Food and Drug Administration, HHS § 201.327

(2) At least as large as the size of the the same font style, size, and color ‘‘Drug Facts’’ title, as required in with the same background color. § 201.66(d)(2). The new warnings infor- (ii) For products that do not mation statement must remain on the pass the broad spectrum test in paragraph PDP of the drug product for at least 1 (j) of this section. The labeling states year from the date the product is ini- ‘‘SPF [insert numerical SPF value re- tially introduced into interstate com- sulting from testing under paragraph merce. (i) of this section]’’. The entire text (c) Requirements to supplement ap- shall appear in the same font style, proved application. Holders of approved size, and color with the same back- applications for OTC drug products ground color. that contain internal analgesic/anti- (2) Water resistance statements—(i) For pyretic active ingredients that are sub- products that provide 40 minutes of water ject to the requirements of paragraph resistance according to the test in para- (a) of this section must submit supple- graph (i)(7)(i) of this section. The label- ments under § 314.70(c) of this chapter ing states ‘‘Water Resistant (40 min- to include the required information in utes)’’. the product’s labeling. Such labeling (ii) For products that provide 80 min- may be put into use without advance utes of water resistance according to the approval of FDA provided it includes at test in paragraph (i)(7)(ii) of this section. least the exact information included in The labeling states ‘‘Water Resistant paragraph (a) of this section. (80 minutes)’’. (b) Statement of identity. The labeling [74 FR 19407, Apr. 29, 2009, as amended at 74 of the product contains the established FR 31180, June 30, 2009; 74 FR 61514, Nov. 25, name of the drug, if any, and identifies 2009] the drug as a ‘‘sunscreen.’’ (c) Indications. The labeling of the § 201.327 Over-the-counter sunscreen product states, under the heading drug products; required labeling based on effectiveness testing. ‘‘Uses,’’ the phrases listed in this para- graph (c), as appropriate. Other truth- The following provisions apply to ful and nonmisleading statements, de- sunscreen products containing amino- scribing only the uses that have been benzoic acid, , , established and listed in this paragraph , , , (c), may also be used, as provided in meradimate, octinoxate, octisalate, § 330.1(c)(2) of this chapter, subject to , , , the provisions of section 502 of the Fed- , , eral Food, Drug, and Cosmetic Act (the , or , FD&C Act) relating to misbranding and alone or in combination. The provi- the prohibition in section 301(d) of the sions do not apply to sunscreen prod- FD&C Act against the introduction or ucts marketed under approved new delivery for introduction into inter- drug applications or abbreviated new state commerce of unapproved new drug applications. drugs in violation of section 505(a) of (a) Principal display panel. In addition the FD&C Act. to the statement of identity in para- (1) For all sunscreen products, the graph (b) of this section, the following following indication statement must be labeling shall be prominently placed on included under the heading ‘‘Uses’’: the principal display panel: ‘‘[Bullet] helps prevent ’’. See (1) Effectiveness claim—(i) For products § 201.66(b)(4) of this chapter for defini- that pass the broad spectrum test in para- tion of bullet. graph (j) of this section. (A) The labeling (2) For sunscreen products with a states ‘‘Broad Spectrum SPF [insert Broad Spectrum SPF value of 15 or numerical SPF value resulting from higher according to the tests in para- testing under paragraph (i) of this sec- graphs (i) and (j) of this section, the la- tion]’’. beling may include the following state- (B) Prominence. The Broad Spectrum ment in addition to the indication in SPF statement shall appear as contin- § 201.327(c)(1): ‘‘[Bullet] if used as di- uous text with no intervening text or rected with other sun protection meas- graphic. The entire text shall appear in ures (see Directions [in bold italic

