DEVELOPMENT OF A VALIDATION METHOD FOR THERMOPLASTIC INJECTION MOLDING PROCESSES FOR THE CONTRACT MEDICAL DEVICE MANUFACTURER

Catherine A. Petretich

A Project Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of MASTER OF INDUSTRIAL TECHNOLOGY May 2005 Committee: John W. Sinn, Chair Donna Trautman Todd C. Waggoner

This project is dedicated to my parents, Catherine and Stephen Petretich, for instilling the values of hard work and dedication, importance of education, and respect for others.

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I would like to extend sincere appreciation to the College of Technology, for the opportunity to further my education, with a graduate assistantship in the Department of Technology Systems. The appreciation extends to the graduate college and departmental staff, especially Kim Strickland and Judy Jennings, who go above and beyond in keeping customers satisfied. Gratitude is extended to my project committee members, Dr. Trautman and Dr. Waggoner. Thank you for participating on my project committee. Your input and areas of expertise added tremendous value to the project. Your participation was instrumental in fulfilling my degree requirements. Special thanks are entitled to Dr. Sinn, my committee chair and graduate advisor. I am very grateful to have you not only as a teacher, but as a mentor as well. You have developed my intellectual abilities and academic background. Additionally, you have managed to contribute to my growth as a Quality Professional, by building my confidence and reinforcing my capabilities. Thank you for expanding my knowledge of this weird stuff! Appreciation is extended to the Woodbridge Corporations Fremont Plant, for granting me an internship and eventually fulltime employment. At Woodbridge, I was able to conduct school projects and experience quality systems in action. My experiences at the Fremont facility were truly valuable and have contributed to my professional development. I would like to thank my current employer, O-I, and especially Dennis Swary, my supervisor, for encouraging my project topic and allowing me to present, at the development park. Thank you for the opportunity to develop new skills, challenge existing abilities, and advance professionally. Finally, I am very thankful for my sisters: Debbie, Chris, Judy, and Cindy! I immensely appreciated all of your charitable donations received during my early graduate school days. Also, I especially appreciated your wisdom and encouragement. Thank you for being my sisters and for your love and support!

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TABLE OF CONTENTS Page CHAPTER I. INTRODUCTION . Nature of the Problem . Problem Statement .. Significance of the Problem . Objectives . Assumption .. Terminology Endnotes .. CHAPTER II. REVIEW OF LITERATURE Process Validation . Injection Molding .. Tools Of The Trade .. CHAPTER III. METHODOLOGY .. Problem Restatement . Research Design . Project Timeline . CHAPTER IV. DELIVERABLES AND GAP ANALYSIS RESULTS .. CHAPTER V. CONCLUSION AND FUTURE IMPLICATIONS.. Bibliography .. 4 4 6 6 8 8 9 10 11 11 13 20 22 22 22 30 XX XX 31

CHAPTER I.
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INTRODUCTION

Nature of the Problem In order to keep a competitive edge, companies are attempting to expand their core competencies. The core expansion may impact a companys regulatory umbrella, since it often involves expansion from industry with minimal regulations to industry with more and stringent regulations. This is most evident in the medical device sector of the healthcare market. Outsourcing part or all of assembly operations is becoming common practice for medical device manufacturers. A June 1999 poll identified that 80% of medical device manufacturers reported outsourcing part of their business, 71% reported use of contract services increased between 6 and 15% in the previous two years, and 35% expected their outsourcing to increase by more than 10% within their companies in the following two years (Sparrow, 1999). The statistics indicate an upward trend in the medical device market for polymerbased products as is evident with increased alliances between medical device manufacturers and the thermoplastic injection molding industry (Hermanson, 1998). Such alliances can pose challenges to quality systems. The medical device manufacturer is challenged by finding contract manufacturers that can understand and assimilate measures into quality systems that assure compliance with their governing body, the Food and Drug Administration (FDA). Changes to the good manufacturing practices (GMPs) in 1996, by the FDA, put more emphasis on medical device manufacturers to place controls on their component suppliers to assure that the components are safe and effective for use as designed. Since then, device owners are requiring their suppliers to

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implement GMP-compliant quality systems, which include process validation (Owens, 2001). In such alliances, the injection molder, as a contract manufacturer, is challenged with meeting expectations of process validation for plastic molding and component assembly processes. In addition, understanding of and assimilation of the applicable regulations, such as those instated by the FDA, must occur in order to be able to communicate with the customer and to meet their needs. Furthermore, not all established quality procedures may be adequate to meet a FDA regulated customers requirements. Device

firms want to be able to evidence, to the FDA during audits, that their device components have been verified or manufactured using validated processes (Owens, 2001). Thus, the injection molder, aspiring to become a contract medical device manufacturer, must review their current infrastructure and quality system to determine changes that must occur in order to achieve compliance to applicable FDA regulations and in turn appeal to medical device manufacturers. One of their biggest undertakings

is comprehension and interpretation of the Quality System Regulation, 21CFR-Part 820. The Quality System Regulation is the FDAs directive for medical device manufacturers. When outsourcing part(s) of the manufacturing process, the device manufacturer often delegates parts of the code to the contract manufacturer. The most delegated code requirement to the injection molder is section 820.75, Process Validation. This section of the regulation dictates: where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established

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procedures (21CFR 820.75). This presents the molder with the challenge of how to qualify related equipment, such as the mold and press as well as the injection process. Although the FDA has published guidelines for process validation, see Quality Management Systems Process Validation Guidance, GHTF/SG3/N99-10:2004 (Edition 2). Contract molders struggle with creating an efficient and well documented method to achieve validation of the molding process. For this reason, a procedure that describes how to conduct, what tools to employ, and what data to document to achieve process validation for injection molding, that is based on FDA guidelines and that would appeal to medical device manufacturers is advocated. Problem Statement The problem of this study is to develop a validation procedure for thermoplastic injection molding processes for the medical device contract manufacturer. Significance of the Problem In the United States, the overseeing body of medical device manufacturing is the Food and Drug Administration (FDA). It is a public safety agency, which was established to correct industry abuses in the early 1900s (Dickinson, 2000). The FDAs directive for medical device manufacturers is the Quality System Regulation, 21CFR-Part 820. Per the regulation, FDA advocates process validation, specifically, section 820.75 Process Validation. For medical device manufacturers, the regulation dictates: where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures (21CFR 820.75). Thus, manufacturers must be able to demonstrate compliance to this regulation, when applicable.

