10. Purchasing and Acceptance Activities
Contractors and Consultants
COMPONENT SELECTION AND VERIFICATION
PURCHASING AND RECEIVING OF PRODUCT
Testing and Inspection of Product
Acceptance and Rejection Records
Obsolete, Deteriorated, and Rejected Components
Written Test Procedures
CONTRACTOR AND CONSULTANT ASSESSMENTS
Process Validation Requirements
Device Servicing Requirements
Quality System Requirements for Contract Sterilization
Bioindicators and Dosimeters
Cycle Parameters and Process Control
Post-sterilization Handling and Aeration
History Records and Review
Finished Device Release
Audits of Both Facilities
FINISHED DEVICE EVALUATION
Labeling and Packaging Inspection
Purchase of Components
Acceptance of Components
Material Receiving and Inspection Procedure
Identification Decals and Forms
Receiving Rejection Notice
This chapter covers component specifications, supplier assessment, receiving components and the services rendered in manufacturing medical devices. Manufacturers of medical devices should maintain a consistent, systematic quality system which, along with other quality assurance activities, should assure that all components, materials, and services involved with the manufacture of medical devices are acceptable for their intended use. This control is a combination of: component and supplier selection and verification; data collection, analysis and corrective action; supplier, contractor, and consultant assessment; identification and status of product including labeling and/or quarantine; and operational procedures.
The establishment and maintenance of requirements, including quality requirements, is essential for the manufacturer when dealing with component suppliers, consultants, and contractors [820.50(a)]. The ability to meet specified requirements is important when evaluating the suppliers and service providers. Assessments of these providers shall be maintained and documented. Possible appropriate methods of accomplishing these goals include audits, checking with other clients, and previous performance data. If prior assessment is not possible, then the manufacturer should assess the service as it is being performed. Assessment shall be documented. Procedures for accepting incoming product shall also be established and maintained. Various acceptance activities may include inspections, tests, and other forms of verification. Acceptance or rejection of components and services shall be documented (820.80).
"Component" is defined in 820.3(c) of the Quality System (QS) regulation as any material, substance, piece, part, software, firmware, labeling, or assembly, which is intended to be included in the finished, packaged, and labeled device. For example, fasteners, blood tubing assemblies and labels are components. This definition excludes "manufacturing materials," which by definition, are not intended to be included as part of the finished, packaged, and labeled device.
According to 820.3(p), "manufacturing material" is any material or substance used in or used to facilitate the manufacturing process, a concomitant constituent, or a byproduct constituent produced during the manufacturing process, which is present in or on the finished device as a residue or impurity not by design or intent of the manufacturer. Examples of manufacturing materials include: cleaning agents, mold-release agents, lubricating oil, or other substance used to facilitate a manufacturing process which is not intended by the manufacturer to be included in the finished device.
Manufacturers of components sold only for further manufacturing of a medical device are not required to comply with the GMP requirements for finished devices. Many components of devices, such as transistors, containers, hardware, etc., are readily available in the marketplace and are not manufactured exclusively for use in devices. Many of these manufacturers supply only a small fraction of their production to finished device manufacturers. However, section 820.1 of the Quality System regulation encourages component manufacturers to use applicable GMP elements as guidance.
If a component is manufactured in the same or proximal facility, and produced for use in finished medical devices, then the component is considered part of the production of the finished devices and is subject to the applicable requirements of the GMP requirements. If the component is manufactured in a separate plant owned by the finished device manufacturer, then the manufacturer has flexibility in handling the quality assurance activities related to the control of components. One satisfactory approach is to have the plant that builds the components operate in full GMP compliance. Under this arrangement, the plant which does the final device assembly would still be responsible for ascertaining that the quality and integrity of incoming components have not been damaged during shipment. Alternately, the component manufacturing plant may not fully comply with Quality System regulation. Then the plant that does final assembly should handle the acceptance of these components with the same degree of control as if the components were purchased from an outside supplier.
For components such as labels, package inserts, packaging, etc., there is additional information in chapter 11, Labeling; and chapter 13, Packaging.
The Quality System regulation applies to manufacturers who produce finished accessories to devices intended to be used for health-related purposes. An accessory is any finished unit distributed separately but intended to be attached to or used in conjunction with another finished device. Therefore, any manufacturer of accessory devices should meet all FDA regulations for a finished device. These regulations include 21 CFR Part 807 Subpart E, Premarket Notification; 21 CFR Part 807 Subparts B, C., and D, Registration and Listing; 21 CFR Part 820, Good Manufacturing Practices (GMP); 21 CFR Part 801, General Device Labeling; 21 CFR Part 809, In Vitro Diagnostic Labeling (if applicable); etc.
Contractors and Consultants
Contractors and consultants generally provide a service rather than a physical component. This service should be treated in basically the same manner as physical components because these services affect the quality of the finished device. The combination of both services and physical components determines the quality of the finished device. Services should be obtained per 820.50, Purchasing Controls, and be controlled upon receipt using the applicable requirements in 820.30, Design Controls, 820.70, Production and Process Controls; 820.80, Receiving, In-Process, and Finished Device Acceptance, etc., depending on the nature of the service.
Verification of physical components is a very important step toward producing a high quality product. Verification of components consists of determining through documented testing that a component will perform its function reliably in the intended application and under the most adverse environmental conditions in which the device is expected to be used. These conditions shall consider the needs of the user and patient [820.30(c)] and shall encompass the manufacturer's labeling claims for the device.
Components have to be carefully selected, using the requirements of the device as a guide. Components should be chosen so that they will not be over-stressed and will be compatible with the internal device environment, as well as the external environment that the device is expected to encounter during manufacture, distribution, and use. The components should then be appropriately tested, alone, and as part of the device, utilizing the specifications established for the component and the device. New components or components used in an unusual application will usually need extensive evaluation. This evaluation should include parameter and life testing as well as compatibility testing for both the internal and external environment. Well known industry standard components that are used in their normal application and that are not over-stressed will need only minor testing, which is usually an integral part of the verification of the device design. A record of any component verification testing should be maintained. This record should include the component identity and the testing methods that were used, as well as the actual test data and results.
