The number of design reviews will depend on the plan and the complexity of the device. FDA also amended the requirements so that the results of a design review include identification of the design, the date, and the individual s performing the review.
Thus, multiple reviews can occur and the manufacturer must document what is being reviewed, when, and by whom. FDA never intended to mandate that an individual without design responsibility conduct the design reviews and, to clarify its position, has rewritten the requirement.
The requirement now states that the procedures shall ensure that each design review includes an individual s who does not have direct responsibility for the design stage being reviewed. In making this change, FDA also notes that it was not FDA's intention to prohibit those directly responsible for the design from participating in the design review. One comment stated that as part of the systematic review of the adequacy of the device design, it is occasionally necessary to produce a prototype device and have it evaluated by a physician who is an expert in the area of the device's intended use.
Thus, the comment stated that the regulation should be revised to allow a means for a manufacturer to ship a prototype device to a physician for evaluation.
One comment questioned whether design verification and validation can be conducted using prototypes or machine shop models. FDA regulations do not prohibit the shipment of prototypes for clinical or [Page ] other studies. Prototypes used in clinical studies involving humans may be shipped in accordance with the IDE provisions in part 21 CFR part FDA understands that it is not always practical to conduct clinical studies on finished production units and, therefore, the use of prototypes in clinical studies is acceptable.
When prototype devices are used on humans they must be verified as safe to the maximum extent feasible. Final design validation, however, cannot be done on prototypes because the actual devices produced and distributed are seldom the same as the research and development prototypes. The final verification and validation, therefore, must include the testing of actual production devices under actual or simulated use conditions. FDA agrees with the comments and has rewritten and reordered this section to be consistent with ISO The language in revised Sec.
Under the revised provisions, the design must be verified and validated. It is important to note that design validation follows successful design verification. Certain aspects of design validation can be accomplished during the design verification, but design verification is not a substitute for design validation. Design validation should be performed under defined operating conditions and on the initial production units, lots, or batches, or their equivalents to ensure proper overall design control and proper design transfer.
When equivalent devices are used in the final design validation, the manufacturer must document in detail how the device was manufactured and how the manufacturing is similar to and possibly different from initial production.
Where there are differences, the manufacturer must justify why design validation results are valid for the production units, lots, or batches. Manufacturers should not use prototypes developed in the laboratory or machine shop as test units to meet these requirements.
Prototypes may differ from the finished production devices. During research and development, conditions for building prototypes are typically better controlled and personnel more knowledgeable about what needs to be done and how to do it than are regular production personnel. When going from laboratory to scale-up production, standards, methods, and procedures may not be properly transferred, or additional manufacturing processes may be added.
Often, changes not reflected in the prototype are made in the device to facilitate the manufacturing process, and these may adversely affect device functioning and user interface characteristics.
Proper testing of devices that are produced using the same methods and procedures as those to be used in routine production will prevent the distribution and subsequent recall of many unacceptable medical devices. In addition, finished devices must be tested for performance under actual conditions of use or simulated use conditions in the actual or simulated environment in which the device is expected to be used.
The simulated use testing provision no longer requires that the testing be performed on the first three production runs. However, samples must be taken from units, lots, or batches that were produced using the same specifications, production and quality system methods, procedures, and equipment that will be used for routine production.
FDA considers this a critical element of the design validation. The requirement to conduct simulated use testing of finished devices is found in the original CGMP in Sec. This requirement has been moved to Sec.
Manufacturers must also conduct such tests when they make changes in the device design or the manufacturing process that could affect safety or effectiveness as required in the original CGMP in Sec. The extent of testing conducted should be governed by the risk s the device will present if it fails. FDA considers these activities essential for ensuring that the manufacturing process does not adversely affect the device.
Design validation may also be necessary in earlier stages, prior to product completion, and multiple validations may need to be performed if there are different intended uses. Proper design validation cannot occur without following all the requirements set forth in the design control section of the regulation.
Several comments stated that adequate controls for verification of design output are contained in proposed Sec. Revised Sec. These sections thus contain different requirements that are basic to establishing that the design output meets the approved design requirements or inputs, including user needs and intended uses.
