Guidance on Premarket Notification 510(k) for Sterilizers Intended for Use in Health Care Facilities

Published: 1993-03-01

Status: Final Type: Guidance Document Category: Premarket (510(k) / PMA / De Novo / IDE) Topics: Premarket, 510(k) Docket: FDA-2020-D-0957

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https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-premarket-notification-510k-sterilizers-intended-use-health-care-facilities PDF: https://www.fda.gov/media/72458/download

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Official Full Text

This guidance was written prior to the February 27, 1997 implementation of FDA's Good Guidance Practices, GGP's. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be up dated in the nstt vision to include the standard elemnts of GGP 's.

Guidance on Premarket Notification [510(k)] Submissions for -. Sterilizers Intended for Use in Health Care Facilities Infection Control Devices Branch Division of General and Restorative Devices March, 1993

I. Introduction Page scope . . . . . . . . . . . . . . . . . . . . . . . . . .

Exclusions Definitions . . . . . . . . . . . . . . . . . . . - . . 4 -6 Classification of Sterilizers . . . . . . . . . . . . . . 7 Related Regulatory Authority. . . . . . . . . . . . . . . 7

11. Documentation Presubmission Considerations for Applicants . - - . . . Recommendations for Protocols and Data Analysis . . . . 8-9 . - Documentation for Traditional Classified Sterilizers. . . 9 EPA Certification . . . . . . . . . . . . . . . . . . . . 9 Reference to Standards, Practices, Technical Reports, Guidelines and Methods . . . . - - . . . . . Labeling. . . . . . . . . . . . . . . . . . . . . . . 11-12
12. Device Markings
13. Information Manual
14. Service Manual Changes to Sterilizers Requiring a New SlO(k) . . . . . . 12 General Description of the Sterilizer . . . . . . . . 12-14
15. Specifications
16. Process Parameters and Process Monitors
17. Software Documentation Cycle Overview . . .

• . - - -
• . . . . - . . . . . 14 Testpacks . . . . . . . . - . . . . . . . . . . . . .1Q-15 Equivalent Devices and Previous Submissions . . - - . . Physical/Chernical Performance Tests . . . . . . . . . . . 16

1. Traditional Steam, Dry Heat, and E t O Sterilizers
2. Other Sterilizers

. . . . . . . . . . . . Biolcgical performance T e s t s 17-26

1. General
2. T e s t Organisms
3. Biological T e s t Battery s p o r i c i d a l Screening T e s t S t e r i l i z a t i o n Process Equivalent Time 0-Value Determination 1/2 Cycle and T o t a l K i l l End P o i n t Analysis Simulated and Actual U s e T e s t s Derivation of the Process Parameters T o x i c i t y of t h e S t e r i l a n t and P r o c e s s By-products . . . . -27 . . . . . . . . . . Elimination o f Toxic Process Residues . . . . . . . Processed Device/Material Q u a l i f i c a t i o n 28-29
4. I n t r o d u c t i o n . -.
5. Process L i f e ~ e t e r m i n a t i o n
6. Functional Compatibility o f A r t i c l e s 4 . Biocompatibility of Component Materials . . . . . . . . . . . . . . F i n a l Process Q u a l i f i c a t i o n . . . . . . . . . . . . . . . . . Contzcts and Addresses . . . . . . . . . . . . . . . . . . . . . . . C h e c k l i s t . . . . . . . . . . . . . . . . . . . . . . . Attachments S i d e by S i d e Comparison Chart

I. I n t r o d u c t i o n A .

scope T h i s document provides guidance concernirq SlO(k) submissions f o r s t e r i l i z e r s intended f o r use i n h e a l t h c r r e f a c i l i t i e s , e.9. , h o s p i t a l s , c l i n i c s , h e a l t h c a r e p r o f e s s i o n a l o f f i c e s . Exclusions T h i s document does n o t address t h e folloving:

1. s t e r i l i z e r s used i n t h e production o r manufacture of medical d e v i c e s which are regulated under FI?X good manufacturinqp r a c t i c e s r e g u l a t i o n s (GMPs) , 2 1 CF. P a r t 820;
2. technologies used only i n t h e zlanufccturing s e t t i n g , e-g., i o n i z i n g r a d i a t i o n ; 3 . devices used s o l e l y 'to preclean o r otherwise d w o n t a m i n a t e medical devices p r i o r t o a . t e r c i n a 1 s t e r i l i z a t i o n process; 4 . s p e c i f i c requirements f o r s t e r i l i z a r i o n wraps, c h e n i c a l and b i o l o g i c a l indicators;
3. s t e r i l i z e r s intended for use w i t h c c n t a c t l e n s e s ( s e p a r a t e guidance a v a i l a b l e from t h e Divisio:; of Ophthalmic Devices/ODE) ; and
4. s t e r i l i z e r s which employ a l i q u i d c k m i c a l s t e r i l i z i n g environment.

D e f i n i t i o n s Bioburden: The naturally occurring microbial contaminatioon a medical device prior to exposure to a microbicidal process. Bioburden Based Sterilization: A sterilization process wi--h parameters based upon the predetermined type and concentration of bioburden on the medical devices to be sterilized. This method is used in manufacturing processes and is not appropriate for health care facilities where the bioburden may fluctuate. Biological Indicator (BI): A measured and calibrated number of microorganisms with high resistance to the node of sterilization being'monitored, placed in or on a carrier a d packaged to maintain the integrity of the carrier and microorganisms. The microorganism count is known and is higher than the bioburden on the medical device to be sterilized. The BI is used to test the effectiyeness of the sterilization process by assessing the microbial lethality of the process. Chemical Indicator (CI): A carrier impregnated or filled with a chemical compound which, when exposed to specific chemical and/or physical conditions, will undergo a known reaction, such as a color change, or produce a measurable quantity of reaction products. A CI indicates that the medical device has been exposed to one or more process conditions, and unless the CI integrates ALL process conditions, it is not an adequate test for assessing the effectiveness of the process. Death Rate Curve (or Survivor Curve): The graphic representation of the microbial sterilization kinetics for a specific microbicidal agent on a defined microbial population. D-value (Dlo): The time required to kill 90%. (one logarithmic cycle) of a homogeneous population of microorganisms. For calculation purposes it is assumed tk?: the killing rate follows first-order kinetics. Inorganic and Organic Load: The naturally occurring or artificially placed inorganic (e-g., metal salts) or organic (e.g., proteins) contaminants on a medical device prior tc exposure to a microbicidal process. The naturally occurrizq organic load is also known as bioburden. Microbial Sterilization Kinetics: The quantitative mechanisms and effects of physical or chemical sterilizati~a agents on the death of microbes.

Overkill Sterilization: A sterilization process that is based upon an arbitrarily established higher initial concentration and resistance of bioburden than that actually expected on the medical devices to be sterilized. Overkill processes typically are based upon a lo6 colony forming unit (CFU)/unit level of bioburden. This method is to be used for establishing process parameters for sterilizers used in health care facilities. Process and Product Qualification: Elements of the sterilization validation program consisting of selected engineering and microbiological demonstrations performed according to predefined protocols to show process' reproducibility and product acceptability.

