS..........................................................................................................vi

LIST OF TABLES....................................................................................................................vii

LIST OF FIGURES.................................................................................................................viii

ABSTRACT.............................................................................................................................. ix

CHAPTER

1. INTRODUCTION..................................................................................................................1

Background.....................................................................................................................1
Statement of the Problem..............................................................................................2
Purpose o f the Study......................................................................................................3
Theoretical Basis for the Study.....................................................................................5
Limitations o f the Study................................................................................................7
Definition o f Terms........................................................................................................ 7

2. REVIEW OF THE LITERATURE.......................................................................................9

Sources........................................................................................................................... 9
Regulatory Requirements: History of the FD A .......................................................... 9
Regulatory and Guidance Documents........................................................................ 11
Quality Risk Management in the FDA-regulated Industry......................................21
Fundamentals o f Risk Management.......................................................................... 22
CHAPTER PAGE

3. METHODOLOGY..............................................................................................................23

Risk Assessment Model Development...................................................................... 34


Integration of the Risk Assessment Model to QRM System .................................. 36
Risk Assessment Model...............................................................................................38
Current System.............................................................................................................39

4. RESULTS AND DISCUSSION......................................................................................... 43

Evaluation o f the Integration of Risk Assessment Model into


the QRM System ....................................................................................................49
Metrics.......................................................................................................................... 55

5. SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS................................... 58

REFERENCES......................................................................................................................... 62

APPENDICES.......................................................................................................................... 68

A: APPLICATION OF RISK ASSESSMENT MODEL........................................ 69


B: AUTHORIZATION COMMUNICATION.........................................................96
LIST OF TABLES

PAGE

1. Current Regulatory and Guidance Documents...................................................................12

2. Excerpts from FDA Warning Letters.................................................................................. 18

3. Current Process Review....................................................................................................... 24

4. Data Collection and Lot Information..................................................................................28

5. FMEA Scale-Risk Priority Number Grading.................................................................... 34

6. 2014-2015 Investigations Opened for Lots Manufactured for

Products A, B, and C ........................................................................................................47

7. Risk Assessment F orm ..............................................................................................48

8. Ratings for Impact Definition.............................................................................................49

9. 2013 Investigations Opened for Lots Manufactured for Products A, B, and C ............. 50

10. Quality Risk Report to Quality Council Form ...............................................................53

11. Quality Goals and Metrics.................................................................................................55

12. Summary of Quality Goals and M etrics...........................................................................57


LIST OF FIGURES

PAGE

1. Risk Management Process - ICH Q 9 .................................................................................15

2. Process M ap ......................................................................................................................... 27

3. Failure Mode and Effects Analysis for the Coating Process............................................31

4. Risk Management Model.....................................................................................................41

5. Risk Management System Workflow.................................................................................54


ABSTRACT

In the pharmaceutical manufacturing industry, it is imperative to have a strong

Risk Management System to assist in identifying product and process risk, evaluate the

risk, and use statistical tools for mitigating risks. While much discussion has taken place

since the issuance o f ICH Guidance Q9, not many companies have integrated this

guidance into their systems for use in decision making.

The Risk Management Model has been created to ensure patients are protected in

terms o f quality, safety, and efficacy. The model is integrated into the organization’s Risk

Management System, ensuring risk-based actions are proactively being assessed and at

the appropriate time. This model has been designed to integrate fully with the Corrective

and Prevention Action system to evaluate and verify the presence of non-conformities

and to devise a strategic plan to correct and prevent their reoccurrence. This model also

can be applied to any process in pharmaceutical manufacturing.


1
CHAPTER 1

INTRODUCTION

Background

It is the goal o f the pharmaceutical manufacturer to establish a robust Quality

System (QS). The QS encompasses the organizational structures, processes, procedures

and resources used to manufacture its products, and these products must be manufactured

in accordance with the applicable regulations. The main objective o f a QS is to provide a

consistent process to manufacture products fit for their intended use, to meet the needs of

the patient, to establish and maintain a state of control, and to facilitate continual

improvement throughout the lifecycle o f the product (International Conference of

Harmonisation [ICH Q10 FDA], 2009). Medical device manufacturers need to ensure

compliance with the QS regulations, as defined by the Federal Drug Administration

(FDA). These regulations are listed in the Code o f Federal Regulation USFDA Title 21

Part 820 (21 C.F.R. § 210) Quality System Regulation (QSR) (USFDA, 2012). For

Europe and several other countries, compliance requirements are listed in the

International Organization for Standardization (ISO) 13485 (ISO 13485,2012).

The key elements o f a Pharmaceutical QS are described in the Medical Devices:

Quality Management: Requirements fo r Regulatory Purposes, published by the ISO (ISO

13485,2012). The QS consists of four key elements:

• Process Performance and Product Quality Monitoring

• Corrective Action and Preventive Action (CAPA)


• Change Management, and Management Review of Process Performance

• Product Quality

Process performance and product quality monitoring systems ensure that

pharmaceutical companies are operating in a state of control. These systems should

provide assurance o f the processes and controls that are in place for the production of

high quality, safe, and effective products. These systems include the risk management

system, referred to as Quality Risk Management (QRM), which is integral to an effective

pharmaceutical QS. The QRM identifies, scientifically evaluates, and controls potential

risks to quality. Quality Risk Management ICH9 provides the guidelines and tools to

effectively apply and establish a risk management process (ICH Q 9 ,2011).

Statement o f the Problem

While many pharmaceutical industries have risk management policies in place as

a result of efforts to align to current industry guidelines, most industries have not

properly institutionalized risk assessment to drive quality decisions pertaining to the

manufacturing process. As a result, the risk assessment documents lose their relevance

quickly if not integrated immediately within the QS; therefore, they could not be used as

tools for decision making. Industries desiring measurable quality improvements need to

go beyond the application o f minimum standards and integrate improvement activities

that focus on meeting quality objectives. Most organizations have been approaching risk

by focusing on risk assessment; however, in order for pharmaceutical manufacturers to

comply with regulatory requirements and to align with current guidelines, a more

complex system is now required. This system is currently called Risk Management. The
purpose of this project was to create a risk-based model to assist in identifying product

and process risks, evaluate the level of risk, and establish a creative method for using

statistical tools to assist in mitigating these risks. This risk management model defined a

process to ensure that errors and risks occurring during the pharmaceutical manufacturing

process were addressed, minimized, and prevented from occurring. This process was

clearly defined by the establishment of a procedure to identify risks and potential risks

and to establish a risk assessment criterion (Pons, 2010). The goal of this project was to

integrate this model into the Risk Management system proactively in order to identify

and control all risks. This type of approach created an innovative, high quality

management system, having a vast impact in the regulated manufacturing pharmaceutical

industry and ultimately protecting the patient by managing the risk to quality. This

system, therefore, should be considered o f prime importance in the manufacturing of

pharmaceuticals.

Purpose of Study

The purpose o f this study was to create a model that could be integrated into the

Risk Management System o f any pharmaceutical manufacturing organization. This model

could become part of the toolkit for quality decision making by connecting Risk

Management to the core quality subsystems (change control, annual product review,

validation deviation management system, complaints, etc.). Quality risk management is

integral to an effective pharmaceutical quality system. It can provide a proactive

approach for identifying, scientifically evaluating, and controlling potential risks to

quality (BSM Consulting, 2011). It facilitates the continual improvement o f process


4
performance and product quality throughout the product’s lifecycle; ICH Quality Risk

Management Q9 provides principles and examples of tools for quality risk management

that are applicable to different aspects of pharmaceutical quality.

Even though additional risk management standards are being developed for

specific industry sectors, research in the literature shows that this approach is not being

implemented currently by manufacturing pharmaceutical industries. For example, the

American Society o f Mechanical Engineers Innovative Technologies Institute LLC

(ASME ITI) has developed the Risk Analyses and Managementfo r Critical Asset

Protection (RAMCAP) for the U.S. Department of Homeland Security (Brashear, 2010).

This guidance document has been created to assess risk analysis and risk management for

critical infrastructure assets (FEMA, 2010).

The type o f approach to risk management proposed in this project would be a

cutting edge, innovative, high quality management system that could have a major impact

on the manufacturing pharmaceutical industry and ultimately protect patients by

managing the risk to quality. This project, therefore, should be considered of prime

importance in the manufacturing o f pharmaceuticals.

The Risk Assessment Model that is the focus of this project used existing quality

practices, requirements, standards, and guidelines within the pharmaceutical industry and

a regulatory environment as its foundation. The implementation of this model could assist

pharmaceutical manufacturing organizations in supporting and maintaining a robust

Quality Risk Management System by:

• Establishing a proactive scientific and data-based system to control all risks.


• Performing a constant review of present quality systems in order to identify
operational deficiencies.

• Enabling a review process for examining the current system and applying
corrective and preventive actions to control risks.

• Developing a contingency plan or control to continually review the process or


system to monitor its progress to that ensure gains and a reduction in errors
are maintained.

The purpose of this project was to implement a model for integrating risk

management as part o f the toolkit for quality decision-making by connecting the Risk

Management System to the overall QS atNoven Pharmaceuticals, Inc. The project was

conducted, using three commercial products manufactured by Noven Pharmaceutical at

its Miami facility. To protect proprietary information, these products were labeled

Products A, B, and C throughout this study.

Theoretical Basis for the Study

Although this project describes the Risk Assessment Model to be integrated into

the Risk Management System, it also covers the establishment of a dynamic risk

management process for ensuring success and compliance. The current regulatory

requirements, ICH guidance documents, ISO risk assessment documentation, and Federal

Drug Administration (FDA) regulations and guidance were used as a basis for this study.

The FDA’s main objective for releasing the guidance document Pharmaceutical cGMPs

fo r the 21st Century was to put a more scientifically-driven QS in place, integrating

quality with risk management and safety considerations (U.S. Food and Drug

Administration [USFDA], 2004). In order to have a robust and compliant quality system

within a regulated industry, having an effective quality risk management approach could
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further ensure the high quality of a product for the customer by providing a proactive

means to identify and control potential quality issues during manufacturing (McCabe &

and Corcoran, 2010).

The manufacturing o f drug products and their components entails assessing all

activities related to product quality and safety. The development of several guidance

documents such as ICH Q8 Pharmaceutical Development (ICH Q8 FDA, 2009), ICH Q9

Quality Risk Management (ICH Q9 FDA, 2011), and ICH Q10 Quality Management

(International Conference o f Harmonisation [ICH Q10 FDA], 2009)has promoted a shift

to creating processes within the pharmaceutical industry that promote process

improvement, innovation, and maintenance of the process in a state of control. All

processes performed within the manufacturing system need to demonstrate with

confidence the ability to fulfill the requirement to manufacture this product. The risk to

quality is just one component of the overall risk, and it is important to understand that

product quality should be maintained throughout the product’s lifecycle. An effective

quality risk management approach provides a proactive means to identify and control

potential quality issues during the manufacturing process. Additionally, the use of a

quality risk management can improve the decision making if a quality problem arises.

This creates a process for assisting in making better and more informed decisions,

providing regulators with greater assurance o f the company’s ability to deal with

potential risks, and beneficially affecting the extent and level of direct regulatory

oversight.
7
Limitations of the Study

The model developed in this study was specifically created for the regulated

pharmaceutical manufacturing process. The facility chosen for the implementation of this

risk-based model was Noven Pharmaceuticals, Inc. The coating process for the laminate

of transdermal samples was the selected process for this model implementation.

Definition of Terms

American Society for Testing and Materials (ASTM): The international association that

develops and publishes international standards for testing.

Change Review Board (CRB1: The cross-functional change review committee

responsible for making decisions regarding whether or not proposed changes are

approved.

Cleaning Process Picture Map (CPPM): A document combining text, pictures, and

symbols to provide standardized instructions for a process used during the cleaning

process o f the 48-Foot coater.

Global Harmonization Task Force (GHTF): Currently called the International Medical

Device Regulators Forum (IMDRF), this organization-composed o f regulatory officials

from all over the world-provides guidance on strategies, policies, directions, and aims to

accelerate international medical device regulatory harmonization and convergence.

Maintenance Process Picture Map (MPPM): A document combining text, pictures, and

symbols to provide standardized instructions for a process used during the maintenance

of the 4 8-Foot coater.


Out o f Specification (QOS): Test results falling outside of the specifications or

acceptance criteria.

Out of Trend (O PT): A test result that does not fall within the established trend analysis

data obtained from previous time points or stability data.

Pharmaceutical Inspectorate (PI): A group of FDA field investigators with specialized

experience and specific training in evaluating pharmaceutical manufacturing.

Picture Process Map (PPM): A document that combines text, pictures, and symbols to

provide standardized instructions for a process.