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There is no doubt, that the validation rule, when applicable, is enforced by the FDA. For instance, Vanguard Medical Concepts, of Lakeland, Fl, received a warning letter, known as a 483, from the FDA for failure to validate a cleaning process with a high degree of assurance per 21 CFR 820.75(a) (Dickinson, 2000). During audits, FDA is expecting to evidence documented validations. This entails having a validation protocol, which explains the methods used to validate a process and a report, which interprets the data collected during validation and concludes if the process has been validated or not. FDA is expecting the device manufacturer to show that their processes are in control. They will be expecting manufacturers to demonstrate that they can maintain control and will be auditing to see how much control they have over their processes (Allen, 2004). Therefore, the device manufacturer will have high expectations for their suppliers. Demand for process control is becoming evident to contract injection molders. According to the injection molder Unimarks Joe Pack, a lot of customers are telling us: Youre required to have your process in control. Injection molders, like DeRoyal Plastics Groups Bill Pittman, claims process monitoring is a big selling point for them (Leventon, 2001). Process validation is the basis for process control. A well orchestrated validation will identify variables that impact the process significantly, challenge the process by assessing performance at the processing extremes, and conclude the optimum processing window. Furthermore, it forces a process to be well defined from the aspects of identifying equipment, materials, inspection systems, and procedures that are required for production. Once a process is defined and the impacting variables are identified, process control can be achieved. Therefore, process validation not only ensures compliance to

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regulations, but encourages process improvement and ensures consistent high-quality output. It also can reduce costs, which is good for business (Sahni-Larsen, 1996). [Find and add stats. of: non-compliance citations to section 820.75 (483s). Cite molders struggling with qual. processes, impacted by time constraints (time-to-market) .] Objectives For this project, four objectives were designed to address the problem. They are as follows: 1. To establish what parts of and related methods for validating an injection molding process. 2. To establish a method for worse-case testing for the injection molding process. 3. To establish a procedure that describes the methods determined in objectives one and two. 4. To establish a template for documenting data collected from performing the procedure, as established in objective three. Each objective is detailed in terms of its accomplishment in chapter III, methodology. Assumptions The following assumptions were made for the project. 1. The developed procedure applies to prospective process validation. 2. Although the scope of the developed procedure includes validation guidelines for assembly, packaging, and finishing processes, the project scope was limited to validation of injection molding processes.

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Terminology There are many terms utilized in the medical device and molding industries, as well as in the process validation discipline. Terms unique to this project are listed below. Footnotes were used to reference the sources, which can be found at the end of this chapter, in the section titled ENDNOTES. Acceptable Quality Level (AQL) - The maximum percent non-conforming (or the maximum number of nonconformities per hundred units) that, for the purposes of sampling inspection, can be considered satisfactory as a process average. Good Manufacturing Practices (GMP) - Original title of the code of federal regulations for medical device manufacturing, today referred to as Quality System Regulation, 21 CFR Part 820. Installation Qualification Establishing documented evidence that process equipment and ancillary systems have been installed according to the manufacturers recommendations and are consistent with the equipment ordered. Operational Qualification Establishing documented evidence that equipment operates as intended in accordance with pre-established limits and tolerances, procedures, and specifications. Performance Qualification Establishing documented evidence that a process is effective and reproducible. Process Validation Establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications. Prospective Validation Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the products characteristics. Thermoplastic Injection Molding A process by which, the plastic material is melted and then injected into a mold cavity and cooled to a shape that reflects the cavity and core. Validation Confirmation by examination and provision of objective evidence that the particular requirement for a specific intended use can be consistently fulfilled. Validation Protocol A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.

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Food and Drug Administration (FDA) The United States regulatory authority charged with, among other responsibilities, granting IND and NDA approvals. ENDNOTES

Medical Device Quality Systems Manual: A Small Entity Compliance Guide

http://www.fda.gov/cdrh/dsma/gmpman.html.

Quality System Regulation, Code of Federal Regulations, 21CFR-Part 820 TECH MOLD INC., What Is A Mold?: An Introduction to Plastic Injection Molding
and Injection Mold Construction, (1993-1999): 2-1. American Society For Quality Control, American National Standard: Sampling Procedures and Tables for Inspection by Attributes, ANSI/ASQC Z1.4-1993.

CHAPTER II.
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REVIEW OF LITERATURE The purpose of this chapter is to examine literature relevant to process validation, thermoplastic injection molding, and the tools used to conduct process validation. PROCESS VALIDATION Per the Quality System Regulation, 21CFR-Part 820, FDA advocates process validation, specifically, section 820.75 Process Validation. For medical device manufacturers, the regulation dictates: where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures (21CFR 820.75). Thus, medical device manufacturers are requiring their contract manufacturers to be capable of process validation. In addition to the regulatory requirements, there are many reasons for validating processes. A properly validated process will yield little scrap or rework and result in increased output. Consistent conformance to specifications will result in fewer complaints and recalls. Also, the validation documentation will contain data that can support improvements in the process or the development of the next generation of the process (http://www.fda.gov/cdrh/dsma/gmpman.html). Process validation is defined, by the FDA, as establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications. According to the FDAs Guideline on the General Principles of Process Validation, it suggests to device manufacturers to include preliminary considerations and five formal elements in a prospective process validation. Prospective validation is a type validation that is conducted prior to the distribution of either a new product, or
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product made under a revised manufacturing process, where the revisions may affect the products characteristics. These elements are; installation qualification, process performance qualification, product performance qualification, revalidation, and documentation (Weese and Buffaloe, 1998). Before process validation can begin, there are preliminary activities that must occur. These activities include defining the product to be produced and how it will be produced. This includes defining the product in terms of performance characteristics, translating the characteristics into specifications, and considering the products end use (Weese and Buffaloe, 1998). Most of these activities are accomplished during product design and confirmed through design validation. In summary, in order to validate, there must be specifications to validate against. Once the specifications are determined, process validation can begin. Process validation can be broken down into three phases: Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). Since injection molding is accomplished using equipment, an installation qualification must be defined for injection molding. The installation qualification creates objective evidence that the equipment to be used in a process is constructed and installed according to the approved design criteria (Schikora, 2000). It establishes by objective evidence that all key aspects of the process and ancillary equipment adhere to the manufacturers approved specifications and that the recommendations of the equipment supplier have been considered. Items to consider for the IQ phase are listed in Table I. Some validation activities may be performed at the equipment suppliers site prior to shipping the equipment. However, it is usually not

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advantageous to rely solely on the equipment suppliers validation results. It is ultimately the medical device manufacturer or sub-contractor that is responsible for evaluating, challenging, and testing the equipment and deciding whether the equipment is suitable for use in manufacturing the device (GHTF/SG3/N99-10:2004(Edition 2)). INSTALLATION QUALIFICATION CONSIDERATIONS Equipment Design Features (i.e. materials of construction cleanability, etc.) Installation conditions (wiring, utilities, functionality, etc.) Calibration, preventative maintenance, cleaning schedules Safety features Supplier documentation, prints, drawings, and manuals Software documentation Spare parts lists Environmental conditions (such as clean rooms requirements, temperature, humidity) Table I: Installation Qualification Considerations Source: GHTF/SG3/N99-10:2004(Edition 2) The operational qualification serves to test any operational aspects of the installed equipment. In addition, it also establishes the operating parameters for the process, in this case- injection molding. The process parameters should be challenged to assure that they will yield a product that meets all defined requirements under all anticipated manufacturing conditions. This challenging is often referred to as worst case testing. Items to consider including into the OQ phase are listed in Table II (GHTF/SG3/N9910:2004(Edition 2)). OPERATIONAL QUALIFICATION CONSIDERATIONS

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Process control limits (time, temperature, pressure, line speed, setup conditions, etc.) Software parameters Raw material specifications Process operating procedures Material handling requirements Process change control Training Short term stability and capability of the process (latitude studies or control charts) Potential failure modes, action levels, and worse-case conditions Use of statistically valid techniques such as screening experiments to establish key process parameters and statistically designed experiments to optimize the process can be used during this phase. Table II: Operational Qualification Considerations Source: GHTF/SG3/N99-10:2004(Edition 2) After the IQ and OQ are completed, the performance qualification can begin. The performance qualification serves to demonstrate that a process will consistently produce acceptable product under normal operating conditions. Items to consider for the PQ phase are listed in Table III (GHTF/SG3/N99-10:2004(Edition 2)). During the PQ, validations lots of the product are produced under both normal and worst-case process parameters with normal operators and normal in-process controls (Schikora, 2000). Since most manufacturing procedures permit a number of process parameters to vary within a set operating window, most manufacturers have difficulty in choosing a reasonable set of extreme operating conditions for the qualification. In addition, the question of the number of lots or batches that should be made and sampled often arises

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during this phase. Statistical rationale should be utilized to determine the amount of product to produce during the PQ run. In the absence of statistical rationale, the common reference of three batches is a suggested minimum (Weese and Buffaloe, 1998).