Precleaning: The removal of foreign material, e.g:, organic or inorganic contaminants, from medical devices prlor to a decontamination, disinfection, or sterilization process, Process Residue: The microbicidal agent or by-products of sterilization remaining on a medical device after completion of the sterilization process. Spore: A dormant state of an organism, typically a bacterium or fungus, which exhibits a lack of biosynthetic activity and reduced respiratory activity. Sterilant: The active agent(s) which achieves sterilization. Sterile: The absolute state where all forms of life have been eliminated. In a practical sense absolute sterility cannot be proven, therefore sterility is considered achieved when organisms are eliminated, inactivated, or destroyed such that they are undetectable in standard media in which they have previously been found to proliferate. Sterility Assurance Level (SAL): A value indicating the probability of a survivor after a sterilization process. For example, an SAL of is the probability of one in one million nonsterile units after exposure to a sterilizat-ion process. Sterilization: An act or process which completely eliminates or destroys all forms of life, particularly microorganisms. Unit: The specified substrate or carrier upon which the specified number of test organisms are inoculated. A unit may be a specified volume, weight, or surface area. For example, a unit could be specified as an entire device, a component of a device (if the device must be disassembled prior to sterilization), or a portion of a device.

19. Vegetative state: A n active growth phase of an organism.
20. Validation: A documented program which provides a high degree of assurance that a specific process will consistently produce a medical device that meets its predetermined specifications and quality attributes.

C. Classification of sterilizers ~ l l

medical devices i n commercial d i s t r i b u t i o n p r i o r t o t h e 19-16 medical device amendments t o t h e Federal Food, Drug, and Cosmetic ~ c t ( t h e a c t ) , or so-called pre-amendments d e v i c e s , w e r e c l a s s i f i e d by FDA i n t o one o f t h r e e regulatory c l a s s e s , C l a s s I, 11, o r 111. The c l a s s e s t a b l i s h e d t h e r e g u l a t o r y c o n t r o l t o be a p p l i e d t o a device i n o r d e r t o provide reasonable a s s u r a n c e of its s a f e t y a n d - e f f e c t i v e n e s s . Class I devices are s u b j e c t t o g e n e r a l c o n t r o l s a s defined i n t h e act ( r e f e r t o DSMA guidance on g e n e r a l c o n t r o l s ) . C l a s s I1 devices a r e s u b j e c t t o g e n e r a l c o n t r o l s and any performance standards promulgated by FDA. C u r r e n t l y , t h e r e a r e no FDA requlatory s t a n d a r d s f o r s t e r i l i z e r s . C l a s s I11 d e v i c e s a r e s u b j e c t t o premarket approval.

Steam, d r y h e a t and e t h y l e n e oxide s t e r i l i z e r s are c u r r e n t l y t h e . o n l y s t e r i l i z e r s i d e n t i f i e d i n .the c l a s s i f i c a t i o n r e g u l a t i o n s . They are a l l C l a s s I1 d e v i c e s ( s e e 21 CFR.880.6860, 880.6870, and 880.6880). A new t r a d i t i o n a l or newer technology s t e a m , d r y h e a t , o r e t h y l e n e oxide s t e r i l i z e r may .be claimed e q u i v a l e n t t o t h e s p e c i f i c r e l a t e d classified device.- Likewise, a - 5 - t e r i l i z e r u s i n g a d i f f e r e n t technology, e.g.,microwave, plasma, etc., may a l s o be claimed equivalent t o one o f t h e c l a s s i f i e d d e v i c e s or t o any o t h e r l e g a l l y marketed sterilizer (a pre-amendments . s t e r i l i z e r or one found e q u i v a l e n t through t h e 510(k) p r o c e s s ) . . Even though a broad range of s t e r i l i z e r technologies may b e eligible f o r equivalency, FDA is n o t precluded from f i n d i n g a s t e r i l i z e r n o t s u b s t a n t i a l l y equivalent, and t h u s .a C l a s s I11 device.

D. Related Regulatory Authority

The U.S. Environmental P r o t e c t i o n Agency (EPA), under t h e a u t h o r i t y o f t h e Federal I n s e c t i c i d e , Fungicide and Rodenticide A c t (FIFRA) , r e g u l a t e s l i q u i d chemical germicides and o t h e r 'microbicidal agents. A s t e r i l a n t used i n a s t e r i l i z e r , t h e r e f o r e , may be subject t o EPA as w e l l as FDA r e g u l a t i o n s . Applicants of 510 (k) s f o r s t e r i l i z e r s t h a t use s e l f contained s t e r i l a n t s ( e - g . , a s t e r i l a n t i n a c a n i s t e r t h a t is connected t o a s t e r i l i z e r ) should c o n t a c t EPA for f u r t h e r d i r e c t i o n regarding any a p p l i c a b l e EPA r e g u l a t i o n s . EPA c u r r e n t l y is s o l e l y r e s p o n s i b l e f o r t h e r e g u l a t i o n of "portabl'e" ethylene oxide s t e r i l i z e r s . This t y p e of s t e r i l i z e r was intended t o include only a bag i n t o which EtO is i n j e c t e d . S t e r i l i z e r s ( o r components t h e r e o f ) regulated both by EPA and FDA must comply with the requirements o f each agency before t h e s t e r i l i z e r can be marketed.

11. Documentation Presubmission Considerations for Applicants Establish that the sterilizer is a medical device subject to 510(k) submission, i-e., it is intended for use in a health care facility to sterilize medical products. Discuss new technologies with FDA prior to 510(lc) submission to identify any unique aspects of testing or documentation. Contact the Chief, Infection Control Devices Branch as indicated in Part 11, Section Q. Determine whether the sterilant must comply with EPA regulations. Prior EPA certification, or concurrent EPA/FDA review is desirable to minimize data redundancy. Ensure that the 510(k) addresses all sections 21 CFR 807.87, Information Required In A Premarket Notification Submission. Ensure that the 510(k) submission addresses all-relevant elements of this guidance, or subnit a thorough justification for omission of information or data. Use the checklist in Section S. Ensure that there are marketed accessories necessary to achieve a functional system, or concurrent submission of 510(k)s for necessary accessories. For example, acceptable sterilization wraps (except for a flash node), biological . and chemical indicators are necessary to provide a complete system for the user. FDA will not find a sterilizer equivalent until a functional system is in place. Prereview submissions. 510(k)s for sterilizers can be extensive. FDA review of a document is facilitated when the document is arranged in a well-structured format that has undergone a thorough presubmission critique by the applicant to eliminate documentation deficiencies. Recommendations for Protocols and Data Analysis Provide all test protocols which include the objectives, experimental methods, controls, observations, statistical analyses, if possible, or other quantitative analysis, and conclusions and coments. Clearly define the aicrobial challenge and justify that it is appropriate for the system under examination. Specify the recove- media and ensure that it contains all the elements for abundant qro.~th. Validace the recovery efficiency of the cedia and submi: a sumrzry of the

v a l i d a t i o n . Define the n e u t r a l i z e r f o r t h e s t e r i l a n t , i f needed, and c o n t r o l f o r its a f f e c t upon microbial growth. Ensure t h a t t h e b i o l o g i c a l tests e v a l u a t e t h e s a f e t y and e f f e c t i v e n e s s of t h e s t e r i l i z e r f o r t h e e n t i r e . s p e c i f i e d range of each process parameter. I d e n t i f y and analyze t h e f a c t o r s t h a t w i l l l e a d t o a f a i l u r e t o achieve t h e required l e v e l o f e f f e c t i v e n e s s and r e f l e c t t h e s e f a c t o r s i n t h e labeling. Provide t a b l e s and graphs t o i l l u s t r a t e the r e s u l t s of t e s t i n g . Provide l i t e r a t u r e r e f e r e n c e s used f o r p r o t o c o l s and analyses. T e s t methods must b e s c i e n t i f i c a l l y sound and r e p r o d u c i b l e , and based upon "state-of-the-art" procedures, i d e a l l y r e f l e c t i n g a g e n e r a l l y recognized consensus o f s c i e n t i f i c opinion. Documentation f o r C l a s s i f i e d S t e r i l i z e r s T h i s guidance i d e n t i f i e s t h e fundamental documentation needed t o e v a l u a t e t h e s u b s t a n t i a l equivalence o f a s t e r i l i z e r . C l a s s i f i e d , t r a d i t i o n a l steam, dry h e a t , a s w e l l as e t h y l e n e o x i d e s t e r i l i z a t i o n processes are w e l l established and much i n f o r m a t i o n is a v a i l a b l e regarding t h e s e t e c h n o l o g i e s and t h e i r l i m i t a t i o n s . A s such, FDA recognizes t h a t some p o r t i o n s o f t h i s guidance are e i t h e r n o t critical t o t h e t h r e e o r i g i n a l l y c l a s s i f i e d t r a d i t i o n a l s t e r i l i z e r s or t h e c u r r e n t i n f o r m a t i o n b a s e o n each t y p e of process is s u f f i c i e n t t o s a t i s f y c e r t a i n ' d a t a provisions.