All the requirements are essential to assuring the safety and effectiveness of devices. FDA does not believe that these requirements place undue burden on designers or require additional documentation with no value added. These basic requirements are necessary to assure the proper device performance, and, therefore, the production of safe and effective devices, and are acknowledged and accepted as such throughout the world. A couple of comments stated that the proposed requirement for design verification, to include software validation and hazard analysis, where applicable, was ambiguous, and may lead an FDA investigator to require software validation and hazard analysis for devices in cases where it is not needed.
One comment stated that FDA should provide additional guidance regarding software validation and hazard analysis and what investigators will expect to see. Another comment stated that by explicitly mentioning only software validation and hazard analysis, FDA was missing the opportunity to introduce manufacturers to some powerful and beneficial tools for better device designs and problem avoidance.
When conducting a risk analysis, manufacturers are expected to identify possible hazards associated with the design in both normal and fault conditions. The risks associated with the hazards, including those resulting from user error, should then be calculated in both normal and fault conditions. If any risk is judged unacceptable, it should be reduced to acceptable levels by the appropriate [Page ] means, for example, by redesign or warnings.
An important part of risk analysis is ensuring that changes made to eliminate or minimize hazards do not introduce new hazards. FDA disagrees with the comments that state the requirement is ambiguous. Software must be validated when it is a part of the finished device. FDA believes that this control is always needed, given the unique nature of software, to assure that software will perform as intended and will not impede safe operation by the user. FDA believes that sufficient domestic and international guidelines are available to provide assistance to manufacturers for the validation of software and risk analysis.
Therefore, FDA need not list all known methods for meeting the requirements. A tool that may be required to adequately verify and validate one design may be unnecessary to verify and validate another design. One comment stated that for some design elements it may be more appropriate to reference data from another prior experimentation rather than conduct new testing, and that the requirement to list verification methods should be modified.
FDA agrees in part with the comment. The revised language of Sec. When using data from previous experimentation, manufacturers must ensure that it is adequate for the current application. ISO discusses this concept in notes 12 and As noted above, it is not always possible to determine the adequacy of the design by successfully building and testing prototypes or models produced in a laboratory setting.
The requirement for testing from the first three production lots or batches has been deleted. While FDA believes that three production runs during process validation process validation may be initiated before or during design transfer is the accepted standard, FDA recognizes that all processes may not be defined in terms of lots or batches. The number three is, however, currently considered to be the acceptable standard. Therefore, although the number requirement is deleted, FDA expects validation to be carried out properly in accordance with accepted standards, and will inspect for compliance accordingly.
This is the same requirement that is contained in Sec. The intent of the requirement was to ensure that all design specifications released to production have been approved, verified, and validated before they are implemented as part of the production process. This requirement is now explicitly contained in Sec. FDA agrees in part with the second set of comments and has moved the requirement that design output be reviewed and approved to current Sec.
Manufacturers are not expected to maintain records of all changes proposed during the very early stages of the design process. However, all design changes made after the design review that approves the initial design inputs for incorporation into the design, and those changes made to correct design deficiencies once the design has been released to production, must be documented.
The records of these changes create a history of the evolution of the design, which can be invaluable for failure investigation and for facilitating the design of future similar products.
Such records can prevent the repetition of errors and the development of unsafe or ineffective designs. The evaluation and documentation should be in direct proportion to the significance of the change.
Procedures must ensure that after the design requirements are established and approved, changes to the design, both pre- production and post-production are also reviewed, validated or verified where appropriate , and approved.
Otherwise, a device may be rendered unable to properly perform, and unsafe and ineffective. Records of this evaluation and its results should be maintained. Several comments recommended that only changes after design validation and design transfer to full-scale production need to be documented.
The safety and effectiveness of devices cannot be proven by final inspection or testing. Product development is inherently an evolutionary process. While change is a healthy and necessary part of product development, quality can be ensured only if change is controlled and documented in the development process, as well as the production process. Again, manufacturers are not expected to maintain records of changes made during the very early stages of product development; only those design changes made after the approval of the design inputs need be documented.
Each manufacturer must establish criteria for evaluating changes to ensure that the changes are appropriate for its designs. One comment on proposed Sec. FDA agrees with the comments and has amended the requirement to permit verification where appropriate. For example, a change in the sterilization process of a catheter will require validation of the new process, but the addition of more chromium to a stainless steel surgical instrument may only require verification through chemical analysis.
Where a design change cannot be verified by subsequent inspection and test, it must be validated. The DMR contains the documentation necessary to produce a device.