PERFORMANCE QUALIFICATION CONSIDERATIONS Actual product and process parameters and procedures established in the OQ Acceptability of the product Assurance of process capability as established in OQ Process repeatability, long term process stability Table III: Performance Qualification Considerations Source: GHTF/SG3/N99-10:2004(Edition 2)

INJECTION MOLDING As previously stated, the foundation for achieving validation is an understanding of the process requiring validation. Since the primary objective of this project is to develop a method for validating an injection molding process, the injection molding process and all related inputs must be understood. Thermoplastic injection molding is defined as a

process by which plastic material is melted and then injected into a mold cavity. Once the melted plastic is in the mold, it cools to a shape that reflects the mold cavity and core. The form obtained is referred to as the finished part (TECH MOLD INC., 1993-1999). Injection Molding Equipment There is equipment specific to injection molding. injection molding is further explained in this section. Press The required equipment for

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There are several types of injection molding machines or presses available with different methods for blending, melting, and injecting the polymer into the mold. They are available in a range of sizes, offer choices in clamp tonnage, machine capacity, and screw design, depending on the needs of the application (Miller, 1996). Injection molding machines can generally be classified into three categories, based on machine function: 1) General-purpose machines, 2) Precision, tight-tolerance machines, and 3) High-speed, thin-wall machines. A typical injection molding machine is comprised of the following major components: 1) Injection System, 2) Hydraulic System, 3) Mold System, 4) Clamping System, 5) Control System. Figure 1 illustrates the major components (http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm).

Figure 1: A single screw injection molding machine for thermoplastics

Source: http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm

The following provides a brief description for each of the major injection molding machine components.

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Injection System The injection system is comprised of a hopper, a reciprocating screw and barrel assembly, and an injection nozzle. Figure 2 illustrates the injection system. This system contains and transports the plastic as it moves through the feeding, compressing, degassing, melting, injection, and packing stages (http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm).

Figure 2: A singles screw injection molding machine for thermoplastics, showing a plasticizing screw, a barrel, band heaters to heat the barrel, a stationary platen, and a movable platen.
Source: http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm

As illustrated by Figure 2, the hopper serves to hold the thermoplastic material that is supplied to molders in the form of small pellets. The pellets are gravity-fed from the hopper into the barrel and screw assembly. The barrel of the injection system supports the reciprocating and plasticizing screw. This screw is used to compress, melt, and convey the material. The nozzle connects the barrel to the sprue bushing of the mold and creates a seal between the barrel and mold. The nozzle temperature should be set to the materials melt temperature and the material suppliers recommendations.

Mold System
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The mold system is comprised of tie bars, stationary and moving platens, as well as molding plates that house the cavity, sprue, and runner systems, ejector pins, and cooling channels, as exhibited in Figure 3. The mold acts as a heat exchanger, where the melted thermoplastic solidifies into the shape and dimensions of the cavity. The mold system, as shown, is an assembly of platens and molding plates typically made of steel and shapes the plastic inside the mold cavity, or cavities, and ejects the molded part (http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm).

Figure 3: A typical three-plate molding system.

Source: http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm

Hydraulic System The hydraulic system of an injection molding machine gives the power to open and close the mold, build and hold the clamping tonnage, turn the reciprocating screw, drive the reciprocating screw, and energize ejector pins and moving mold cores. The hydraulic system is comprised of several components including pumps, valves, hydraulic motors, hydraulic fittings, hydraulic tubing, and hydraulic reservoirs (http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm).

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Clamping System The clamping system serves to open and close the mold and supports and carries the other mold parts. It also creates force to prevent the mold from opening (http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm). Control System The control system permits consistency and repeatability in machine operation. It monitors and controls the processing parameters, including temperature, pressure, injection speed, screw speed and position, and hydraulic position. The process control has a direct impact on the final part quality and the process economics (http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm). This system will be key for validation. Injection Molding Cycle Now that there is a basic understanding of the injection molding equipment, the injection molding process must be understood. The injection molding cycle can be broken down into four phases: fill, pack, hold, and cooling/plastication. See Figure 4. The process begins with mixing and melting of resin pellets. The molten polymer moves through the barrel of the machine and is forced, through injection, into the steel mold. As the plastic fills and packs the mold, the part takes the molds shape and begins to cool. The molded part is then ejected from the mold and ready for any finishing steps and/or assembly (Miller, 1996).

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The Injection Molding Cycle

End Start

Eject Fill Pack Hold Cool/Plastication

Figure 4: The Injection Molding Cycle

Source: TECH MOLD INC., What Is A Mold? : An Introduction to Plastic Injection Molding and Injection Mold Construction, (1993-1999): 2-1.

Process Parameters Machine selection, material properties, and part design are factors that can impact the injection molding output. However, there are five specific injection molding processing variables that can have as much or more impact on the processs success. The variables are: injection velocity, plastic temperature, plastic pressure, and cooling temperature and time. Controlling these variables during the injection cycles phases, can help to improve part quality, reduce part variations, and increase overall productivity (Miller, 1996). During phase 1, or fill, the screw advances and plastic flows into the mold. Flow characteristics are determined by melt temperature, pressure, and shear rate. Injection velocity, the rate at which the screw moves, is the most critical variable during the fill phase. A polymer flows more easily as injection velocity is increased. If injection velocity is too high, it can cause excessive shear and result in problems such as splay and

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jetting. Also, heat from a higher shear rate can degrade the plastic, which negatively impacts the properties of the molded part (Miller, 1996). The way plastic flows during fill is also affected by their viscosity, or resistance to flow. High viscosity polymers are thick and those with low viscosity are thin and flow more easily. Melt temperature affects viscosity and should be maintained within the suppliers recommended temperature range (Miller, 1996). Plastic pressure also plays a part during fill, since it increases sharply. The melted plastic can be under greater pressure than is indicated by the hydraulic pressure. Therefore, it is important to understand the flow characteristics of the material being used and to operate the process consistently (Miller, 1996). In phase 2, or pack, the melted plastic is compressed and more material is added to make-up for any shrinking during cooling. Approximately 95% of the material is added during the fill phase and a remaining 5% is added during pack. Plastic pressure is the impacting variable during the pack phase. The screw maintains the pressure for the melt, making-up for any shrinkage, which can cause sinks and voids. Cavity pressure variations are the main cause of deviations in plastic parts. Therefore, it is important to completely fill the mold and to avoid over packing and under packing, since pack pressure determines part weight and part dimensions. Over packing can result in dimensional problems and difficulty in part ejection. On the other hand, under packing can result in short shots, sinks, part-weight variations, and warping (Miller, 1996). Phase 3, or hold, is impacted by all five process variables stated earlier: injection velocity, plastic temperature, plastic pressure, and cooling temperature and time. After the mold is packed, the plastic remains in the mold until it is partially solidified and the