Component quality is maintained through correct specifications, procurement, incoming acceptance, storage, handling, installation, and change control. To monitor the adequacy of these activities and procedures, feedback from the quality system is needed. Corrections are made if necessary. In addition to maintaining quality, the manufacturer shall also establish and maintain procedures for identifying product during all manufacturing stages from receipt through installation (820.60 and 820.86). Product includes components, manufacturing materials, in-process devices, finished devices, and returned devices.
Component specifications are required as part of the device master record. Components are selected and their specifications are documented during the design of the device. The specifications should be well designed, achievable, and acceptable to suppliers. They should adequately describe the quality characteristics, dimensions, design, materials, performance, and any other features necessary to assure receipt of the item desired. For unusual, vital, new or key components the specification data is derived primarily from the verification data with minor details from the catalog data. For routine components, such as those that have been used for a long time or have a known performance history, a catalog designation may be adequate to describe a component and assure its purchase. For some components such as transistors, the catalog number also may be used to obtain complete specifications from a reference manual. Specifications should reflect both design requirements and quality/reliability needs. The quality level for each component should be specified. Components usually are available in several quality levels such as reagent grade, commercial grade, military grade, etc. In some cases, a significant increase in component quality can be obtained for a modest increase in cost by specifying a higher grade, thus reducing the probability of future quality problems and the possibility of significant associated costs.
A major factor in obtaining high quality components is the selection of suppliers. Although a manufacturer's knowledge of supplier operations may be limited and information about the operations difficult to obtain, the GMP requirement that a manufacturer is responsible for quality remains undiminished. To the maximum extent feasible, selection and qualification of suppliers by audits, performance analysis, etc., should be part of a quality system. If the manufacturer does not have the capability to test components for conformance to specifications, then supplier test data or outside lab results are acceptable provided that components are tested and inspected in a statistically valid manner to show their acceptability for use in the finished device. Any outside test results should be accompanied by relevant raw data used for the test so that judgments of authenticity may be made by the finished device manufacturer. Excluding a supplier whose components are unreliable from supplying components may help prevent problems with the final device and is certainly worthwhile as a cost reduction effort.
It is important to remember that raw components acquire cumulative value as they are processed through receiving, assembly, test, inspection, and as they ultimately become part of the finished device. If a component fails during assembly, or as part of the device, additional costs will be incurred for fault isolation, removal, replacement, inspection, testing, etc. When field failures occur, the ultimate cost of the component becomes even higher because its replacement requires travel, trouble-shooting, and retrofit. In addition, customer dissatisfaction, user injury, product liability action, medical device reporting, or regulatory action may result. Usually, the initial cost of a component is relatively insignificant compared to the later cost should the component prove to be defective or improper for the selected use. Many recalls occur because manufacturers fail to qualify components properly or to assure that a supplier's manufacturing methods and quality system are adequate.
Written instructions are necessary to assure that components, manufacturing materials, etc. are properly identified, processed, and stored when received. Written inspection and test procedures are necessary to prescribe the:
- acceptance activities performed;
- dates acceptance activities are performed;
- the results;
- signature of the individual(s) conducting acceptance activities; and
- where appropriate, the equipment used.
Before acceptance, all components should be either physically separated (quarantined) or clearly identified as not yet accepted. The decision to separate or tag not-yet-accepted product should be made based on the characteristics of the device, the potential for mixups, plant conditions, and manufacturing practices.
Although 820.80 requires a written procedure for accepting components, the Quality System regulation in 820.5 allows discretion in the quality system. Thus a very small manufacturer, usually 10 or fewer employees, may only need very brief written acceptance procedures referencing the purchase orders and receiving tickets. As the size of the operation, the numbers of activities, and number of people involved increase, the need for comprehensive written instructions generally increases.
Manufacturers should have specific acceptance criteria for components. Acceptance criteria are the attributes of a component that determine its acceptability, such as appearance, dimension, purity, performance characteristics, etc. Typically, acceptance criteria are made a part of the inspection/test procedure. For example, if component specifications or a drawing adequately describe the attributes needed in order for the component to perform in its intended manner, these may be used as the acceptance criteria. If components or the suppliers of the components have a history of good performance, the components may be accepted for use after a visual check to assure they are the items intended and that they are not damaged or contaminated. Components, which need only a visual inspection, may be accepted using the purchase order data as acceptance criteria. The purchase order and/or receiving ticket should at a minimum contain the following information:
- name of supplier;
- description of the component or other product; and
- quantity shipped.
For a standard component, the catalog number may be used as a description. QA personnel should determine whether the use of any "abbreviated" criteria are adequate during their audit of production rework, history records, complaint files, and service records.
Testing and Inspection of Product
The minimum acceptance activity per current practice requires that all incoming components and other product receive at least a visual inspection for contamination and/or damage and be identified as the component specified on the purchase order. A manufacturer accepting the product has the discretion to determine when and where product should be inspected, sampled, and tested for conformance to specifications depending upon the risk that failure of that component may pose. As appropriate, product may be tested and/or inspected by:
- the supplier;
- when received;
- during manufacture of the device; or
- as part of the finished device.
If components are tested as part of the finished device, the testing should be able to reveal failed and "out-of-spec" components and not just that the finished device does not meet specifications. This determination, of course, may be performed after removing the component from the device. The rejection shall be documented [820.80(b)].
