Premarket Notification [510(k)] Submissions for Chemical Indicators - Guidance for Industry and FDA Staff
Published: 2003-12-18
Status: Final Type: Guidance Document Category: Premarket (510(k) / PMA / De Novo / IDE) Topics: Premarket Docket: FDA-2020-D-0957
Official Source
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-notification-510k-submissions-chemical-indicators-guidance-industry-and-fda-staff PDF: https://www.fda.gov/media/72010/download
Official Full Text
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a top should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agenc so L The issues identified in this guidance document represent those that we believe need to be addressed before your device can be marketed. In developing the guidance, we carefully considered the relevant statutory criteria for Agency decision-making. We also considered the burden that may be incurred in your attempt to follow the guidance and address the issu we have identified. We believe that we have considered the least burdensome approach to resolving the issues presented in the guidance document. If, however, you believe that there is a less burdensome way to address the issues, you should follow the procedures outl the “A Suggested Approach to Resolving Least Burdensome Issues” document. It is a .
II. Background .2800 (b), Physical/chemical sterilization
process indicator identifies these devices as:
A. Scope
This document provides guidance concerning the content and format of 510(k) submissions for chemical indicators intended to monitor sterilization processes in health care facilities. Chemical indicators for use in health care facilities are class II devices. The product code is JOJ. Section 21 CFR 880 vice . these parameters is indicated by a visible change in the device. s, the following three types of chemical ind t care facilities:1 • air removal indicators for test packs. Therefore, this guidance addresses only these three types of chemical indicators.
l Evaluation, if you have any questions before submitting a 510(k) for chemical indicators. ent does not cover the following chemical indicators and indicator related pro c rilants2 ing setting dicators used for radiation sterilization. of the
A physical/chemical sterilization process indicator is a de intended for use by a health care provider to accompany products being sterilized through a sterilization procedure and to monitor one or more parameters of the sterilization process The adequacy of the sterilization conditions as measured by
FDA has cleared, through the 510(k) proces ica ors for use in health • process indicators • chemical integrators
The FDA encourages you, the 510(k) submitter, to contact DSMICA or the Infection Control Devices Branch, Division of Anesthesiology, General Hospital, Infection Control, and Denta Devices, Office of Device
B. Exclusions This docum du ts: • chemical indicators intended to be used with liquid chemical ste • chemical indicators intended for use in a manufactur • chemical in
C. Definitions
The following are definitions of terms used throughout the document. Many definitions have been standardized by organizations such as the International
1 These devices react physically or chemically during sterilization. For purposes of being consistent with terminology used in consensus standards, we refer to them as chemical indicators throughout this document.
2 For these devices, please refer to Guidance for Industry and FDA Reviewers – Content and Format of Premarket Notification [510(k)] Submissions for Liquid Chemical Sterilants/High Level Disinfectants, Section III.K. at http://www.fda.gov/cdrh/ode/397.html. Organization for Standardization (ISO), the American National Standards Institute (ANSI), and the Association for the Advancement of Medical Instrumentation (AAMI). The standards cited for each definition are cited in full in XII. References.