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gate freezes. A drop in plastic pressure reveals the amount of shrinking that occurs from cooling. This phase can be optimized by decreasing the hold time until the part weight changes. At this time, the gate is no longer sealed and resin backflows out of the mold. Continuing hold, after the gate seals, increases cycle time, which uses more time and energy to produce the part. Therefore, it is important to maintain pressure on the plastic until the gate freezes (Miller, 1996). Phase 4, or cooling and plasticizing, is usually the longest part of the molding cycle, often 80% of the cycle time. Substantial gains in productivity can be yielded by optimizing cooling time. Since gates are sealed during this phase, cooling temperature and time are the only variables at work. The cooling phase can be optimized by balancing the desire to cool rapidly against the quantity of molded-in stress that the final part can withstand (Miller, 1996). [Insert more info. on val. & the molding process] TOOLS OF THE TRADE As with most trades, it is advantageous to have tools that assist with accomplishing the task at hand. The procedure created for this project describes the tools and their use in validating the injection molding process. The following provides background on the tools selected. Master Validation Plan The value of a good planning tool should never be underestimated! A Master Validation Plan, or MVP as often referred to in the medical device field, is an essential planning tool for the validation process. The MVP serves to outline all the equipment/processes requiring validation for a given medical device manufacturing
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project. Although the MVP can be formatted in many ways, it usually contains the following (Swain, 1999): Project Overview/Scope- A brief discussion of the projects scope should be included. Equipment Listing- Each piece of equipment included in the scope should be described. Rationale- A brief explanation should be included stating which machines are being validated and which machines are not. Methodology- A brief explanation of the methods and sampling employed should be included. Responsibility Matrix- A listing of tasks with the corresponding team member responsible should be included. General Acceptance Criteria- The acceptance criteria should be briefly stated. Calibration and Testing- A list of auxiliary programs required to support the project. Schedule- A timeline for executing all listed activities may be included. Design of Experiments By using statistical techniques during process validation, medical device manufacturers can improve quality, cut costs, and increase confidence in results (Buffaloe-Weese, 1998). One of the statistical tools for validation is design of experiments (DOE). It is helpful in identifying factors requiring control in order for a system or product to pass a ruggedness test (Anderson-Anderson, 1999). Protocol

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Protocol = written document describing the method (s) utilized and data to be collected Report Report = written document that interprets data collected and concludes if/ if not the process was validated [Insert more info. on validation tools]

CHAPTER III. METHODOLOGY This chapter lists the methods used to develop and to prove regulatory compliance of a procedure for validating an injection molding process, which was the projects focus. This chapter begins with a restatement of the problem followed by research design, procedure outline, documentation template outline, gap analysis, and the project timeline. Problem Restatement The problem for this study is to develop a validation procedure for thermoplastic injection molding processes for the medical device contract manufacturer. Research Design Research was conducted to investigate methods used to validate injection molding processes. As discussed in Chapter 2, the validation process is typically divided into three phases: Installation Qualification, Operational Qualification, and Performance Qualification. The following explains the phases with respect to injection molding.

Installation Qualification

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For injection molding, the installation qualification pertains to verifying that the injection press is installed properly and capable of running the related mold. The installation qualification protocol should describe the necessary test procedures to verify that the press is installed as specified. These qualifications generally include check sheets that describe: testing of emergency stops, guards, and interlock features, wiring verification, and identification of critical spare parts (Schikora, 2000). The installation qualification protocol template developed for the project will include checks for safety features, equipment documentation, control system verification, and electrical and supporting utilities. Operational Qualification The operational qualification, for injection molding, is comprised of three aspects: 1) verification of the injection press operational aspects, 2) engineering studies, and 3) a four hour capability/mold acceptance run. Figure 5 displays the operational qualification outline. Injection Molding Operational Qualification

Press Operational Aspects

Test & Critical Instrument Calibration Verification Control Screens Verification Controls Verification Alarm Verification Reject Mechanism Verification Report Verification Security Verification Training Verification

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Engineering Studies Engineering Studies

Viscosity Testing Gate Freeze Testing Hold Time Testing Process Characterization

Mold Acceptance Run

4 Hour Capability Run

Figure 5: Injection Molding Operational Qualification As outlined in Figure 5, the press operational aspects are those key to running the press. Test and critical instruments requiring calibration and used in the molding process must be documented. Control screens verification consists of verifying the presss control system screen navigation features per the equipment suppliers documentation. Controls verification verifies that all system controls identified are functioning per the equipment suppliers documentation and assures parameter settings established for the mold. Alarm verification serves to verify that they function as required. Reject mechanisms, if applicable, should be confirmed that they operate as specified. A verification of generating any system reports, if applicable, should be conducted. Training verification should be conducted to assure that all appropriate personnel are trained in the applicable manufacturing and inspection procedures. Attachments specific to all of the described press operational aspects will be created and included in the molding protocol template. The procedures engineering studies involve the activities during process development. Chapter 2 provides a discussion of the injection molding process

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parameters. It identified five specific molding processing variables that can have as much or more impact on the processs success. The variables were: injection velocity, plastic temperature, plastic pressure, and cooling temperature and time. It was also noted that controlling these variables during the injection cycles phases, can help to improve part quality, reduce part variations, and increase overall productivity (Miller, 1996). Based on the processing variables potential impact, the following verifications were incorporated into the validation: Viscosity Testing, Gate Freeze Testing, and Hold Time Testing. Test results will be summarized into a process data packet. Moreover, an important aspect to the operational qualification and in achieving validation is challenging the process to determine what happens when conditions arise that cause stress, worse case testing. These challenges are collectively referred to as process characterization. During process characterization, key process elements are varied and sources of variation having the most impact on the process are determined. One statistical tool proven to determine variability source is Design of Experiments (DOE) (Kim and Kalb, 1996). The Design of Experiment technique is not new to the health-care industry. Medical researchers have long understood the importance of carefully designed experiments. Recent focus by FDA on process validation highlights the need for well-planned experimentation. Such experiments can provide data that will enable device manufacturers to identify the causes of performance variations and to eliminate or reduce such variations by controlling key process parameters, therefore improving product quality (Kim and Kalb, 1996).

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The process characterization included in the procedure will be considered worse-case testing through a 4-corner window study. It is considered to be worse-case testing for both the mold and injection press. This testing, employing DOE, serves to identify the influence of the equipment on the mold by understanding the effects of the process parameters on critical part dimensions and quality characteristics. This method will challenge the high and low settings with respect to the machines process parameters of pressure and temperature. It will challenge the ability of the press and mold to produce a capable part at the extremities, high and low, of pressure and temperature combinations. Figure 6 displays the combinations. Pressure and Temperature Combinations High Temperature / High Pressure High Temperature / Low Pressure Low Temperature / High Pressure Low Temperature / Low Pressure Figure 6: Process Parameter Challenge Combinations The window study will be executed using the information developed and recorded in the process data packet. The press settings will be set at each corner and centerline and run for at least 1 hour. After a 15-minute settle time, samples will be labeled and collected throughout the runs. Part critical quality characteristics, as determined by the customer, will be sampled and evaluated according to ANSI/ASQC Z1.4, single, normal, level II. In addition, there will be an inspection of critical part dimensions, as determined by the customer and ANSI/ASQC Z1.9-1993. The acceptance criteria for the window study will employ additional statistical tools, Statistical Process Control (SPC) charting and process capability (Cpk). SPC charting, used since the 1940s for monitoring production results, provides a visual method for identifying samples that are outside of normal, expected variability. With sufficient

