Medical Device & Diagnostic Industry Magazine
MDDI Article Index

Originally Published July 2000

Jan Schikora

Assembly and handling technology is used to create solutions for a wide variety of tasks and products. Application of the technology to the manufacture of medical products has been a key area of focus, including the design of assembly systems for infusion sets, inhalers, dialysis sets, and disposable needles. Suppliers of high-speed assembly machines for the medical industry are often asked to assist with the qualification of these machines. Keeping a few key elements in mind can help manufacturers efficiently and rapidly manage the qualification of their assembly processes.

A properly validated assembly process can help reduce product development time.

Regardless of whether a manufacturer will be producing cars or medical devices, once an assembly machine is acquired for a certain product, the goal is to begin production as soon as possible. Medical device manufacturers, however, must consider the validation of the manufacturing process. The preparation of necessary validation tests and documentation can be both costly and time consuming if it is performed solely by the manufacturer, prompting some companies to order a qualification package together with the assembly machine.

The contents of the qualification package depend on the specific requirements of the manufacturer. Some require only the performance and documentation of a risk assessment. Others need complete validation documentation, including design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). In some instances, IQ and OQ tests must be performed following on-site installation of the assembly machine.

PROCESS VALIDATION OVERVIEW

Process validation usually requires six basic steps to completion, including planning, DQ, IQ, OQ, PQ, and review of process and product data (see Table I). A process can be called validated if the whole procedure, from planning to review of the process and product data, is completed and documented.

Table I. Overview of the process validation sequence.

PLANNING

The first step in qualifying a high-speed assembly machine is to consider the reasons for the process validation, the regulatory requirements, and the available guidelines.

Reasons for Process Validation. There are various reasons for process validation. One reason is that a validated process, coupled with proper design control, helps reduce development time. This can lead to a faster market launch for new products. Increased customer satisfaction, improved product quality, and cost reductions are other common reasons for process validation. The primary reason for process vali- dation for most medical device manufacturers, however, is that national or international regulations often require validation to be performed for special processes.

Regulatory Requirements. Regulatory requirements for medical device manufacturers differ between the European Union and the United States. For manufacturers producing medical devices for the European market, there is no requirement for a process validation with the formal DQ, IQ, OQ, and PQ steps. Instead, it is necessary to have a quality management system that complies with ISO 9001 and EN 46001. To produce medical devices for the U.S. market, companies must manufacture their products according to the U.S. quality system regulation found in the Code of Federal Regulations, part 820.

As a result of the increasing number of warning letters issued by FDA since 1995 concerning medical devices, part 820 has been revised and now contains more requirements on design validation and process validation.

Part 820 states that, where the results of a process cannot be fully verified by subsequent inspection and testing, the process shall be validated and approved according to established procedures. The text of this section does not provide a detailed definition of process validation. In addition, the FDA definition of the term does not include much information about necessary procedures.

FDA defines process validation as establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications. In plain English, this means that validation is good engineering, with every step fully documented and signed off.

Guidelines for Process Validation. Currently, the most important tools for process validation are guidelines. The most important of these are FDA's guideline on the general principles of process validation, its process validation guidance draft, and the good automated manufacturing practices known as GAMP 3.

The guideline on general principles of process validation can be found on the FDA home page under SEARCH "process validation." The contents of the process validation guidance draft are similar to the guidelines on general principles of process validation. The difference between the two is that the draft contains detailed information about the necessary steps, methods, and tools for process validation, and examples of IQ, OQ, and PQ reports. GAMP 3 is produced by the GAMP Forum and is distributed by the International Society of Pharmaceutical Engineering. GAMP 3 focuses on computer systems and software validation.

DEFINITIONS OF PROCESS VALIDATION TERMS

During the qualification process, it is necessary for everyone to speak the same validation language. The first step is to clearly define the terms and definitions that will be used during the project. For example, the following terms and definitions might be used.

Prospective Process Validation. The validation process that starts at the beginning of product design and planning to purchase the production equipment.