to of the air removal phase in the steam sterilization process. NSI/AAMI, 1999) ing a defined resistance to a ecified sterilization process. (ANSI/AAMI/ISO, 2002) remove air from the chamber and prevent air re-entrainment. (ANSI/AAMI, 002)
Air Removal Indicator: A chemical indicator to be used in the standard test pack determine the efficacy (A
Biological Indicator: Microbiological test system provid sp
Bowie Dick Test: A diagnostic test of a dynamic-air-removal steam sterilizer’s ability to Chemical Indicator: System that reveals change in one or more predefined process variables based on a chemical or physical change resulting from exposure to a process. (ANSI/AAMI/ISO, 2002)
Chemical Integrator: A chemical indicator designed to react to all critical parameters over a specified range of sterilization cycles. (ANSI/AAMI, 1996)
Critical Parameters: Parameters identified as being essential to the sterilization process. (ANSI/AAMI, 1996)
D-Value: The time or radiation dose required to achieve inactivation of 90% of a population of the test microorganism under stated exposure conditions.3 (ANSI/AAMI/ISO, 2002)
Endpoint: The observable change specified by the manufacturer that occurs after the chemical indicator has been exposed to certain predefined physical conditions. (ANSI/AAMI, 1996)
Indicator Agent: An active ingredient or combination of ingredients that is contained in a chemical indicator. (ANSI/AAMI, 1996)
Medical Device: As defined in the Act (21 USC §321(h)):
[a]n instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or
3 This is the definition for D-value in the standard cited. However, radiation sterilization is not discussed in this guidance document because it is not a sterilization method generally used in health care facilities. related article, including any component, part, or accessory, whi
nized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to
er onditions, or in the cure, mitigation, treatment, or 3. intended to affect the structure or any function of the
ls and which is not dependent upon being metabolized for the achievement of its primary intended
ct to be sterilized and to constitute a defined challenge to the sterilization process, and used to assess
tainers) to demonstrate that the unit has been exposed to the sterilization process and to distinguish between processed and unprocessed units.
tion tion ) erred to as a Biological Indicator Evaluator Resistometers (BIER) or Chemical Indicator Evaluator Resistometer (CIER) test t you include a section or table comparing the new device to the legally of the type of information that y ch is
- recog them,
- intended for use in the diagnosis of disease or oth c prevention of disease, in man or other animals, or
body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other anima purposes. Process Challenge Device (PCD): Item designed to simulate produ the effective performance of the process. (ANSI/AAMI/ISO, 2002) Process Indicator: A chemical indicator that is intended for use with individual units, (e.g., packs, con (ANSI/AAMI, 1996) Resistometer: A test instrument designed to rapidly produce and precisely control critical parameters associated with a given sterilization process. Notes: 1) In addi to routine quality system testing of indicator performance consistency, it is used to characterize cause and effect relationships associated with the given steriliza process and devices used to evaluate the efficacy of the sterilization process, and 2 Resistometers were formerly ref systems. (ANSI/AAMI, 2002)
III. Device Comparison DA recommends tha F
marketed predicate device. The following table is an example ou should provide. Table 1- Comparison of the New Device to the Predicate ELEMENT
Intended use, e.g., process indicator, tor, Bowie Dick Test
chemical integra
Device design
Indicator agent
Sterilization method and cycles
Endpoint specifications
NEW DEVICE PREDICATE
Shelf-life
IV. Device Description
You should provide a detailed description of your chemical indicator. The description for your chemical indicator should include the general characteristics regarding the device design and manufacturing specifications. The bulleted list below is an example of the type of informa e may request add n, or performance warrant. reagent tended or is intended to monitor the endpoint ring substances or conditions • stability of the endpoint reaction, e.g., the stability of the endpoint color tion that you should provide in the description for your device. W itional information, if the differences in design, formulatio • chemical name of indicator agent, e.g., ink, dye, chemical • chemical composition or formulation of the indicator • reaction that takes place to achieve its intended endpoint • sterilization cycles for which the chemical indicator is in • critical parameters that the indicat • minimum exposure parameters to achieve • recommended storage conditions • any interfe • shelf life
V. You are exa se for each type of indicator.
onstrate ed goods and porous loads. The test pack is usually positioned over the chamber drain in an otherwise empty chamber. An inefficient air removal stage, an air leak, or non-condensable gases in the cause an incomplete change in the air Bowie Dick Test is not an indication et specified acceptance criteria f conformity to the standard in lieu of data 4 Please note that testing must be completed before submitting a declaration of n, refer to the FDA guidance, Use of Standards in Substantial Equivalence eterminations; Final Guidance for Industry and FDA, http://www.fda.gov/cdrh/ode/guidance/1131.html Intended Use should clearly state the intended use of the chemical indicator. The following mples of intended u
A. Process indicator
The process indicator is intended to be used by a health care provider with sterilization wraps, containers, cassettes, or pouches to distinguish between processed and unprocessed units.