• S p e c i f i c s e c t i o n s of t h e guidance w i l l i n d i c a t e when t h e i n f o r m a t i o n requested is not needed for a c l a s s i f i e d , t r a d i t i o n a l s t e r i l i z e r . For now, s m a l l t a b l e t o p s t e a m o r EtO u n i t s are n o t c o n s i d e r e d t r a d i t i o n a l f o r purposes of t h i s document, b u t FDb m a y . i n c l u d e t h e s e devices once i n d u s t r y performance s t a n d a r d s a r e e s t a b l i s h e d . D . EPA c e r t i f i c a t i o n I f a p p l i c a b l e , provide any r e g i s t r a t i o n number assigned by EPA co an EPA regulated s t e r i l a n t used with t h e s t e r i l i z e r , o r i n d i c a t e whether a review by EPA is pending i n o r d e r t o f a c i l i t a t e EPX/FDA i n t e r a c t i o n on d a t a . Provide a summary of t h e d a t a submitted t o EPA For r e g i s t r a t i o n purposes.

E . Reference to Standards, Practicos, ~ e c h n i c a l Reports, Guidelines and Method- Identify a l l published standards, practices, technical r e p o r t s , guidelines, codes, and test methods upon which t h e design, labeling, and t e s t i n g of t h e s t e r i l i z e r a r e based. I n d i c a t e any deviations from the referenced docunents. There a r e c u r r e n t l y no FDA regulatory standards, specifications, o r test methods applicable t o s t e r i l i z e r s . The applicant should carefully consider t h e content o f referenced standards, technical reports, guidelines, codes, and test methods i n regard t o additional design, t e s t i n g , and documentation provisions not indicated i n t h i s guidance. The referenced .documents may i n d i c a t e s p e c i f i c s t h a t are p e r t i n e n t and unique t o t h e subject s t e r i l i z e r , whereas this guidance is generalized, i-e., a baseline document. FDA may r e f e r t h e applicant, i f necessary,.to additional published documents germane t o t h e s u b j e c t s t e r i l i z e r . f o r further guidance. A summary of a l l tests, conducted i n accordance with t h e ret'crenced documents and i n addition t o t h i s guidance, should be submitted. The s u b m i t t e r incurs a n obligation t o abide by an). document which t h e s t e r i l i z e r is claimed t o m e e t as supportive evidence o f s a f e t y and effectiveness. The following documents provide a . s i ? n i f i c a n t amount o f information on validation of new s t e r i l i z e r s , and have been used a s references i n developing t h i s CpziLance: AAMI S t e r i l i z a t i o n Standards f o r steam and EtO Block, S.E., Disinfection. S t e r i l i z a t i o n , and Preservation, Fourth Edittan, Lea & Febiger, Phila. Pa. 1991. S t e r i l e Medical Devices, A GMP workshop Manual, FDA Publication 884-4174

F . Labeling The applicant must submit labeling for the sterilizer. Labeling describes the intended use of the device, its operating characteristics, and limitations. These factors are essential in establishing whether the device is equivalent to other legally marketed sterilizers.

1. Device Markings Indicate the information affixed to the device. Markings may include identifying information, warnings, directions for use, or system requirements. Provide labeling for any accessory sterilants used with the sterilizer, e-g., a chemical agent. Chemical agents regulated by EPA also require mandatory labeling in accordance with EPA regulations.
2. Information Manual Submit the instructions for use manuals which shall include: the intended use of the sterilizer (listing the medical devices, specific types of materials, and other compatible medical products that can be sterilized by the process) ; limitations of use (medical devices,types of materials, and medical products that are incompatible); name and address of the manufacturer; type and model designation; .installation instructions; detailed operating instructions for all modes; storage and preparation of the sterilant, if applicable; error or fault indications, their cause; and response; interpretation and use of indicator gauges: how to prepare articles for processing including precleaning recommendations and required packaging; post processing information including residue information and sterilant exposure guidance; environmental or other factors affecting efficacy and 1 1

s a f e t y of t h e d e v i c e ; n. any a p p l i c a b l e warnings, hazards, and precautions; o. i n s t r u c t i o n s f o r r o u t i n e monitoring i n c l u d i n g u s e of chemical, b i o l o g i c a l i n d i c a t o r s , and test packs; and p. o t h e r r e l e v a n t information regarding t h e u s e o f t h e s t e r i l i z e r and a source of f u r t h e r information should t h e u s e r have a question. 3. S e r v i c e Manual [NOT NEEDED FOR TRADITIONAL STERILIZERS] Submit t h e s e r v i c e manual f o r t h e d e v i c e which includes: a. a d e t a i l e d d e s c r i p t i o n o f a l l t h e tasks that must be accomplished t o maintain t h e s t e r i l i z e r i n p r o p e r operating condition, e-g., r o u t i n e maintenance and inspection i n s t r u c t i o n s , c a l i b r a t i o n of instruments, etc. ; b. t h e schedule f o r t h e s e t a s k s , and; c. who is responsible f o r t h e t a s k s ( u s e r o r a u t h o r i z e d s e r v i c e personnel) .

G. Changes to a S t e r i l i z e r Requiring a New SlO(k)

The S l O ( k ) r e g u l a t i o n s t a t e s t h a t a new 510(k) is needed whenever t h e d e v i c e o r t h e manufacturing process is changed i n a manner t h a t may s i g n i f i c a n t l y a f f e c t its s a f e t y and e f f e c t i v e n e s s . The following a r e s o m e t y p e s o f conditions which r e q u i r e submission of a new 510(k) f o r a s t e r i l i z e r :

1. A n e w model number d e s i g n a t i o n u n l e s s it is s o l e l y a l a b e l i n g i d e n t i f i c a t i o n change. .2. Any change i n s t e r i l i z a t i o n v e s s e l dimensions. 3 . A change t o software o r firmware from a mechanical c o n t r o l .