Retrospective Process Validation. Validation is based on accumulated historical manufacturing, testing, control, and other data for a product already in production and distribution.

Validation Master Plan. This document describes the exact focus of validation efforts and necessary documents.

Design Qualification (DQ). DQ establishes by objective evidence that the equipment specifications conform with user needs and intended use.

Installation Qualification (IQ). This process establishes by objective evidence that equipment is constructed and installed according to approved design criteria.

Operational Qualification (OQ). OQ establishes by objective evidence the parameters that result in a product that meets all predetermined requirements.

Performance Qualification (PQ). This process entails establishing through consideration of objective evidence that the process under anticipated conditions, including worst-case conditions, consistently produces a product that meets all predetermined specifications.

Once all of the terms and definitions are specified, the next step is to define the processes that should be validated.

PROCESSES THAT SHOULD BE VALIDATED

Device manufacturers must be able to determine which processes should be validated, and what level of evaluation and documentation is required for validation. Many small manufacturers are understandably concerned about the costs and resources required to validate a manufacturing process. In order to minimize validation costs, these firms can determine if any part of the production process does not affect product performance or human safety. The manufacturer may then want to exclude these parts of the production process from validation. The validation plan should include written justifications for the exclusions.

FDA's process validation guidance draft document contains an example of a process validation decision tree that can guide decisions on whether a process needs to be validated or whether the product or process should be redesigned. This decision tree should only be used to exclude certain parts of the production process from validation after the equipment manufacturer has assessed the risks of the production process for product quality and human safety. Failure mode effects analysis (FMEA) can be used for this risk assessment. FMEA is a systematic analysis technique that helps identify potential failure modes and determine their possible causes. FMEA also provides an analysis of the associated risks, and generates a record of corrective actions. FMEA is performed during the design phase of the machine development project.

MACHINE DESIGN

It is useful at the beginning of the qualification project to develop a qualification project plan (QPP) that gives a schematic overview of the main steps of validation and qualification, and a detailed list of provided documents and their contents. The QPP also specifies responsibilities.

At the beginning of machine design there is the user requirement specification (URS). The URS describes the assembly process and the devices to be manufactured using this process. With the URS, three documents can be created: functional, hardware, and software design specifications. The hardware design specification includes a schematic of main components, such as frequency converters and vision systems. For an inspector who reviews this document it is always helpful to have a high-level approach to the system, where the inspector can evaluate what is important, and where details can be examined more closely. The software design specification includes a description of the software used and the software functions. It also provides a list of fault messages. Additionally, flow charts of the software modules are created.

After specification work is complete, design is started, beginning with the overview drawings. It is common practice to have a design review at this stage. There is an additional requirement of a formal risk assessment in qualification projects. An FMEA of the product will often be required. For validation of the assembly process, it is essential to have an FMEA that focuses on both the assembly process and the product. The FMEA is performed either before or together with the design review. The process often includes assembly system designers, electrical and software engineers, project engineers, validation engineers, and perhaps quality assurance personnel. During the FMEA, the assembly machine is assessed station by station using a rating table to determine the risks for product and human safety. The results of the FMEA are documented in the FMEA report. The report contains a description of each station number, followed by a short functional description, potential failure mode, potential effects of failure with rating, potential causes of failure with rating, and the current controls with rating.

In the FMEA report, an additional column labeled "Critical Software Function?" is included. Software functions must be examined during the assembly process FMEA to determine whether or not they are critical . If software is used to control the assembly process, a separate software FMEA is needed. For many assembly machines, however, a software FMEA is not needed because mechanical assembly functions are cam driven and software is used only to control the sensors, to open grippers, and for the good parts–bad parts counter.

QUALIFICATION DOCUMENTATION

During construction of an assembly machine, the qualification documentation is prepared in parallel with construction progress. The first part of the documentation includes a description of the assembly process to be validated, followed by an explanation of terms and abbreviations used in the documentation. There is also a description of the validation team and its responsibilities, the documentation files, and the revalidation actions to be performed if there are changes to the machine or the production process. If PQ documentation is provided, this part of documentation is the validation report with production approval.