Processing Process Picture Map (PPPM): A document that combines text, pictures, and

symbols to provide standardized instructions for the manufacturing process, using the 48

Foot coater.

Threading Process Picture Map (TPPM): A document that combines text, pictures, and

symbols to provide standardized instructions for a process used during the threading of

laminate rolls on the 48-Foot coater.


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CHAPTER 2

REVIEW OF RELATED LITERATURE

Sources

For the pharmaceutical organization, the goal o f quality risk management is to

raise the level of protection for patients by reducing the risk to which they are exposed.

This only can be achieved when the pharmaceutical organization implements a risk

management policy in compliance with or exceeding regulatoiy guidelines.

The literature review was conducted to identify the current requirements related to

the subject o f this project. This review assisted in providing a greater understanding of

current regulatory guidelines and the current processes, permitting the identification of

areas o f deficiencies. The baseline for this research plan and the tools to be used and

implemented within the plan were based on the guidelines proposed in ICH Q9 (ICH Q9

FDA, 2011). Other guidelines, various regulatory documentations, books, and articles

pertaining to this subject also were reviewed.

Regulatory Requirements:
History of the FDA

The precursor to the current FDA can be traced back to 1848 when it was

established in the U.S. Department o f Agriculture. Regulatory functions for this agency

began with the passage o f the 1906 Pure Food and Drugs Act, prohibiting interstate

commerce for adulterated and misbranded food and drugs (USFDA, 2013).
10
The FDA and its duties and responsibilities have changed tremendously since its

inception. The Food, Drug, and Cosmetic Act of 1938 expanded the rights of the FDA to

include factory inspections and control of product advertising. This new law also

introduced the concept of “pre-approval,” mandating pre-market approval of all new

drugs. With passage o f this law, the FDA began to exercise greater control over adequate

labeling and directions for the safe use of drugs and added additional enforcement tools

to the agency. As a result of the therapeutic disaster o f Thalidomide, the Kefauver-Harris

Amendment of 1962 was passed. This amendment required safety and efficacy to be

proven before the approval o f any drug and authorized the FDA to use rules for Good

Manufacturing Practices (GMP) in the manufacturing, packaging, or holding of finished

products (USFDA Review, 2013). By 1978, the GMP was updated with Current

Manufacturing Practices (cGMP) (USFDA, 2014) and has had several minor changes

since then.

The enforcement laws pertaining to GMP are regulated under the Code o f Federal

Regulations (CFR), specifically 21 C.F.R. § 210 (USFDA, 2013). The FDA has

published Guidance fo r Industry: Quality Systems Approach to Pharmaceutical Current

Good Manufacturing Practice Regulations to assist manufacturers with the

implementation o f modem quality systems and management approaches for meeting the

requirements of this code (USFDA, 2006). With the publication o f this guidance

document, a connection has been established between the 1978 regulations and the

development of a quality system for helping manufacturers achieve compliance.


11
Regulatory and Guidance Documents

Quality Risk Management has become a mandatory regulatory requirement for

healthcare organizations. While much discussion has taken place in the pharmaceutical

industry on the meaning and importance of understanding and mitigating risks in a highly

regulated environment since the issuance of ICH Q9, not many companies have

implemented these programs into their systems to use them for routine decision making.

Many industries perceive the requirements stated in this document as difficult to interpret

and implement. In addition to the guidelines established in ICH Q9 it was critical to this

project to obtain a wider knowledge o f risk management in order to propose a risk

management model. This led to expanding the literature review to obtain more

information on the regulatory requirements and other published materials related to this

topic. Table 1 lists the various regulatory and guidance documents reviewed for this

project.
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Table 1

Current Regulatory and Guidance Documents

Document Document Title Description


ASTM Standard Guide for Risk Assessment and Provides specific information on the risk
E2476-09 Risk Control as it Impacts the Design, assessment and risk control phases for
Development, and Operation o f PAT Process Analytical Technology. This
Processes for Pharmaceutical Manufacture document serves as a companion to ICH
(Guide was purchased from ASTM, Part 09.
No. E2476-09)
FDA Guidance for Industry - Quality Systems This guidance assists manufacturers
UCM070337 Approach to Pharmaceutical CGMP implement modem quality systems and
Regulations risk management approaches meeting
(http://www.accessdata.fda.gov) CGMP regulatory requirements as
described in 21 CFR parts 210 and 211.
FDA Pharmaceutical CGMPs for the 21st This report summarizes the FDA
UCM071836 Century - A Risk-Based Approach, Final assessment o f all CGMP programs and
Report creates a framework for the regulatory
(http://www.accessdata.fda.gov) oversight o f manufacturing quality-based
quality systems and risk management
approaches.
FDACFR Quality System Regulation This part o f the regulation establishes
Title 21 (http://www.accessdata.fda.gov) requirements for handling non­
Section conformities.
820.90
FDACFR Quality System Regulation This part o f the regulation establishes the
Title 21 (http://www.accessdata.fda.gov) requirements to create procedures for
Section implementing corrective and preventive
820.100 actions.
FDA White Innovation and Continuous Improvement This summary report develops a
Paper in International Manufacturing, framework to facilitate innovation, and
Pharmaceutical CGMPs for the 2131 application o f scientific principles o f
Century modem quality management systems in
(http://www.accessdata.fda.gov) pharmaceutical manufacturing.

GHTF/SG3/ Implementation o f Risk Management Integration o f risk management principles


N15R8 Principles and Activities within a Quality into the existing risk management system
Management System is presented in this document.
(http://www.imdrf.org)
ICHQ9 Quality Risk Management A systematic approach to quality risk
(http://www.ich.org) management is presented in this
document, ft complements existing quality
practices, requirements, standards, and
guidelines within the pharmaceutical
industry.
13
Table 1 Continued

Document Document Title Description


ICHQ10 Pharmaceutical Quality System This guidance assists the pharmaceutical
(http://www.ich.org) manufacturers by describing a model for
an effective quality management system.
Quality concepts included in these
guidelines compliment guidelines
established in ICH Q9.
ISO 13485 Medical Devices - Quality Management This document provides specific
Systems —Requirements for Regulatory requirements for the establishment o f a
Purposes quality management system for
(http://www.iso.org) manufacturers o f medical devices.
ISO 14971 Medical Devices-Application o f risk Requirements contained in this document
management to medical devices provide manufacturers with a framework
(http://www.iso.org) to apply risk management policies,
procedures, and practices to the tasks o f
analyzing, evaluating, controlling, and
monitoring risk.
ISO 31000 Risk Management- Principles and This document lists the principles required
Guidelines to develop, implement and continuously
(http://www.iso.org) improve a framework whose purpose is to
integrate the process o f managing risk into
the organization’s strategy, planning,
management, reporting processes, and
policies.
ISO 31010 Risk Management- Risk Assessment The risk assessment techniques listed in
Techniques this document give guidance on how to
(http://www.iso.org) identify, manage, and treat risks.
WHO World Health Organization (WHO) This document assists with the
QAS/10.376 Guideline on Quality Risk Management development and implementation o f an
(http://www.who. int/publications/en/) effective Quality Risk Management
system.
WHO Annex 2 - WHO Guideline on Quality Guidelines previously published have
TRS981 Risk Management been updated in this annex. International
(http://www.who.int/publications/en/) guidances are added to this document
along with how to prepare for regulatory
filings.
Note. Developed from the References section in this paper by the author of this paper.
14
Quality Risk Management is a systematic process for the assessment and control

of risk for the quality o f a drug. ICH Q9 provides a model for the quality risk

management process. The risk management process may vary depending o f the

organization’s need; however, a robust process should include a structured process for

controlling risks. The risk management process identified in ISO 31000:2009 Risk

Management—Principles and Guidelines (ISO 31000,2009) assisted with the construction

of the Risk Assessment Model by providing a set o f components providing the

foundation for identifying, analyzing, evaluating, treating, monitoring, and controlling

risks. The typical quality risk management process presented in ICH Q9 is shown in

Figure 1.
15
Initiate
Risk Management Process

Risk A ssessm ent

Risk Analysis

Risk Evaluation

Risk Control
Risk Mitigation
(ind. elimination and avoidance)
_______ [Severity]_______
C £
Risk Reduction
[Probability]

Risk A cceptance

Risk Communication

Output / Results of the Review


Risk Management Process (e.g. Inspections/Audits, Complaints)

No additional risk

Figure 1. Risk management process-ICH Q9. Note. Retrieved from the ICH Harmonised
Tripartite Guideline Quality Risk Management Q9 Website at http://www.ich.org

Each component o f this model, or framework, works to create a robust risk

management process. Each o f the levels and steps o f this model need to be understood

and followed in order to construct a new model that specifically targets the organization’s

needs, regulations, and guidance as they relate to the risk management framework.

ICH Q9 (ICH Q9 FDA, 2011) identifies the two primary principles of quality risk

management as:
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• The evaluation o f 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 o f the quality risk


management process should be commensurate with the level of risk.

As the management process is initiated, a plan to evaluate the risk needs to be

formulated. When the FDA inspects manufacturing facilities, they use a risk-based

approach ensuring that effective quality systems have been implemented. These quality

systems have been described in documents such as Guidance fo r Industry: Quality

Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations

(USFDA, 2006), and Pharmaceutical CGMPs fo r the 21st Century-a Risk-based

Approach (U.S. Food and Drug Administration [USFDA], 2004). The guidelines and

requirements outlined in these documents harmonize with the current regulatory

requirements of 21 C.F.R. § 210 and § 211.

The objectives o f a strong risk management program are: (1) to ensure

compliance with rules and regulations, and (2) to determine the action needed to ensure

proper correction has been implemented. When these objectives are met, it leads to

appropriate identification and assessment of risk. Efficient risk management requires

developing quality standards to address the implementation of risk measurements to

ensure product conformance with the specified requirements. All FDA-regulated

pharmaceutical manufacturers are required to comply with these requirements. The FDA

regulates pharmaceutical manufacturers to ensure drugs manufactured and available for

consumption meet quality standards and consistently maintain these quality levels

throughout their lifecycles. It is the responsibility o f every manufacturer to ensure the


17
manufacturing quality o f its products. By publishing the GMPs guidelines, the FDA

facilitates the implementation o f a manufacturing process, consistently producing

pharmaceuticals o f high quality and creating a change control system to support

continuous process improvements (USFDA, 2009).

The type o f oversight the FDA maintains over a particular manufacturing facility

depends on the complexity o f the manufacturing process. The FDA needs to ensure the

manufacturer is in control o f its process, maintaining a robust quality system and fully

controlling the process. The FDA looks into each manufacturer’s risk-based quality

assessments to verify the manufacturing process maintains the product’s quality and

safety for the patient as required by regulations. Having the authority to inspect facilities,

the FDA regularly conducts inspections to ensure compliance and adherence to

regulations. During an inspection, the FDA also has the regulatory authority to issue

Form 483 and warning letters noting observances o f non-compliance. A warning letter is

the official notification that the FDA uses to inform a regulated industry manufacturer of

significant violations. Warning letters are issued only for violations of regulatory

significance (USFDA, 2012).

A review o f recent inspection reports for several pharmaceutical companies shows

the importance o f having an established risk management system integrated into the QS.

Excerpts from various warnings letter are shown in Table 2.


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Table 2.

Excerpts o f FDA Warning Letters

Warning Letter
Reference FDA Comments - Warning Letter Excerpts
Number
W/L 48-11 “your firm failed to perform a “Root Cause Investigation: Risk Assessment” to
determine the inpact, severity and safety concerns resulting from the verified root
causes o f product failure”
http://www.fda.gov/iceci/enforcementactions/wamingletters/2011 /ucm268244.htm
SEA 12-31 “failure to adequately investigate the cause o f nonconformities related to product,
processes and the quality system, as required by 21 CFR 820.100(aX2)”

http://www.fda. go v/iceci/enforcementactions/wamingletters/2012/ucm318613 .htm


WL: 320-13-09 “you did not identify the true root cause(s) other various deficiencies. Accordingly
the actions taken often did not prevent recurrence o f the problems”
http://www.fda.gov/iceci/enforcementactions/wamingletters/2013/ucm344476.htm
WL: 320-13-08 “our investigator found that you do not determine and implement corrective and
preventive actions (CAPAs) in a timely manner to prevent recurrence o f
manufacturing deviations”

http://www.fda.gov/iceci/enforcementactions/wamingletters/2013/ucm341683 .htm
Note. Taken from selected FDA letters by the author o f this project.