Manufacturers who decide not to sample or test specific components should be able to justify that decision based on such factors as knowledge of the supplier's previous performance in providing high quality components, the component performance history, and application of the components in the device. Manufacturers may rely on component suppliers to conduct testing if the manufacturer specifies or is knowledgeable about the supplier's quality system, particularly the inspection and test programs and the supplier has specifications that properly define the manufacturer's acceptable limits for the component or material parameters. These specifications may be used to meet the device master record requirements for component specifications, if these accurately reflect the parameters, composition, and configuration required for the component to perform the function for which it was selected. Supplier specifications are usually adequate for standard components. However, a manufacturer who relies on supplier specifications usually has no control over changes in these and, therefore, should assure at an appropriate point in the manufacturing process that the components received meet the desired specifications.
If components are tested by the supplier, acceptance of components can be based on certification and review of test data submitted by the supplier for the specific components provided. Certification should accompany each lot of components. When certification is used, the manufacturer should periodically verify the validity of the certification through an assessment of the supplier.
Where historical data shows that certain components or other product have been substandard and resulted in a device failing to meet specifications, or where performance history has not been established, specific steps should be taken to assure components meet specifications. Typically, this task is accomplished by sampling and testing each lot of components to assure that the components meet specifications. Where appropriate, all significant or high risk components should be sampled and tested.
Manufacturers may test entire assemblies of components rather than individual components. If, however, testing an assembly cannot assure fitness-for-use of the components, then components should be tested on an individual or lot basis, whichever is appropriate. For example, assemblies with an internal feedback circuit could have a very marginal component. Because of the circuit design, the condition of the marginal component might not be detected by testing the entire assembly. Therefore, the feedback loop in the assembly should be opened during one of the tests, or the individual components should be tested.
When using a contract laboratory to test production components, the laboratory becomes an extension of the device manufacturer's quality system. The device manufacturer is responsible for assuring that the contractor's test and inspection procedures are acceptable. This assurance maybe obtained by audits of the laboratory, by the lab staff, and by the finished device manufacturer.
Inspection and testing will not improve the quality of components or other product; however, if the inspection and testing is appropriate and performed adequately, these activities can be used to prevent or significantly reduce the use of low-quality or defective product. Through feedback into the overall quality system, data on products will help identify basic causes of problems and lead to solutions (820.100). If problems are found, actions such as design changes, tighter acceptance criteria, supplier assessments, or change of suppliers may be appropriate.
Acceptance and Rejection Records
Adequate records shall be maintained to provide objective evidence that components were inspected and accepted, or rejected. These records are a part of the device history record and should be maintained in a format that facilitates review. The records, however, are not required to be maintained in a single file with other production history records, and are typically filed in the receiving or quality control area according to part number or component nomenclature. Small manufacturers may use purchase orders or packing slips to record acceptance and rejection if they contain adequate information.
The Quality System regulation specifies in 820.80(b) that a record of component acceptance and rejection be maintained. Typically, acceptance/rejection records should contain:
- acceptance or rejection documentation;
- number and type of deficiencies;
- quantity approved;
- quantity rejected; and
- nature of corrective action taken.
Obsolete, Deteriorated, and Rejected Components
Obsolete, deteriorated and rejected components shall be identified (820.60, 820.86, and 820.150) as such and be placed in a separate quarantine area or specially identified area to prevent mixups. If practical, components should be individually identified as rejects. Where it is not feasible to tag each rejected component, as in the case of transistors, bolts, bottles, etc., containers or packages of rejected lots should be clearly marked and otherwise appropriately segregated from accepted components. See 820.86 for clarification. Manufacturers should determine the need for a separate written procedure for handling these components based on the size of the manufacturer and complexity of their devices and operations. Disposition of nonconforming product shall be documented [820.90(b)].
Records for rejected components should state whether the components were returned, scraped, reworked, etc. In very small manufacturers, disposition can be recorded directly onto the purchase order, receiving ticket, or other associated document. Small-to-medium sized manufacturers generally record disposition on the form used to receive components. Most large manufacturers record disposition of rejected components on standard forms such as a Nonconforming Material Report (NMR).
When components, materials, etc., become obsolete, many manufacturers assign new identification numbers to the new version of these components etc. The obsolete items are retained for other uses, such as repair parts, engineering projects, etc. In these cases, the old and new items should be adequately segregated and/or identified to prevent inadvertent use of obsolete components in production.
Each manufacturer shall establish and maintain procedures for control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed. When the quality of product deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, its condition shall be assessed as appropriate. 820.150 procedures shall be established and maintained that describe methods for authorizing receipt from, and dispatch to, storage areas and stock rooms.
Although not a direct requirement, all raw materials and components used in the finished device should be received through a central control point. Centralized receiving leads to orderly storage, limits access to stored material, and aids a manufacturer in meeting other GMP requirements. Components and other product should be identified or stored so that it is obvious at all times that product has been accepted, rejected, or is awaiting a disposition decision. A quarantine area can be either a physically secure area or simply limited access area identified as a quarantine area. If special environmental storage conditions are required such as for many biologically derived components, these conditions should be controlled and monitored and the associated specifications included in the device master record.
When the device is to be sterilized, storage conditions should be selected, as appropriate, to prevent contamination of components and packaging by bacteria or filth. Also, temperatures should be controlled as necessary to prevent or reduce the growth of bacteria. The higher bioburden (bacteria, etc.) levels may challenge the sterilization cycle to an extent greater than the capability established during process validation and, thereby, result in a sterility assurance level that may not meet the finished device specification. Some components, particularly those used in the manufacture of in vitro diagnostic devices, if not stored properly, may support growth of bacteria.
The criteria as stated in 820.65 for determining the need to have traceability via a unit, lot, or batch control number of a device specifies devices intended for surgical implant into the body or those that support or sustain life and whose failure to perform, when properly used in accordance with instructions for use provided in the labeling, can be reasonably expected to result in a significant injury to the user. Identification of traceable devices should be based on the health hazard presented if a device fails to meet its performance specifications when operated as intended. Because of the design control requirements (820.30), user error and the environment are not considered by FDA as a means for excusing the lack of device performance. User error is not a performance failure, although it could be considered a result of inadequate directions for use, other inadequate labeling, or poor human factors design. The environment could result in failure of a device but it should not effect the result of the device failure.