4 . A change i n t h e s p e c i f i c s t e r i l a n t used i n t h e device. There w i l l be a s e p a r a t e p o l i c y a v a i l a b l e from FDA i n April 1993 on changes t o c e r t a i n EtO mixtures. H . General Description of t h e S t e r i l i z e r

1. S p e c i f i c a t i o n s : Design, Construction, Components a . Provide a complete physical d e s c r i p t i o n of t h e s t e r i l i z e r . The d e s c r i p t i o n can c o n s i s t o f d e t a i l e d drawings, photographs and brochures. The e x t e r i o r and

i n t e r i o r d i m e n s i o n s and component l O C a t i 0 n ~ should be indicated. b. Describe t h e materials used t o construct t h e major components of t h e s t e r i l i z e r , e.g., t h e s t e r i l i z a t i o n vessel, jacket, s t e r i l a n t generator, etc., and c e r t i f y t h a t t h e materials m e e t the s t e r i l i z e r requirements. c. I d e n t i f y a l l manual o r automatic c o n t r o l s , instrumentation, recorders, v e n t s , inputs, o u t l e t s , f i l t e r s , and s a f e t y features. d. Indicate device i n s t a l l a t i o n requirements, e - g . , e l e c t r i c a l , venting, plumbing, etc.. e. Describe t h e s t e r i l a n t formulation and its c o n t a i n e r , i f provided a s a stand alone accessory t o t h e s t e r i l i z e r , i. e. , s t e r i l a n t provided i n c a r t r i d g e form, etc.. Provide s h e l f - l i f e data on t h e s t e r i l a n t i n its container, including t o t a l l i f e i f i n a multidose container. . f . Describe a l l accessories marketed with t h e s t e r i l i z e r such as racks, t r a y s , c a r t s , etc. C e r t i f y t h a t t h e accessories are compatible with t h e s t e r i l i z e r process. 2 . Process Parameters a. Describe a l l physical and/or chemical process parameters, whether primary t o t h e process or secondary. For example, microwave h e a t generation may be t h e primary s t e r i l a n t but W i r r a d i a t i o n may be generated secondarily. Parameters may include, f o r example, t i m e , temperature, pressure, humidity, . wavelength, i n t e n s i t y , concentration, preprocessing conditions, and postprocessing conditions. . b. Provide t h e s p e c i f i c a t i o n s f o r each parameter. 3 . Process Monitors a. Describe t h e gauges, c h a r t recorders, displays, etc. which monitor t h e process parameters. Include information on s p e c i f i c a t i o n s o f t h e ' instruments and sensors (accuracy, precision, range, specificity', s e n s i t i v i t y ) and r e l a t i o n t o recognized standards. b. Describe t h e sensor locations within the s t e r i l i z a t i o n vessel. Since s t e r i l i z i n g c o n d i t i o n s , e.g., temperature, may vary i n d i f f e r e n t l o c a t i o n s i n a v e s s e l , i n d i c a t e how t h e sensor locations correspond t o the r e l e v a n t "cold spot" i n t h e v e s s e l ( l e a s t favorable

l o c a t i o n f o r s t e r i l i z a t i o n ) - Describe hou t h e "cold s p o t w was d e t e r a i n e d , e . y . , thermocouples. S t a t e now a l l load c o n d i t i o n s were considered when cctermining t h e dynamics i n s i d e the chamber. c. C e r t i f y t h a t t h e monitors c o r r e l a t e t o a c x a l chamber conditions. d. Describe a l l f a u l t c o n d i t i o n s r e l a t e d t o =3ch o f t h e p r o c e s s parameters, including under what a n d i t i o n s a f a u l t is d e t e c t e d and how t h e s t e r i l i z e r r+sponds (e-g., i n d i c a t o r , p r i n t o u t , etc. ) . 3. Software Documentation Provide t h e data i n d i c a t e d i n t h e FDA Software X e v i e w e r s Guide ( a v a i l a b l e from FDA Division o f Small Mazufacturers Assistance) f o r 510(k). Unless otherwise directed by FDA, s t e r i l i z e r s a r e considered i n t h e 'moderate* r i s k c a t e g o r y d e s c r i b e d i n t h e software guidance.

I. Cycle Overview

Provide a d e t a i l e d overview of t h e s t e r i l i z a t i c n process, i n order t o provide a foundation f o r e v a l u a t i o n 05 t h e device and test d a t a . Supplement the d e s c r i p t i o n hy .=?arts, graphs o r o t h e r v i s u a l s d e t a i l i n g a l l parameters and i a d e s . J.

• T e s t Packs T e s t packs a r e used i n v a l i d a t i n g performance %id i n r o u t i n e monitoring of t h e device once it is commerciall:~ a v a i l a b l e . The test pack is constructed t o r e p r e s e n t a r i y a r o u s c h a l l e n g e t o t h e s t e r i l i z e r . A b i o l o g i c a l aoni=or is placed i n t h e pack and t h e pack is placed i n a worst a s e load i n t h e cold spot. There should be a test pack f o r each type of l o a d i n d i c a t e d i n l a b e l i n g . For example, tier^ a r e f a s r i c , l i q u i d , and wrapped instrument test packs i d e n z i f i e d f o r steam s t e r i l i z e r s . The a p p l i c a n t should r e f e r to r e l e v a n t standar& f o r t e s t pack s p e c i f i c a t i o n s , when a p p l i c a b l e . Applicanzs of tlrpes of s t e r i l i z e r s with no v a l i d a t :. 3 "stand---'" Y,U t e ~ = pack ( e - g . , t a b l e top u n i t s and dry heat) :!~ould still devise and v a l i d a t e e i t h e r test packs Tot : I s @ with t h e i r !?vice, o r a t l e a s t t e s t load c o n d i t i o n s for :mrposes of roc:ine monitoring. Submit a d e t a i l e d d e s c r i p t i o n . :' t h e t e s t pack 5) used i n v a l i d a t i n g t h e performance of ' .te d e v i c e , 2nd ::?at w i 1 l be used i n r o u t i n e performance rnt. . t o r i n g b;. -,he _ ~ e r .

Describe the rationale for the composition of the test pack including how the test packs represent a rigorous challqnge to the sterilization process- Describe how the test pack itself was validated. Describe the pack and how it is to be used in labeling.

K. Equivalent Devices and Previous submissions ,

Identify and compare the subject sterilizer to another legally marketed sterilizer. A finding of equivalence is facilitaked the closer the technology of the legally marketed device matches the subject sterilizer. Reference the 510(k) numbers for the claimed predicate devices, if known. Side bv side comparisons, whenever possible are desirable (See Attachment 1).

1. Submit labeling for the claimed equivalent sterilizer, if possible. 2 . Compare and contrast the technologies.

2. Compare and contrast the specifications.

3. Traditional Steam, Dry Heat, and EtO Sterilizers Certify that the sterilizer will achieve and maintain the relevant physical cycle specifications (time, temperature, sterilant concentration, humidity, pressure, etc.)' within specifications under appropriate test load conditions. The required lethal conditions are those determined by biological performance tests (see following sections).

4. Other Sterilizers a. Describe the rationale for the process parameters and specifications. Briefly summarize how the biological performance test results described in the following sections were used to define the parameters. b. Provide a summary of physical tests which demonstrate that the sterilizer achieves and maintains the required physical/chemical process lethality conditisms within specifications. These data should be from repeated runs with varying load conditions.

5. Dialogical Performance Tests

6. General The applicant must unequivocally demonstrate that the device can sterilize, to an acceptable SAL, all the medical products identified in the labeling, when used.in -accordance with the directions for use.

7. Test Organisms Since a consistent type and concentration of bioburden cannot be assured or realistically evaluated in a health care facility, an overkill sterilization is necessary. The sterilization cycle is based upon an initial concentration of at least lo6 CFU (or Plaque Forming Units - PFU)/unit of a highly resistant organism to the process. Typically, the most resistant organism to a sterilization process is used based upon determination of D-values. Table 1 lists the commonly recognized test organisms for the classified . sterilizers. TABLE 1 TEST ORGANISMS FOR CLASSIFIED STERILIZERS Sterilizer Organism steam Bacillus stearothermo~hilus (ATCC 7953) dry heat Bacillus subtilis var. niger (ATCC 9372 or 19659) EtO . Bacillus subtilis var. niger (ATCC 9372 or 19659) The biological lethality profile of a nontraditional ' sterilization technology must be exhaustively evaluated since the most resistant organism is initially unknown. Table 2 identifies recommended organisms t= test for determination of the most resistant organism.