ICH Q9 provides principles and examples of tools used for the establishment o f a

robust risk management system. The guidelines established in this document complement

existing quality requirements, standards, and guidelines within the pharmaceutical

industry and regulatory environment. Several other published risk management standards

facilitate this task by harmonizing regulatory requirements for quality. ISO 13485:

Medical Devices—Quality Management Systems—Requirements fo r Regulatory Purposes

approaches the creation o f a quality management system from a holistic aspect. In this

document, the quality system is broken down into several subsystems, each with its own

type o f requirement (ISO 13485, 2012). CGMP regulations, that are covered under

Section 820 (USFDA, 2012) of the Code o f Federal Regulations, require the

establishment o f procedures to control non-conformities. Section 820.90 is for the


19
identification, documentation, evaluation, segregation, and disposition of the

nonconforming product. Section 820.100 establishes the implementation o f a corrective

and preventive actions system to deal with the causes o f nonconformities. This part of the

regulation ensures there is continuous improvement implemented throughout the

organization. Requirements set forth in 21 C.F.R. § 820 are similar to the requirements

established in ISO 13485.

A well-constructed risk management system is to have a process capable of

identifying all relevant risks. For this project, the study o f the use of risk quality tools

assists in establishing the status of the present system and identifying potential and

existing risks. ISO 31010 lists many risk assessment tools and techniques. The decision

to select a tool or several tools to apply for risk analysis depends on the complexity of the

problem. One o f the tools identified in the literature to be used when gathering potential

risks is Failure Mode and Effect Analysis (FMEA), explained in ISO 31010 and ISO

60812. All o f the ISO documents provide guidance on the selection and application of

various techniques and risk analysis tools to be used for risk assessment. The principle of

risk assessment is to provide fact-based information and analysis to make informed

decisions on how to treat a particular risk (ISO 31010, 2009).

Another step in the risk assessment process for this project was the risk

evaluation, which utilized models appropriate for the system under study. Literature in

the research provided some theoretical risk management models, but there currently did

not appear to be a unique risk analysis model operating within the manufacturing

pharmaceutical industry. The Global Harmonization Task Force, currently called


20
International Medical Device Regulators Forum (IMDRF), offered guidance on how to

implement risk management principles and activities within a Quality Management

System (Global Harmonization Task Force [GHTF], 2005). This guidance provided a

model o f a risk management system and provided practical examples on how to

implement and document this process to maintain compliance. The generalized model

provided in this document suggested integrating risk management procedures,

documents, and records directly into the quality management system process. Following

this guidance, the creation of a model designed specifically for the manufacturing

pharmaceutical industry was created. This model provided a unique risk management

approach to enable any organization to make informed quality-minded decisions. With

the implementation o f the model, a continual process evaluating risks was established. At

the implementation phase, the recommended controls, procedures, appropriate corrective

actions, and change control steps were used to process the newly encountered risks and to

propose a plan o f action to mitigate these risks.

As previously stated, CAPA controls are covered in 21 C.F.R. § 820.100. In

addition, CAPA guidelines and change control activities to periodically monitor and

review processes are defined in the WHO Guideline on Quality Risk Management (WHO,

2012) and in its subsequent Annex 2 (WHO, 2013), which defines processes for the

establishment and maintenance of a quality process. One of the most important sections

in the WHO guideline is the establishment o f a verification process for the quality risk

management system. The verification o f risk management activities is necessary to

determine whether all risks have been identified and effectively controlled. This is part of
21
the continual improvement step as stated in sections 8.2.4 through 8.5.3 o f ISO 13485

and sections 4.5 and 4.6 o f ISO 31000. When an effective and systematic review is

performed, decisions are made on how the risk management framework and process can

be improved. This type o f decision leads to improvements and establishes robustness in

the organization’s quality risk management system.

Quality Risk Management in the


FDA-regulated Industry

Quality Risk Management in the FDA-regulated Industry (Rodriguez-Perez,

2012) is a reference book that offers a systematic and comprehensive approach to quality

management. It has been written to assist manufacturers with the integration of a risk

management system or risk management principles and activities into their existing QS

by providing practical explanations and examples. It should be the goal of all

pharmaceutical manufacturers to maintain compliance with regulatory requirements. The

appropriate use of quality risk management can facilitate this task. In the first three

chapters of his book, Rodriguez-Perez (2012) delves into explaining each of the ISO

standards associated with risk management and manufacturing.

This in-depth explanation by Rodrigues-Perez (2012) assisted in this project by

providing extensive information on regulatory compliance and a deeper understanding of

the different guidelines used by the pharmaceutical industry. In subsequent chapters, the

author provided information regarding the quality risk management process. Rodriguez-

Perez (2012) also used tables, graphs, and process maps throughout his book to illustrate

the different risk tools.


22

Fundamentals of Risk Management

The book Fundamentals o f Risk Management offers a comprehensive introduction

to the theory and application o f risk management (Hopkin, 2012). In the first half o f this

book, Hopkin introduces risk and risk management, while the second half of the book

concentrates on the application o f risk management tools and techniques.

For the project that is the focus o f this paper, the second half of the book by

Hopkin (2012) was most useful in providing guidance on risk management

documentation, approaches to risk assessment, and risk assessment techniques. Although

every pharmaceutical organization sets out to define its own risk strategy and framework,

the risk strategies and protocols described by Hopkin were consistent with the guidelines

established in ISO 31000 (ISO 31000,2009). While there were many approaches that

could be used in risk management, this book provided various techniques the

organization could identify with and apply. Some of these techniques are further

discussed in Chapter 3 o f this paper.


23
CHAPTER 3

METHODOLOGY

In a Quality Risk Management System, product risk minimization and control is a

continuing process. This study has demonstrated how the establishment of the Risk

Assessment Model introduces a structured methodology for continuously identifying,

measuring, developing mitigation plans, implementing corrective actions, and

continuously monitoring and tracking the implementation process to ensure successful

risk reduction.

Noven Pharmaceuticals, Inc. in Miami, Florida has sponsored the testing and

implementation o f the Risk Management Model. Noven is a specialty pharmaceutical

company engaged in the research, development, manufacturing, marketing, and sale of

prescription pharmaceutical products.

In the evaluation o f the current Quality Risk Management System, the existing

quality practices of the pharmaceutical organization needed to be reviewed. The

evaluation o f the current process (“as is”) included the review of the following:

• Manufacturing process

• Procedural documents (Standard Testing Procedures [STP], Standard


Operating Procedures [SOP], checklists, picture process maps)

• Batch records

• Change management process

• Deviation management, complaints, investigations, and CAPA system


processes
24
The importance o f a thorough investigational step to assist in building the

foundation for the risk assessment cannot be minimized. See Table 3 for a tabulated

example o f this review.

Table 3

Current Process Review

Compliance with
current guidelines
Process Examined Items Examined Follow-up Action
and regulatory
requirements
Manufacturing a) Knowledge o f the process: via ASTM E2476-09 a) Created Process
Process interview with the manufacturing ISO 13485 Map with the
personnel, ISO 31010 assistance o f subject
b) Training: review o f training matter expert (SME),
records to determine if personnel b) Completed review
was appropriately trained for the o f the Human error
activity being performed records related to the
manufacturing process
Procedural a) Documents: SOPs and PPMs 21CFR § 820 a) Updated SOP and
Documents: SOPs, clearly explain the manufacturing ICHQ9 PPM, as needed to
STPs, checklists, process, ISO 13485 clarify procedural
and PPMs b) Error proofing tools: a ISO 31010 steps,
checklist, for the startup o f the b) Determined the
manufacturing process, is being need to create a
used to ensure all related checklist for the after
instrument/equipment have been start-up process check
properly setup
Batch Records Conducted review o f batch 21CFR § 211 Gaps in
records to determine gaps in ICHQ7 documentation were
process and documentation corrected. Training
was conducted for the
manufacturing and
reviewing personnel
Change Reviewed the change ICHQ10 Changes to ensure
Management management process for the continual
creation/update/ revision of improvement were
documents related to process established
Note. Developed by the author of this paper as part of the project.
25
Table 3 Continued

Current Process Review

Compliance with
current guidelines
Process Examined Items Examined Follow-up Action
and regulatory
requirements
Deviation a) Records related to 21CFR § 820 a) Gaps in deviation
Management, manufacturing process under ASTM E2476-09 management process
complaints, study were reviewed, b) Obtained ICHQ9 identified,
investigations and a list o f those investigational ISO 13485 b) All investigations
CAPA system records directly related to non­ generated for the study
(non-conformities, conformities or system failures, period were collected,
system failures, c) Determined which risk c) Additional risk tools
human error) management tools are currently for process
being utilized, improvement were
d) Determined how failures are identified,
tracked (if a Notice o f Event or d) Tracking system
OOS investigation is initiated). examined and
improvements
developed
Note. Developed by the author of this paper as part of the project.

These quality processes were evaluated against the current procedures,

requirements, standards, and guidelines within the pharmaceutical industry and the

regulatory environment. The evaluation conducted ensured that the manufacturing facility

was maintaining its level of compliance and, most importantly, that the patient was

protected by managing the risk associated with the product. The commonality found in

the warning letter excerpts from several organizations listed in Chapter 2 was the failure

of each organization to perform the appropriate action to remediate the problem. These

pharmaceutical manufacturers needed to demonstrate to the regulatory agency their

capability to identify root causes for adverse events. It was o f the utmost importance to

the regulators to be ensured a manufacturer could respond timely, could apply the correct

root cause analysis tools, would be able to conduct an effective investigation, and could
26
apply the correction, implementing corrective and preventive actions to drive significant

continuous improvement.

To understand the current workflow and identify the manufacturing process risks,

interviews were conducted with the manufacturing personnel involved in the process

under examination at the pharmaceutical company that is the focus o f this project. The

objective o f these interviews was to identify and assess risks with the subject matter

experts (SME) and to focus on the specific critical risks in order to develop mitigating

actions. During this brainstorming activity, the SMEs were able to contribute by sharing

their knowledge and real-life experiences in regard to the area of study. As a result of the

brainstorming activity, a process map was constructed. The process map was useful for

documenting processes and providing a reference on how tasks are performed. The

process map was created for better understanding of the current process and assisted in

revealing opportunities to improve the manufacturing process. The process map

displayed in Figure 2 shows the coating process for the laminate sample. The information

relevant to the process was gathered and organized in a display, assisting all involved in

this project to visualize the process and identify the current risks. The next step in this

review of the current process was to gather previous information regarding investigations,

complaints, and Out o f Specifications/Out o f Trends (OOS/OOT) records for the

manufacturing process from previous years. Determining the data to be reviewed was

defined at the beginning of the project with the SME’s. It was determined that for this

project, one years’ worth o f data review would be sufficient. See Table 4 for the statistics

on the data collected.


27

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project based on the data obtained as part of the study.
28
Table 4

Data Collection and Lot Information

Total Number of Lots


Number o f Products
Year Manufactured and
Reviewed
Reviewed
2013 3 133
Note. Data tabulatec by the author of this paper as part o f the project.

Once the data collection was completed, failures were classified. As the failures

were reviewed, they were segregated by kind (material, human error, equipment, etc.).

Once the different kinds of failures were determined, the next step was to define a

quantitative analysis o f the risk (numeric ranking) through the construction of a Failure

Mode and Effect Analysis (FMEA) or in a qualitative ranking (e.g., high/medium/low)

which was performed through a risk analysis matrix. The risk analysis matrix utilized

in this project for the risk assessment is discussed in Chapter 4. The information

collected from the review o f the data and the process map was used to construct the

FMEA.

Generally, FMEAs were used to identify the ways in which components,

systems, or processes failed to fulfill their design intent. Six Sigma specialists,

manufacturing supervisors and production operators were employed to assist in the

identification o f risk and in their assessment. The FMEA provided an objective basis

for analyzing the product or process failure and its causes, and the main purpose for its

construction was to emphasize the most critical risks that existed and to rank them

according to severity, occurrence, and detection. The FMEA constructed for the
29
coating process is shown in Figure 3. The risk ranking scale used for the FMEA is

listed in Table 5.

Unacceptable process outputs created at each o f the process steps, their causes,

severity, and the control method to prevent or detect the potential unacceptable process

outputs were identified in the FMEA. The analysis provided by the FMEA also

identified possible ways in which non-conformities could occur in the process and

documented actions (controls/mitigations) taken to prevent these non-conformities.

Once the failure modes were established through the construction of the FMEA, risk

reduction was initiated for those failure modes with a high-risk priority number (RPN).

For the current evaluation process, the failure modes targeted for risk reduction had a

RPN o f 100 or higher.

