Guidance fr Industry and FDA Staff 30-Day Ntices, 135-Day Premarket Apprval (PMA) Supplements and 75- Day Humanitarian Device Exemptin (HDE) Supplements fr Manufacturing Methd r Prcess Changes Dcument Issued n: April 13, 2011 This dcument supersedes 30-Day Ntices and 135-Day PMA Supplements fr Manufacturing Methd r Prcess Changes, issued n February 19, 1998. Fr questins regarding this dcument cntact Anastacia Bilek at 301-796-5588 r at anastacia.bilek@fda.hhs.gv at CDRH r the Office f Cmmunicatins, Outreach and Develpment (CBER) at 301-827-1800 r 800-835-4709. U.S. Department f Health and Human Services Fd and Drug Administratin Center fr Devices and Radilgical Health Office f Cmpliance Center fr Bilgics Evaluatin and Research
Cntains Nnbinding Recmmendatins Preface Public Cmment Written cmments and suggestins may be submitted at any time fr Agency cnsideratin t the Divisin f Dckets Management, Fd and Drug Administratin, 5630 Fishers Lane, Rm 1061, (HFA-305), Rckville, MD, 20852. Alternatively, electrnic cmments may be submitted t http://www.regulatins.gv. Please identify yur cmments with the dcket number listed in the ntice f availability that publishes in the Federal Register annuncing the availability f this guidance dcument. Cmments may nt be acted upn by the Agency until the dcument is next revised r updated. Additinal Cpies Additinal cpies are available frm the Internet. Yu may als send an e-mail request t dsmica@fda.hhs.gv t receive an electrnic cpy f the guidance r send a fax request t 301-847-8149 t receive a hard cpy. Please use the dcument number (1687) t identify the guidance yu are requesting. OR Office f Cmmunicatin, Outreach and Develpment, HFM-40 Center fr Bilgics Evaluatin and Research Fd and Drug Administratin 1401 Rckville Pike, Suite 200N, Rckville, MD 20852-1448 Phne: 800-835-4709 r 301-827-1800 Internet: http://www.fda.gv/bilgicsbldvaccines/guidancecmplianceregulatryinfrmatin/defau lt.htm
Cntains Nnbinding Recmmendatins Table f Cntents 1. Intrductin...1 2. What Changes Qualify Fr Submissin Of A 30-Day Ntice?...2 3. What Changes D Nt Qualify Fr Submissin Of A 30-Day Ntice?...5 4. Cntents Of A 30-Day Ntice...6 5. Actin On A 30-Day Ntice, 135-Day PMA Supplement, Or 75-Day HDE Supplement...7 6. Submissin Of A 30-Day Ntice...8 7. Exceptins T User Fees Fr 30-Day Ntices...8
Cntains Nnbinding Recmmendatins Guidance fr Industry and FDA Staff 30-Day Ntices, 135-Day Premarket Apprval (PMA) Supplements and 75-Day Humanitarian Device Exemptin (HDE) Supplements fr Manufacturing Methd r Prcess Changes This guidance represents the Fd and Drug Administratin's (FDA's) current thinking n this tpic. It des nt create r cnfer any rights fr r n any persn and des nt perate t bind FDA r the public. Yu can use an alternative apprach if the apprach satisfies the requirements f the applicable statutes and regulatins. If yu want t discuss an alternative apprach, cntact the FDA staff respnsible fr implementing this guidance. If yu cannt identify the apprpriate FDA staff, call the apprpriate number listed n the title page f this guidance. 1. Intrductin Sectin 515(d)(6)(A) f the Federal Fd, Drug, and Csmetic Act (the Act) prvides that PMA supplements are required fr any change t a device subject t an apprved applicatin that affects safety r effectiveness, unless such change is a mdificatin in a manufacturing prcedure r methd f manufacturing. 21 U.S.C. 360e(d)(6)(A). The Act states that changes in manufacturing prcedures r methd f manufacturing that affect safety r effectiveness require a 30-day ntice. Where FDA finds such ntice inadequate, FDA will infrm the applicant that a 135-day PMA supplement r 75-day HDE supplement must be submitted. 21 CFR 814.39(f), 814.108. 1 The purpse f this dcument is t prvide guidance n the changes FDA believes may qualify fr the 30-day ntice and the changes that generally d nt qualify. This dcument replaces the guidance entitled, 30-Day Ntices and 135-Day PMA Supplements fr Manufacturing Methd r Prcess Changes, issued February 19, 1998. This new guidance includes updates t reflect the current review prcess, additinal 1 An HDE hlder must submit supplements in accrdance with PMA requirements under 21 CFR 814.39, except that requests fr a new indicatin fr use f a HUD must cmply with 21 CFR 814.110. 21 CFR 814.108. Hwever, the timeframe fr reviewing HDE supplements is 75 days. 21 CFR 814.108 and 814.114. Thus, changes that wuld require a 135-day supplement fr a PMA wuld require a 75-day supplements fr an HDE. 1