TABLE 2 TEST ORGANISMS FOR NONTRADITIONAL S T E R I L I Z E R S

A. B a c t e r i ~ l Spores

B a c i l l u s s u b t i l i s var. n i q e r (ATCC 9372 o r 1 9 6 - 5 9 ) B a c i l l u s s t e a r o ~ h e r m o p h i l u s (ATCC 7 9 5 3 ) C l o s t r i d i u z n sporoqenes (ATCC 3584) M y c o b a c ~ e r i u m tuberculosis var. b& (or other representative m y c o b a c t e r i u m ) C . N o n l i p i a V i r u s e s poliovirus Type I1

D. Fungi Tricophvton rnentacmophvtes ( w i t h conidia)

E. V e q e t a z i v e B a c t e r i a S t z ~ h v l 3 c o c c u s aureus S a l m o n e l l a choleraesius Pseudomnes a e r ~ q i n o s a

F. L i p i d V i r u s e s herpes s i m p l e x

G. T E LI'i3RATURE OR OTHER I N P O N C X T I O N MAY SUGGEST A D D I T I O N A L T E S T OXGABISMS DEPENDING UPON THE TECHNOLOGY O R T H E T Y P I C A L BIOBUR@2N SNCOCNTERED BY THE A R T I C L E S INTENDED F O R REI3ROCZSSING I!; T E E S T E R I L I Z E P . ;.

3 . Biological Test Battery The biological test data shall include the following: a. a summary of the sporicidal screenins test (NA* FOR TRADITIONAL STERILIZERS]: b. the sterilization process equivalent time (F value) [STEAM AND DRY HEAT ONLY]: * c. determination of D-values based upon (1) survivor curve analysis, and (2) fraction negative analysis [NA POR STEAM AND DRY HEAT or as alternative to item b. above for steam and dry heat) ; d. 1/2 cycle Analysis, and Total Kill End Point Analysis [NA FOR TRADITIONAL STERILIZERS except 1/2 Cycle Certification for Traditional Sterilizers]; e. simulated AND in-use tests with representative medical products indicated in labeling [NA FOR TRADITIONAL STERILIZERS except as noted]; and f. comprehensive analysis of all biological test data and determination of the process parametars.

• XA = Not generally applicable but could be requested if other 3ata or information are equivocal.

Sporicidal screening Test The applicant must provide a summary of the American Association of Official Analytical Chemists (AOAC) Sporicidal Test, Section 966.04, Volume 1, Page 141 [Horowitz, William, ed. Sporicidal test - official final action. Official Methods of Analysis of the Association of Official Analytical Chemists. Current Edition. Association of Official Analytical Chemists, Washington, D.C.]. This test is also used for EPA registration purposes. If EPA accepts or requests another test for registration purposes for an EPA regulated sterilant used with the subject device then a summary of the results from that test should be provided. Indicate the specified time for sterilization. . - Sterilization Process Equivalent Time Thermal resistance.of microorganisms can be considered in terms of equivalent process times (F,) at a given temperature. Saturated steam and dry heat sterilizers are special~cases where equivalent times are useful for evaluating the acceptability of the process conditions. Typically, dry heat and gravity steam sterilizers each employ similar operating modes and process conditions as a group (e.g., 121° C and 15 psi for a regular steam cycle). Some dry heat and steam sterilizers may vary from the norm. As a general rule, a higher temperature results in a higher rate of death of microorganisms. Still, there are constraints to saturated steam and dry heat process conditions in order to maintain acceptable lethality conditions. Physical parameters and microbicidal effectiveness with standard test organisms have been extensively characterized for steam and 'dry heat sterilizers. Actual operating temperatures can be correlated to a sterilization process equivalent time, or Fo -value (a special case equivalent time), at standard temperatures. Saturated steam operating temperature can be converted to equivalent microbial lethality anticipated at 121°C while dry heat temperatures can be converted to 170°C equivalent process times. An Fo of 12 (minutes) for both processes is minimally acceptable (12 log reduction). The method for conversion of proc=ss parameters is beyond the scope of this document. Mathematical methods are extensively described in the literature. Submit the equivalent process time and its method of derivation for the saturated steam or dry heat sterilizer for all modes of operation.

D-Valuc Determination The D-value of an organism exposed t o a s p e c i f i c s t e r i l i z a t i o n process can be established by one of two methods, survivor curve analysis o r fraction negative analysis. For unclassified s t e r i l i z e r s t h e resistance p r o f i l e of a battery of t e s t organisms should be determined using survivor curves. Once the most r e s i s t a n t test organism is identified ( o r possible candidates t h a t require more testing) with preliminary D-values from survivor curves, then tests should be conducted using t h e f r a c t i o n negative method. A survivor curve is a necessary precursor t o f r a c t i o n negative analysis t o roughly estimate t h e quanta1 region (the lo2 - lo-* CFU/unit vs t i m e region) f o r a p a r t i c u l a r test organism. I f d i f f e r e n t types of loads a r e provided i n labeling (e-g. ; liquid, fabric, instruments) then t h e applicant must evaluate t h e k i n e t i c s i n each type of load. . h he following is a b r i e f overview of methods and data t o be reported. For m o r e d e t a i l , r e f e r t o t h e l i t e r a t u r e . Survivor Curve BY D i r e c t Enumeration . -. A survivor curve p l o t s the surviving microorganisms a g a i n s t a c r i t i c a l process parameter, usually t i m e . The curve provides an important graphic representation of t h e k i n e t i c s of t h e microbicidal process. The curve should be based upon a t l e a s t 5 r e p l i c a t e d data points using t h e test organism. Separate curves should be established f o r "clean" test organisms and f o r test organisms prepared i n an inorganic and organic load of hard w a t e r and serum, respectively. The organic load s h a l l be a t l e a s t 59 bovine serum. The organic load s h a l l be hard water a s defined under AOAC test method 960.09 E. (referenced above). Controls must be f u l l y described. I n one v a r i a t i o n of a survivor curve determination, a s p e c i f i e d 'concentration o f the test organism is prepared on a c a r r i e r . The test organism is placed i n t h e s t e r i l i z e r i n a simulated load configuration. The most rigorous load conditions may vary with t h e s t e r i l i z e r technology and mode of operation and it is up t o t h e applicant t o determine t h e most rigorous load conditions. The process proceeds f o r a fraction of t h e t o t a l process t i m e ,

• t h e test organisms a r e withdrawn and neutralized, if necessary, extracted from the c a r r i e r , i f necessary, s e r i a l l y d i l u t e d , and placed.onto validated growth media. The surviving organisms a r e d i r e c t l y enumerated. In t h i s method multiple f r a c t i o n a l tests a r e needed t o assemble s u f f i c i e n t data t o define the survivor curve. The tests a r e repeated and curves established with d i f f e r e n t loads t o evaluate v a r i a b i l i t y i n process k i n e t i c s and optimal load configurations. T h i s information defines t h e process conditions t h a t are noted i n labeling. O t h e r test v a r i a t i o n s may use B I s and B I s i n test packs, but t h e applicant m u s t j u s t i f y t h a t whatever method was used represents worst case