FDA is concerned about the failure of components that would result in sudden or catastrophic device failure, which can reasonably be expected to result in significant injury to the user, such as:
- no output from an implantable cardiac pacemaker;
- fracture of an implanted orthopedic implant;
- runaway in an implanted cardiac pacemaker;
- misfiring of a synchronized defibrillator; etc.
A manufacturer should know in detail how the device functions and the purpose of each component in the finished device. If as a result of a failure, the performance, lack of performance, or effect on safety or effectiveness of the finished device could result in significant injury to the user when the device is properly used in accordance with instructions in the labeling, the component under consideration may require increased control and traceability. The effect that each component will have on finished device performance, should the component fail to perform as intended, should be determined. Thus, manufacturers should carefully study the possible failure modes of their devices and decide which components are truly critical under the various modes. This determination may be time-consuming with respect to some devices, but it is necessary. It will, in the long run, save manufacturers liability, repair, and replacement costs. To make such a determination, manufacturers should conduct reliability tests and failure effects analyses during the design phase in order to accurately identify critical components.
The number of components that need to be considered as potentially needing to be handled as traceable components can be reduced by considering the reliability of components and whether they "reasonably" can be expected to fail. For example, power cords, clamps, plugs, etc. seldom fail. Therefore, manufacturers may not need to consider extensive tracing requirement of these components. Also, manufacturers can consider a subassembly as a component and, thereby, reduce the number of identification and record keeping activities, but all rationale and justification should be documented.
Written Test Procedures
A device manufacturer shall establish and maintain procedures to ensure that all purchased and otherwise received product conforms to specified requirements (820.50) and establish and maintain procedures for acceptance activities [820.80(a)]. The manufacturer shall assure that all lots of components or other products are accepted, sampled, tested and/or inspected using written procedures. The inspection/test procedure for each component shall be correct [820.30(d), Design Output and 820.30(h) Design Transfer], dated, and approved. The design verification procedures usually may be used to develop production test procedures. The procedure should specify, as appropriate,:
- items to which it applies,
- product characteristics to be inspected/tested,
- acceptance/rejection criteria,
- test method(s),
- data forms,
- sampling plans, and
- necessary test inspection equipment and tools.
When assuring that components and other products meet acceptance criteria, manufacturers may test either all components or may test a portion of the components using a sampling plan based upon an acceptable statistical rationale (820.250). A manufacturer shall be prepared to demonstrate the statistical rationale for any sampling plan used. Plans should be developed by qualified mathematicians or statisticians, or be taken from established standards such as ANSI Z1.4. It should be recognized that all sampling plans have a built-in risk of accepting a bad lot.
This sampling risk is typically determined in quantitative terms by deriving the "operating characteristic curve" for the selected plan. Each sampling plan has a characteristic curve. ANSI Z1.4 contains operating characteristic curves for sampling plans presented in the standards, and it can be used to determine the risk a sampling plan presents. A manufacturer should be aware of the risks the chosen plan presents. Operating characteristic curves are a means of graphically showing the relationship between the:
- quality of lots submitted for sampling inspection, usually expressed in percent defective, but may be expressed in defect per hundred units; and
- the probability that the sampling plan will yield a decision to accept the lot, described as the "probability of acceptance."
Manufacturers of surgically implantable or life sustaining devices whose failure to perform when properly used can be reasonable expected to result in a significant injury shall establish and maintain procedures for identifying with a control number each unit, lot, or batch of finished devices and when appropriate components. Control numbers should be assigned to each unit, lot or batch of components that were manufactured under similar conditions over the same time period so that defects can be traced to the component manufacturer and the cause of the defects determined and corrected. If a subassembly is regarded as a traceable component by the manufacturer, a control number for that traceable subassembly shall be recorded in the device history record.
Manufacturers shall establish and maintain the requirements, including quality requirements, that will be met by contractors/consultants that perform a service for them. To aid in accomplishing this task each manufacturer shall:
- evaluate and select contractors/consultants based on their ability to meet specified requirements, including quality requirements. This evaluation shall be documented.
- define the type and extent of control to be exercised over the contractors/consultants based on the evaluation results.
- establish and maintain records of acceptable contractors/consultants.
Contractors and consultants often provide information or a service rather than a physical component. However, the thought and control processes are similar whether one is working with services or with physical product. The input from contractors and consultants have a definite impact on the finished device. Services may include: design activities, various product verification/validation activities, sterilization, routine maintenance, and calibration of equipment.
Each manufacturer shall provide adequate resources and trained personnel to properly assess the activities of their contractors and make adjustments as necessary. Contractors and consultants maybe assessed based on their applicable education, experience, ability, resources such as facilities and equipment, list of clients, patents, technical reports, etc. Assessment may include conducting internal quality audits [820.20(b)(2)]. Therefore, each manufacturer that is having important work done by a contractor should inform the contractor that their quality system and activities may be audited. These services may include janitorial, consultants, design work, calibration, sterilization, laboratory, and maintenance.
At various stages of product development the manufacturer may need to interface with different groups. If a need for this interface relationship arises during the design phase, a plan shall be developed describing the interface with different groups or activities during the design process [820.30(b)]. By planning for outside services, and including these providers in selected design review meetings, a manufacturer increases the probability of receiving a service that meets requirements. Also the manufacturer is held responsible for work done by outside contractors or consultants. Thus, it is in the manufacturer's best interest to keep providers adequately informed and to monitor contractors to ensure that the correct design, production, or process controls are applied to contractor services to ensure the service or finished product conforms to its specifications (820.30, 820.50, 820.70, and 820.80).