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font]), decreases the risk of skin cancer (j) of this section. The labeling states and early skin aging caused by the ‘‘[bullet] Sun Protection Measures. [in sun’’. bold font] Spending time in the sun in- (3) Any labeling or promotional ma- creases your risk of skin cancer and terials that suggest or imply that the early skin aging. To decrease this risk, use, alone, of any sunscreen reduces regularly use a sunscreen with a Broad the risk of or prevents skin cancer or Spectrum SPF value of 15 or higher early skin aging will cause the product and other sun protection measures in- to be misbranded under section 502 of cluding: [Bullet] limit time in the sun, the FD&C Act (21 U.S.C. 352). especially from 10 a.m.–2 p.m. [bullet] (d) Warnings. The labeling of the wear long-sleeved shirts, pants, hats, product contains the following warn- and sunglasses’’. ings under the heading ‘‘Warnings’’. (3) For products that satisfy the water (1) For all sunscreen products. (i) The resistance test in paragraph (i)(7) of this labeling states ‘‘Do not use [bullet] on section. The labeling states ‘‘[bullet] re- damaged or broken skin’’. apply: [Bullet] after [select one of the (ii) The labeling states ‘‘When using following determined by water resist- this product [bullet] keep out of eyes. ance test: ‘40 minutes of’ or ‘80 minutes Rinse with water to remove.’’ of’] swimming or sweating [bullet] im- (iii) The labeling states ‘‘Stop use mediately after towel drying [bullet] at and ask a doctor if [bullet] rash oc- least every 2 hours’’. curs’’. (4) For products that do not satisfy the (2) For sunscreen products that are water resistance test in paragraph (i)(7) of broad spectrum with SPF values of at this section. The labeling states ‘‘[bul- least 2 but less than 15 according to the let] reapply at least every 2 hours [bul- SPF test in paragraph (i) of this section or let] use a water resistant sunscreen if that do not pass the broad spectrum test swimming or sweating’’. in paragraph (j) of this section. The first (f) Other information. The labeling of statement under the heading ‘‘Warn- the product contains the following ings’’ states ‘‘Skin Cancer/Skin Aging statement under the heading ‘‘Other Alert [in bold font]; Spending time in information:’’ ‘‘[bullet] protect the the sun increases your risk of skin can- product in this container from exces- cer and early skin aging. This product sive heat and direct sun’’. has been shown only to help prevent (g) False and misleading claims. There sunburn, not [in bold font] skin cancer are claims that would be false and/or or early skin aging.’’ misleading on sunscreen products. (e) Directions. The labeling of the These claims include but are not lim- product contains the following state- ited to the following: ‘‘Sunblock,’’ ments, as appropriate, under the head- ‘‘sweatproof,’’ and ‘‘waterproof.’’ These ing ‘‘Directions.’’ More detailed direc- or similar claims will cause the prod- tions applicable to a particular product uct to be misbranded under section 502 formulation may also be included. of the FD&C Act (21 U.S.C. 352). (1) For all sunscreen products. (i) As an (h) Labeling of products containing a option, the labeling may state ‘‘For combination of sunscreen and skin pro- sunscreen use:’’. tectant active ingredients. Statements of (ii) The labeling states ‘‘[bullet] identity, indications, warnings, and di- apply [select one of the following: ‘Lib- rections for use, respectively, applica- erally’ or ‘generously’] [and, as an op- ble to each ingredient in the product tion: ‘And evenly’] 15 minutes before may be combined to eliminate duplica- sun exposure’’. tive words or phrases so that the re- (iii) As an option, the labeling may sulting information is clear and under- state ‘‘[bullet] apply to all skin ex- standable. Labeling provisions in posed to the sun’’. § 347.50(e) of this chapter shall not (iv) The labeling states ‘‘[bullet] chil- apply to these products. dren under 6 months of age: Ask a doc- (i) SPF test procedure—(1) UV source tor’’. (solar simulator). (i) Emission spectrum. A (2) For sunscreen products with a Broad single port or multiport solar simu- Spectrum SPF value of 15 or higher ac- lator should be filtered so that it pro- cording to the tests in paragraphs (i) and vides a continuous emission spectrum