conditions Plot t h e survivor data on semi-logarithmic paper and c a l c u l a t e a l i n e of b e s t f i t , y = mx + b where: m = slope x = t i m e y = log of number of survivors b = t h e y i n t e r c e p t a t t i m e 0. S t a t i s t i c a l l y evaluate t h e d a t a using regression analysis (ANOVA) and submit t h e analysis. Any adjustment of t h e curve o r analysis, e-g., dropping of points, must be f u l l y j u s t i f i e d . The D-value is t h e negative reciprocal of t h e slope of t h e survivor curve ( - l / m ) . This a n a l y s i s is v a l i d i f t h e dynamics of microbial k i l l follow first o r d e r k i n e t i c s , e-g., data a r e linear. Linear c o r r e l a t i o n is evaluated a s . p a r t of t h e ANOVA analysis. Care.must be taken not t o underestimate a D-value which occurs when (1) t h e r e are i n s u f f i c i e n t r e p l i c a t e s (2) t h e i n t e r c e p t r a t i o ( r a t i o of t h e y i n t e r c e p t t o t h e i n i t i a l inoculum I R = Yo/logNo) of t h e survivor curve is one o r greater, o r (3) t h e death r a t e curve is inappropriately extrapolated. An i n i t i a l test inoculum g r e a t e r than lo6 CFU/unit, i f possible, is recommended i n order t o minimize t h e e f f e c t of counting inefficiency below the lo2 CFU/unit l e v e l and t o extend t h e assurance of Linearity of l e t h a l i t y beyond a 6 logarithmic range. Fraction Nesative Method The f r a c t i o n negative method is another means t o derive D-values. I n one v a r i a t i o n of a f r a c t i o n negative test, r e p l i c a t e test organisms as described above are exposed t o a f r a c t i o n of t h e t o t a l process t i m e t h a t c o r r e l a t e s t o t h e quanta1 region ( l o 2 t o CFU/unit v s t i m e region), then t h e r e p l i c a t e s a r e t r a n s f e r r e d t o validated growth media, and incubated. A s above, repeated tests w i t h clean test organisms and those prepared i-n an inorganic and organic load should be accomplished.' Controls must be f u l l y described. The f r a c t i o n of samples i n a test group negative f o r each t i m e i n t e r v a l a r e used i n deriving t h e D-value using e i t h e r (1) the Stumbo-Murphy-Cochran Method, o r ( 2 ) the Spearman-Karber Method. Again, r i q o ~ o u s load conditions must be considered.

1. Stumbo-Murphy-Cochran Method: The Most Probable Number o f organisms a t esch time p o i n t a r e determined using t h e Halvorsen-ziegler equation Nu = 2 - 3 0 3 l o g (r/q) x (r) where: r = number o f r e p l i c a t e s q = t h e number of n e g a t i v e r e p l i c a t e s Nu = t h e number of s u r v i v o r s i n r r e p l i c a t e s The D-value is t h e n d e r i v e d by D = U/Log a - Log b where: U = t h e process t i m e Log a = t h e i n i t i a l number of organisms Log b = Log Nu.
2. Spearman-Karber Method: T h i s method -uses a mean t i m e u n t i l s t e r i l i t y t o c a l c u l a t e a D-value. T h i s c a l c u l a t o n is somewhat m o r e r i g o r o u s s i n c e it permits a v a l u a b l e statistical evaluation of t h e d e r i v e d D-value. The following equa5.on is used D, = US Jlog No + 0.2507 where: Us, = Spezrman-Karber heatinq t i m e e s t l m a t e No = initial inoculum D, = D-vzlue Whenever possijle, t h e Spearman-Karber method should be used and s t a t i s t i c z l e v a l u a t i o n submitted. cycle v a l i d a t i o n , 2 n d Total X i 1 1 End Point V a l i d a t i o n once a D-value and preliminary ?recess parameters are e s t a b l i s h e d ( e . g . , t o achieve an SAL o f 10.😃. t h e e f f e c t i v e n e s s of t h e p r o c e s s should be f u r t h e r confirmed bf a 1/2 c y c l e V a l i d a t i o n and a T o t a l K i l l End Point Bracket 7alidz:ion. The t w o tests can be combined. I n a 1/2 c y c l e v a l i d a t i o n for z r a d i t i o n a l s t e r i l i z e r s , r e p l i c a t e s o f t h e most r e s i s t a n t organism 3n a p p r o p r i a t e c a r r i e r s (or BIs i n test packs) a r e placed i n a s i x l a t e d worst c a s e c o n d i t i o n l o a d a t t h e c o l d s p o t and exposed t z 1/2 i5e s t e r i l i z a t i o n , process. The test organisms a r e then i n n b a t e d i n v a l i d a t e d media under a p p r o p r i a t e c o n d i t i o n s a l o n g wi-A c o n r r o l s . The media should.-not e x h i b i t any growth. What c o n s r i t u t e s a 1/2 c y c l e f o r a n o n t r a d i t i o n a l s t e r i l i z e r (e .g., a m u l t i s t e p process) should b e w e l l defined. It may c o n s i s t cf a r a z i o of steps, and/or may r e q u i r e several tests of holdizq o n e s t e p c o n s t a n t while v a r y i n g o t h e r s t e p s . F o r t r a d i t i o n a l s t e r i l i z e r s , FCZ v i l l a c c e p t a c e r t i f i c a t i o n of expected performance f o r t h e 1;2 Cycl* T e s t . I n t h e T o t a l X i 1 1 End P o i n t B r ~ c k e t '=lidation a somewhat more r i g o r o u s procedure, r e p l i c a t e s u n i t s v i t h a 10' CFU/unit i n o c u l a t i o n o f t h e m o s t resistcit tesr organism ( o r B I s i n test packs) are placed i n a t e s t loc5 s i m u l a t i n g t h e worst c a s e c o n d i t i o n a t t h e c o l d spot. A z e s t 13ad is exposed t o 1/2 t h e s t e r i l i z a t i o n process (typical::, 1 / 2 --he process t i m e ) and o t h e r test l o a d s a t incremental times g r e a r s r t h a n and less t h a n t h e c a l c u l a t e d 1/2 c y c l e . A t leas: f i v e increments above and f i v e below t h e 1/2 c y c l e t i m e are reconmen5ed with a t l e a s t 110 t o t a l test u n i t s evaluated (10 p e r t i x e p o i n t i n c l u d i n g t h e 1/2 c y c l e ) . The t i m e increments should spa:: 1/2 c: t h e t o t a l process t i m e ( f r o m 1 / 4 c y c l e t o 3/4 c y c l e ) . A l t e r z a t i v e methods should be 'described i n d e t a i l and j u s = i f ied. The test organisms a r e then grz-3 i n zedia t h a t support abundant growth and a r e p r e s e n t a t i v e nui3er f r ~ m each time p o i n t a r e grown a t d i f f e r i n g c o n d i t i o n s t o G r o x t e gr3wth o f . i n j u r e d organisms. I n c u b a t i o n times should be s x t ~ n d e d c3 a t l e a s t 3-4 weeks t 7 ~ o p t i m i z e t h e p o t e n t i a l f o r r e c x e r y 2:d growth o f - v i a b l e organisms. The d a t a should i d e n t i f y no gr=:-th a: c o n d i t i o n s equal t o and beyond t h e 1 / 2 c y c l e ( e , no "s:<ips") and corresponding growth under c o n d i t i o n s l e s s than r h e 1/2 cyzle. A s always, a p p r o p r i a t e c o n t r o l s should be run c o n c - ~ r r e a t l y . Skips o r o t h e r f a i l u r e s beyond t h e 1 / 2 c y c l e must b= tl-.2rougily evaluated and discussed i n t h e submission. Adjustmsnt J E t h r c y c l e parameters may be r e q u i r e d t o ensure s t e r i l i t y .