B. Chemical Integrators
The chemical integrator is intended to be used by a health care provider to dem that the parameters over a specified range of sterilization cycles have been met in a specified sterilization wrap, container, cassette, or pouch.
C. Air Removal Indicators
The air removal indicator is intended to be used by a health care provider in a standardized test pack, e.g., Bowie Dick Test Pack, to assess the ability of a prevacuum sterilizer to remove air and allow steam to penetrate into wrapp steam supply are some of the conditions that could removal indicator, e.g., uneven color change. The that the sterilizer has reached the parameters for sterilization.
VI. FDA-Recognized Standards
If any part of the device design or testing relies on an FDA-recognized standard, you may submit (1) a statement that testing will be conducted and me before the product is marketed, or (2) a declaration o . conformity to a recognized standard. (Section 514(c)(1)(B) of the act). For more informatio D .
are discussed in the following
Recognized standards that apply to chemical indicators sections.
VII. Performance Characteristics
You should provide sufficient information to allow FDA to evaluate the endpoint ecifications and performance of the chemical indicator. In order to provide the user with
ou should provide the critical parameters to which the chemical indicator is intended to respond. For the traditional sterilization processes that are generally used in the health care faci . References in Table 2 as c
T ritical Parameters of Tr ion Processes sp adequate instructions for use, there should be a high visual contrast between the initial and endpoint appearance or physical/chemical change that takes place after processing the chemical indicator, e.g., colors change.
Y lity, ANSI/AAMI ST 60 (see XII ritical. ) specifies the parameters shown able 2 – C aditional Sterilizat STERILIZATION PROCESS CRITICAL PARAMETERSa Steam Time, temperature, saturated steam Dry Heat Time, temperature Ethylene Oxide (EO) Time, temperature, humidity, and EO concentration aThe critical parameters not normally tested for chemical indicators are steam quality or degree of saturated steam in a steam sterilization process and relative humidity in a EO sterilization pro
n cess. The performance of the chemical indicator is evaluated while controlling these critical parameters under specified conditions. These specified , referred to
g value for EO relative humidity is g t
FDA re ing information in your 510(k):
• description of the sterilization process used in health care facility for which the erilization cycle for which the indicator is 21°C
• ults obtained from a resistometer
• information on the resistance of the biological indicator used in the parallel study, if conditions are called limiting values. The limiting values for saturated steam as dryness values, are 0.85 –1.0. The limitin rea er than 30%. commends that you provide the follow
• clear statement of the study objective(s) indicator is intended, e.g., steam, EO
• description of the health care facility st intended, e.g., gravity cycle for 15 minutes at 1 • critical parameters to which the indicator responds • specifications for the pass/fail criteria pass/fail res
• pass/fail results from an actual sterilization cycle used in a health care facility applicable sed a statistically valid sample size, e.g., 3 lots from 3 different manufacturing runs (i.e., one lot from each manufacturing run)
conclusion drawn from study.
f tors.
FDA also recommends that the submission include pass/fail results showing how the process indicator would react in an actual sterilizer used in a health care facility. These results should be compared to the resistometer vessel results. If there is a discrepancy betw e this info s
s r not less than 90 minutes, the indicator does not reach its endpoint. This test is done without EO present.
The following table provides the criteria that a process indicator should meet according to the consensus standard ANSI/AAMI ST 60 for the indicated sterilization methods. • information showing that you u
• description of the positive and negative controls •
If easible, you should also provide actual samples of unprocessed and processed indica
A. Process Indicators
You should provide the following information for process indicators.
To characterize the process indicator and demonstrate substantial equivalence, you should provide pass/fail results demonstrating how the indicator reacts to the critical parameters in a resistometer. FDA recommends that the resistometer used for chemical indicator performance testing meet ANSI/AAMI ST 44 (see XII. References). een the resistometer and health care facility sterilizer results, you should provid rmation in the labeling.