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from 290 to 400 nanometers (nm) with a in accordance with 5 U.S.C. 552(a) and 1 limit of 1,500 Watts per square meter CFR part 51. You may obtain a copy (W/m2) on total irradiance for all wave- from the ISO Copyright Office, Case lengths between 250 and 1,400 nm. Postale 56, CH–1211, Geneva 20, Switzer- (A) The solar simulator should have land, telephone +41–22–749–01–11 or fax the following percentage of erythema- +41–22–74 -09–47. http://www.iso.org. You effective radiation in each specified may inspect a copy at the Center for range of wavelengths: Drug Evaluation and Research, 10903 New Hampshire Ave., Bldg. 22, Silver SOLAR SIMULATOR EMISSION SPECTRUM Spring, MD 20993, call 301–796–2090, or at the National Archives and Records Wavelength range (nm) Percent erythemal contribution 1 Administration (NARA). For informa- tion on the availability of this mate- < 290 ...... < 0.1 290–300 ...... 1.0–8.0 rial at NARA, call 202–741–6030, or go 290–310 ...... 49.0–65.0 to: http://www/archives.gov/ 290–320 ...... 85.0–90.0 federallregister/ 290–330 ...... 91.5–95.5 290–340 ...... 94.0–97.0 codeloffederallregulations/ 290–400 ...... 99.9–100.0 ibrllocations.html. The solar simulator 1 Calculation of erythema action spectrum described in output should be measured before and § 201.327(i)(1)(ii) of this section. after each phototest or, at a minimum, (B) In addition, UVA II (320–340 nm) at the beginning and end of each test irradiance should equal or exceed 20 day. This radiometer should be cali- percent of the total UV (290–400 nm) ir- brated using side-by-side comparison radiance. UVA I (340–400 nm) irradiance with the spectroradiometer (using the should equal or exceed 60 percent of the weighting factors determined accord- total UV irradiance. ing to paragraph (i)(1)(ii)(A) of this sec- (ii) Erythema action spectrum. (A) Cal- tion) at the time of the annual culate the erythema action spectrum spectroradiometric measurement of the solar simulator as described in weighting factor (Vi) at each wave- length λ: paragraph (i)(1)(iv) of this section. (iii) Operation. A solar simulator (1) Vi (λ) = 1.0 (250 < λ ≤ 298 nm) 0.094 * (298-λ) should have no significant time-related (2) Vi (λ) = 10 (298 < λ ≤ 328 nm) fluctuations (within 20 percent) in radi- 0.015 * (140-λ) ation emissions after an appropriate (3) Vi (λ) = 10 (328 < λ ≤ 400 nm) warm-up time and demonstrate good (B) Calculate the erythema-effective beam uniformity (within 20 percent) in UV dose (E) delivered by a solar simu- the exposure plane. The delivered dose lator as follows: to the UV exposure site must be within 10 percent of the expected dose. (iv) Periodic measurement. To ensure that the solar simulator delivers the appropriate spectrum of UV radiation, λ Where Vi( ) = erythema action spectrum the emission spectrum of the solar sim- weighting factor at each wavelength λ I(λ) = irradiance (Watts per square meter) ulator should be measured at least an- at each wavelength λ nually with an appropriate and accu- t = exposure time (seconds) rately calibrated spectroradiometer system (results should be traceable to Erythema-effective dose (E) is ex- the National Institute for Standards pressed as effective Joules per square and Technology). In addition, the solar meter (J/m2-eff). simulator must be recalibrated if there (C) The emission spectrum must be is any change in the lamp bulb or the determined using a handheld radiom- optical filtering components (i.e., fil- eter with a response weighted to match ters, mirrors, lenses, collimating de- the spectrum in ISO 17166 CIE S 007/E vices, or focusing devices). Daily solar entitled ‘‘Erythemal reference action simulator radiation intensity should be spectrum and standard erythema monitored with a broadband radiom- dose,’’ dated 1999 (First edition, 1999– eter with a response weighted to match 12–15; corrected and reprinted 2000–11– the erythema action spectrum in ISO 15), which is incorporated by reference 17166 CIE S 007/E entitled ‘‘Erythemal