Cntains Nnbinding Recmmendatins examples f manufacturing changes that may be submitted under this prgram, and a discussin f user fees. The Medical Device User Fee and Mdernizatin Act f 2002 (MDUFMA) (P.L. 107-250) amended the FD&C Act t prvide FDA new respnsibilities and authrities. One significant prvisin f the Act, as amended by MDUFMA, Sectin 738, 2 required FDA t cllect user fees fr certain premarket submissins r supplements received n r after Octber 1, 2002. MDUFMA established user fee rates that varied depending n the type f submissin. Hwever under MDUFMA, 30-day ntices were nt amng the file types that were subject t user fees. The Fd and Drug Administratin Amendments Act f 2007 (FDAAA) (P.L. 110-85) later amended the Act t require user fees fr 30-day ntices. 21 U.S.C. 379j(a)(2)(A)(vi). FDA's guidance dcuments, including this guidance, d nt establish legally enfrceable respnsibilities. Instead, guidances describe the Agency's current thinking n a tpic and shuld be viewed nly as recmmendatins, unless specific regulatry r statutry requirements are cited. The use f the wrd shuld in Agency guidances means that smething is suggested r recmmended, but nt required. 2. What Changes Qualify fr Submissin f a 30-Day Ntice? Changes, which affect the safety r effectiveness f the device, that may qualify fr submissin as a 30-day ntice, are: changes t the manufacturing prcedure; r changes in methd f manufacture; When these changes, hwever, als alter perfrmance r design specificatins r the designated physical r chemical specificatins f the finished device, a 30 day ntice is nt apprpriate. 3 In these cases, a PMA hlder shuld submit a 180-day PMA supplement 4 r a real-time review PMA Supplement, 5 as apprpriate. Similarly, in these instances, an HDE hlder must submit a 75-day HDE supplement. 21 CFR 814.108. 2 All references t Sectins 738 in this guidance dcument refer t Sectin 738 f the Federal Fd, Drug, and Csmetic Act (the FD&C Act). 21 U.S.C. 379j. 3 Changes in the perfrmance r design specificatins, circuits, cmpnents, ingredients, principle f peratin, r physical layut f the device, must be submitted as a PMA supplement. 21 CFR 814.39(a)(6) 4 A 180-day supplement is a supplement t an apprved premarket applicatin r premarket reprt under sectin 515 that is nt a panel-track supplement and requests a significant change in cmpnents, materials, design, specificatin, sftware, clr additives, r labeling. 21 U.S.C. 379i(4)(C) 5 A real-time supplement is a supplement t an apprved premarket applicatin r premarket reprt that requests a minr change t the device, such as a minr change t the design f the device, sftware, sterilizatin, r labeling, and fr which the applicant has requested and the agency has granted a meeting r similar frum t jintly review and determine the status f the supplement. 21 U.S.C. 379i(4)(D) 2
Cntains Nnbinding Recmmendatins Examples belw are manufacturing prcedure changes r changes t the methds f manufacture, that when they affect the safety r effectiveness f the device, wuld likely qualify fr a 30-day ntice. Sterilizatin Prcess Parameters within the Same Facility Generally, a 30-day ntice may be apprpriate fr changes in: sterility dse auditing; aeratin time used at sterilizatin site; Autmating Existing Prcesses Generally, a 30-day ntice may be apprpriate when yu change frm: a manual cutting prcess t an autmated cutting prcess; manually cntrlled machining t manufacturing prcesses that use cmputer numeric cntrl (CNC) machining; manual sewing t autmatin f the sewing prcess; an existing manual sldering prcess t adding an alternate