The Risk Assessment Model begins its process by targeting the failures, along

with the other risks identified through the review of the current state of the company’s

Risk Management System. A high priority number triggers the need to initiate a

corrective action; however, each manufacturer uses the numeric value o f the RPN to

determine the risk reduction process for that particular step. The RPN is the risk priority

and not a measure o f risk.

Since RPN ratings for this project were relative to a particular analysis or process,

the evaluating team selected the rating scale best able to assist in the potential problem

identification. For this reason, the high RPNs were determined to be o f higher priority

and these were the processes the team targeted first.


30
General guidelines and procedures for the use and application of the FMEA can

be found in IEC 60812. Other risk analysis techniques are available and are listed in

ISO 31010. Additional risk analysis techniques may be used as appropriate to enhance

understanding o f the process under study and to assist in the mitigation of the risks.
31
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developed by the author based on the data obtained as part of the study for this project.
FMEA Template was retrieved from the ASQ Website at
http://asq.org/leam-about-quality/tools-templates.html
32
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Figure was developed by the author based on the data obtained as part o f the study for
this project. FMEA Template was retrieved from the ASQ Website at http://asq.org/leam-
about-quality/tools-templates.html
33
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Figure was developed by the author based on the data obtained as part of the study for
this project. FMEA Template was retrieved from the ASQ Website at http://asq.org/leam-
about-quality/tools-templates.html
34
Table 5

FMEA Scale—Risk Priority Number Grading

Severity of Effect: Occurrence Rating Detection:


1. None 1. Extremely Remote 1. Almost
<.01/1000 Certain
2. Very slight effect 2. Remote - 0.1/1000 2. Very High
3. Slight effect w/o equipment service 3. Slight Chance - 3. High
0.5/1000
4. Slight effect w/ equipment service 4. Some Occurrences - 4. Moderate
1/1000 High
5. Minor effect w/o equipment service 5. Occasional 5. Moderate
Occurrences - 2/1000
6. Minor effect w/ equipment service 6. Low
6. Moderate - 5/1000
7. Moderate effect leading to 7. Frequent - 10/1000
7. Very Low
equipment/process failure
8. Significant effect leading to 8. High - 20/1000 8. Remote
equipment/process failure
9. Critical effect leading to 9. Very High 50/1000 9. Very Remote
equipment/process failure. Affects
operator, or maintenance personnel;
safety and/or affects non-compliant with
government regulations with warning
10. Hazardous, permanently disabling 10. Certain 10. Absolute
equipment/process. Affects operator, or Occurrence > 100/1000 Uncertainty
maintenance personnel; safety and/or
affects non-compliant with government
regulations without warning
Note. Adapted from DMAIC Tools Six Sigma Training Resources Website at
http://www.dmaictools.com/dmaic-analyze/pfmea

Risk Management Model Development

All the materials gathered from the from the review of diverse literature for this

project were compiled and used along with the existing data as the support for the

construction o f the Risk Management Model. The literature studies ran in parallel with

the data collected and the mapping o f the current system in order to develop the improved
35
system. The on-going approach and the review o f the scientific data assisted in

maintaining an efficient risk management system. This type of approach was essential for

the maintenance o f a current risk analysis system and for maintaining the product quality.

For the development of the model, all information collected in the first phase of

the project was assembled to create a “living” document. This model was based on a

well-defined risk assessment process for promoting quality and transparency and for

enhancing the manufacturing company’s Risk Management System. In designing this

model several important factors were taken into consideration; these included a risk

treatment to control or minimize existing risks and a plan to prevent future risks,

maintaining the gains achieved by the establishment of the newly developed Risk

Management Model. Contributions from manufacturing personnel were used in the

building of this model, since the observations they gave provided invaluable input for the

construction o f the model. Process users often revealed issues and gaps that were causing

process and operational problems. Furthermore, personnel might be more willing to

participate in a process change (improvement or correction) and provide ideas when they

were directly involved. This type of approach helped to increase the probability of

success and encouraged a higher level of involvement and agreement within the

organization.

The proposed model includes the following:

• Monitoring o f non-conformities related to the manufacturing process.


Generation o f a non-conformities report including all recorded events from
engineering, manufacturing, and quality systems.
36
• Reviewing the process for all investigations associated with the manufacturing
process. These investigations include internal investigation as well as product
complaints.

• Tracking of all tasks and activities associated with risk control by a master
system for better monitoring and control of the non-conformities.

• Establishing a risk management process for the categorization and evaluation


of risks. Quick assessment of the risks is made and a subsequent action is
determined in order to establish a mitigation plan.

• Monitoring and feedback. All records and documents reviewed under the
model are monitored at the specified frequency. Corrective action is initiated
when evaluated risk exceeds critical control measures.

Integration of the Risk Assessment


Model to QRM System

The Risk Management Model was integrated into the current Risk Management

System by linking its process flow to the existing quality data management system. Risk

Management activities, production, process controls, change control, and the CAPA

systems were all encompassed within the Risk Management System. The CAPA system,

as established by internal procedure, required a corrective action implementation task

with required due dates. The effectiveness check section of the system ensured the

appropriate plan for correction had been established and working as defined. The

effectiveness check plan monitored gains obtained by the corrective action. All the steps

encompassed in the CAPA system were reviewed and monitored by a quality assurance

assessor in charge o f monitoring CAPAs, the CAPA documentation review, and the

evidence o f all task completions.

The appropriate personnel or quality manager for the quality system was charged

with facilitating the continual improvement for the process throughout the product
37
lifecycle. To ensure the appropriate measurement controls were enabled, the management

review process included a well-designed system for assisting the stakeholders with the

evaluation o f each of the processes in order to make appropriate decisions based on these

evaluations, leading to the appropriate actions taken. The internal company procedure

defining the process for SICODS (Systems, Investigations, Customer Complaints, Out of

Specifications, and Deviations) and non-conformance quality events (Out o f Trends and

other failures) defined the tracking and collection o f information related to these systems.

These types of investigations were recorded into an enterprise quality management

system (EQMS).

The EQMS system centralizes processes in a single, integrated system to help the

organization gain efficiencies and to achieve compliance by integrating related events

and actions, automating workflow, and facilitating trending and reporting across quality

systems. Regulated industries continue to face pressure to maintain the highest level of

quality in every facet of their operations. The efficiency and effectiveness of these quality

systems are improved through interactive integration with other existing quality systems

or software. In general, most pharmaceutical manufacturing facilities have a well-

established EQMS.

The Risk Assessment Model proposed in this project made use of this resource

already existing within the company. By using an established electronic tracking system,

the pharmaceutical company was able to integrate the workflow o f the Risk Assessment

Model with the quality process by performing the following tasks:


38
• Track complaints, investigations, CAPAs, and OOS/OOT. Corrective action
and effective check plans were documented in this system with a defined due
date for completion.

• Track deviations to the established system processes and effectiveness


verification.

• Implement material, equipment, and process change by means of a change


control system.

• Document management activities by providing employees access to controlled


quality documents and perform document lifecycle management activities
from within the EQMS.

Through this system and by SOP requirements, the Quality Assurance group was

able to generate a monthly metrics report. This model established the metrics report to be

provided to upper management and to the Quality Council on a frequent basis. Each

company could establish the frequency for the report gathering and presentation

according to the company’s needs and requirements.

Risk Assessment Model

The creation of the Risk Assessment Model was one of the most important phases

o f this project. As described in Chapter 1, the purpose o f this model was to ensure patient

protection in terms o f quality, safety, and efficacy. As this model became embedded in

the organization’s process and practices, the Quality Council was assured that the pro­

active risk management system would be operating to confirm the correct action was

taken, based on a comprehensively assessed risk at the appropriate time. It was proposed

through this project that this model would become part o f the Risk Management System

and incorporated into the existing Risk Management Program.


39
Current System

It is standard practice for any pharmaceutical manufacturing area to conduct the

production area in a manner as described and defined by the company’s SOPs.

Operational conditions and Batch Records requirements are specified in these methods.

In a regulated industry, such as pharmaceutical manufacturing, these batch records and

conditions become regulatory commitments. The manufacturing operators are then

expected to reproduce these same sets o f conditions in compliance with the written

documentation. The adherence to stated conditions in the SOPs and laboratory testing of

in-process and finished products provides assurance that manufactured products have the

safety and efficacy profiles outlined in the approved product label. Sometimes this type

of operation is called a static manufacturing operation. In a static manufacturing

operation, it is reasoned that once a product is approved and validated, it does not change.

Process control is predominantly based on documented evidence o f conformance to SOPs

that generally includes a fixed process time and laboratory-based testing o f in-process

materials.

One o f the most important and strategic aspects of risk avoidance or a risk

reduction process is the benefit from existing company’s risk analysis tools already in

place. A review of the current manufacturing system included:

1. Batch Records: Many steps occur at the manufacturing floor during the
manufacturing process. All these steps are documented in the batch record. In
order to determine if the process is functioning as designed, a completed batch
record examination is required. Batch records contain all required and
pertinent information; therefore, if deficiencies are found in these records,
suggestions for improvement to this document should be made. Some
manufacturers have found it useful to implement error-proofing tools, such as
checklists, in their processes. In general, if “Start-Up” and “In-Process”
40
checklists are used during the manufacturing process, the check and
verification step by two operators is normally the best approach to be used to
ensure the effectiveness o f the process.

2. Maintenance schedule o f the manufacturing equipment: The engineering


group should have a structured system by which most of the equipment used
in the manufacturing/production area is maintained as part of a scheduled
maintenance program.

3. Investigations, Quality Records, and Complaints: The EQMS is reviewed to


examine all recorded events associated with the manufactured product or
products. Some of the results obtained through this review may be used to
construct the FMEA (see Figure 4). The EQMS review should reveal if any
corrective actions have been recorded for failures occurring during the
manufacturing process. Once the risk management model has been
established, information gathered through the EQMS is to be utilized to
determine the effectiveness o f the risk management process and the
prevention measures and the documentation of newly identified risks events.

After completing the evaluation of the “as is” process and through the use of

various risk management tools (i.e., Process Map and FMEA), the Risk Management

Model was created. This model took into account negative effects or threats to be

considered when performing risk analysis and improvement opportunities to be integrated

into the manufacturing operation. With this premise in mind, it was imperative for the

success o f this project to have the operation of the whole manufacturing system evaluated

in order to build the Risk Management Model. The Risk Management Model is shown in

Figure 4.
41
Manufacturing Non­ Engineering Non­ Quality System
Product Manufacturing
conformities/ conformities/ Non-Conformities/
Complaints Delays Log Defects Defects Defects

Start-up In -P ro cess Production a n d P a rts O n -scheduie Data


Complaints Checklist Checklist Non-conform ities repairs analysis/trending

Action
Required?

Com plaints e n te re d into


Com plaint Handling S y stem

Known Risk Management


Problem? Process
-
: (D

CAPA Process
(i.e. Investigate
Cause,
analysis/trending document
rationale for no
investigation,
etc.) 'r
Y es ‘ i
Action Possible CAPA Actions:
Required? • Product Change
;• Process Change
• Supplier Change Notice
• Input for New Products
• Input to RM process start
Continue
Monitoring

(1) The relationship will depend upon the output of the investigation. This process can be interactive.

Figure 4. Risk management model. This figure was developed by the author as part of
this study, utilizing CAPA process retrieved from the GHTF/SG3/N15R8 Website at
http://www.imdrf.org

The integration and application of the Risk Assessment Model into Noven’s Risk

Management program was initiated as a pilot study. The results o f the pilot study were

compared with the baseline data generated previous to the initiation of the study. Through

the execution of the pilot study, it was determined all project goals for this study were
42
achieved. Pilot study execution is summarized in Appendix A, and details o f the project’s

results are provided in Chapter 4.


43
CHAPTER 4

RESULTS AND DISCUSSIONS

One o f the objectives of this project was to better understand the current risk

management regulations and guidance and to identify current gaps within the Risk

Management System at Noven Pharmaceuticals in order to design and implement a Risk

Management Model. At this stage o f the project, the literature review and the project’s

phases methodology were used to assist in the execution of this objective. The

preeminent goal o f the project was the application o f a controlled, robust risk

management system for the pharmaceutical manufacturing process. This was

accomplished by an introduction of the model into Noven’s Risk Management program

by way of a controlled pilot study.

Many domestic and international medicines regulatory authorities are

recommending that pharmaceutical manufacturers adopt a risk management system,

identifying and evaluating all risks, determining probability of occurrence, and enabling a

system to mitigate this occurrence (WHO, 2013). As delineated in Chapter 3, after the

current system was evaluated and the successful integration of the Risk Assessment

Model was completed, the improved risk management process could be established

throughout the entire organization.