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reference action spectrum and standard tography (HPLC) procedure to verify erythema dose,’’ which is incorporated the concentrations of padimate O and by reference in paragraph (i)(1)(ii)(C) of oxybenzone in the SPF standard: this section. If a lamp must be replaced (A) Instrumentation. (1) Equilibrate a due to failure or aging during a suitable liquid chromatograph to the phototest, broadband device readings following or equivalent conditions: consistent with those obtained for the original calibrated lamp will suffice (i) Column .. C–18, 250 millimeters until measurements can be performed (mm) length, 4.6 mm with the spectroradiometer at the ear- inner diameter (5 mi- liest possible opportunity. crons) (2) SPF standard—(i) Preparation. The (ii) Mobile 85:15:0.5 methanol: SPF standard should be a formulation Phase. water: acetic acid containing 7-percent padimate O and 3- (iii) Flow 1.5 milliliters (mL) per percent oxybenzone. Rate. minute (iv) Tem- Ambient COMPOSITION OF THE PADIMATE O/OXYBENZONE perature. SPF STANDARD (v) Detector UV spectrophotometer Percent by at 308 nanometers Ingredients weight (vi) Attenu- As needed ation. Part A: Lanolin ...... 4.50 Cocoa butter ...... 2.00 (2) Use HPLC grade reagents for mo- Glyceryl monostearate ...... 3.00 bile phase. ...... 2.00 Padimate O ...... 7.00 (B) Preparation of the HPLC reference Oxybenzone ...... 3.00 standard. (1) Weigh 0.50 gram (g) of Part B: oxybenzone USP reference standard Purified water USP ...... 71.60 Sorbitol solution ...... 5.00 into a 250-mL volumetric flask. Dis- Triethanolamine, 99 percent ...... 1.00 solve and dilute to volume with Methylparaben ...... 0.30 isopropanol. Mix well. Propylparaben ...... 0.10 Part C: (2) Weigh 0.50 g of padimate O USP Benzyl alcohol ...... 0.50 reference standard into a 250-mL volu- Part D: metric flask. Dissolve and dilute to Purified water USP ...... QS 1 volume with isopropanol. Mix well. 1 Quantity sufficient to make 100 grams. (3) Pipet 3.0 mL of the oxybenzone so- Step 1. Add the ingredients of Part A lution and 7.0 mL of the padimate O so- into a suitable stainless steel kettle lution into a 100-mL volumetric flask. equipped with a propeller agitator. Mix Dilute to volume with isopropanol and at 77 to 82 °C until uniform. mix well. Step 2. Add the water of Part B into (C) HPLC system suitability. (1) Make a suitable stainless steel kettle three replicate 10-microliter injections equipped with a propeller agitator and of the HPLC reference standard (de- begin mixing at 77 to 82 °C. Add the re- scribed in paragraph (i)(2)(ii)(B) of this maining ingredients of Part B and mix section). The relative standard devi- until uniform. ation in peak areas should not be more Step 3. Add the batch of Step 1 to the than 2.0 percent for either oxybenzone batch of Step 2 and mix at 77 to 82 °C or padimate O. until smooth and uniform. Slowly cool (2) Calculate the resolution (R) be- the batch to 49 to 54 °C. tween the oxybenzone and padimate O Step 4. Add the benzyl alcohol of Part peaks from one chromatogram as fol- C to the batch of Step 3 at 49 to 54 °C. lows: Mix until uniform. Continue to cool batch to 35 to 41 °C. Step 5. Add sufficient water of Part D to the batch of Step 4 at 35 to 41 °C to obtain 100 grams of SPF standard. Mix Where t = retention time for oxybenzone until uniform. Cool batch to 27 to 32 °C. o tp = retention time for padimate O (ii) HPLC assay. Use the following Wo = oxybenzone peak width at baseline high performance liquid chroma- Wp = padimate O peak width at baseline

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If the resolution (R) is less than 3.0, ad- (iii) Step 3. Cool to room temperature just the mobile phase or replace the (15 to 30 °C) and dilute to volume with column. isopropanol. Mix well. (D) SPF standard assay—(1) The SPF (iv) Step 4. Pipet 5.0 mL of the prepa- standard is diluted to the same con- ration into a 50-mL volumetric flask centration as the HPLC reference and dilute to volume with isopropanol. standard according to the following Mix well. steps: (2)(i) Inject 10-microliter of diluted (i) Step 1. Weigh 1.0 g of the SPF SPF standard from paragraph standard (described in paragraph (i)(2)(i) of this section) into a 50-mL (i)(2)(D)(1) of this section and calculate volumetric flask. the amount of oxybenzone and (ii) Step 2. Add approximately 30 mL padimate O as follows: of isopropanol and heat with swirling until contents are evenly dispersed.