autmated sldering prcess fr jining the high vltage capacitr wires t the high vltage printed circuit bard assembly (PCBA) cnnectr pads. Jining Prcesses Generally, a 30-day ntice may be apprpriate fr changes in: the resistance weld that bnds the feedthrugh wire t the implantable pulse generatr s (IPG s) cnnectr wire t add a spt laser weld; a manufacturing prcess change frm a resistance weld t a laser weld; the bnding equipment t replace existing equipment with a different mdel heat bnder. (Nte: A validated change that replaces the equipment with identical equipment that uses the same parameters as riginally validated wuld nt require a 30-day ntice.) Cleaning Methds Used t Remve Manufacturing Materials Generally, a 30-day ntice may be apprpriate when yu: change the wash prcess fr the Printed Circuit Bard Assembly (PCBA) sequence t increase the efficiency f the prcess and t reduce cst; replace the current manual cleaning prcess fr remving residual manufacturing materials frm equipment with a semi-autmatic substrate washer. Manufacturing Materials Generally, a 30-day ntice may be apprpriate fr changes t: machining lubricants; the flux used fr slder rewrk. 3
Cntains Nnbinding Recmmendatins Envirnmental Cnditins f the Manufacturing, Strage r Distributin Facilities Generally, a 30-day ntice may be apprpriate fr: a change that adds a new cleanrm t existing manufacturing space 6 ; a change frm an ISO Class 4 envirnment t an ISO Class 5 envirnment; a relcatin f a frmulatin rm within a manufacturing facility. Suppliers 7 f Cmpnents, Materials r Services, where Specificatins Are Unchanged Generally, a 30-day ntice may be apprpriate when: using an additinal supplier fr the laser welding f cmpnents; adding a raw material supplier; adding an alternate supplier fr the UV chrmphre fr an intracular lens; making a change in sterilizatin test site fr sterilizatin test samples. These changes shuld be submitted as 30-day ntices nly when the material was critical t the perfrmance f the device, as determined by the manufacturer. If the material is nt critical t the perfrmance f the device, then any change shuld be submitted as part f the peridic reprt (ften reffered t as the annual reprt). 21 CFR 814.39(b). Nte, hwever, that if a manufacturing change invlves adding a secnd supplier f a critical cmpnent, and the specificatins f that cmpnent are different, a 30-day ntice is nt apprpriate because the specificatins have changed. 21 CFR 814.39(a)(6). A PMA hlder shuld submit a 180-day PMA supplement r a real-time review PMA Supplement, as apprpriate. Similarly, in these instances, an HDE hlder shuld submit a 75-day HDE supplement. 21 CFR 814.108. Quality Cntrl Testing Generally, a 30-day ntice may be apprpriate fr changes t quality cntrl testing used n incming cmpnents, raw materials, the in-prcess device, r the finished device, fr example: perfrming end-prduct pyrgen testing n nn-sterile samples prir t sterilizatin; 6 Fr the purpses f this guidance, existing manufacturing space can include newly cnstructed space r buildings prvided that they are included under a single Firm Establishment Identifier (FEI). 7 Fr the purpses f this guidance dcument, a supplier is anyne that is independent frm the manufacturer s quality management system that prvides the manufacturer cmpnents, materials, r services. This includes a supplier that may be part f the manufacturer s rganizatin but perates under a separate quality management system. (i.e., this supplier is knwn as an internal supplier). In ther wrds, if the supplier is nt a part f the manufacturer s internal audit (quality audit) scpe, then the supplier is under a separate quality management system and is cnsidered an internal supplier. Internal suppliers are t be cntrlled in a similar way as external suppliers are cntrlled and 30-day ntices wuld be needed fr changes that wuld rdinarily be submitted fr supplier changes. 4