As previously mentioned, the FDA has published several guidance resources,

including (Guidance fo r Industry: Quality Systems Approach to Pharmaceutical CGMPs

Regulations and Risk-Based Method fo r Prioritizing CGMP Inspections o f


44
Pharmaceutical Manufacturing S ite s -A Pilot Risk Ranking Model). Both o f these

resources encourage the adoption of innovative manufacturing technologies. These

guides and others, as mentioned in this report, have provided assistance in implementing

an innovative approach with the design o f a new Risk Management Model.

The Risk Management Model proposed in this project has the capability for

continual improvement and enhancement as it becomes embedded in the quality process

and the Risk Management System of any pharmaceutical manufacturing. The literature

review reveals the need for the creation of a model such as the one being proposed in this

project. Throughout this project, careful consideration has been taken to create a model

that meets most o f the pharmaceutical company’s quality objectives and supports the

strategic plan.

The Risk Management Model shown in Figure 4 integrates all the processes

affecting a typical manufacturing process. These processes are:

• Product Complaints: Complaints are received by the Complaints Group and


logged into the EQMS. In most pharmaceutical companies, this group is
supervised by the Quality Assurance Department. Complaints are received
from customers, pharmacies, and physicians. As soon as a complaint is
received by the company, an investigation is to be initiated. The scope and
depth o f a complaint investigation needs to be captured in a Complaints SOP.
This document needs to undergo systematic periodic review through the
Documentation Control system.

• Manufacturing Delays: Start-up and in-process delays are recorded in the


appropriate checklists within the batch record. In this log, any observations,
missed steps, human errors, instrument errors, or process errors are recorded.
This log is to be included in the batch record system and becomes a controlled
form. All controlled forms are managed through the Documentation Control
system and undergo periodic review. The periodic review interval for all
documents is defined in the Documentation Control SOP for the periodic
review process of SOPs, Policies, STPs, and Quality Standards.
45
• Manufacturing Non-conformities:

o Purchase Part Non-conformities: Manufacturing Operations


communicates failures of manufacturing parts to the Engineering
Group by generating a work order. The Engineering Group is
responsible for enabling a solution to the non-conformity. Non­
conformities are logged into the EQMS. All investigations logged into
this system are able to be tracked and are to be included in the monthly
metrics report.

o Production Non-conformities: Manufacturing Operation failures (Out


of Trend or Out of Specification) are also logged into the EQMS. The
Manufacturing group leads the investigation for the non-conformity
failures.

• Engineering Non-conformities: These include all “non-schedule” repairs.


These repairs could be originated by the manufacturing group by means of
phone calls, e-mails, or paper requests. The Engineering group is responsible
for logging these into the engineering repair database. Evaluation of each of
these non-conformities is made by the Engineering group along with the
Manufacturing group. If these groups determine an investigational record
needs to be opened, either group may open the record in the EQMS.

• Quality System Non-conformities:

o For in-process drug material sent for testing, the Quality Control
Laboratory is responsible to initiate the investigation for any non­
conformance results found during testing. Quality Control, along with
Manufacturing, trends data for any drug material determined to have
non-conformities.

o For completed batches sent to Quality Assurance for material release,


the Product Release group initiates the investigation for any non­
conformance result found during the documentation review.

■ A written SOP defines the process for initiating and evaluating


the non-conformity and delineates the process for opening and
tracking the investigation in the company’s EQMS.

All of these processes are integrated into the company’s Corrective and

Preventive Action (CAPA) system. This is a critical step for this model. It is essential for
46
each o f these steps to be fully evaluated and verified for the presence o f non-conformities

and to device the strategic plan to correct and prevent their reoccurrence.

The Risk Management System, as designed for this project, was managed by the

Quality Engineering (QE) group with the assistance o f a Six Sigma specialist, since Six

Sigma professionals are skilled in identifying and evaluating key factors under

consideration for this process (American Society for Testing and Materials, 2009). This

group gathered and reviewed the information and took appropriate action for all

documented activities referenced in the Risk Management Model. One of the most

important responsibilities for this group was to evaluate all incidents, logged

investigations, and complaints and to initiate corrective actions, as necessary. The CAPA

review’s main objective was to discover any previously missed risk and to measure the

effectiveness o f the established risk control measures. The Risk Assessment Form (see

Table 7) was used to evaluate and identify the level of risk and to assist in prioritizing

any control measures to be undertaken. The Risk Assessment Form was based on a risk

assessment matrix commonly used in risk assessment activities. Investigations reviewed

during the Risk Assessment Model project’s period of study are listed in Table 6.
Table 6

2014-2015 Investigations Openedfor Lots Manufactured fo r Products A, B, and C

Responsible
Lot Reason for Investigation
Group
141006 QC Retention time shift due to environmental conditions in QC Laboratory
(OOS).
141021 QC Incorrect preparation o f sample in QC laboratory yielding an OOS result
(human error).
141029 MAG At the end of the coating process, batch size was not updated in the
electronic batch record by the coating operators.
141106 QC OOT results obtained during QC laboratory testing (DU testing).
OOT results obtained during QC laboratory testing (Potency testing).
141211 MAG Wrinkles observed on the material prior to coating, material rejected.
CAPA opened.
141212 MAG Cleaning Failure for Pump parts during 48-Foot Coater Line Clearance.
150106 MAG Evidence of oil noticed in the bottom o f the 48-Foot coater oven during
the B-Clean. CAPA opened.
150108 MAG Particles were observed in the rollers during A cleaning.
150203 ENG 48-Foot Coater shut down during coating process, oxidizer panel stated
"Flame Guard Fault" as reason for the shutdown. CAPA and EC
opened.
Note. Tabulated by the author of this paper as part of the project.

The examination o f the nine investigations opened and processed through the

CAPA review system determined that a total o f three corrective actions were opened for

all of the records processed through the Risk Assessment form (see Table 7 and Table 8).

No further corrective action needed to be taken because all had been properly

categorized. For these three records, effectiveness checks had not been completed, for all

of these records were still open, and corrective actions were still being applied.
48
Table 7

Risk Assessment Form

Probability o f Occurrences Catastrophic Critical Moderate Minor Negligible


Definition Value
Frequent

Occasional
Seldom
Improbable
Note. Form adapted by the author as part o f this project, utilizing a risk chart retrieved
from the U.S. Department o f Health & Human Services, Public Health Emergency
Website at http://www.phe.gov

A description o f the risk levels are as follows:

• Risk is High for codes 5A, 5B, 5C, 4A, 4B, and 3A.

• Risk is Medium for codes 5D, 5E, 4C, 3B, 3C, 2A, and 2B.

• Risk is Medium Low for codes 4D, 4E, 3D, 2C, 1A, and 1B.

• Risk is Low for codes 3E, 2D, 2E, 1C, ID, and IE.
49
Table 8

Ratings fo r Impact Definitions

Definition Meaning Value


Catastrophic • Regulatory / compliance violations / issues
• Material breech A
• Production delays
• Technical miscommunications
Critical • A non-compliance finding resulting in process, or operational degradation
• A security finding requiring immediate corrective action prior to continued
operation B
• Production errors containing regulatory violations with direct consequence
to the operation
Moderate • Production element errors potentially posing indirect consequences to the
C
operation
Minor • No regulatory action anticipated
• No compliance impact anticipated
D
• Minor errors in procedures
• Production errors containing manufacturing opportunities for improvement
Negligible • No regulatory / compliance violation
• On-time production
E
• Properly executed communications
• “Clean” product
Frequent • Occurs frequently
5
• Will be continuously experienced unless action is taken to change events
Likely • Occur less frequently if process is corrected
• Issues identified with minimal audit activity 4
• Process performance failures evident to trained auditors or regulators
Occasional • Occurs sporadically 3
Seldom • Unlikely to occur 2
Improbable • Highly unlikely to occur 1

Note. Form adapted by the author as part of this project, utilizing a risk chart retrieved
from the U.S. Department o f Health & Human Services, Public Health Emergency
Website at http://www.phe.gov

Evaluation o f the Integration of the Risk


Assessment Model into the QRM System

Prior to the initiation of the pilot study for this project, data for the three products

under study were compiled, and all investigations generated within this time period were

reviewed. This information was tabulated, as shown in Table 9. By examining each


50
investigation, it was determined that four departments had yielded a total of 18

investigations and six o f these investigations were classified as being caused by human

error. After the integration o f the model, the investigations rate decreased to nine

investigations (a 50% drop), with only one human error event.

Table 9

2013 Investigations Openedfor Lots Manufacturedfor Products A, B, and C

Prior to model After model


Lots manufactured in Lots manufactured in
2013 and 2014 2014 (Q4) and
(Q1 to Q3) 2015 (Q l)
Total Number o f Investigations
Manufacturing Delay log One (1) Zero (0)
Manufacturing
Eight(8) Five (5)
Non-conformance delay log
Engineer
One (1) One (1)
Non-conformance delay log
QC Laboratory Data
Analysis/Data Trending and Five (5) Three (3)
Non-conformance reports
Quality Systems Investigations Three (3) Zero (0)
Investigations due to human
Six (6) One (1)
error
Investigations Total Number 18 9
Note. Prepared by the author of this paper as part o f the project.

The application o f this model provides a three-step approach: (1) evaluate if risks

are within control or out o f scope; (2) initiate a risk review for out-of-scope risks, which

may involve revisiting the FMEA, using the risk assessment matrix or the application of

other risk analysis tools; and (3) initiate changes through the CAPA and change control

systems (Mollah, Long, & and Baseman, 2013). In order to maintain the Risk
51
Management Process as a “living” process, newly evaluated risks need to be integrated

into the change control system, for this system is a key component in any quality review

process. The system also is utilized to manage all tasks and actions related to change

control management, including impact assessments and effectiveness checks. By

integrating the Risk Management System into the change control system, both the quality

and the speed o f decision making, pertaining to risk management, is improved. Members

o f a Change Review Board (CRB) objectively review all change control submissions and

recommend how to proceed with the proposed changes and how these changes impact the

existing risk assessment document. The CRB normally is comprised of a cross-functional

change review team, and all departments throughout the organization at Noven are

represented on this board.

Some of documents submitted for change control were the SOPs associated with

this process and all forms included in this report, which were specifically created for this

project.

Implementation o f this system ensures a continual review of the risk-acceptance

decisions previously evaluated. Through the periodic verification process and

confirmation of the data accessed, several conclusions can be made. Then, the expected

results are verified as being achieved, results of the risk assessment techniques as being

properly applied, and the risk treatment as being effective (Rodriguez-Perez, 2012).

The results compiled by the Six Sigma specialist for this project were assessed

and documented on the Quarterly Risk Report to Quality Council form, as shown in

Table 10. For the purpose of the project, the data compiled on this form encompassed the
52
pilot’s project time duration. Data assessed included fourth quarter data from 2014 and

first quarter data from 2015.

Once the data was compiled, the specialist reviewed the results and determined

whether a new risk control measure needed to be initiated or a previously initiated risk

event needed to be revised. Since this activity is performed on a quarterly basis, the

specialist reviewed only the data gathered for the reporting quarter. Newly generated

investigations were evaluated through the FMEA template regardless o f the RPN rating,

as shown in Figure 3. As detailed in the Risk Management System Workflow, the Six

Sigma specialist, along with a SME risk team, determined whether further action would

need to be taken for the newly generated risks. This process became part of the CAPA

activities and was integrated into the Risk Management Model.

The Six Sigma specialist is responsible for presenting the risk assessment report,

on a quarterly basis, to the Quality Council. The Risk Management System workflow is

the process the Six Sigma specialist uses to complete the risk assessment review. Figure 5

shows this process step in a workflow diagram.


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Start Date: 10/1/2014

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3/31/2015

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*3.

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the study for this project.


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O

Corrective Evaluation/
I

of Events/ Process/Product Control Method ControlMeth


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Process Name Measurement Technique

-o
Reports Reviev
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Failure Used/Inflated Action Date


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tin
s-

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*

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*

-*

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Complaints

ff
J?
Quarterly Risk Report to Quality Council Form

Incident Log

* Complaint data not considered for this project.


M: monitor vendor
Material,
M:resolvng issue with M: replacement and process for
Manufacturing Non- Instrumenl/ckanng, M: 7/20/15

«y~>
vendor, process review, reoccurrence,
Conformities-Defects electronic batch 1:12/19/14
I: to be inspected I: bearings replaced I: bearitgs inspection
record entry ereor
added to PM

Fault enw to be
Engineering Non- Equipment in Coating Replaced oxidizer, Monitor for flame fault
investigated, instrument 9/15/2015
Conformkks - Defects room cleaned lines error reoccurrence
replace, if needed

OOS - contacted
Quality Systems Non- Engineering,
c*->
Temperature control
Confomuties- Defects QC Laboratoiy OOT-material related, 1/21/2015 3/15/2015
o
o

O
oo

«N
and daily monitorag
(=?