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sampling, a process capability index, Cpk, can be calculated to determine how well the process results are centered within a specification range and how well variability is controlled. When results vary greatly, a greater percentage of the results have the tendency to fall outside the specifications. This means the process is less capable, resulting in a lower Cpk value (Weese and Buffaloe, 1998). By employing the statistical tools of SPC charting and process capability (Cpk), the window study acceptance criteria will be as follows: 1) Stability must be demonstrated through control charting for all critical part dimensions. 2) All critical part dimensions must demonstrate a value of Cpk 1.33 per mold cavity and a Cpk 1.00 for overall cavity to cavity average. 3) All critical quality characteristics must meet the accept/reject requirements for the applicable acceptable quality level (AQL). It should be evident that the engineering studies are the key aspect of the operational qualification phase. By executing the described phases, the result should be a processing window that is well defined for the press and mold requiring validation. These results can then be confirmed through a 4 hour capability study. The capability study is a 4 hour run using the determined optimum process parameter settings. After a 15 minute settle time, one full shot of parts will be collected every 10-minutes totaling 24-shots. Customer specified critical dimension and attribute inspections will be conducted according to the ANSI/ASQC Z1.9-1993 and ANSI/ASQC Z1.4-1993 sampling plans. The acceptance criteria for the run are as follows: 1) All critical dimensions must demonstrate a value of Cpk 1.33 for each individual cavity and a Cpk 1.00 for overall cavity-to-cavity average and 2) All critical quality characteristics must meet the defined AQL.

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Performance Qualification The performance qualification serves to prove that a process is reproducible and effective. Performance qualifications typically measure results from normal operating conditions (Weese and Buffaloe, 1998). The performance qualification template developed for the project serves to address the reproducibility aspect. It will consist of molding three lots of the desired product within the process parameters established from the operational qualification. The qualification should be carried out to simulate a production run with all operating procedures having been established and with all participants having been trained in the applicable procedures. The protocol will define the lot size. Part sampling for the customer required dimensional and attribute inspections will be conducted according ANSI/ASQC Z1.9-1993 and ANSI/ASQC Z1.41993 sampling plans. The acceptance criteria for each lot are as follows: 1) All critical dimensions must demonstrate a value of Cpk 1.33 for each individual cavity and a Cpk 1.00 for overall cavity-to-cavity average and 2) All critical quality characteristics must meet the defined AQL. If all three lots meet the acceptance criteria, the process will be considered validated. Product from a performance qualification can be saleable product provided it meets the acceptance criteria. Procedure Outline Standard operating procedures (SOPs) are essential for any plants effectiveness and efficiency. Procedures provide information about how to perform tasks safely, efficiently, and effectively. They describe processes and important steps in the processes, and help workers remember how to perform tasks. Procedures are also useful in training employees. Figure 7 lists elements of a good procedure (Kieffer, 2003).

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The procedure created for this project will establish generalized process validation standards and guidelines for medical classified product for a team oriented organization. It will identify the following: Process Owner, Purpose, Scope, and Responsibilities. It will describe the general validation activities from pre-validation to re-validation. It will list related terminology, references, forms, and templates, with the most attention being placed on the Injection Molding Template. This template will include evaluation criteria and documentation for all three qualification phases: IQ, OQ, and PQ.

PROCEDURE ELEMENTS Describes the purpose of the process or activity. Emphasizes critical steps and does not contain trivia, unimportant details, or fundamental information that the user is certified as knowing from experience or training. Defines responsibilities. Lists activities sequentially. The core of a good procedure can be a process flow diagram. Gives guidance in case of a problem and clearly defines decision points. Written simply, preferably by users. At minimum, it is validated by the users. Is concise, ideally, 3-4 pages long. The likelihood of reading, remembering, and complying decreases with the number of pages. Is simple and should be written for 6th- to 8th-grade readability. Makes liberal use of visual aids such as flow diagrams, photos, drawings, and color. A chart that is appropriately numbered and controlled could be considered a procedure. Includes forms that ideally are self explanatory. Figure 7: Elements Of A Good Procedure
Source: R Kieffer, Procedures: Improving Their Quality, Pharmaceutical Technology (January 2003): 66.

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Gap Analysis In order to prove that the procedure developed would meet the provisions for process validation set forth by the Quality System Regulation 21 CFR-Part 820, a Gap Analysis was created to assess the procedures content against the regulations section for Process Validation, 820.75. Gap Analysis is a technique which permits a comparison of a current situation to a desired state. It is often used to evaluate existing quality systems for compliance to new standards. [Source Further] The gap analysis created served to prove that the procedure developed was adequate to achieve compliance to section 820.75, Process Validation, of the Quality System Regulation, 21CFR-Part 820. This was identified as the desired state in the gap analysis document. See Appendix X, for the Process Validation Gap Analysis that was created to assess the procedure developed for this project. The procedures state was assessed by answering a questionnaire, which was developed from the regulation, 21 CFR-Part 820, Subpart G- Production and Process Controls, Section 820.75 Process Validation. The questionnaire was designed to identify gaps in methods established for process validation. Therefore, a questionnaire format was selected instead of listing the requirements or guides in statement form. For response to the questionnaire, three options were provided: Yes, No, and N/A. The Yes option was reserved for cases where requirements were met or guides have been incorporated. The No option was reserved for cases where requirements were not met, indicating a gap. It also indicated that the related procedural element

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required an adjustment, to meet a requirement. The N/A option was reserved for cases where a requirement or guide may not be applicable to the organizations situation. To support each response, the questionnaire allotted space for recording evidence, as to whether or not the requirement was meant. The results of the gap analysis for the procedure can be found in Chapter IV.

Project Timeline A Gantt chart was developed to show the time allocated for each of the major project activities.
2004 TASK Sept. Review of Literature Proposal Development Submit Proposal Develop Procedure Outline Develop Documentatio n Template Prepare Final Drafts Formulate Conclusion and submit project Oct. Nov. Dec. Jan. Feb. 2005 Mar.

Apr.

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CHAPTER IV. DELIVERABLES and GAP ANALYSIS RESULTS This chapter lists the developed procedure and all related supporting documentation, as stated in the objectives of Chapter I. In addition, the results of the Gap Analysis are stated, which was conducted to prove the procedures compliance to the 21CFR Part 820, section 820.75 Process Validation. Deliverables There were four objectives designed to address the problem. The project objectives were met by creating ten deliverables. Table X lists all the deliverables and a brief description. Each deliverable is further explained in detail below. PROJECT DELIVERABLES Deliverable 1. Validation Procedure- Validation Practice for Medical Product 2. Master Validation Plan Description A document providing standards and guidelines for conducting process validation A planning tool which outlines all processes that require validation for a medical device project. It identifies, at minimum, the process, scope, methods, and evaluative characteristics to achieve validation A document which tracks all validation protocols, test method verifications, and master validation plans through numerical listings and descriptions A planning tool which documents a team review of related project aspects to assure that validation activities can begin A document stating the methods to perform, the data to collect, and the acceptance criteria for conducting installation and operational qualifications
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4. Pre-Validation Checklist 5. Injection Molding IOQ Protocol Template