Process Validation Requirements
Regardless of whether a manufacturer or a contractor performs the actual work, the manufacturer is responsible for establishing and maintaining control of the process parameters for the validated process (820.75). Established procedures for validation and the validation results should offer a high degree of assurance that the process consistently produces an output that meets pre-established specifications. Validated processes shall be performed by a qualified person(s) and be documented regardless of whether the manufacturer or an outside contractor performs the validation activities. For more information see Process Validation, chapter 4.
Device Servicing Requirements
If a manufacturer contracts for device service with another party, the assessment and selection of such contractors shall be done according to 820.50 Purchasing Controls. Such service activities and reports should be periodically reviewed to assure that the service activities meet GMP servicing requirements as briefly described below.
Device servicing performed by contractors and/or consultants shall be conducted using established procedures for performing and verifying that the service meets specified requirements (820.50 and 820.200). A written report on the servicing shall include:
1. the name of the medical device serviced;
2. any device identification(s) and control number(s) used;
3. the date of service;
4. the individual(s) servicing the device;
5. the service performed; and
6. the test and inspection data.
Each manufacturer should analyze the service reports they receive directly, as well as the ones they receive from contractors, using the appropriate statistical methodology referenced in 820.100. It is important that this service data be collected and organized such that it can be analyzed to determine if quality problems exist. See Chapter 15, Complaints, for more details. If the report represents an event which is reportable to FDA under medical device reporting (MDR) requirements in 21 CFR part 803 or 804, these reports shall be handled as complaints using 820.198.
Contract agreements between the manufacturer and contractors and/or consultants will vary in their degree of complexity. The most comprehensive is probably the agreement between the manufacturer and the contract sterilizer. Thus, the contract sterilization agreement is an excellent example of what is involved in setting up a contract between the device manufacturer and a contractor. The steps necessary for an agreement may be less extensive with other contracts than it is with the sterilization contract; however, the sterilization contract does provide a good basis for understanding this contractual agreement.
Manufacturers of medical devices frequently use contract sterilizers to provide sterilization processing for their devices prior to distribution. Contract sterilization of medical devices shall be performed so that the device manufacturer and the contract sterilizer meet the applicable parts of both the QS regulation and the labeling requirements of 21 CFR 801.
Manufacturers of sterile devices commonly label devices as sterile at one establishment and ship them to another facility or to a contract sterilizer for sterilization. Shipments of nonsterile devices labeled as sterile are clearly misbranded and adulterated, and they may be diverted into consumer channels, thus creating a health hazard. FDA recognizes that this longstanding practice is an economic necessity for many manufacturers. Therefore, to meet the needs of these manufacturers in a way that will also assure the protection of the public health, FDA added Part 801.150(e) to the Code of Federal Regulations (CFR). This part identifies the necessary markings for such shipments and requires a written agreement which specifies the sterilization process. Part 801.150(e) It is reprinted below:
(e) As it is a common industry practice to manufacture and/or assemble, package, and fully label a device as sterile at one establishment and then ship such device in interstate commerce to another establishment or to a contract sterilizer for sterilization, the Food and Drug Administration will initiate no regulatory action against the device as misbranded or adulterated when the nonsterile device is labeled sterile, provided all the following conditions are met:
(1) There is in effect a written agreement which:
(i) Contains the names and post office addresses of the manufacturers involved and is signed by the person authorizing such shipment and the operator or person in charge of the establishment receiving the devices for sterilization.
(ii) Provides instructions for maintaining proper records or otherwise accounting for the number of units in each shipment to insure that the number of units shipped is the same as the number received and sterilized.
(iii) Acknowledges that the device is nonsterile and is being shipped for further processing, and
(iv) States in detail the sterilization process, the gaseous mixture or other media, the equipment, and the testing method or quality controls to be used by the contract sterilizer to assure that the device will be brought into full compliance with the Federal Food, Drug and Cosmetic Act.
(2) Each pallet, carton, or other designated unit is conspicuously marked to show its nonsterile nature when it is introduced into and is moving in interstate commerce, and while it is being held prior to sterilization. Following sterilization, and until such time as it is established that the device is sterile and can be released from quarantine, each pallet, carton, or other designated unit is conspicuously marked to show that it has not been released from quarantine, e.g., "sterilized awaiting test results" or an equivalent designation.
Quality System Requirements for Contract Sterilization
The sterilization process are performed in compliance with applicable parts of the Quality System regulation for medical devices because sterilization is a manufacturing process. Thus, the contract sterilizer is a manufacturer [(820.3(o)] and the device master record (DMR) shall contain, or refer to, the location of sterilization process specifications. Process specifications may be generated by either the manufacturer, contract sterilizer, or by both parties, although overall responsibility rests with the finished device manufacturer. The device manufacturer is ultimately responsible for assuring that its devices are sterile. The responsibility for specific tasks may be delegated to a contract sterilizer, but the device manufacturer retains the ultimate responsibility. The contract sterilizer is subject to those parts of the QS regulations that apply to the operations that it performs for the finished device manufacturers, e.g., equipment maintenance and calibration, in-process controls, and associated record keeping, etc. Thus, both the manufacturer and the contract sterilizer share the responsibility to comply with the QS regulation in assuring effective sterilization.
Because the responsibility for effective sterilization is shared between the device manufacturer and the contract sterilizer, it is essential that the two parties clearly define in writing the division of responsibility for every aspect of the sterilization process. The QS arrangements between the manufacturer and the contract sterilizer may be in the same written agreement used to cover the 801.150(e) labeling requirements. It is the manufacturer's and contractor's responsibility to assure the agreement is a workable practical document and is followed by both parties. FDA inspects finished device manufacturers and contract sterilizers to determine compliance. The following is QS related information that should be in the written agreement for contract sterilization and implemented during production, sterilization, and release.
The manufacturer and contract sterilizer should designate the individual(s) at each facility responsible for coordinating the flow of information between establishments and for approving changes in procedures. All technical, procedural, and other information that pertains to the sterilization process and associated activities should pass through these designees. The manufacturer and the contractor shall agree to inform one another of any device or process changes, especially those that may require cycle requalification.