(Data Analysis) monitoring of stab iy


stud)

Note. Form was developed by the author based on first-hand experienced and as part of
53
54

Gather documents

Evaluate data collected


from documents

FMEA Risk
Assessment
Form

Assemble Risk team

No
Risk Action
needed

Yes

Initiate CAPA am
Change Control
Process

Receive approval o f
CRB

Complete approved
changes

Report to Quality
Council

Figure 5. Risk management system workflow. Figure developed by author based on first­
hand experienced and as part of the study for this project.
55
Metrics

The establishment o f this system includes the tracking of metrics as established by

the organization as part of the strategic objective. When an organization defines metrics,

the cross-functional team and the Quality Council is able to review the metrics to ensure

the key performance indicators are operating as designed. Even if quality metrics are

collected by the QE group or by a Six Sigma specialist, ownership of the issue belongs to

the operating unit generating the data.

Targets and Goals

In general, most organizations establish targets and goals at the beginning o f the

year. These are intended to assist in the operation of a more effective quality system.

Table 11 displays the quality goals and metrics used for this model.

Table 11

Quality Goals and Metrics

Task Goal/Metric/T arget


Quality Records:
Complaints
CAPA On time closure o f all quality records
Investigations (manufacturing)
Quality Systems investigations

Engineering work orders On time closure o f all work orders

Reduction of human error rate.


Human error (Incident Log) Decrease of human-related errors by
50% from previous year.
Note. Prepared by the author of this paper as part of the project.
56
Targets and goals established through this project include the following:

• Quality Records: CAPAs are one of the most important issues in compliance,
for these tend to display the overall health of the quality system. Generally,
this is an area on which external auditors mostly focus. Because of their
importance, CAPAs need to be addressed thoroughly and promptly.
Recording, tracking, and preventing reoccurrence of non-conformities are the
main objective of the CAPA system. In the establishment of this model,
several verification steps have been created to ensure that correct actions are
being successfully implemented and reported.

• Engineering Work Orders: Instrument or part failures can cause a delay in


production and increase the waste of material. The engineering metric also
measures the on-time performance of the preventive maintenance program
and the availability/downtime of the machines/instruments.

• Human Errors: A lot of information is gained by understanding the causes of


these types of errors. When many non-conformities are attributed to human
error, re-training may not resolve the true root cause. By examining these
types o f errors, it is most commonly discovered that an effective action plan
may not have been enabled. These types of errors need to be fully studied to
enable the appropriate corrective action.

Upper management was expected to review model performance metrics and take

the appropriate action to enable the tools necessary to maintain compliance and

improvement efforts across the organization. At the completion o f this project, the quality

goals and metrics review collected during the execution of the pilot study showed that all

the established targets were met. See Table 12 for the goals and metrics summary.
57
Table 12

Summary o f Quality Goals and Metrics

Task Goal/ Metric/Target Accomplishment


Quality Records: On time closure > 90% Target met
Complaints of all quality
CAPA records
Investigations
(manu facturi ng)
Quality Systems
investigations
Engineering work On time closure > 90% Target met
orders of all work orders
Human error Reduction of < 50% from Target was met.
(Incident Log) human error rate previous years Human errors were
total decrease by >80%
Note. Tabulated by the author of this paper as part of the project.

The successful integration of the Risk Assessment model into Noven

Pharmaceuticals’ Risk Management System involved the cooperation of many

departments, not just the Quality team. Results obtained through this project

demonstrated a reduction in critical events and investigations by the application of the

model.
58
CHAPTER 5

SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS

Through the life cycle of a product, monitoring the risks can continue to ensure

the product remains acceptable and can determine if new risks have been encountered.

Information gathered from the Risk Management System and its model assists with this

monitoring.

As stated in Chapter 1, the purpose of this project was to create a Risk

Assessment Model could integrate risk assessment as part of the toolkit for quality

decision making by including risk assessment as part of the core quality subsystems

(change control, annual product review, validation, deviation management system,

complaints, etc.).

The objective o f risk management is rarely to eliminate all risk, but rather to

reduce risk to an acceptable level while maintaining feasibility and functionality (Global

Harmonization Task Force [GHTF], 2005).

The establishment o f this model assisted Noven with identifying and evaluating a

suspected quality-related risk and facilitating quick actions to minimize the quality

impact on the product and consequently ensuring the patient’s safety. This model was

designed to be integrated easily into the Risk Management program by utilizing the

existing processes in place for the control, tracking, and monitoring o f quality-related

matters. Benefits and process improvements incurred at any pharmaceutical

manufacturing facility by the implementation of this model include (ISO 14971,2012):


59
• Allows the company to leverage the risk assessment for use in other critical
activities, such as validation, in order to reduce effort required during
validation processes, as well as allow for more targeted validation
requirements.

• Allows for a more compliant state as risk assessments are built directly into
quality activities.

• Reduces the need for rationale documents or other non-routine documents in


quality activities.

• Maintains risk assessment in “current state,” thereby demonstrating


compliance with the ICH Q9 guidelines.

• Reduces potential errors by continually reviewing new potential risks and


enabling mitigation steps for unacceptable risk.

The Risk Management System, as restructured in this project, evaluated the data

collected through the Risk Assessment Model, measuring risks against established risk

performance indicators to determine if risks were sufficiently controlled. Periodic

reviews, established by the Risk Management System, determined the progress or

deviation from risk analysis tools. These tools, or risk assessment techniques, determined

if expected results were achieved and if risk assessment techniques or tools were being

properly used. The system, as established, uses the CAPA and change control systems to

maintain continuous improvements, determine preventive actions, and implement

reduction o f risks to prevent reoccurrences.

Advantages in the establishment of the Risk Management System and its model

include the following:

• It is a scientific and data-driven process; therefore, subjectivity is eliminated


from the process.
60
• It allows the ranking of risks and determines a prioritization of risks, reducing
product risk and ultimately benefiting the patient.

• It improves decision making by utilizing systems, providing consistency and


traceability.

• It encourages a corrective and preventive approach by utilizing a proactive


control o f risks and the expertise knowledge of a risk management team.

• It improves transparency by building trust between the organization and


regulators.

• It increases the awareness and knowledge of risk-based decisions, ultimately


assisting quality improvement professionals by placing the focus on
preventative actions rather than reactive actions

• It aids in maintaining a compliant state meeting all regulatory requirements


and guidelines.

The use o f an EQMS assists with the evaluation of key performance indicators.

The established system allows for the collection of data, the analysis of this data,

performance feedback, and the enabling o f an action plan. A basic indicator of

compliance is how the company measures its performance against a set of compliance

objectives. As previously stated, it is the goal of every the organization to ensure its

product is delivered on time and safely. The established Performance Metrics system

measures the number o f open investigations and CAPA action plans, the number of

effectiveness checks, timelines o f investigation closures, and reductions in investigations

(reduction of non-conformities). The goal of this model is to ensure continuous

monitoring and evaluation of non-conformities associated with the manufacturing area.

Because all systems are reviewed, the risks with the highest impact or highest-ranking

priority number are targeted for mitigation. Improvements in the QS are to be measured
61
through the evaluation o f the event, cause of the event, evaluation of failure, or gaps in

the process step. Performance and CAPA metrics establish a proactive measure to reduce

reoccurrences and mitigate risks.

As a result o f the implementation of this risk-based model, the pharmaceutical

manufacturing industry benefits by being able to make value-added decisions related to

the manufacturing of any product. Gains to be obtained by the establishment of this

model are the improvement of the quality system and related quality processes, the

manufacturing processes, and the targeted product.


REFERENCES
63
REFERENCES

American Society for Testing and Materials. (2009). Standard guide fo r risk assessment

and risk control as it impacts the design, development, and operation o f PA T

processes fo r pharmaceuticals manufacture [E2476-09], West Conshohocken,

PA: Author.

Brashear, J. P. (2010). Risk analysis and managementfo r critical asset protection

[RAMCAP Plus]. Hoboken, NJ: A. John Wiley & Sons, Inc.

BSM Consulting. (2011, January). Risk management in ERP Projects [White paper].

Retrieved from BSM Consulting: http://bsm-usa.com/publications/life-

sciences/risk-management-erp-projects-bsm-white-paper

FEMA. (2010). Review o f the Department o f Homeland Security's approach to risk

analysis. Retrieved from www.nap.edu/catalog/12972.html:

http://www.fema.gov/pdEgovernment/grant/2011/fyl l_hsgp_risk.pdf

Global Harmonization Task Force [GHTF]. (2005, May). Implementation o f risk

management principles and activities within a quality management system: Final

document. Retrieved from http://www.imdrf.org/docs/ghtf/final/sg3/technical-

docs/ghtf-sg3-nl5r8-risk-management-principles-qms-050520.pdf

Hopkin, P. (2012). Fundamentals o f risk management. Understanding, evaluating and

implementing effective risk management [2nd ed.]. London, UK: KoganPage.

ICH Q8 FDA. (2009, November). Pharmaceutical Development. Retrieved from

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf
64
ICH Q9. (2011, January). Quality risk management. Retrieved from

http://www.ema.euroija.eu/docs/en_GB/document_library/Scientific_guideline/20

09/09/WC500002873.pdf

ICH Q9 FDA. (2011, January). Q9: Quality risk management. Retrieved from

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073511 .pdf

International Conference of Harmonisation [ICH Q10 FDA]. (2009, April). Guidance fo r

the industry Q10 pharmaceutical quality system. Retrieved from

http://www.fda.gov/downloads/Drugs/Guidances/ucm073517.pdf

ISO 13485. (2012, July). ISO 13485:2003 [E]: Medical devices: Quality management

systems: Requirements fo r regulatory purposes. Retrieved from

http://webstore.ansi.org/FindStandards.aspx?SearchString=iso+13485%3a2012 &

SearchOption=0&PageNum=0&SearchTermsArray=null%7ciso+l 3485%3a2012

%7cnull

ISO 14971. (2012, July). ISO 14971:2012 Medical devices: Application o f risk

management to medical devices. Retrieved from

http://webstore.ansi.org/RecordDetail.aspx?sku=DIN+EN+ISO+14971 %3a2013

ISO 31000. (2009, November). ISO 31000:2009: Risk management: Principles and

guidelines-Risk assessment techniques. Retrieved from

http://www.iso.org/iso/home/standards/iso31 OOO.htm
ISO 31010. (2009, October). ISO 31010:2009: Risk management-Risk management

techniques. Retrieved from

http://webstore.ansi.org/FindStandards.aspx?SearchString=IEC%2fISO+31010+E

d.+l .0+b%3a2009&SearchOption=0&PageNum=0&SearchTermsArray=null%7c

IEC%2flSO+31010+Ed.+1.0+b%3a2009%7cnull

McCabe, S., & and Corcoran, L. (2010, September). Risk-based quality excellence. A

roadmap from product concept to process control [White paper]. Retrieved from

www.gxpsystems.com:http://www.gxpsystems.com/downloads/white-paper.pdf

Mollah, A. H., Long, M., & and Baseman, H. S. (2013). Risk management applications in

pharmaceutical and biopharmacuetical manufacturing. Hoboken, NJ: A. John

Wiley & Sons, Inc.

Pons, D. J. (2010). Strategic risk management: Application to manufacturing. Retrieved

from http://www.benthamscience.com/open/toimej/articles/V003/13TOIMEJ.pdf

Rodriguez-Perez, J. (2012). Quality risk management in the FDA-regulated industry.

Milwaukee, WI: ASQ Press.