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for an injection molding process 6. Injection Molding PQ Protocol Template A document stating the methods to perform, the data to collect, and the acceptance criteria for conducting a performance qualification for an injection molding process 7. Validation Report Template A document summarizing the results and evidencing whether or not the requirements were met for all executed protocols 8. Protocol Addendum Template A document created as part of the corrective action process, when the validation criteria for an original protocol were not completely satisfied 9. Process Sheet A form used to record injection molding process settings 10. Discrepancy and Deviation Form A form used to document any cases where the approved protocol methods were deviated from or the stated protocol acceptance criteria was not met Table X: Project Deliverables Validation Procedure The primary deliverable was the Validation Procedure, which can be found in Appendix X. As stated in Chapter III, the procedure created for the project would establish generalized process validation standards and guidelines for medical classified product, for a team oriented organization. Therefore, the procedure was entitled Validation Practice for Medical Product and consists of eight pages. The document addresses general procedural aspects, such as roles and responsibilities, see page one of the procedure. It identifies a process owner, the individual who would be responsible for overseeing the procedure. The procedure defines a purpose and scope. It also lists the team members and their responsibilities. Methods for the validation process begin on page two. Pre-validation activities are explained, along with the use of the Pre-Validation Checklist. These activities encourage a team review of the project, with respect to accomplishing validation. It
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serves to assure that all supporting items are in place prior to scheduling of an operational qualification. The Qualification Log and the planning tool, Master Validation Plan (MVP), are introduced, followed by an explanation of each validation phase. Page three of the procedure introduces the concept of a validation protocol, which is defined as a document that describes the validation phase, the testing methods, and the evaluative characteristics that will be utilized to qualify a process. It also lists the protocol content that should be addressed at each validation phase. The protocol templates for injection molding are mentioned, in this section as well. The significance of acceptance criteria and data forms are presented, along with how to obtain protocol approval on page four. Protocol deviations and discrepancies are explained on page five. Page five also addresses validation scheduling and reporting, including report content and report approvals. Further, the purpose of a validation addendum is provided, along with reference to the protocol addendum template. Page six of the procedure contains definitions for terms that are unique to the validation topic. This page also provides explanation of re-validation. Page seven contains sections for listing related references, documents, records or forms, appendices, revision history, and suggested individuals for training. Master Validation Plan The master validation plan (MVP) is a planning tool for the validation process. See Appendix X, for the MVP template developed for use with the procedure. This document, which should be assigned a control number from the Qualification Log, is designed to consider all equipment and processes requiring validation for a medical

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device project. It establishes guidelines for employing statistical tools for analyzing data related to accepting and qualifying molded component(s), assembly equipment and processes. In addition to defining the relationship between quality characteristics, classifications, and acceptable quality levels (AQL), it states the basis for attribute and variable sampling plans. Besides providing statistical and sampling rationale, the MVP contains a Validation Matrix, see pages five and six of the plan, which lists all items to be qualified, such as molds, purchased components, instrumentation, and assembly equipment. It also tracks the qualification task needing performed, such as IQ, OQ, and PQ. For all validation tasks identified, the matrix has a section for documenting the responsible party, for each task. Beginning with page seven of the MVP, sheets are provided for detailing each qualification in its entirety. The sheets can be customized to account for each items unique requirements. For example, a sample sheet is provided for a molded component. It details each qualification phase, IQ, OQ, and PQ, that must be completed. Subsequently, it lists the key quality characteristics, along with their acceptance criteria that must be evaluated at each phase. There are also additional qualification outline sheets that are provided for adapting to finishing equipment and purchased components. Qualification Log The purpose of the qualification log is to control all validation protocols and reports, test method verifications, and master validation plans, by documenting an assigned number for each. See Appendix X, for the log. The log is comprised of three sheets, a sheet for each qualification type. There is a sheet to track all validations, known as the

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Validation Control Log. The Validation Control Log contains four columns. One column, labeled Document #, documents the number assigned, along with the VAL prefix to designate that it is a validation. In addition, there are columns for identifying the related project, type of qualification (IQ, IOQ, OQ, or PQ), description, and comments. There is also a sheet for recording test method verifications, known as Test Methods Control Log. This log provides for documenting numbers assigned to test method verification documents, documents which may outline how a measurement instrument will be verified prior to implementation. The number assigned will also contain a prefix, TM, to designate that it is a test method verification. This sheet also contains columns for identifying the related project, description, and comments. The log also provides a sheet for controlling all master validation plans, identified as Master Validation Plan Control Log. This log provides for documenting numbers assigned to master validation plans. The number assigned will also contain a prefix, MVP, to designate that it is a master validation plan. This sheet also contains columns for identifying the related project, description, and comments. Pre-Validation Checklist The pre-validation checklist, see Appendix X, was created for use with the validation procedure. It is a supplemental document used to record that the necessary pre-validation activities were completed. A review of the checklist will indicate that key aspects to achieving validation, such as specifications, training, and procedures, have been reviewed and are in place prior to beginning an operational qualification.

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Injection Molding IOQ Protocol Template The installation and operational qualification requirements for injection molding were addressed by combining both qualifications into one document, entitled an Installation and Operational Qualification and abbreviated as IOQ. See appendix X, for the IOQ Protocol Template. A template was created to standardize the protocol documentation and to facilitate protocol development. The first five pages of the template consist of a cover page, which identifies the protocol number, a table of contents page, an approval page, and a participant identification log. An introduction section follows, which lists the objective, purpose, and scope of the qualification. It also identifies responsibilities of the qualification team and commonly used abbreviations. Another section, entitled Data Collection and Documentation Procedures, provides instructions for data collection and documentation, while executing the protocol. It also explains the use of attachments, for documenting the qualification data. Furthermore, there are sections that describe the use of the deviation and discrepancy form and an equipment listing. On page eleven of the template, begins the installation qualification verifications. The verifications are comprised of a test description, test procedure, acceptance criteria, and test results. The verifications have a corresponding attachment for listing the items checked, related acceptance criteria, actual results, and required sign-offs. A majority of installation verifications are focused on safety and are based on the Plastics MachineryHorizontal Injection Molding Machines- Safety Requirements for Manufacture, Care, and Use, ANSI/ SPI B151.1-1997.

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In addition to safety, the IQ covers environmental and documentation/certification requirements. It assesses any critical instrumentation, auxiliary equipment, and control systems that may comprise the injection system. There are verifications for electrical and supporting utilities. It contains verifications for operator training and cleaning procedures and schedules. The template also has checks for verifying that a preventative maintenance and spare parts program has been established for the injection system. The Operational Qualification is represented in the IOQ, by a separate section. The initial verifications in the OQ consist of verifying the operational aspects of the injection press and the mold. The verifications are formatted similar to those for the IQ. They are comprised of a test description, test procedure, acceptance criteria, and test results. They also have a corresponding attachment for listing the items checked, related acceptance criteria, actual results, and required sign-offs. The initial tests confirmed identification of critical instrumentation and training and procedural aspects for the OQ. There were also verifications that assessed that the control, alarm, and security features of the injection press were functioning per the equipment specifications. The next section of the OQ is entitled Engineering Studies, see page 19 of the IOQ template. The engineering studies involve activities required during initial process development. These studies are formatted according to a test description, test procedure, and criteria to proceed. The activities consist of identifying the required settings for the window, viscosity, gate seal, and hold time tests. This development testing is described in the Process Development sub-section of the engineering studies. The results are to be recorded on the Processing Sheet, see Appendix X.