Steam Process Indicator You should demonstrate, as specified in ANSI/AAMI ST 60, that the chemical indicator does not reach its endpoint when exposed to dry heat at 140°C for 30 minutes. EO process indicator You should evaluate EO process indicators as specified in ANSI/AAMI ST 60 to show that after being exposed to 60°C±2°C at greater than 85% relative humidity fo Table 3 - Process Indicators Criteria METHOD TEMPERATURE GAS CONCENTRATION ENDPOINT REACTION Steam 121°C N/A 2 min - 10 min Steam 132°C – 135°C±3°C N/A 20 sec - 2 min EO 30°C ±1°C 600±30 mg/l 5 min - 10 min Dry Heat 160°C ±5°C N/A 20 min - 40 min
B. Chemical Integrators
The testing described in Section VII. Performance Characteristics and VII. A. Process Indicators also applies to chemical integrators, with the exception of the performance criteria shown in Table 3. There are no specific performance criteria established for chemical integrators in any published consensus standard. You should provide the specifications for the endpoint reaction for each critical parameter identified and provide the following pass/fail results to support the specifications.
Critical Parameters You should describe the pass/fail criteria for each critical cycle parameter and provide the pass/fail results to show how the chemical integrator reacts to all the critical parameters in the sterilization cycle for which it is intended. We recommend that you evaluate one parameter at a time in a resistometer while holding the other parameter or parameters constant. The reproducibility of the endpoint reaction should be within the 15% tolerance level of the stated value, as specified in ANSI/AAMI ST 60.
Side-by-Side Testing with the Biological Indicator You should conduct side-by-side testing of the biological indicator and the subject s e r
chemical integrator in an appropriate resistometer. You should use a biological indicator in the study that is legally marketed for the intended sterilization proces and cycles. You should also state the D-value for the biological indicator used in th study. The chemical integrator should parallel the performance of an appropriate biological indicator. The results of this study should demonstrate that the integrato does not reach its endpoint before the biological indicator is inactivated, as specified in ANSI/AAMI ST 60.
C. Chemical Integrator Test Packs
Chemical integrators may be used in test packs to simulate products being sterilized.5 These test packs are intended to create a challenge to the sterilization process that is equal to or greater than the most difficult item routinely processed.
For chemical integrator test packs, you should provide the following information:
• pass/fail results comparing the performance of the chemical integrator in the test pack to the AAMI reference biological indicator test packs in their respective processes (The AAMI standardized test packs are considered the “gold” standards.)
• information to show that the integrator test pack provides an equivalent or greater challenge than the AAMI standardized test pack
• additional information to show that the integrator test pack provides a greater challenge to the process than the integrator by itself.
D. Process Indicators for New Technology Sterilizers
There are no specific performance criteria for chemical indicators for use with new technology sterilizers; however, we believe that the criteria outlined above can be used to evaluate the performance of these chemical indicators. Chemical indicators intended to monitor new technology sterilizers, e.g., vaporized hydrogen peroxide, microwave, gas plasma, ozone, may be determined substantially equivalent to any legally marketed chemical indicator, including a pre-amendments chemical indicator or a chemical indicator found substantially equivalent through the 510(k) process. You should provide pass/fail results characterizing your chemical indicator according to its indications. In general, you should:
• identify the critical parameters of the sterilization cycle, e.g., temperature, time, sterilant concentration
• identify the minimum exposure parameters needed to affect the change of the indicator • establish the pass/fail criteria • describe in detail the endpoint reaction or change that is intended to occur • provide pass/fail results demonstrating how the chemical indicator reacts to the critical parameters specified in an appropriate resistometer vessel, if available, for characterization and compare it to the results obtained above • demonstrate reproducibility using a statistically valid number of samples.
5 These test packs are also called process challenge devices (PCDs).
E. Chemical Integrators for New Technology Sterilizers
The testing described in sections VII. B. Chemical Integrators and VII. D. Process Indicators for New Technology Sterilizers also applies to new technology sterilizer integrators.