U.S. Food and Drug Administration [USFDA]. (2004, September). Pharmaceutical

cGMPs fo r the 21st century-A risk based approach: Second progress report and

implementation plan. Retrieved from

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/Questio

nsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/ucml37175

.htm
66
USFDA. (2006, September). Guidance fo r industry quality systems approach to

pharmaceutical cGMP regulations. Retrieved from

http://www.fda.gov/downloads/Drugs/.. ./Guidances/UCM070337.pdf

USFDA. (2009, September). Questions and answers about current good manufacturing

practices fo r drugs. Retrieved from

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/

QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UC

M071836

USFDA. (2012, April). 21 CFR § 820: Quality system regulation. Retrieved from

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcff/CFRSearch.cfm7CFRPart

=820&showFR= 1

USFDA. (2012, August). 4-1: Warning letters. Retrieved from

http://www.fda.gov/ICECI/ComplianceManuals/RegulatoryProceduresManual/uc

ml76870.htm

USFDA. (2013, April 1). 21 CFR § 210: Current good manufacturing practice in

manufacturing, processing, packing, or holding o f drugs: General. Retrieved

from

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm7CFRPart

=210&showFR= 1

USFDA. (2013, May). About FDA: History. Retrieved from

http://www.fda.gov/aboutfda/whatwedo/history/default.htm
67
USFDA. (2014, June). Quality system [QSJ regulation/medical device good

manufacturing practices. Retrieved from

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketR

equirements/QualitySystemsRegulations/

USFDA Review. (2013). FDA Review. Retrieved from

http://www.fdareview.org/history.shtml

WHO. (2012, August). Retrieved from World Health Organization [WHO] guideline on

quality risk management:

http://www.who.int/medicines/services/expertcommittees/pharmprep/QualityRisk

Management-QASl 0-376 18082010.pdf

WHO. (2013). Annex 2: World Health Organization [WHO] guidelines on quality risk

management. Retrieved from

http://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2TR

S-981.pdf

WHO. (2013). General management topics: Risk management. Retrieved from

http://www.who.int/management/general/risk/en/
APPENDICES
APPENDIX A

APPLICATION OF RISK ASSESSMENT MODEL


70
TABLE OF CONTENTS

PAGE

TABLE OF CONTENTS......................................................................................................... 70

INTRODUCTION.................................................................................................................... 71

PROJECT CHARTER............................................................................................................. 72

SME MEETING LO G ............................................................................................................. 73

DATA GATHERING................................................................................................................ 74

PROCESS M AP....................................................................................................................... 75

FMEA TEMPLATE................................................................................................................. 76

PROTOCOL..............................................................................................................................80
71
INTRODUCTION

The purpose o f the pilot study was to demonstrate the potential for the integration

of the Risk Assessment Model intoNoven’s Quality Risk Quality Management System.

This pilot study was executed through the creation of a protocol; through this protocol

execution, all forms, templates, and workflows developed for the Risk Assessment Model

were utilized.

The pilot study was limited in its execution to include only the coating process at

the manufacturing stage. No other manufacturing process was analyzed through the

model.

Samples generated at the coating process (laminate units) continued through the

normal manufacturing and plant process in order to evaluate the effectiveness of the

model. The remaining departments-Engineering, Quality Assurance, Quality Control,

and Compliance-participated in the pilot study in their roles as described in the model.

All activities related to the execution of the pilot study were detailed in the

protocol. The protocol was successfully executed with results and conclusions provided

in the protocol report.


72

P roject C h arter
Project Title: Integrating Risk Base Modeling In Manufacturing To Drive Quality Decisions
Project Team
Executive Sponsor: Vice President o f Quality
Project Leader: Ivette Larralde-Valdes
Core Team: Six Sigma Specialist
Director o f Manufacturing
Manufacturing Supervisor
Sr. Director o f QA Manufacturing
Director o f Quality Compliance
Scope: Integrate Risk Assessment model into the manufacturing process.
Current State: Currently, risk management at Noven is governed by two SOPs; however these
SOPs are not aligned across areas o f the business such as with the change control,
investigations, complaints, and manufacturing processes. Procedures lack details
on defined tools/templates/data collection for risk assessment tasks to be used for
the evaluation and mitigation o f risks.
In order to continue on a path towards the relentless pursuit o f excellence, a Risk
Assessment Model will be integrated into the Risk Management program to
establish processes and procedures for quality risk assessments for our business
decision process.
Benefit to Customers/ Foster a culture o f proactive versus reactive assessment of risk through the
Business: delivering o f these:
• Provide a standardized approach to assessing the risk o f investigation(s),
CAPAs, and change controls;
• Provide better history/traceability/reference to support risk assessments;
• Enhance the assessment o f quality systems to ensure appropriate control o f risks
and regulatory compliance, and reduce liability;
• Improve identification, communication, and mitigation o f risks;
• Reduce patient risks and increase customer satisfaction;
• Provide a more science-risk based decision making process;
• Provide a systematic approach to risk management;
• Establish a cross-functional understanding o f risk management;
• Establish a risk lifecycle approach to monitoring.
Goals/Measurable • Establish a current state map;
Targets: • Review, revise and update risk management documents;
• Collect appropriate data and establish future state;
• Create and integrate model into manufacturing process;
• Collect performance metrics
• Evaluate gains
Timeline
Milestones Due Date
Plan Create Project Charter 6/23/2013
Do Define “as is” process, gather data, create Process Map, FMEA 8/22/2014
Do Development o f Model, pilot implementation o f model in manufacturing 10/3/2014
Check Evaluate effectiveness o f model, 2/2/2015
Act New process (model) implementation in all other areas o f the company 12/18/2015
73
SME meetings

SME Meeting Log for Integrating Risk Base Modeling In Manufacturing To


Drive Quality Decisions Project
Date Description SME
7/8/14 Coating room - overview of process Coating, Blending and Slitting
(CBS) 1st Shift Supervisor
7/11/14 Coating room - observe setup o f CBS 1st Shift Supervisor, CS
coating process, gathered information operators (6)
on all documents use for process
7/15/14 Coating room —observe coating CBS 1st Shift Supervisor, CBS
process in its entirety for Product A 2nd Shift Supervisor, CS
operators (12)
7/18/14 Coating room - observe coating CBS Supervisor, CS operators
process in its entirety for Product C (7)
7/21/14 Review o f Batch Records Product Release specialist
7/21/14 Review and examination of all CBS 1st Shift Supervisor, CS
documents used during operators (3)
manufacturing of Products A, B, and
C - draft Process Map
7/22/15 Review and examination o f all CBS 2nd Shift Supervisor
documents used during
manufacturing of Products A, B, and
C - draft Process Map
7/25/14 Finalize Process Map of “as is CBS 1st Shift Supervisor, CBS
process” 2nd Shift Supervisor, Director of
Manufacturing
7/31/14 Draft o f FMEA Director o f Manufacturing
8/5/14 Review of FMEA draft CBS 1st Shift Supervisor, CS
operators (3), Director of
Manufacturing
8/8/14 Review of FMEA draft/Finalizing CBS 2nd Shift Supervisor, CBS
FMEA 2nd Shift Supervisor, Director of
Manufacturing
8/11/14 Review of lot data for pilot 1. Larralde-Valdes, Six Sigma
implementation baseline Specialist 1, Six Sigma Specialist
2, QC Senior Scientist
74
Data Gathering

Year Number o f Products Total Number o f Lots Total number o f lots with
Reviewed Manufactured and investigations
Reviewed
2013 3 133 18

Responsible
Lot Reason for Investigation
Group
130205 QC Incorrect Swabs method used for testing (human error).
130201
130202
130306 QS Ethyl Acetate results for laminate lot 130306 were incorrectly stated on
LIMS Certificate o f Analysis.
ENG Pressure gauge o f roller sample station was found to be out o f calibration
(human error).
130424 QS LIMS lists the result for the average o f Product B laminate instead o f the
specified individual units; this misrepresents the status o f the results in
cases where some individuals do not meet spec for the product code.

130504 QC Extraneous Peak above LOQ (0.1%) found in Product A Laminate at RT


approx. 6.8 minutes for both active and placebo laminate.
QC Three lots o f Product A Polymer Blend produced OOT results for Total
Solids.
130614 MAG QAI noticed wrong pages (checked-marked as Product C) on Batch
record for Product A Laminate (human error).
130710 QC Sample preparation error cause OOS result for Product B (human error).
130725 MAG During coating process o f Product C laminate lot 130725 defect
(smudged print) was observed in the text o f the printed backing film.
130822 MAG During the coating process for Product A laminate lot 130822, smudged
print was observed on backing material roll 1.
130919 QS Ethyl Acetate results for Product B laminate lot 130919 were incorrectly
stated on LIMS Certificate o f Analysis (human error).
131004 QC Extraneous Peak above LOQ (0.1%) found in Product C Laminate at RT
approx. 6.8 minutes for both active and placebo laminate.
131011 MAG Incorrectly identified batch record pages; pages checked-marked as
Product A for Product C Laminate lot # 131011 batch record at time of
QAI inspection (human error).
131118 MAG Bubbles in the laminate during the coating process.
131123 MAG Expired Pouchstock material was used during pouching o f Product B lot
# 131123.
131209 MAG Product C backing material has ink smudges within the print.
131212 MAG Defective backing material discovered during the coating process
75
Process Map

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FMEA for the Coating Process Form Template

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parameters by operator
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part Material wasted material
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delivered 2) ln-process verification , 2) Coater head nozzle
of rollers movement inspection
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FMEA Page 1 of 3
76
77
FMEA for the Coating Process Form Template (cont’d)

FMEA Page 2of 3


78
FMEA for the Coating Process Form Template (cont’d)
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FMEA for the Coating Process Form Template - Risk Priority Number Grading

Severity o f Effect Occurrence Rating Detection


1. Extremely Remote
1. None 1. Almost Certain
<0.1/1000
2. Very slight effect 2. Remote <0.1/1000 2. Very High
3. Slight Chance -
3. Slight effect w/o equipment service 3. High
0.5/1000
4. Some Occurrences -
4. Slight effect w/ equipment service 4. Moderate High
1/1000
5. Occasional
5. Minor effect w/o equipment service 5. Moderate
Occurrences - 2/1000
6. Minor effect w/ equipment service 6. Moderate - 5/1000 6. Low
7. Moderate effect leading to
7. Frequent - 10/1000 7. Very Low
equipment/ process failure
8. Significant effect leading to
8. High -20/1000 8. Remote
equipment/ process failure
9. Critical effect leading to equipment/
process failure. Affects operator, or
maintenance personnel; safety and/or 9. Very high 50/1000 9. Very Remote
affects non-compliant with government
regulations with warning.
10. Hazardous, permanently disabling
equipment/ process. Affects operator, or
10. Certain Occurrence > 10. Absolute
maintenance personnel; safety and/or
100/1000 Uncertainty
affects non-compliant with government
regulations without warning.
80

nD\/en
P H A R M A C E U T I C A L S . INC.
Integrating Risk Base Modeling In
Manufacturing To Drive Quality Decisions
Protocol
09/05/14

Author Signature Date

Senior QC Compliance Yvette ‘JLarrafde- 08/25/14


Specialist
Ivette Larralde Valdes Date

Author Signature Date

09/02/14
Director of Manufacturing directorof'ZfiCanuj'acturiny
Director of Manufacturing Date

Author Signature Date

08/29/14
Director of Quality 'foirectcr afity ‘Xjontref
Control Director of Quality Control Date

Author Signature Date

09/05/14
Director of Change 3&irector Z^Canajement
Management Director of Change Management Date
81
TABLE OF CONTENTS

PAGE

1. OBJECTIVE......................................................................................................................... 82

2. INTRODUCTION............................................................................................................... 82

3. RESPONSIBILITIES.......................................................................................................... 82

4. EXECUTION OF PROTOCOL..........................................................................................83

5. RESULTS AND CONCLUSIONS.................................................................................... 87

6. ATTACHMENT.................................................................................................................. 91

7. SIGNATURE PA G E........................................................................................................... 95
82
1. OBJECTIVE

The objective of this Protocol is to pilot the Risk Management model in the
manufacturing area for the coating process o f Products A, B, and C.

2. INTRODUCTION

A risk-base model has been created to identify product and process risks, evaluate the
level o f risk, and establish a method to use statistical tools to assist in the mitigation
o f these risks. This model will be integrated into the Quality System and will become
part of Risk Management system.

3. RESPONSIBILITIES

This pilot is to be executed by the Core Team. Areas o f execution and responsibilities
are listed in the following sections.

3.1. MANUFACTURING

3.1.1. Provides the personnel required to carry out the manufacturing process and
execution o f processes established in model.

3.1.2. Adheres to protocol and/or appropriate documents.

3.1.3. Ensures all personnel involved in the execution of the protocol are properly
trained and adhere to all Good Manufacturing Practices (GMP) and
applicable Noven Standard Operating Procedures (SOPs).

3.1.4. Reviews and approves protocol, execution of protocol, and subsequent


report.

3.2. ENGINEERING

3.2.1. Provides personnel to carry out any repairs, performance maintenance,


calibration or unexpected repairs, as required.

3.2.2. Ensures all personnel involved in the execution o f the protocol are properly
trained and adhere to all Good Manufacturing Practices (GMP) and
applicable Noven Standard Operating Procedures (SOPs).

3.3. QUALITY SYSTEMS


3.3.1. QUALITY ASSURANCE

3.3.1.1 .Ensures all manufacturing process adhere to all GMP.

3.3.1.2.Reviews all manufacturing batch records and executes material final


disposition/release of material and samples to manufacturing and for
testing.