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A key aspect of validation, worse case testing, is addressed by the engineering studies. It is represented by a four corner window study. This study serves to identify the influence of the equipment on the tool, by understanding what effects the process parameters will have on the critical part dimensions and quality characteristics. It will challenge high and low settings with respect to the machines process parameters of pressure and temperature. The window study challenges the ability of the press and mold in producing a capable part at the pressure and temperature combination extremes: high temperature / high pressure, high temperature / low pressure, low temperature / high pressure, and low temperature / low pressure. During these challenges, the molded parts will be taken to their fracture point. A fracture is defined as a condition where the parts begin to exhibit attribute defects. Once the fracture point is identified, the settings for both temperature and pressure will be reduced until an acceptable molded part is obtained. These settings will be considered the worse case parameters capable of producing a part within specification. The corner settings established during the process development activities and recorded on the processing sheet are used during the window testing. Once the window study yields the four processing corners and a process centerline, a mold acceptance run can be conducted. The acceptance run serves to confirm the settings established during the process development phases. It consists of a four hour capability study run at the process centerline. During the run, parts will be collected at required intervals and inspected for the defined quality characteristics. All critical part dimensions must achieve a Cpk 1.33 per cavity and a Cpk 1.00 for overall cavity-tocavity average. All part attributes must meet the required accept/reject criteria per the

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specified AQL. The acceptance run activities are described beginning on page 20 of the template. They are formatted according to a test description, test procedure, and acceptance criteria. The test results are recorded on a corresponding attachment. The remaining sections of the IOQ template relate to documentation. There is a section that offers concluding remarks and reporting instructions. This section is entitled, Conclusion and Protocol Reporting. The final section, entitled Reference Documents, is for listing references, which are the protocol basis. Injection Molding PQ Protocol Template A separate protocol template was developed to document the performance qualification (PQ) methods for injection molding. As discussed in Chapter 3, a PQ serves to prove that a process is reproducible and effective. The PQ template describes the methods employed to verify a repeatable molding process. The template is formatted similar to the IOQ template. The first five pages of the template consist of a cover page, which identifies the protocol number, a table of contents page, an approval page, and a participant identification log. An introduction section follows, which lists the objective, purpose, and scope of the qualification. It also identifies responsibilities of the qualification team and commonly used abbreviations. Another section, entitled Data Collection and Documentation Procedures, provides instructions for data collection and documentation, while executing the protocol. It also explains the use of attachments, for documenting the qualification data. Furthermore, there are sections that describe the use of the deviation and discrepancy form and an equipment listing.

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The X section of the template describes the practice of molding three lots of the desired product within the process parameters established during the operational qualification. The protocol will define a lot size. Part sampling, for the required quality inspections, will be conducted according to the ANSI/ASQC sampling plans, Z1.9-1993 for dimensions and Z1.4-1993 for attributes. Lot acceptance is based on all critical part dimensions meeting a Cpk 1.33 per cavity and a Cpk 1.00 for overall cavity-to-cavity average. In addition, all attributes must meet the defined AQL. If all three lots meet the acceptance criteria, the process will be considered validated. With the acceptance criteria being met, the product produced during the PQ can be saleable. Validation Report Template A reporting template was created for use with the validation procedure. See Appendix X, for the report template. For each executed protocol, per the procedure, there must be an accompanying report. The report template can be used for any type of validation protocol, IQ, IOQ, OQ, PQ, or even an addendum. The report summarizes validation results and presents evidence that the protocol requirements were or were not met. The report template developed is comprised of several sections. It contains an introduction, which includes an objective statement, approval section, and applicable document listing. It includes an executive summary, which provides a summary of the results. It contains a section, labeled as the system description, for documenting the equipment involved in the qualification. A testing results section is included for stating the results of the protocol testing and explaining any deviations or discrepancies that

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might have occurred. A conclusion section is provided for stating whether or not the requirements of the protocol have been met. There is also a section, entitled ongoing controls, for assuring that the validated system remains in a state of validation. In addition, an appendix can be created to file all data compiled during protocol execution. Protocol Addendum Template The validation procedure permits use of a protocol addendum, as part of a corrective action process. An addendum protocol may be used to supplement the results of an original protocol, when the original protocol requirements were not met. See Appendix X, for the protocol addendum template. A protocol addendum is similar to the original protocol, except that the introduction should reference the original protocol and explain the discrepancy or incident that the addendum is to address. The addendum may include all or part of the original protocol and must be reported, reviewed, and approved. Each addendum must be assigned a number from the validation control log. The number should be followed by the letters PA to distinguish a protocol addendum. The related report should be distinguished by the letters RA. Process Sheet A form, entitled Process Sheet, was created for use with the validation procedure, for documenting all key injection molding process parameters and information. See Appendix X, for the form. The process sheet contains a general section for identifying the mold, number of cavities, material, additives, shot weight, and cycle time. Specific to processing, it contains records for plastic temperature, plastic fill rate, plastic pressures after transfer, plastic cooling, and clamping/ejection.

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Discrepancy and Deviation Form Another form, entitled Discrepancy and Deviation Form, was created for use with the validation procedure. This form documents any case where the approved protocol methods were deviated from, defined as a deviation by the procedure, or where the stated protocol acceptance criteria was not met, defined as a discrepancy by the procedure. See Appendix X, for the form. The top portion of the form identifies the related protocol and allows for a selection between a deviation and a discrepancy. Depending upon which is selected, the form user is directed to the appropriate section for further completion. The information required to enter a deviation is the assignment of a consecutive number, the protocol section/page that was affected, and a brief description of the change. Spaces are provided for the person making the entry, to date and sign. For a discrepancy entry, a consecutive number must be assigned, the protocol section/page that was affected, and a brief description of the occurrence must be completed. The person entering must sign and date the entry as well. The investigation and root cause section must be completed by an assigned individual, who should sign and date the entries. The corrective action section should be completed by the assigned individual, who should sign and date their entry. A section for documenting that the discrepancy was reviewed and resolved accordingly should be completed, by an individual responsible for the protocol corrective actions. Gap Analysis Results For the project, a gap analysis was conducted to prove that the procedure developed achieved compliance to section 820.75, Process Validation, of the Quality System

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Regulation, 21CFR-Part 820. The procedures compliance state was assessed by answering a questionnaire, which was developed from the regulation, 21 CFR-Part 820, Subpart G- Production and Process Controls, Section 820.75 Process Validation. The questionnaire was designed to identify gaps in methods established for process validation. Appendix X contains the gap analysis that was completed for the project. Five questions were created for the assessment. All five questions were answered, by the researcher. For each response, supporting evidence was provided. Supporting evidence consisted of referencing the applicable section of the procedure or related documentation. The related documentation could have been forms, templates, plans, or logs that were created specifically for use with the procedure. The first question assessed whether a method exists for documenting validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated. A Yes response was noted, for the developed procedures compliance to this aspect of the regulation. Several sections from the developed procedure were referenced as supporting evidence. Section 4.4 of the procedure stated that a protocol must be written to describe validation activities. Section 4.7 of the procedure required employing forms to support thorough collection of data during validation. The procedures Section 4.12 stated that a report is required for summarizing the results. Finally, Sections 4.8 and 4.13 of the procedure accounted for approval signatures. The second question addressed if the procedure required that procedures be established to monitor, maintain control of process parameters, and ensure that the specified requirements continue to be met. A Yes response was noted, for the