Cntains Nnbinding Recmmendatins eliminating certain in-prcess r final device tests, t eliminate test redundancy, waste, r use test samples selected during prcessing mre efficiently; changing sample size in a bacterial endtxin test assay; remving a rejectin criterin fr cmpnent acceptance in an in-prcess inspectin step; adding inspectin steps in direct respnse t field failures f the device. Type f Manufacturing Prcess Changing the type f prcess used, e.g., a change frm machining a particular part t injectin mlding the part may be apprpriate fr submissin as a 30-day ntice. Changes that qualify fr a "Special PMA Supplement - Changes Being Effected" under 21 CFR 814.39(d)(2) fr changes in quality cntrls r manufacturing prcess that add a new specificatin r test methd, r therwise prvide additinal assurance f purity, identity, strength, r reliability f the device can be submitted either as a "Special PMA Supplement - Changes Being Effected" r a 30-day ntice. The manufacturing changes that may be reviewed as a Special PMA Supplement are generally thse that add a step t the quality cntrl r manufacturing prcess t enhance safety but d nt impact effectiveness. If efficacy is als affected, thse changes shuld be submitted as a 30-day ntice. The examples abve are nly illustrative and are nt intended t be exhaustive. Additinal examples f changes apprpriate fr submissin as 30-day ntices may be fund in the guidance entitled, Mdificatins t Devices Subject t Premarket Apprval (PMA) - The PMA Supplement Decisin-Making Prcess. 8 3. What Changes D Nt Qualify fr Submissin f a 30- Day Ntice? Examples f changes FDA believes d nt qualify fr submissin as a 30-day ntice include any change in manufacturing needed t accmmdate a change in: manufacturing/sterilizatin site f a finished device 9 ; device design r perfrmance specificatins; material specificatins r device perating sftware. FDA recmmends that submissins fr these changes be in the frm f a 180-day PMA supplement, a 75-day HDE supplement, r anther alternate submissin, e.g., real-time supplement, as apprpriate. 8 http://www.fda.gv/medicaldevices/deviceregulatinandguidance/guidancedcuments/ucm089274.htm 9 A finished device is defined in 21 CFR 820.3(l) as any device r accessry t any device that is suitable fr use r capable f functin, whether r nt it is packaged, labeled, r sterilized. 5
Cntains Nnbinding Recmmendatins Changes t the manufacturing prcedure r methd f manufacturing that d nt affect the safety r effectiveness f the device must be submitted in the peridic reprt, that is usually referred t as an annual reprt. 10 21 CFR 814.39(b), 814.126(b)(1). If a 30 day-day ntice cntains device design r labeling changes in additin t manufacturing changes, then the submissin will autmatically be cnverted t a 180-day PMA r 75-Day HDE supplement and reviewed accrdingly. 12 CFR 814.39(a). 4. Cntents f a 30-Day Ntice A 30-day ntice must cntain 11 : a descriptin f the change (any illustrative pictures shuld als be included); a summary f the data r infrmatin supprting the change, e.g., a few cncise pages summarizing the key results; and a statement that the change has been made under the requirements f 520(f) f the FDCA and 21 CFR. Part 820. A 30-day ntice shuld als cntain: a descriptin f the device; identificatin f the manufacturing facilities where the change will be implemented; reasn fr the change, including a descriptin f any adverse events r field failures that have ccurred; appendices f supprting data, where apprpriate. The summary f the data r infrmatin supprting the change, shuld include: a summary f the prcedures established fr the identificatin, dcumentatin, validatin, review, and apprval f the manufacturing changes submitted in the 30- day ntice; the statistical ratinale fr the sampling methd, if yu plan t verify the changed prcesses by rutine sampling and independent measurement; a descriptin f hw yu will mnitr and cntrl any manufacturing prcess yu intend t change; a summary f the cmpleted validatin study that demnstrates that the manufacturing change can be made withut significantly changing the peratin f the final device. This summary shuld be include: a descriptin f the acceptance criteria; 10 Devices subject t premarket apprval under sectin 515 f the Act are als subject t peridic reprt requirements impsed by the PMA apprval rder (21 CFR 814.82(a), 21 CFR 814.84(b)). FDA typically specifies that a PMA hlder submit a reprt ne year frm the date f apprval f the riginal PMA and annually thereafter. Therefre, the peridic reprt is usually referred t as an annual reprt. 11 21 U.S.C. 360e(d)(6)(A)(i) and 21 CFR 814.39(f). 6