In addition, FDA recommends that the biological indicator used to validate the new technology sterilizer cycle also be used to validate the performance of the chemical integrator. The integrator should not reach its endpoint before the biological indicator is inactivated.
F. New Technology Chemical Integrator Test Packs
For new technology integrator test packs, there are no “gold” standards. We recommend that you use the performance criteria for traditional sterilization methods to demonstrate the resistance of the new technology chemical integrator. These performance criteria are identified in ANSI/AAMI ST 46 and ST 41 (see XII. References). You should provide pass/fail results demonstrating that the test pack provides a greater challenge to the process than the biological indicator that was used to validate the new technology sterilization process and the integrator itself. For example, the challenge should be equivalent to the increase in the D-value that is provided by the ANSI/AAMI ST 46 and ST 41 standard biological indicator test packs in their respective processes.
G. Air Removal Indicators
For air removal indicators, FDA recommends that you determine the following performance criteria and endpoint specifications inside a test pack (Bowie Dick Test).
You should provide pass/fail results demonstrating that the indicator does not reach its endpoint when exposed to dry heat at 140±2°C for 30 minutes.
You should also provide pass/fail results demonstrating the tolerances for the detection of air in a prevacuum sterilizer. You can simulate this fault condition by injecting air or by not pulling a complete vacuum to produce a non-uniform change in the indicator agent. You should include a thermocouple graph showing the decrease in temperature during the fault condition at the different locations in the cycle.
The thermocouple graph demonstrating a failed result should be compared to the graph showing that the indicator passed. As specified in ANSI/AAMI ST 66, the test temperature within the test pack should be less than 0.5°C for a pass.
For greater sensitivity in detecting air over a larger area, FDA recommends that the air removal indicator sheet in the test pack measure approximately 8 inches by 10 inches (ANSI/AAMI ST 60). The indicator agent should cover a large percentage of the test should be uniform. sheet and it You should provide specification for the porosity of the material used to construct the air removal indicator. The standard, ANSI/AAMI ST 66 (see XII. References) recommends using a standard densitometer to measure the time required for a given volume of air (25ml to 300ml) to flow through a standard area of the indicator being tested to measure the porosity of the test material.
VIII. Biocompatibility
There is the possibility that an active ingredient in some chemical indicators may leach onto the surgical instruments when it comes in contact. You should address this concern by demonstrating that your chemical indicator does not release any substance known to be toxic in sufficient quantities to cause a health hazard or deleterious effect to the user or the devices that are sterilized.
IX. Endpoint Stability for Chemical Indicators
You should demonstrate the stability of the specified endpoint reaction (e.g., color stability) for the chemical indicator at the end of its shelf life.
X. Shelf Life
You should demonstrate that the specification for the endpoint reaction of the chemical indicator is maintained throughout its labeled shelf life. For all studies, you should test at least 3 lots of the production chemical indicators using a sample size that is statistically significant. You should use storage conditions described in the device labeling.
You should provide the following information about shelf life:
• labeled shelf life of the chemical indicator • dates and length of time for each testing interval, e.g., 0, 6 months, 1 year, 2 years • resistometer vessel data for each testing interval that demonstrates that the established endpoints are maintained.