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developed procedures compliance to this aspect of the regulation. Supporting evidence was also noted. Section 4.1.4 of the procedure identified pre-validation activities, which consist of verifying that the manufacturing process has been defined and documented in controlled procedures. Question three inquired if the validation procedure ensured that validated processes were performed by qualified individuals. A Yes response was noted, for the developed procedures compliance to this aspect of the regulation. Section 4.1.8 and the protocol templates of the procedure were listed as supporting evidence. Section 4.1.8 stated that pre-validation activities consist of verifying that operators are trained and that training is documented. Further, the IOQ and PQ protocol templates developed, for use with the procedure, include training verifications. The fourth question addressed if the procedure requires documenting monitoring and control methods, data, date performed, and where appropriate the individual(s) performing the process or the major equipment used for validated processes. A Yes response was noted, for the developed procedures compliance to this aspect of the regulation. Section 4.1.4 and the process sheet of the procedure were listed as supporting evidence. Section 4.1.4 addressed pre-validation activities, which consisted of verifying that the manufacturing process has been defined and documented in controlled procedures. These procedures would then contain specifics on the required documentation. The process sheet represents the data that should be documented for an injection molding process. Question five inquired if the procedure addressed and provided documentation for revalidation. A Yes response was noted, for the developed procedures compliance

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to this aspect of the regulation. Section 4.15 was listed as supporting evidence. This section addressed revalidation. CHAPTER V. CONCLUSION AND FUTURE IMPLICATIONS This chapter serves to establish that the objectives for the project were met. It provides a conclusion and future implications for the project. Conclusion Chapter I listed four objectives that were designed to address the problem, which was to develop a validation procedure for thermoplastic injection molding processes for the medical device contract manufacturer. The four objectives were: 1. To establish what parts of and related methods for validating an injection molding process. 2. To establish a method for worse-case testing for the injection molding process. 3. To establish a procedure that describes the methods determined in objectives one and two. 4. To establish a template for documenting data collected from performing the procedure, as established in objective three. The first and second objectives are represented by the procedures IOQ Template. The template Future Implications Since validation is best achieved through a collaborative team effort, the planning stage may require input from manufacturing, quality, purchasing, design, and the business sectors. The validation planning stage permits each department to be engaged

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early in the product development process. A validated process should yield a well defined process and identify any pitfalls of the process, further up stream verses downstream in process development. The results of proper process validation can yield useful information and assure input early on, from all facets of the development team/manufacturing process. This aspect of validation relates to Quality Functional Deployment (QFD). QFD is a tool used to incorporate customer input into the product early on during development. For this reason, it is often referred to as the house of quality. Process validation has the potential to be a quality deployment method for achieving internal customer satisfaction.

BIBLIOGRAPHY American Society For Quality Control, American National Standard: Sampling Procedures and Tables for Inspection by Attributes, ANSI/ASQC Z1.4-1993. American Society For Quality Control, American National Standard: Sampling Procedures and Tables for Inspection by Variables For Percent Nonconforming, ANSI/ASQC Z1.9-1993. A Sahni and C Larsen, Meeting FDA Process Validation Requirements, Medical Device & Diagnostic Industry, (July 1996): 1-6. D Allen, FDA Wants You in Control, Pharmaceutical and Medical Packaging News, (April 2004): 10. D Bonanomi, The State of Validation, Pharmaceutical Technology, (February 2004): 98-102. D Weese and V Buffaloe, Conducting Process Validations with Confidence, Medical Device & Diagnostic Industry, (January 1998): 1-12. E Swain, Developing A Master Plan for Complex Validation Projects, Pharmaceutical and Medical Packaging News, (May 1999): 1-5. Injection Molding Machine: http://www.scudc.scu.edu/cmdoc/dg_doc/develop/process/control/b1000001.htm
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J Schikora, Qualifying High-Speed Assembly Machines as Part of Process Validation, Medical Device & Diagnostic Industry, (July 2000): 1-11. JG Dickinson, Washington Wrap-Up, On Reprocessors and Research, FDA Gently Yields, Medical Device & Diagnostic Industry, (February 2000): 1-6. JS Kim and JW Kalb, Design of Experiments: An Overview and Application Example, Medical Device & Diagnostic Industry, (March 1996): 78-88. N Sparrow, Special Report: Outsourcing in the Device Industry, European Medical Device Manufacturer 10, no. 3 (1999): 78-82. N Squeglia, Zero Acceptance Number Sampling Plans, Fourth Edition NJ Hermanson, Growth of Plastics Use in Medical Devices is Spurred by Cost-Cutting, Modern Plastics, (November 1998): A-30. M Anderson and P Anderson, Design of Experiments for Process Validation, Medical Device & Diagnostic Industry, (January 1999): 1-9. Medical Device Quality Systems Manual: A Small Entity Compliance Guide http://www.fda.gov/cdrh/dsma/gmpman.html. Plastics Machinery-Horizontal Injection Molding Machines- Safety Requirements for Manufacture, Care, and Use, ANSI/SPI B151.1-1997. R Kieffer, Procedures: Improving Their Quality, Pharmaceutical Technology, (January 2003): 64-72. TECH MOLD INC., What Is A Mold? : An Introduction to Plastic Injection Molding and Injection Mold Construction, (1993-1999): 2-1. T Miller, Injection Molding, Medical Device & Diagnostic Industry, (April 1996): 2-5. T Owens, Enhancing Device Development through Early Supplier Involvement, Medical Device & Diagnostic Industry, (July 2001): 1-6. Quality System Regulation, Code of Federal Regulations, 21CFR-Part 820 Quality Management Systems Process Validation Guidance, GHTF/SG3/N9910:2004(Edition 2) W Leventon, Innovations Remake Plastic Injection Molding, Medical Device & Diagnostic Industry, (November 2001): 1-9.

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Cathy, Points to consider as you clean this up, take next steps, for presentation to committee:

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1. 2. 3.

4. 5. 6. 7. 8.

9.

10. 11. 12. 13.

Need to make sure the indents and all other formatting issues and specifications are on target per APA and BGSU guidelines and standardsmust be sure all are consistentnot bad be sure to double check all. The work should be converted to be past tense throughout since you have done the work nowit is pastor will be at the point of presentation. Review of literature should be driven by assuring that all elements of the work have been disclosed and pursued sufficientlymy sense is this is the case and you can be done with this. May want to use a summary statement on the tail end of the chapter to explain what was accomplished, consistent with what was initiated at the outset, and done throughout, per key headings. Headings used throughout, must be per APA and BGSU guidelines/standards to identify level and type of importance assigned. Chapter III, page 25, needs to be started as a fresh section. Chapter III needs to present each objective and identify steps taken to address the objective. Do not explain (in chapter III) what was found for each objective or step, but simply what the steps were to address the objective. At chapter IV, again state each objective, one by one, and what steps were taken to address the objective (consistent with chapter III). However, now, at each step, you should discuss what was found, how it was analyzed and so on. At chapter V, similar to previous chapters III and IV, you now need to explain what can be concluded based on the objectives and steps, and each set of findings and analysis for the samebut as conclusions. These also become, then, and therefore, the recommendations for other work to follow. Parts 6, 7 and 8 above, while seemingly fairly redundant, are at the core of good researchand if you will use the threaded logic inherent in this repetition, generally this will help to flush out what was accomplished, and why, as well as what then can be stated as legitimate findings, conclusions and recommendations. Also based on points 6, 7 and 8 above, it is possible that the problem and objectives will shift somewhat as you go back and actually state what you did. Consider changing the problem statement, page 7, to, The problem for this study was to develop a validation procedure for thermoplastic injection molding processes for medical device contract manufacturers. Consider changing first objective, page 9, to, To establish what parts of, and related methods, are necessary for validating an injection molding process. Bibliography needs to be started as a fresh section.

I suggest you make the adjustments identified by me, and that you had already indicated in your emailor as agreed in the yellowed areas of your text, and get it finalized for presentationand let me see the final draft before you give others a copy. JWS, 2-26-05

R10 02/21/05