Documentation such as device master record procedures, device history records, etc., to be used and maintained should be specified. If changes are made to the documentation, both parties should agree on the manner in which the changes are to be made. These documentation changes shall comply with QS requirements in 820.70(b) and .75(c) for manufacturing and process specification changes, and with 820.40(b) for changes in device master records.
The device manufacturer has primary responsibility for the validation of the process used to sterilize its devices. Commonly, responsibility for portions of the validation study are delegated to the contract sterilizer in the written agreement. The manufacturer should work with the contract sterilizer to assure that the facilities, equipment and processing parameters (including preconditioning and aeration steps) will provide for effective sterilization and will not adversely affect the devices or their packaging. Validation is required for every device or device family. The written agreement should identify responsibility for all aspects of validation and define the criteria, frequency, and responsibility for requalification. Likewise, the agreement should identify the documentation that is maintained for validation studies.
Bioindicators and Dosimeters
The agreement should specify responsibility for placement, retrieval, handling, and processing of product samples and any biological, chemical, or physical indicators. The agreement should include instructions for packaging and shipment of indicators and samples to test laboratories for analysis.
The loading parameters for each lot of device(s) or device family should be specified. The routine product load configuration should conform to the validated load configuration. It is not recommended that a contract sterilizer mix products from different manufacturers in processing cycles unless validation studies have proven the effectiveness of the cycle for those mixes or worst case mixes, and the customers are informed about the practice.
The agreement should address preconditioning requirements for external preconditioning and/or in-chamber conditioning if required by the sterilization process.
Cycle Parameters and Process Control
The written agreement should specify the cycle parameters to be achieved during processing. After the process is qualified, the contract sterilizer is responsible for maintaining control over the process to make certain that process specifications are routinely achieved. Cycle parameters should be clearly defined in written specifications, accurately monitored, and the actual parameter values achieved during each run should be recorded.
The primary manufacturer should produce the product under a quality system, which includes appropriate environmental control procedures such as bioburden control. Thus, the product is the "same" product as that for which the original process was developed or specified.
Post-sterilization Handling and Aeration
The agreement should address procedures for post-sterilization quarantine of the product before release for distribution. While waiting for release, the pallets, cartons, or designated unit shall be marked to indicate the status of the product; for example, "sterilized: awaiting test results," or an equivalent statement. If an aeration period is required, it should be specified. Both parties should acknowledge that the product is not to be shipped for commercial distribution until it is properly approved for distribution in accordance with procedures in the agreement.
If correctly labeled, a device that has been sterilized may be shipped to a controlled distribution point before final release by the manufacturer. Routine distributors are NOT considered to be "controlled distribution points." Shipments to a company warehouse or to another finished device manufacturer may be acceptable as long as the manufacturers are able to show that they have control of the product until final release and could recall it if necessary. See CFR 801 Subparts A & E and QS sections 820.160, Distribution, and 820.80(d), Final Acceptance Activities.
History Records and Review
Both the manufacturer and contractor should agree on the procedures and responsibility for reviewing and approving the device history records.
Finished Device Release
The agreement should include device release procedures. Individuals responsible for approving device release for distribution should be identified. A contract sterilizer may handle the final release of a batch of sterilized devices. The manufacturer should make sure, however, that this agreement is part of a written contract. In addition, the manufacturer should: audit or have a consultant audit the contract sterilizer; review the contractor's own QA audit report; or obtain written certification of compliance to assure that personnel and procedures are adequate to meet the requirements of 820.160, Distribution, and, 820.80(d), Final Acceptance Activities.
Audits of Both Facilities
The device manufacturer should audit his quality system and assure by audits or other means such as a review of the contractor's own QA audit that the contractor has adequate control over the sterilization process. The agreement should cover the extent and frequency of the audit, corrective actions, records, confidentiality, and the auditor(s).
The manufacturer should assure that the entire sterilization process is performed and controlled by properly trained operators. The agreement should provide the manufacturer access to applicable training records during agreed upon audits.
Both parties should mutually agree to inform one another if the device or process deviates from the agreed upon specifications. As appropriate, the nonconformance should be investigated, evaluated, and, if necessary, corrective actions should be instituted. The parties should consider and agree on conditions requiring corrective action and document all reprocessing. The agreement should specify the individuals that should be contracted regarding any changes or deviations in the manufacturing or sterilization process. It should also specify the individual at the manufacturer that should be contacted when product is damaged to determine how the product should be handled at the contract sterilizer.
It is highly recommended that manufacturers of sterile medical devices read Sterile Medical Devices-A GMP Workshop Manual. This publication may be obtained from National Technical Information Services (NTIS), phone: 703-487-4650. The ordering number is: PB84188713. As of 7/96 the price is $71.50 for a paper copy and $12.50 for a microfiche copy.
Finished device inspection is typically a final test and review of safety, performance, labeling, appearance, and configuration characteristics to assure the device meets the acceptance criteria established in the DMR. For many medical devices this assurance requires an analysis, electrical test, mechanical test, or other technical tests. For some simple devices, however, such as eyeglass frames, a visual or dimensional check may be sufficient to prove acceptability. For both simple and complex devices the manufacturer shall have written specifications or criteria for determining the acceptability of the finished device. It is important that the device characteristics to be evaluated are defined and also, where applicable, the equipment, environment, and handling procedure should be defined and established.
To show the manufacturing process is operating in a state-of-control, the process may need to be validated as explained in chapter 4, Process Validation. Testing product by using a sampling plan based upon an acceptable statistical rationale may demonstrate that the process continues to operate in a state of control. A manufacturer should be prepared to demonstrate the statistical rationale for any sampling plan used. Plans should be developed by qualified mathematicians or be selected from established standards such as ANSI Z1.4. Copies of this standard may be obtained by writing to: American National Standards Institute, 11 West 42nd Street, 13th Floor, New York City, NY 10036, or phone 212-642-4900.