(ii) The percent of oxybenzone and or systemic medication that is known padimate O in the SPF standard should to alter responses to UV radiation. De- be between 95 and 105. termine that each subject has no his- (3) Test subjects—(i) Number of subjects. tory of sensitivities to topical products A test panel should include enough and/or abnormal responses to sunlight, subjects to produce a minimum of 10 such as a phototoxic or photoallergic valid test results. A maximum of three response. subjects may be rejected from this (iii) Physical examination. Conduct a panel based on paragraph (i)(5)(v)) of physical examination to determine the this section. presence of sunburn, suntan, scars, ac- (ii) Medical history. (A) Obtain a med- tive dermal lesions, and uneven skin ical history from each subject with em- tones on the areas of the back to be phasis on the effects of sunlight on the tested. A suitable source of low power subject’s skin. Determine that each UVA, such as a Woods lamp, is helpful subject is in good general health with in this process. If any of these condi- skin type I, II, or III as follows: tions are present, the subject is not (1) Always burns easily; never tans qualified to participate in the study. (sensitive). The presence of nevi, blemishes, or (2) Always burns easily; tans mini- moles will be acceptable if, in the phy- mally (sensitive). sician’s judgment, they will neither (3) Burns moderately; tans gradually compromise the study nor jeopardize a (light brown) (normal). subject’s safety. Subjects with (4) Burns minimally; always tans dysplastic nevi should not be enrolled. well (moderate brown) (normal). Excess hair on the back is acceptable if (5) Rarely burns; tans profusely (dark the hair is clipped. Shaving is unac- brown) (insensitive). ceptable because it may remove a sig- (6) Never burns; deeply pigmented nificant portion of the stratum (insensitive). corneum and temporarily alter the (B) Skin type is based on first 30 to 45 skin’s response to UV radiation. minutes of sun exposure after a winter (iv) Informed consent. Obtain legally season of no sun exposure. Determine effective written informed consent that each subject is not taking topical from all test subjects.