3.3.1.3.Reviews and approves protocol, execution of protocol, and subsequent


report.

3.3.2. QUALITY CONTROL

3.3.2.1 .Provides the personnel necessary to perform testing.

3.3.2.2.Ensures adherence to protocol.

3.3.2.3 .Ensures all personnel involved in the execution of the protocol are
properly trained and adhere to all GMP, applicable Noven SOPs, and
Standard Testing Procedures (STPs).

3.3.2.4.Reviews and approves protocol, execution of protocol, and subsequent


report.

3.3.3. QUALITY COMPLIANCE

3.3.3.1 .Reviews all Complaints per product.

3.3.3.2.Reviews all investigations generated per product (Notice of Events,


SIC O D s- Systems Investigations Customer Complaints Out of
Specifications and Deviations, OOS/OOT - Out of Specifications/Out
of Trends).

3.3.3.3.Generates reports for all investigations and assists in data analysis

EXECUTION OF PROTOCOL

4.1. Coating

Coating of the selected product is executed in accordance to the established


documents. Coat Product A (or B or C) at the target setting in accordance with
the batch record and associated SOP.
84
Samples within the coat weight guideline would be expected to meet
specification, whereas samples not within the coat weight guideline may or may
not meet specifications. The need for culling is not unexpected and would not
constitute a process failure.

Process

Process Parameters recorded in the Master Batch Record.

Table 1

Coating Process Parameters

Parameter Setting
Web Speed 10RPM
Drying Temperature Zone 1 170°F
Tolerance 165-175T
Drying Temperature Zone 2 180°F
Tolerance 175-185T
Drying Temperature Zone 3 200°F
Tolerance 195-205 °F
Drying Temperature Zone 4 200°F
Tolerance 195-205 °F
Air Flow Zone 1 Inlet 18CFM
Tolerance 15-21 CFM
Air Flow Zone 2 Inlet 18CFM
Tolerance 15-21 CFM
Air Flow Zone 3 Inlet 30 CFM
Tolerance 27-33 CFM
Air Flow Zone 4 Inlet 30 CFM
Tolerance 27-33 CFM
Laminator Pressure 70 PSI
Tolerance 60-80 PSI
Kettle Speed 10RPM
Tolerance 9-11 RPM
Coat Width 19.4375 inches

These are the parameters and conditions used during the execution of the
protocol. Any issues encountered during the coating process were processed
through the FMEA fo r the Coating Process Form and process was re-adjusted
85
accordingly. Any Engineering work orders for non-scheduled work generated
during this pilot test was appropriately documented.

4.2. Quality Control Laboratory Analysis

Samples were tested in accordance with the established testing procedures. The
QC Laboratory reported test results and compared results to acceptance criteria.

As applicable, the QC Laboratory initiated investigations when the acceptance


criteria were not met.

Analytical testing

Table 2

Analytical Testing Parameters

Test Specification
Appearance A translucent, pressure-
sensitive adhesive with a
translucent, printed
backing on one side and a
release liner on the other.
Identification (by HPLC) Compares to standard
Potency
Average for Lot 3 .2 7 -3 .9 9 mg/unit
90-110%LC
Individual Units 3.27 - 3.99 mg/unit
90-110%LC
Residual Solvents
Ethyl Acetate <0.15%
Isopropyl Alcohol < 0.5%
Toluene < 0.089%

Testing was conducted as per Specification and STP.

4.3. Change Control Management

The Change Control specialist provided all documents used during the execution
of the protocol. Batch Record numbers were not required as all batch records
were generated electronically through the MES (Master Electronic System). All
specifications, STPs, SOPs and forms used during the execution of protocol were
86
current and were made available, as requested. No Planned Departures were
initiated during this protocol execution; therefore no request for a Planned
Departure number was initiated.

4.4. Quality Systems Support Group

4.4.1. Investigations Specialist

The Specialist was responsible to gather all information from previous lots
investigations (designated previous years) for evaluation and current lots
investigations. A total of 119 lots were reviewed from 2011 - 2013 and a
total o f 125 lots from 2014 - 2015 (Q l). Related product investigations
opened for the products under study was compiled. Results are detailed in
Table 3.

4.4.2. Complaints Specialist

The Specialist reported if any complaints for Product A (or B or C) were


recorded for previous lots (for the designated years in this evaluation) and
current lots. Compiled metric report and measured results against metrics.
Complaints data will not be considered for this pilot because the protocol
execution timeframe did not allow for enough time to see release lot data
vs. client information data from market as it relates to client complaints.

4.4.3. Six Sigma Specialist

The Specialist collected all documentation and data results from the
coating/manufacturing and QC laboratory groups. The following items
were reviewed: Manufacturing Delays Log (from Batch Record),
Engineering Repair Work Orders, QC Laboratory non-conformities
reports, and manufactured lots Investigations.

Analysis o f results through model are shown in Table 3


87
Table 3

Tabulation o f results prior to model implementation and after model implementation

Prior to model After model


Lots manufactured Lots manufactured
in 2013 and 2014 in 2014 (Q4) and
(Q1 to Q3) 2015 (Q l)

Client Complaints * *
No critical events
Manufacturing Delay log One (1) event
recorded
Manufacturing
Non-conformance delay Eight (8) events Five (5) events
log
Engineer
Non-conformance delay One (1) event One (1) event
log
QC Laboratory Data
Analysis/Data Trending
Five (5) events Three (3) events
and Non-conformance
reports
Quality Systems
Three (3) events Zero (0) events
Investigations
Investigations due to
Six (6) One (1)
human error
* Complaints data will not be considered for this pilot because the protocol execution
timeframe did not allow for enough time to obtain release lot data vs. client information
data from market as it relates to client complaints.

5. RESULTS AND CONCLUSION

At the close o f the execution o f this protocol, lots of Product A, B, and C were processed
through the model. A total of 125 lots were manufactured from October 1, 2014 to March
31,2015.

Coating Process

All parameters and conditions were met during the execution of the protocol.
Any issues encountered during the coating process were analyzed through the
FMEA fo r the Coating Process Form (see Attachment) and process was re­
adjusted accordingly. The FMEA fo r the Coating Process Form used was the
template created for the project. Only new risks encountered during this protocol
execution were evaluated through the FMEA regardless of the RPN rating. This
88
evaluation was performed to determine which appropriate action was required to
be executed for the reduction, control and mitigation of the risk. Engineering
work orders for non-scheduled work were not generated during this pilot test.

Quality Control Laboratory Results for Testing

Testing was conducted as per Specification and STP. A total of 125 lots were
received and tested during the protocol execution period:

Twenty-one (21) lots were investigated for Out o f Trend (OOT) results

Three (3) lots were investigated for Out of Specification (OOS) results

A total of four (4) investigational records were opened

- One (1) investigational record was determined to have occurred due to


human error

A reduction in the number o f investigational records opened during the protocol


execution was demonstrated; in addition, all the established metrics for the project were
met. Investigations opened during the protocol execution are listed in Table 4.
89
Table 4

Investigations generated after integration o f the model

Number of Products Total Number o f Lots


Year
Reviewed Manufactured and Reviewed
2014 4th Quarter to
3 125
2015 1st Quarter

Responsible
Lot Reason for Investigation
Group
141006 QC Retention time shift due to environmental conditions in QC Laboratory
(OOS).
141021 QC Incorrect preparation o f sample in QC laboratory yielding an OOS result
(human error).
141029 MAG At the end o f the coating process, batch size was not updated in the
electronic batch record by the coating operators.
141106 QC OOT results obtained during QC laboratory testing (DU testing).
OOT results obtained during QC laboratory testing (Potency testing).
141211 MAG Wrinkles observed on the material prior to coating, material rejected.
CAPA opened.
141212 MAG Cleaning Failure for Pump parts during 48-Foot Coater Line Clearance.
150106 MAG Evidence o f oil noticed in the bottom o f the 48-Foot coater oven during
the B-Clean. CAPA opened.
150108 MAG Particles were observed in the rollers during A cleaning.
150203 ENG 48-Foot Coater shut down during coating process, oxidizer panel stated
"Flame Guard Fault" as reason for the shutdown. CAPA and EC
opened.

O f the number of events investigated during the protocol execution, only (1) of the events
was processed through the FMEA. The other four (4) events did not affect coating
process as these events were discovered prior to coating o f material. Updated FMEA is
shown in the Appendix.

Evaluation o f all opened investigations determined of the ten (10) total investigations,
three (3) corrective actions (CAPAs) and one (1) effectiveness check (EC) were opened.
Evaluation o f these records through the Risk Assessment model and the Risk Assessment
Form (risk matrix) determined all the appropriate actions were taken to evaluate risk and
to establish the risk treatment. All CAPAs have been closed, however the one EC remains
open. Evaluation of the results has concluded the Quality Goals and Metrics were met
during this pilot project. Metrics are summarized in Table 5.
90
Table 5

Quality Goals and Metrics

Task Goal/ Metric/Target Accomplishment


Quality Records: On time closure > 90% Target met
o f all quality
Complaints records > 90% Target met

CAPA > 90% Target met

Manufacturing > 90% Target met


Investigations
Quality Systems > 90% Target met
Investigations
Engineering work On time closure > 90% Target met
orders o f all work orders
Human error 1. Reduction of 1. < 3 . 5 errors 1. Target met. Only
(Incident Log) human error per month (per one (1) event per
rate, site) protocol execution
2. Decrease of 2. < 5 0 % from timeline
human-related previous years 2. Human errors were
errors. total decrease by > 80%.
Target met

It has been concluded the Risk Assessment model was successfully integrated into the
manufacturing process, specifically the coating process. Lastly, by the integration of the
model, a reduction in the number o f investigations was obtained.

All quality goals and metrics for this project have been met.
91
ATTACHMENT
Failure Mode and Effects Analysis
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92
ATTACHMENT (cont’d)
Failure Mode and Effects Analysis

FM EAPag:2of3
93
ATTACHMENT (cont’d)
Failure Mode and Effects Analysis

FMEA Pin 3 of3


94
Table 6

FMEA Scale —Risk Priority Number Grading

Severity o f Effect: Occurrence Rating Detection:


1. None 1. Extremely Remote <.01/1000 1. Almost Certain
2. Vety slight effect 2. Remote - 0.1/1000 2. Very High
3. Slight effect w/o equipment service 3. Slight Chance - 0.5/1000 3. High
4. Slight effect w/ equipment service 4. Some Occurrences - 1/1000 4. Moderate High
5. Minor effect w/o equipment service 5. Occasional Occurrences - 5. Moderate
2/1000
6. Minor effect w/ equipment service 6. Moderate - 5/1000 6. Low
7. Moderate effect leading to 7. Frequent- 10/1000 7. Very Low
equipment/process failure
8. Significant effect leading to 8. High - 20/1000 8. Remote
equipment/process failure
9. Critical effect leading to 9. Veiy High 50/1000 9. Very Remote
equipment/process failure. Affects
operator, or maintenance personnel; safety
and/or affects non-compliant with
government regulations with warning
10. Hazardous, permanently disabling 10. Certain Occurrence 10. Absolute
equipment/process. Affects operator, or >100/1000 Uncertainty
maintenance personnel; safety and/or
affects non-compliant with government
regulations without warning
6. SIGNATURE PAGE
Prepared by:

Ivette Larralde-Valdes
Senior QC Compliance Specialist

Reviewed by:

d ir e c to r iiCy X jo n tre f ol / 15/15

Director of Quality Control

Reviewed by:

■f)irt‘c t e r r / "\ 4<zntijtirturin(j ol/l;% /l

Director of Manufacturing

Approved by:

d e n ie r d i r e c t o r cj^'&grffcZfyCanuJ'acturing o l / l l / l ‘t

Senior Director QA Manufacturing

Approved by:

3& irectcr l i t y X jom y/iance 0 1 / 2 / /

Director of Quality Compliance


APPENDIX B

AUTHORIZATION COMMUNICATION
97

nD\/en
From: Jones, Joseph
Sent: Tuesday, July 30, 2013 7:51 AM
To: Larralde-Valdes, Ivette
Cc: Amanatides, Peter
Subject: Authorization to Use Information for Master’s Thesis Project

Dear Ivette:
Peter Amanatides and I have reviewed your materials and plan for th e M aster's Thesis
Project "Integrating Risk Based Modeling in Manufacturing to Drive Quality Decisions"
and you have our authorization to use th e Noven information as described in th e
materials. Please feel free to share this authorization docum ent with Dr. Krivokuca and
others at California State University Dominguez Hills involved in th e project.
Regards,
Joe Jones

Joseph C. Jones
Vice President - Corporate Affairs
Noven Pharmaceuticals, Inc.
305-964-3101