Chemical indicators may be unstable at elevated temperatures; therefore, accelerated aging tudies may be inappropriate and are not recommended. s
In lieu of complete real time shelf life data, the FDA will consider preliminary real time shelf life data (e.g., 6 months) along with a detailed protocol and sampling plan for an ongoing real time (e.g., 2 years) study that you will continue after your device is cleared. These study protocols should include the shelf life information listed above. We also recommend that you document the resul Requirements (21 CFR ts in your design history file as a part of the Quality Systems 820.30). he premarket notification should include labeling in sufficient detail to satisfy the ng suggestions are aimed at assisting you in preparing labeling that satisfies the requirements of 21 CFR 807.87(e).6
FDA suggests that you provide in the labeling: ill needs
escriptions of
•
for interpretation of the endpoint results or provide a mechanism efined endpoint can be determined by the user, if the endpoint is nder specific storage conditions
• point color reaction tegrators only)
In addition to the above, labeling for a Bowie Dick Test Pack should contain the following: •
XI. Labeling T requirements of 21 CFR 807.87(e). The followi
• performance characteristics, so that users can determine whether your indicator w meet their • any interfering substances or conditions known to affect the performance of the indicator
• clear description of the physical change that is designed to occur, with d the indicator both before and after the change, if applicable any intermediate changes between the initial and endpoint appearance • adequate directions by which a clearly d not clearly obvious
• storage conditions
• expiration date of the unused indicator u
• any safety precautions required during use stability of the end
• the minimum exposure parameters necessary to affect the change (for chemical in
statement indicating that the device is for use in determining air removal
6 Although final labeling is not required for 510(k) clearance, final labeling must comply with the requirements of 21 CFR 801 before a medical device is introduced into interstate commerce. Labeling recommendations in this guidance are consistent with the requirements of part 801. • warning indicating that extending the manufacturer’s recommended time for the Bowie Dick Test may result in false endpoints developing because entrapped air diffuses over time
• warning indicating that Bowie Dick Test should be performed in an empty chamber.
XII. References
ANSI/AAMI ST 41:1992, Good Hospital Practice: Ethylene Oxide Sterilization and Sterility Assurance
ANSI/AAMI ST 44:2002, Resistometers for Characterizing the Performance of Biological and Chemical Indicators
ANSI/AAMI ST 46:1993, Good Hospital Practice: Ethylene Oxide Sterilization and Sterility Assurance
ANSI/AAMI ST 60:1996, Sterilization of Health Care Products - Chemical Indicators, Part 1: General Requirements
ANSI/AAMI ST 66:1999, Sterilization of Health Care Products – Chemical Indicators – Part 2: Class 2 Indicators for Air Removal Test
ANSI/AAMI/ISO TIR 11139:2002, Sterilization of Health Care Products - Vocabulary
FDA: “Labeling: Regulatory Requirements for Medical Devices” (HHS Publication FDA 89-4203) Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850, 1989 (http://www.fda.gov/cdrh/dsma/470.pdf). 17
XIII. Chemical Indicator 510(k) Checklist Yes No N/A Item
510(k) Summary or Statement
Indication for Use Statement
Truthful and Accurate Statement
Comparison of new chemical indicator to the predicate
Description
Formulation of indicator ink
Chemical reaction with sterilant
Design description and type of indicator, e.g., process, integrator, Bowie Dick
Critical parameters to which the indicator responds
Pass/Fail criteria or minimum exposure parameters that effect the change
Performance
Data supporting endpoints with pass/fail criteria
Data supporting integrator parameters
Additional data for the Bowie Dick Test
Data demonstrating tolerance for detection of air
Porosity of paper carrier
Biocompatibility information
Data supporting shelf-life
Data supporting endpoint color stability
Labeling
Name and address of manufacturer
Intended use including the sterilization process and cycles
Adequate directions for use
A clear description of the change that is designed to occur (for color changes examples of the color both before and after the change)
The storage conditions both before and after use
Expiration date of the unused indicator under specific storage conditions
Lot number or other identifiers
Any safe precautions required during use
Stability of the endpoint color change
For integrators, the minimum exposure parameters necessary to effect the change
Labeling for a Bowie Dick Test should also include:
Statement indicating that the device is for use in determining air removal
he Warning indicating that extending the manufacturer’s recommended time for t Bowie Dick Test may result in false endpoints because entrapped air diffuses over time
ndicating that the Bowie Dick Test should be performed in an empty chamber Warning i
Footnotes
[^4]: See Required Elements for a Declaration of Conformity to a Recognized Standard (Screening Checklist for All Premarket Notification [510(K)] Submissions), http://www.fda.gov/cdrh/ode/reqrecstand.html.