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(4) Sunscreen application. (i) Test site. (ii) UV exposure for initial MEDu. For Test sites are locations on each sub- each test subject, administer a series of ject’s back, between the beltline and UV radiation doses expressed as J/m2- the shoulder blades (scapulae) and lat- eff (as determined according to para- eral to the midline, where skin re- graph (a)(2) of this section) to the test sponses to UV radiation are deter- subsites within an unprotected test mined. Responses on unprotected skin site using an accurately calibrated (no test material applied) and pro- solar simulator. Select doses that are a tected skin (sunscreen test product(s) geometric series represented by 1.25n or SPF standard applied) are deter- (i.e., each dose is 25 percent greater mined at separate unprotected and pro- than the previous dose). tected test sites, respectively. Test (iii) UV exposure for final MEDu, sites should be randomly located in a ssMEDp, and tpMEDp. For each subject, blinded manner. Each test site should determine the final MEDu, ssMEDp, and be a minimum of 30 square centimeters tpMEDp by administering a series of and outlined with indelible ink. five UV doses to the appropriate test (ii) Test subsite. Test subsites are the sites. The middle dose (X) in each of locations to which UV radiation is ad- these dose series (i.e., the third dose) ministered within a test site. At least should equal the initial MEDu times five test subsites should receive UV the expected SPF. Note that the ex- doses within each test site. Test pected SPF equals 1 and 16.3 for the subsites should be at least 0.5 square final MEDu and ssMEDp, respectively. centimeters (cm2) in area and should be The remaining UV doses in the series separated from each other by at least depend upon the expected SPF value of 0.8 cm. Each test subsite should be out- the sunscreen test product(s). lined with indelible ink. For products with an expected SPF less than 8, administer UV doses that (iii) Applying test materials. Apply the increase by 25 percent with each suc- sunscreen test product and the SPF cessive dose (i.e., 0.64X, 0.80X, 1.00X, standard at 2 milligrams per square 1.25X, and 1.56X). For products with an centimeter (mg/cm2) to their respective expected SPF from 8 to 15, administer test sites. Use a finger cot compatible UV doses that increase by 20 percent with the sunscreen to spread the prod- with each successive dose (i.e., 0.69X, uct as evenly as possible. 0.83X, 1.00X, 1.20X, and 1.44X). For prod- (iv) Waiting period. Wait at least 15 ucts with an expected SPF higher than minutes after applying a sunscreen 15, administer UV doses that increase product before exposing the test sites by 15 percent with each successive dose to UV radiation as described in para- (i.e., 0.76X, 0.87X, 1.00X, 1.15X, and graph (i)(5)) of this section. For water 1.32X). resistant sunscreen products, proceed (iv) Evaluation of test subsites. In with the water resistance testing pro- order that the person who evaluates cedure described in paragraph (i)(7) of the test subsites is not biased, he/she this section after waiting at least 15 should not be the same person who ap- minutes. plied the sunscreen drug product to the (5) UV exposure—(i) Definition of mini- test site or administered the UV doses. mal erythema dose (MED). The minimal After UV doses are administered, all erythema dose (MED) is the smallest immediate responses should be re- UV dose that produces perceptible red- corded. These may include an imme- ness of the skin (erythema) with clear- diate darkening or tanning, typically ly defined borders at 16 to 24 hours grayish or purplish in color, which after UV exposure. The MED for unpro- fades in 30 to 60 minutes; an immediate tected skin (MEDu) is determined on a reddening at the subsite, due to heat- test site that does not have sunscreen ing of the skin, which fades rapidly; applied. The MED for protected skin and an immediate generalized heat re- (MEDp) is determined on a test site sponse, spreading beyond the subsite, that has sunscreen applied. An MEDp is which fades in 30 to 60 minutes. After determined for the SPF standard the immediate responses are noted, (ssMEDp). An MEDp is determined for each subject should shield the exposed the sunscreen test product (tpMEDp). area from further UV radiation until 100