The final design output from the design phase, which is maintained or referenced in the DHF, will form the basis or starting point for the DMR. Thus, those outputs must be referred to or placed in the DMR. The total finished design output includes the final device, its labeling and packaging, and the DMR that includes device specifications and drawings, as well as all instructions and procedures for production, installation, maintenance, and servicing.
The DHF, in contrast, contains or references all the records necessary to establish compliance with the design plan and the regulation, including the design control procedures. The DHF illustrates the history of the design, and is necessary so that manufacturers can exercise control over and be accountable for the design process, thereby maximizing the probability that the finished design conforms to the design specifications. A few comments stated that the proposed requirements in Sec. FDA agrees with the comments.
The intent of the DHF is to document, or reference the documentation of, the activities carried out to meet the design plan and requirements of Sec. A DHF is, therefore, necessary for each type of device developed. The DHF must provide documentation showing the actions taken with regard to each type of device designed, not generically link devices together with different design characteristics and give a general overview of how the output was reached.
Such records are necessary to ensure that the final design conforms to the design specifications. Depending on the design, that may be relatively few records.
Manufacturers who do not document all their efforts may lose the information and experience of those efforts, thereby possibly requiring activities to be duplicated. Document Controls Subpart D One comment stated that removal of obsolete or unneeded documents should be performed to maintain the integrity of the product configuration and the quality system.
The comment suggested adding a requirement for a verification step for document distribution and removal to ensure this important element of a quality system is performed correctly.
A few comments stated that proposed Sec. FDA agrees with the first comment and has changed the title accordingly. FDA agrees in part with the second comment. The verification of document distribution and removal is very important and can directly affect the quality of a product. FDA agrees in part with the last set of comments and has rewritten the section, following ISO , to be a general requirement for procedures to control documents that are required under the regulation.
The procedures established must, among other things, ensure control of the accuracy and usage of current versions of the documents and the removal or prevention from use of obsolete documents, as well as ensure that the documentation developed is adequate to fulfill its intended purpose or requirement. FDA retained the requirement that the procedures ensure that documents meet the requirements of the regulation because that is the purpose of controlling the documents.
FDA is aware that many documentation systems are now maintained electronically, and is in the process of developing an agency-wide policy that will be implemented through rulemaking on the use of electronic signatures. FDA recommends that manufacturers use the two Federal Register documents as guidance until the regulation is finalized. In response, FDA has deleted the section. The requirements for making documents available at all appropriate locations ISO , section 4.
Several comments suggested major changes to proposed Sec. Others stated that the requirements related to validation should be rewritten and moved to another section under this part, because Sec.
Several comments stated that the reference to determining whether a k or PMA supplement is required after making changes to a device should be deleted because it is covered under different parts of the act and regulations. FDA agrees with many of the comments and has substantially rewritten Sec.
The requirements are now very similar to the ISO requirements in section 4. FDA has retained the requirement that the approved changes must be communicated in a timely manner to appropriate personnel. FDA has had many experiences where manufacturers made corrections to documents, but the changes were not communicated in a timely manner to the personnel utilizing the documents.
The result of these untimely communications was the production of defective devices. In addition, FDA has moved the requirement for validating production and process changes to Sec.
The intent of the requirement is to ensure that those who originally approved the document have an opportunity to review any changes because these individuals typically have the best insight on the impact of the changes. The requirement is flexible, however, because it permits the manufacturer to specifically designate individuals who did not perform the original review and approval to review and approve the changes.
To designate such individuals, the manufacturer will need to determine who would be best suited to perform the function, thus ensuring adequate control over the changes. In this way, review and approval will not be haphazard.
Two comments suggested replacing the section with the requirements of section 4. FDA has deleted Sec. The general requirement of Sec.
The procedures must cover the requirements listed in Sec. The other requirement in Sec. FDA has retained this requirement and has moved it into Sec. FDA believes Sec. Purchasing Controls Subpart E One comment stated that the proposed CGMP regulation omits any discussion of contract reviews, such as that contained in ISO , section 4.
Rather than leaving these procedures to the interpretations of individual manufacturers and investigators, the comment stated that FDA should explicitly state its general policy regarding contract reviews in the regulation. FDA agrees with the concepts underlying the contract review requirements of ISO , but believes these principles are already reflected in requirements in the regulation, such as Secs. One comment stated that the requirements in Sec. The comment stated that components are purchased by providing a specification sheet.