All sampling plans have a built-in sampling risk of shipping devices that do not meet product specifications. Each sampling plan can be graphically illustrated to show the relationship between: the quality of lots submitted for sampling inspection and the probability that the sampling plan will yield a decision to ship the lot. ANSI Z1.4 contains operating characteristic curves for sampling plans presented in them. These curves can be used to determine the risk each sampling plan presents.
When sampling plans are used, there exists the possibility that a few defective devices will be shipped to the user. Thus, manufacturers should be aware of the risks a particular plan presents to the manufacturer and to the user. Questions such as those listed below should be considered before selecting a sampling plan.
- Will the defect be obvious to the user? If not, what are the consequences of using the defective device?
- What is the state-of-the-art technology for 100% valid testing of this device?
- Is the testing destructive?
- Does the competition use sampling?
- What is the probability of a product liability suit?
- What are the regulatory consequences?
- Does the marketplace expect or accept devices that have been sample tested and/or inspected?
Manufacturers should recognize that straightforward logical answers to these questions may not always be suitable. Acceptance status for devices may be influenced by the price the user is willing to pay -- 100 percent testing usually costs more than sampling. Destructive testing makes 100 percent testing impossible. Whether sample testing and inspection of a particular family of devices is acceptable to the user also changes with technology. Where 100% valid automatic testing is not feasible, validation of the process and the product with a follow up sampling plan is usually the preferred method of establishing and maintaining a quality system, which can continuously produce a device that meets specifications.
Each manufacturer shall establish and maintain procedures for rework, to include retesting and reevaluation of the nonconforming product after rework, to ensure that it meets its current approved specifications. Rework and reevaluation activities, including a determination of any adverse effect from the rework upon the product, shall be documented in the device history record (DHR) [820.90(b)(2)].
When a device fails testing, it should not be repeatedly retested until it passes. The problem should be corrected. If a manufacturer's acceptance procedures allow acceptance after repeated testing and rework, there should be a valid basis for such an acceptance procedure. Failed devices shall be identified and segregated from acceptable devices and from the flow of the production process.
Labeling and Packaging Inspection
The manufacturer shall establish and maintain procedures to control labeling. This control includes the label's integrity, inspection, storage, control numbers, and labeling related operations (820.120).
The manufacturer shall control labeling and packaging operations to prevent labeling mixups. The label and labeling used for each production unit, lot, or batch shall be documented in the DHR [820.120(d)]. Where a control number is required by 820.65, that control number shall be on, or shall accompany, the device through distribution [820.120(e)]. The DHR shall include or refer to the location of the primary identification label and labeling used for each production unit [820.184(e)].
The manufacturer shall ensure that the device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution (820.130, Device Packaging). This may include containers and packaging examination as applicable to assure they are not damaged or misbranded. All devices shall have the correct labels, package inserts, and/or manuals as specified in the DMR.
A DHR is a compilation of records containing the production history of a finished device [820.3(i)]. However, procedures for establishing and maintaining DHR shall be developed. These records demonstrate the device is manufactured in accordance with the DMR. The DHR shall include or note the location [820.80(e), 820.184] of:
- dates of manufacture;
- quantity manufactured;
- quantity released for distribution;
- acceptance records demonstrating the device is manufactured in accordance with the DMR;
- - date of acceptance
- - results of acceptance activities
- - signature of person(s) performing acceptance activities
- - where appropriate, equipment used
- primary identification label and labeling used for each production unit; and
- any device identification(s) and control number(s) used.
The DHR should be reviewed before distribution because these records are used to show that finished devices are manufactured in accordance with, and meet, the specifications in the DMR.
Beside these requirements, some device manufacturers should fulfill an additional traceability requirement if their device is intended for surgical implant into the body or to support or sustain life and whose failure to perform when properly used in accordance with the label instructions for use can be reasonably expected to result in a significant injury to the user. For these devices procedures shall be established and maintained to identify a control number for each unit, lot, or batch of finished devices and, where appropriate, components. The control number is used to trace a defective lot and facilitate corrective action. Identification of devices shall be documented in the DHR (820.65).
Finished device manufacturers shall have sufficient controls to assure that only devices that have passed test and inspection are released as discussed in chapter 14, Storage, Distribution and Installation. The manufacturer shall establish and maintain procedures for identifying product during all stages of receipt, production, distribution, and installation to prevent mixups (820.60). Each manufacturer shall establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria. To prevent mixups, not-yet-accepted and rejected devices shall be controlled to prevent mix up with devices that have been through final evaluation and accepted for release [820.80(d)]. Methods of controlling non-releasable product include storage location, boxing, or manifest tagging. The desired end result is to assure operations are in a state-of-control. Finished devices should not be released for distribution until:
- the activities required in the manufacturers DMR are completed;
- the associated data and documentation are reviewed;
- the release is authorized by the signature of a designated individual(s); and
- the authorization is dated.
Examples of forms that may be used for purchasing, accepting, receiving, and inspecting components are exhibited at the end of this chapter. These examples show the types of information required by the Quality System regulation. Procedures and forms for a particular situation may be more or less comprehensive than these, and may assume other formats or arrangements according to need.
Purchase of Components
This exhibit is a specification for purchasing a zener diode and is typical of device master record documents that are used to purchase components. This spec describes the diode in sufficient detail for the correct part to be procured.
Acceptance of Components
This example is intended as an acceptance procedure that may be followed by a small to medium size manufacturer. The procedure has space for the number, revision level, and a blank for "ECN History." The history blank is for adding brief notes about changes that have been made to this procedure. Included as part of this procedure is a "Receiving History Log" which immediately follows the procedure. The other forms mentioned in the procedure are not reprinted; however, similar forms are included with the "Procedure for Receiving and Inspection of Material" described below with the example located immediately following the "Receiving History Log."