Qualification documentation for an assembly machine will include design, installation, operational, and performance qualification.

Design Qualification. The DQ documentation consists of a collection of all documents created or used during design of the assembly machine. These documents must include the user requirement specification and a description of the parts to be assembled. They also should include the functional, hardware and software specifications, design changes, the qualification project plan, the FMEA report, and the list of critical software.

Installation Qualification. Simply put, IQ asks: Is the system installed correctly? Thus, the IQ protocol describes all necessary test procedures to verify that the assembly machine is installed as specified. IQ generally encompasses documentation approval, the qualification report with approval for operational qualification, the IQ test sheets, and deviation reports. The IQ test sheets describe:

The deviation reports describe all deviations found during execution of the IQ protocol. This documentation includes a detailed description of each deviation, a description of recommended corrective actions, and results.

Operational Qualification. Some portions of OQ procedure are similar to the corresponding portions of the IQ process. The OQ procedure entails providing descriptions of the purpose and the responsibilities for executing the OQ protocol. Descriptions are also included of what constitutes correct documentation of test results and the actions to be taken in the event of deviations. This is followed by documentation approval, which should be signed off by quality and/or production management before the OQ protocol is executed.

The Qualification Report for OQ, including approval for PQ, provides a summary of executed tests and the test results. This report should also be signed off before the OQ protocol is executed.

OQ Test Sheets. Examples of these tests of general machine functions include:

Software module test sheets are used when software design is modular. Each function controlled by software has a separate software module, which must be tested. Examples of software module tests include:

Calibration certificates for all sensors that may have an influence on product quality need to be included in the OQ documentation.

Performance Qualification. Documentation of PQ requires a significant amount of information and documentation concerning the production process. These documents describe the procedures used to generate the evidence that the process consistently produces a product that meets all predetermined specifications. Examples of information needed are:

During the PQ, validation lots are produced under both normal and worst-case process parameters with normal operators and normal in-process controls.

When IQ and OQ are finished, the performance qualification can be initiated. Although IQ and OQ tests are performed by validation engineers, the execution of PQ has different requirements. During PQ, validation lots of the product must be produced with normal and worst-case production parameters. These validation lots are produced with normal operators, normal in-process controls, and normal machine settings.

At the end of PQ, the production data are reviewed, and approval for production is signed off by quality management. Following PQ, a validated process requires a review of production and product data at regular intervals.

IN-HOUSE TESTING

When the assembly machine is constructed and the IQ and OQ protocols are prepared, all tests described in these protocols are performed. The reason for doing this is to check the IQ and OQ documentation. This process also provides a check of the machine. The machine is thus shipped in a qualified status. Nevertheless, the IQ and OQ tests must be repeated after the machine is set up in the device manufacturer's facility.

ON-SITE TESTING

When the assembly machine is set up in the manufacturer's facility, the IQ and OQ tests must be repeated. The on-site testing begins with the execution of the IQ protocol. After IQ tests are completed, the manufacturer's quality management team must review the test results and approve the execution of the OQ protocol.

REVALIDATION

If a change of machinery or in the actual assembly process could affect product quality, it may be necessary to revalidate the assembly process. The need for revalidation should be evaluated and documented. If there is a change of the machine or in the assembly process, the following procedure must be initiated:

If risks are recognized, the following procedures are needed to revalidate the assembly process:

CONCLUSION

The manufacture of most devices entails the use of assembly equipment—a part of the manufacturing process that generally requires validation. Completing the validation tests and compiling adequate documentation to satisfy regulatory requirements typically necessitates a substantial commitment of company resources. In many cases, contracting with an assembly equipment supplier to include the validation process as part of the qualification package can minimize time and costs. However, whether these functions are outsourced or performed in-house, clear communication and careful advance planning are among the key elements for ensuring effective assembly validation.

Jan Schikora is validation manager at Sortimat Technology GmbH (Winnenden, Germany).

Photos courtesy of Sortimat Technology Production Systems

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