They are then inspected upon receipt, and defective components are returned. According to the comment, under Sec. Another comment stated that the cost of the quality assurance documentation program is going to be significantly higher for a company that runs a Just In Time JIT program than what FDA estimated.
The failure to implement adequate purchasing controls has resulted in a significant number of recalls due to component failures. Most of these were due to unacceptable components provided by suppliers.
Since FDA is not regulating component suppliers, FDA believes that the explicit addition to CGMP requirements of the purchasing controls of ISO is necessary to provide the additional assurance that only acceptable components are used. To ensure purchased or otherwise received product or services conform to specifications, purchasing must be carried out under adequate controls, including the assessment and selection of suppliers, contractors, and consultants, the clear and unambiguous specification of requirements, and the performance of suitable acceptance activities.
Each manufacturer must establish an appropriate mix of assessment and receiving acceptance to ensure products and services are acceptable for their intended uses. The specifications for the finished device cannot be met unless the individual parts of the finished device meet specifications. The most efficient and least costly approach is to ensure that only acceptable products and services are received. This means that only suppliers, contractors, and consultants that meet specifications should be used.
The regulation has been written to allow more flexibility in the way manufacturers may ensure the acceptability of products and services. Under the requirements, manufacturers must clearly define in the procedures the type and extent of control they intend to apply to products and services. Thus, a finished device manufacturer may choose to provide greater in-house controls to ensure that products and services meet requirements, or may require the supplier to adopt measures necessary to ensure acceptability, as appropriate.
FDA generally believes that an appropriate mix of supplier and manufacturer quality controls are necessary. However, finished device manufacturers who conduct product quality control solely in-house must also assess the capability of suppliers to provide acceptable product. Where audits are not practical, this may be done through, among other means, reviewing historical data, monitoring and trending, and inspection and testing. After evaluation of all of the comments on Sec. Thus the degree of supplier control necessary to establish compliance may vary with the type and significance of the product or service purchased and the impact of that product or service on the quality of the finished device.
In addition, the requirement for manufacturers to establish assessment criteria has been deleted but the evaluation still must include a description how the assessment was made according to what criteria or objective procedure and the results must be documented. Each manufacturer must now define the type and extent of control it will exercise over suppliers, contractors, and consultants. This is consistent with the version of ISO Thus, FDA believes that the flexibility of the regulation will allow manufacturers to implement JIT procedures without additional cost.
In fact, the new regulation is more conducive to JIT practices by permitting the assessment or evaluation of product or services up front, thereby lessening the degree of in-house control that may be necessary. FDA agrees with the comments and has deleted the phrase. The phrase was intended to mean product and services which were purchased or processed in some manner by other organizations.
FDA emphasizes that the requirements apply to all product and service received from outside of the finished device manufacturer, whether payment occurs or not. The first sentence of the introductory text of Sec. All manufacturers are expected to apply controls to manufacturing materials appropriate to the manufacturing material, the intended use, and the effect of the manufacturing materials on safety and effectiveness. For example, the procedures necessary to ensure that a mold release agent conforms to specified requirements may be less involved than the procedures for controlling latex proteins.
The provision allows the manufacturer the flexibility of establishing the procedures to meet its needs and to ensure that the product conforms to specified requirements. One comment said that FDA should delete the last sentence of the introductory text of proposed Sec. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent.
You also have the option to opt-out of these cookies. But opting out of some of these cookies may have an effect on your browsing experience. Necessary Necessary. Necessary cookies are absolutely essential for the website to function properly. The ISO system pays more attention to the management of the firm and places a number of reporting loops in the firm to ensure attention to issues.
The QSR system is more focused on the manufacturing systems, and the validation of those systems. We are compliant with ISO Thus, the preamble contains valuable insight into the meaning and intent of the QS regulation. Because the regulation must apply to so many different types of devices, the regulation does not prescribe in detail how a manufacturer must produce a specific device. Rather, the regulation provides the framework that all manufacturers must follow by requiring that manufacturers develop and follow procedures and fill in the details that are appropriate to a given device according to the current state-of-the-art manufacturing for that specific device.
Manufacturers should use good judgment when developing their quality system and apply those sections of the QS regulation that are applicable to their specific products and operations, 21 CFR Operating within this flexibility, it is the responsibility of each manufacturer to establish requirements for each type or family of devices that will result in devices that are safe and effective, and to establish methods and procedures to design, produce, distribute, etc.
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