Other Methods A t o t a l k i l l v a l i d a t i o n is a l s o d e s c r i b e d i n l i t e r a t u r e where r e p l i c a t e runs a r e evaluated f o r t o t a l k i l l . T h i s process is less r e l i a b l e a s f a r as b a s i c c y c l e v a l i d a t i o n is concerned, b u t it conceivably could be a p p r o p r i a t e f o r a p a r t i c u l a r t y p e of s t e r i l i z e r technology t h a t is n o t amenable t o t r a d i t i o n a l forms o f a n a l y s i s . A l i m i t e d t o t a l k i l l method is used i n t h e f i n a l q u a l i f i c a t i o n v a l i d a t i o n a s d e s c r i b e d below i n Section Q. Simulated and In-Use T e s t s Simulated or in-use tests are n o t r e q u i r e d f o r t r a d i t i o n a l , c l a s s i f i e d s t e r i l i z e r s except when articles a r e i n d i c a t e d i n t h e l a b e l i n g f o r t r a d i t i o n a l s t e r i l i z e r s t h a t a r e n o t i d e n t i f i e d i n ' p r e d i c a t e devices, or are n o t g e n e r a l l y recognized i n t h e l i t e r a t u r e and by t h e i n f e c t i o n c o n t r o l community a s u s u a l l y being s t e r i l i z e d with t h e - p a r t i c u l a r process. P u b l i c h e a l t h r i s k . concerns may demand. that FDA r e q u i r e a d d i t i o n a l t e s t i n g from t i m e t o t i m e t o ( r e ) v a l i d a t e t r a d i t i o n a l s t e r i l i z e r e f f e c t i v e n e s s . For example, a d d i t i o n a l t e s t i n g h a s been requested f o r d e n t a l handpieces. S t e r i l i z e r s t h a t are t e s t e d i n h e a l t h care f a c i l i t i e s are s u b j e c t t o t h e i n v e s t i g a t i o n a l device exemptions (IDE) r e g u l a t i o n , 2 1 CFR P a r t 812, i f t h e processed m e d i c a l product is intended t o be r e t u r n e d t o service without first undergoing a follow up s t e r i l i z a t i o n procedure with a l e g a l l y marketed s t e r i l i z e r . S i ~ u l a t e d U s e T e s t s . S t e r i l i z e r m i c r o b i c i d a l performance must be t e s t e d under simulated use conditions. The a p p l i c a n t must j u s t i f y how t h e s i m u l a t i o n c o r r e l a t e s t o in-use w o r s t case conditions. ' S e l e c t a r e p r e s e n t a t i v e sample o f medical' products i n d i c a t e d i n l a b e l i n g . The tests must c o n s i s t o f r e p l i c a t e s o f devices and t y p e s of m a t e r i a l s t h a t a r e i n d i c a t e d f o r s t e r i l i z a t i o n , e - g . , metals, polymers, elastomers, adhesive r e s i n s , paper, and f a b r i c s . The a r t i c l e s . s e l e c t e d f o r each m a t e r i a l should e x h i b i t design c o n f i g u r a t i o n s t h a t w i l l provide t h e g r e a t e s t challenge t o ' p e n e t r a t i o n of t h e s t e r i l a n t , e - g . , lumens, mated s u r f a c e s , hinges, gnarled s u r f a c e s . T e s t l o a d s should be a s noted i n l a b e l i n g , packaged properly, and o r i e n t e d h ~ c o r d i n g t o l a b e l i n g . The test a r t i c l e s must be i n o c u l a t e d with a 10' CFU/unit of t h e most r e s i s t a n t test organism prepared w i t h an inorganic and orqanic load. Allow t h e inoculum t o d r y on t h e a r t i c l e before placement i n t h e s t e r i l i z e r . The inocula m u s t be placed i n v a r i o u s l o c a t i o n s on t h e test a r t i c l e s including those l e a s t favorable t o p e n e t r a t i o n and c o n t a c t w i t h the s t e r i l a n t , e . g . , l u ~ e n s , mated s u r f a c e s , hinges. Include c o n t r o l s for each type

of article. In Use Tests Sterilizer performance must also be verified under in-use conditions. Articles sampled.after use should be precleaned (or decontaminated) according to the normal operationat reprocessing protocol of the health care facility where the samples are obtained. Assurance of meeting a stringent precleaning protocol is not a precondition since the robustness of the sterilization pr.ocess is part of this evaluation. Multiple tests with differing load conditions as indicated in labeling should be reported. 'fter processing, the test articles are neutralized, if . necessary. The articles are immersed in the growth media, if possible, or subjected to an extraction method with the extract placed in growth media. Publications and the literature contain suitable extraction methods. Derivation of the Process Parameters The process parameters for the sterilizer shall be derived from the screening test, process equivalent times, D-valuecalculations, simulated or actual use testing, 1/2 cycle and End Point tests, and any additional safety factors. For process validation an SAL of at least based upon the most resistant test organism, shall be demonstrated. Provide a thorough description of the derivation of the process parameters.

N . Toxicity of the s t e r i l a n t and Process By-Products The s t e r i l a n t and/or t h e by-products of s t e r i l i z a t i o n may be toxic. The applicant musc determine t h e t o x i c i t y p r o f i l e of t h e s t e r i l a n t , and t h e nature and l e v e l of t h e s t e r i l i z a t i o n byproducts and t h e i r toxicity p r o f i l e . Toxicity d a t a f o r t h e s t e r i l a n t and its by-products may be p a r t of a submission f o r EPA r e g i s t r a t i o n . I f so, a summary of the data should be submitted i n t h e 510 (k) . Selection of t h e appropriate test protocol and experimental conditions t o e s t a b l i s h the t o x i c i t y of t h e s t e r i l a n t ( s ) and byproducts is influenced by several f a c t o r s , including t h e p o t e n t i a l routes of exposure, the anticipated magnitude of exposure, and physical/chemical properties of c o n s t i t u e n t s of t h e agent o r its by-products. The t e s t i n g may vary depending upon t h e antimicrobial agent, its intended use, and d i r e c t i o n s f o r use. It is incumbent upon t h e applicant t o select r e l i a b l e state-of-the-art m&thodologies t o demonstrate t h e s a f e t y of t h e antimicrobial agent f o r its intended use. Data submitted t o EPA may not address a l l o f the above factors.

Details of the types of t e s t s necessary t o derive t o x i c i t y d a t a a r e beyond t h e scope of t h i s document. The submitter should refer t o t h e T r i p a r t i t e Biocompatibility Guidance f o r Medical Devices, t h e l i t e r a t u r e , and other relevant publications f o r more information. 0. Elimination of Toxic P r o c e s s Residues The sponsor must establish what s t e r i l a n t o r by-products residues remain on/in t h e medical product.. The concentration of residue may vary depending on the product. The i d e n t i t y of the residue, its concentration on/in the various materials processed (scope of m a t e r i a l s defined in l a b e l i n g ) , and a comparative analysis of 'these values t o a known t o x i c level must be determined and presented i n t h e 510 (k) .