Material Receiving and Inspection Procedure
This document is a more extensive receiving procedure than the one discussed above and it can be used by a medium to large manufacturer. As part of this procedure you will note an extensive revision record section. Also, part of the procedure is a flow chart which outlines the steps in the procedure and the branches for each step. Next is a "Daily Report of Goods Received" which includes the supplier name, quantity received, lot number or item number, purchase order or requisition number, and information on where the item was sent. The next item in the procedure is a "Receiving and Inspection Report" which contains information about the item and the sampling and testing performed on the item. The report includes an acceptance or rejection slot along with a space for the cause for rejection. The procedure continues with a "Daily Inspection Log" which is a summary of the items received and their disposition, either accepted or rejected. Finally, as part of the procedure, we find examples of the decals to be used to accept, reject, or quarantine the incoming items.
Identification Decals and Forms
Examples of decals and travelers used to identify materials, components and in-process assemblies are exhibited. Two of the decals deal with components and can be used as a means of assuring proper disposition of these items. A "Material Lot Identification" is exhibited which is used to identify components in a container. This form has space for, among other information, lot number, expiration date, quantity in the subject container, date it was issued to stock, and the person who received the container. The final example in this group is a "Stock Requisition" form, used whenever items are being released from stock to production. This form contains information such as, part number, quantity ordered and issued, and lot number. Note that part of this form is used to indicate if the issued item is to replace a defective item.
Receiving Rejection Notice
This form is used when incoming components and materials are rejected and includes sections for the inspector's report listing the sampling plan, specification tested for, number of defects, and a description of the defects. There is a section for a preliminary review, if necessary, and finally a section for the Material Review Board (MRB) decision on the disposition of the rejected lot. A MRB may accept temporary deviations that do not affect safety and effectiveness. These deviations or changes should be approved by the MRB or other designee. MRB activities should be performed per a written procedure and otherwise meet GMP requirements. The MRB should not change a device master record (DMR) drawing or be used as a substitute for the primary change control system of a manufacturer.
Sheet 1 of 1
TITLE: IN4278 ZENER DIODE SPECIFICATION NUMBER
Drafted by App. Date
REV. ECN History Date
1. SCOPE: This specification describes a onewatt zener diode used for voltage reference in the XYZ Stimulator.
2. ELECTRONIC CHARACTERISTICS
2.1 Zener Voltage: 3.1 vdc @ 76 madc
2.2 Maximum Zener Impedance: 10 ohms @ 76 madc
2.3 Reverse Leakage Current: (25%) 100 microamps (max) @ l vdc
3. TESTING: All diodes shall meet the requirements of JANTX IN4278 as specified in MILS19500/127G.
4. PHYSICAL CHARACTERISTICS
4.1 Diodes shall be packaged in a voidfree silicone case.
4.2 Leads shall be readily solder able.
5.1 The cathode shall be identified by a color band.
5.2 An identification number and lot number or date code shall represent a specific manufacturing period.
5.3 All markings shall be permanent such that cleaning solutions will not remove the markings.
6.1 A certification of compliance with this specification and a test data sheet must accompany each lot shipped.
6.2 Certification must include a statement that no changes have been made in materials or physical or electrical characteristics.
7. APPROVED SUPPLIERS
TITLE: ACCEPTANCE OF COMPONENTS Sheet 1 of 3
No. Rev. ECN History
Drafted by App. by Date
These procedures are to be followed in the receipt, inspection, and storage of product such as raw materials, components, parts, manufacturing materials, etc., used in the manufacture of the XYZ Stimulator, a device that does not require traceability per 820.65.
2.1 All incoming shipments must be examined for external signs of damage. If the shipment is damaged, immediately notify Purchasing and move the shipment to the unloading Hold area until disposition is decided by Purchasing.
2.2 Upon receipt, check each shipment against the corresponding purchase order and verify identity and quantity. The purchase order may include, reference, or have attached purchase specifications.
2.3 Enter the appropriate data into the Received Goods Log for each shipment received.
2.4 After completing the data entry, attach a yellow "HOLD" tag to the product and immediately move the products to the receiving quarantine area. The pink copy of the purchase order must accompany the product.
2.5 Notify Quality Control when materials requiring inspectionare received in the quarantine area. This information is obtained from the device master record specification for the item ordered.
2.6 Quality control shall, after examining the product for damage and identity, move the product, etc., to be inspected to the Receiving Inspection area.
3.1 Pull the inspection history file for the product to be inspected. This file contains the Receiving History form and inspection procedure. Enter the appropriate data from the purchase order onto the Receiving History form and perform the inspection per the procedure.
Sheet 2 of 3
3.2 The QC manager shall assign a five digit lot number to each supplier lot received and enter the number on the Receiving History form.
3.3 After the inspection is completed, enter on the Receiving History form:
a. the quantity accepted and sent to stock;
b. the quantity rejected; and
c. your signature and the date.
4.1 Receiving and test data for each shipment are sent to the designated individual for review and the decision regarding the acceptability of the lot.
4.2 For accepted product, enter the quantity accepted, date accepted, and lot number on a green "ACCEPTED" tag, attach the tag to the product, etc., and move it the stockroom.
4.3 For rejected product attach a red "REJECTED" tag to the rejected product and complete a Rejected Material form. Place all rejected product in the rejected quarantine area and forward the Rejected Material form to Quality Engineering for disposition.
5.1 All items entering the stockroom must be accompanied by a green "ACCEPTED" tag.
5.2 Components and other materials shall be stored and issued per SOP 17320.
5.3 Components and other materials will be issued from the stockroom on a first-in, first-out basis. All materials with a limited shelf life or requiring controlled storage conditions will be stored appropriately per SOP 17321.
Note: Sheet 3 is the Receiving History log for this procedure. The other forms mentioned in this procedure are not reprinted. However, similar forms are included with another procedure located later in this chapter.