Cntains Nnbinding Recmmendatins infrmatin n hw, using valid statistical methds, yu analyzed the test data; infrmatin that describes the statistical ratinale fr sample sizes; a list f any deviatins that ccurred; and a determinatin f the impact f the deviatin n the results; an explanatin f hw change cntrl prcedures were implemented, including whether yu mdified the manufacturing r quality cntrl instructins, r the manufacturing specificatins. In additin, yu shuld include a summary f hw purchasing cntrl prcedures were implemented t evaluate any new supplier r cntractr, if the manufacturing change invlves: changes in suppliers f cmpnents r raw materials that are critical t the perfrmance f the device; r the use f a new cntractr fr a manufacturing prcess r quality cntrl testing. Yu shuld als describe the type and extent f cntrl t be exercised ver the cmpnent r raw material, including specificatins fr the incming material and a descriptin f in-cming acceptance activities. Additinally, yu shuld describe any testing that was cmpleted t evaluate the use f the cmpnent r material and include a summary f the data. Nte: If the cntract manufacturer is manufacturing a finished device as defined in 21 CFR 820.3(l), then a 30-day ntice is nt apprpriate and the change shuld be submitted as a manufacturing site change supplement. See 21 CFR 814.39(a)(3). 5. Actin n a 30-Day Ntice, 135-Day PMA Supplement, r 75-Day HDE Supplement If the change qualifies fr a 30-day ntice and yu have submitted cmplete infrmatin in the 30-day ntice t FDA, yu may distribute the device 30 days after the date n which FDA received the ntice, unless FDA ntifies yu with thse 30 days that the ntice is inadequate. Hwever, if the infrmatin yu have submitted is nt adequate, within 30 days f receipt FDA will infrm yu in writing that a 135-day PMA supplement (r fr HDE hlders, a 75- day HDE supplement) is needed and shall describe additinal infrmatin r actin that is required fr acceptance f that change. 21 CFR 814.39(f), 814.108. If n actin ccurs within 30 days f receipt f yur 30-day ntice and payment f the user fee, yu may distribute the device withut further actin frm FDA. 12 12 Sectin 515(d)(6)(A)(ii) and 738(a)(2)(A)(vi) f the Act. 7
Cntains Nnbinding Recmmendatins 6. Submissin f a 30-Day Ntice T facilitate the review f yur 30-day ntice, yu shuld clearly and cnspicuusly indicate in yur cver letter that the submissin is a 30-day ntice; large type and bld face are desirable, e.g., 30-DAY NOTICE. Failure t prperly identify the submissin may cause FDA t prcess it as a supplemental PMA r HDE. Applicants are requested t submit three cpies t: Fd and Drug Administratin Center fr Devices and Radilgical Health Dcument Mail Center - WO66-G609 ATTN: 30-day Ntice 10903 New Hampshire Ave. Silver Spring, Maryland 20993-0002 Or Fd and Drug Administratin Center fr Bilgics Evaluatin and Research (CBER) Dcument Cntrl Center, HFM-99 ATTN: 30-day Ntice 1401 Rckville Pike, Suite 200N Rckville, MD 20852-1448 The current fee structure fr 30-day ntices may be fund at: http://www.fda.gv/medicaldevices/deviceregulatinandguidance/hwtmarketyur Device/PremarketSubmissins/PremarketApprvalPMA/ucm048161.htm 7. Exceptins T User Fees Fr 30-Day Ntices In accrdance with Sectin 738(a)(2)(B) f the Act, the submissins listed belw are nt subject t user fees. HDEs and HDE supplements, including HDE supplements that are reprted as 30-day ntices; any PMA r PMA supplement intended slely fr a pediatric ppulatin; r PMAs r PMA supplements submitted by a state r federal gvernment entity unless the device invlved is t be distributed cmmercially. 8