The applicant must describe t h e means t o reduce a t o x i c l e v e l of residue t o an acceptable l e v e l . Test data must be submitted which demonstrate t h a t t h e procedure t o reduce t h e residue is

• e f f e c t i v e under a l l potential conditions. Labeling must include the procedure.

p . Processed Device/Naterial Qualification Introduction Labeling for a sterilizer indicates the types of medical devices and other medical products and/or the component materia-1s of a medical device or product that are compatible with the sterilization process (noted in this section as "articles"). Data shall be provided which attest to the compatibility of each of the listed articles with the sterilization process. The data shall address the effects of the process on the safety and effectiveness, e-g., functionality/specifications, of the claimed compatible articles, and the effects on the biocompatibility of the articles. The applicant must carefully consider labeling and the implications of the scope of the compatible articles on the potential test regimen. If the articles in the intended use statement in labeling are limited and specifically characterized then the scope of testing is a relatively simple matter. As the intended use becomes more generalized the scope of testing becomes more complex. For example, if ASTM 316 stainless steel instruments are indicated as compatible devices then the test article is basically defined. On the other hand, reference to "metal" instruments connotes a plethora of material possibilities. The same is true regarding a general reference to "polymers" rather than a specific class and type of polymer. When the labeling indicates a general class of articles that could be differentially affected by the sterilization process, the applicant must specify and justify a representative sample of articles from the class for testing. Even after 510(k) submission the applicant should- continue with a vigorous program to analyze new products and those articles that were not tested in the defined class. These data may serve as a basis for 'labeling revisions or as a resource for users on the compatibility of the sterilizer- A s noted in the labeling ' ssction, users should be directed to call the manufacturer to obtain any current information on devices and materials not listed in the labeling. Even though testing may qualify an article for the'subject sterilization process the labeling ef the article may identify a specific type of sterilization process to be used. In this case, the labeling for the subject sterilizer cannot supersede the device labeling. The applicant may choose to communicate with the manufacturer of the qualified arricle to modify the labeling for the article. Ic may be possible that certain elt.:...-ents of this battery of testing can be combined with the bi>loqical tests noted in S2cticn K in order to minimize tes' 'J .

process L i f e Determination A f a c t o r i n a l l compatibility tests is t h e d u r a t i o n of c o m p a t i b i l i t y , i - e . , how many cycles a n a r t i c l e can withstand before it f a i l s or is o t h e r d i s e unusable. A r t i c l e s t h a t are compatible with a s t e r i l i z e r a r e t h o s e t h a t r e t a i n thei-r s a f e t y and e f f e c t i v e n e s s f o r their intended u s e a f t e r an a c c e p t a b l e number o f reprocessing cycles. The a c c e p t a b l e number of c y c l e s t o f a i l u r e can be c o r r e l a t e d t o t h e c l a s s i f i e d s t e r i l i z e r s o r based on u s e r preference. Unless t h e r e is adequate j u s t i f i c a t i o n , i n no case should an a r t i c l e f a i l when exposed t o fewer c y c l e s t h a n p o s s i b l e w i t h a c l a s s i f i e d s t e r i l i z e r . Data s h a l l be submitted on t h e process l i f e of t h e claimed compatible a r t i c l e s . I n soae cases, t h e test a r t i c l e may n o t e x h i b i t s i g n i f i c a n t , q u a n t i f i a b l e d e t e r i o r a t i o n a f t e r numerous cycles. I f t h i s is t h e case, t h e a p p l i c a n t may submit a j u s t i f i c a t i o n f o r a projected c o m p a t i b i l i t y of t h e m a t e r i a l o r device based upon a n a l y t i c a l methods i n order t o minimize t h e e x t e n t o f t e s t i n g . Functional c o m p a t i b i l i t v of A r t i c l e s C h a r a c t e r i z e t h e e f f e c t of repeated s t e r i l i z a t i o n p r o c e s s e s on t h e f u n c t i o n a l i t y of r e p l i c a t e s of t h e r e p r e s e n t a t i v e test a r t i c l e s . The f u n c t i o n a l i t y parameters can be determined on t h e b a s i s o f use requirements, s p e c i f i c a t i o n s of t h e d e v i c e and t h e component m a t e r i a l s . The nethods o f e v a l u a t i o n should be o b j e c t i v e , whenever possible, e-g., t e n s i l e p r o p e r t i e s , f l e x u r a l p r o p e r t i e s , impact r e s i s t a ~ c e , hardness, compressive s t r e n g t h , b u r s t s t r e n g t h , t e a r s t r e n c t h , color, dimensions, p e r m e a b i l i t y , o p t i c a l transmission, e l e c t r i c a l r e s i s t a n c e , e t c . . The tests must i n c o r p o r a t e simulzted u s e c o n d i t i o n s on t h e test articles between processes. There .=re e x t e n s i v e published test methods f o r each parameter and t h e a p p l i c a n t should r e f e r t o t h e s e methods i n devising test protocols. Biocompatibility of Conoon~-nt Materials The applicant s h a l l i d e n t i f y t h e test a r t i c l e s and' t h e tests conducted on each a r t i c l e . The T r i p a r t i t e Biocompatibility Guidance f o r Medical Devices should be used a s a r e f e r e n c e t o i d e n t i f y t h e a p p r o p r i a t e t e s t s . The a p p l i c a n t should i d e n t i f y any o t h e r reference used f o r determination of t e s t s . IS0 1 9 4 can be used as 2 reference. For m e t a l s , some s u r f a c e tssts may be u s e f u l , e . g . , SEM, c o n t a c t angle. I d e n c i f y any o t h e r s u r f a c e o r m a t e r i a l degradation e f f e c t s r o include d i s c o l o r a t i o n , c o r r o s i o n , cracking, c r a z i n g , embrittlemen:, e t c .

Q . F i n a l Process Q u a l i f i c a t i o n A summary of d a t a from a f i n a l q u a l i f i c a t i o n r e s t b a r t e r y shouid be submitted. The q u a l i f i c a t i o n documentation submirted should i n c l u d e t h r e e c o n s e c u t i v e runs t i m e s t h e v a r i z b l e s of o p e r a t i o n ( e - g . , t h r e e r u n s f o r each mode of o p e r a t i o n ) under --'oqst c a s e loading c o n d i t i o n s i n d i c a t e d i n l a b e l i n g . S t z n d a r d . = e s t packs should be used. . The a p p l i c a n t must s u b m i t d e z a i l e d locumentation o f f a i l u r e s and c o r r e c t i v e measures and r e t e s c s . A summary of acceptance criteria s h o u l d b e s u j m i t t e d r e g a r d i n g p r o c e s s parameters, m i c r o b i c i d a l e f f e c t i v e n e s s a n d processed d e v i c e performance. C e r t i f i c a t i o n t h a t t h e system performs i n accordance with s p e c i f i c a t i o n s should be provided.

R. Contacts and Addresses

General q u e s t i o n s regarding t h e submission of premarket a p p l i c a t i o n s should be d i r e c t e d t o t h e Division of -all Manufacturers ~ s s i s t a n c e a t (800) 638-2041. Questions regarding t h i s guidance document shauld be d i r e c t e d t o t h e following address: FDA Division of General and R e s t o r a t i v e Devices (HFZ-410) I n f e c t i o n Control Devices Branch 1390 Piccard D r . Rockville, MD. 20850 (301) 427-1307

S. checklist 510 (k)

:

Sponsor: Date: Reviewer:

Y/N Element

1. EPA certification and Summary of Data References to Standards Labeling markings manual service manual Description design, construction, components . process parameters process monitors software Cycle Overview Test Packs Comparison to Predicate Physical/Chemical Performance Tests Biological Test Battery screen F value D values 1/2 cycle and Total Kill Endpoint Simulated and In-Use Tests Summary Toxicity Residues Processed Device Qualification process life functionality biocompatibility Final Qualification

Attachment 1 Comparison ~ a b l o F e a t u r e EPA R e g i s t e r e d Component Y/N Labeling/Intended U s e Design, Construction, Com~onents T h i s t a b l e i l l u s t r a t e s the t y p e o f comparisons t h a t s h o u l d b e made, n o t n e c e s s a r i l y t h e amount of information. P r o c e s s Parameters: t i m e temp p r e s s u r e s , e t c . Process Monitors : r e c o r d e r s gauges p r i n t o u t s , etc. Software/Firmware C o n t r o l l e d Cycle ( s) Comparison Process Equivalent Time ( f o r steam and d r y heat) N e w Device -

P r e d i c a t e