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the MED is determined. Determine the (7) Determination of water resistance. MED 16 to 24 hours after UV exposure. The following procedure should be per- Because erythema is evaluated 16 to 24 formed in an indoor fresh water pool, hours after UV exposure, the final whirlpool, and/or hot tub maintained MEDu, ssMEDp, and tpMEDp are typi- at 23 to 32 °C. Fresh water is clean cally determined the day following de- drinking water that meets the stand- termination of the initial MEDu. Evalu- ards in 40 CFR part 141. The pool and ate the erythema responses of each test air temperature and the relative hu- subsite using either tungsten or warm midity should be recorded. white fluorescent lighting that pro- (i) Water resistance (40 minutes). The vides at least 450 lux of illumination at labeled SPF should be determined after the test site. For the evaluation, the 40 minutes of water immersion using test subject should be in the same posi- the following procedure: tion as when the test site was irradi- (A) Step 1: Apply the sunscreen as de- ated. scribed in paragraph (d) of this section. (v) Invalid test data. Reject test data (B) Step 2: Perform moderate activ- for a test subject if erythema is not ity in water for 20 minutes. present on either the unprotected or (C) Step 3: Rest out of water for 15 protected test sites; or erythema is minutes. Do not towel test site(s). present at all subsites; or the responses (D) Step 4: Perform moderate activ- are inconsistent with the series of UV ity in water for 20 minutes. doses administered; or the subject was (E) Step 5: Allow test sites to dry noncompliant (e.g., the subject with- completely without toweling. draws from the test due to illness or (F) Step 6: Apply the SPF standard work conflicts or does not shield the as described in paragraph (d) of this exposed testing sites from further UV section. radiation until the MED is deter- Step 1. Expose test sites to UV doses mined). as described in paragraph (e) of this section. (6) Determination of SPF. (i) Calculate (ii) Water resistance (80 minutes). The an SPF value for each test subject labeled SPF should be determined after (SPF ) as follows: i 80 minutes of water immersion using the following procedure: (A) Step 1: Apply the sunscreen as de- scribed in paragraph (d) of this section. (ii) Calculate the mean (B) Step 2: Perform moderate activ- ity in water for 20 minutes. (C) Step 3: Rest out of water for 15 minutes. Do not towel test site(s). and the standard deviation (s) from the (D) Step 4: Perform moderate activ- ity in water for 20 minutes. SPFi values. Calculate the standard error (SE), which equals s/√n (where n (E) Step 5: Rest out of water for 15 equals the number of subjects who pro- minutes. Do not towel test site(s). vided valid test results). Obtain the t (F) Step 6: Perform moderate activ- value from Student’s t distribution ity in water for 20 minutes. table corresponding to the upper 5-per- (G) Step 7: Rest out of water for 15 cent point with n—1 degrees of free- minutes. Do not towel test site(s). dom. Determine the labeled SPF value, (H) Step 8: Perform moderate activ- which equals the largest whole number ity in water for 20 minutes. less than (I) Step 9: Allow test sites to dry completely without toweling. (J) Step 10: Apply the SPF standard as described in paragraph (d) of this In order for the SPF determination of section. a test product to be considered valid, (K) Step 11: Expose test sites to UV the SPF value of the SPF standard doses as described in paragraph (e) of should fall within the standard devi- this section. ation range of the expected SPF (i.e., (j) Broad spectrum test procedure—(1) 16.3 ± 3.43). UV Spectrometry. (i) Plate. Use optical-

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grade polymethylmethacrylate should be applied in a series of small (PMMA) plates suitable for UV trans- dots over the entire PMMA plate and mittance measurements. The plate then spread evenly using a gloved fin- should be roughened on one side to a ger. Spreading should be done with a three dimensional surface topography very light spreading action for approxi- measure (Sa) between 2 and 7 microm- mately 30 seconds followed by spread- eters and must have a rectangular ap- ing with greater pressure for approxi- plication area of at least 16 square cen- mately 30 seconds. The plate should timeters (with no side shorter than 4 then be allowed to equilibrate for 15 cm). minutes in the dark before the pre-irra- (ii) Sample holder. The sample holder diation described in paragraph (c) of should hold the PMMA plate in a hori- this section. zontal position to avoid flowing of the (3) Sunscreen product pre-irradiation. sunscreen drug product from one edge To account for lack of photostability, of the PMMA plate to the other. It apply the sunscreen product to the should be mounted as close as possible PMMA plate as described in paragraph to the input optics of the spectrometer (b) of this section and then irradiate to maximize capture of forward scat- with a solar simulator described in sec- tered radiation. The sample holder tion 352.70(b) of this chapter. The irra- should be a thin, flat plate with a suit- diation dose should be 4 MEDs which is able aperture through which UV radi- equivalent to an erythemal effective ation can pass. The PMMA plate should dose of 800 J/m2 (i.e., 800 J/m2-eff). be placed on the upper surface of the (4) Calculation of mean transmittance sample holder with the roughened side values. After pre-irradiation described facing up. in paragraph (c) of this section, mean (iii) Light source. The light source transmittance values should be deter- should produce a continuous spectral mined for each wavelength λ over the distribution of UV radiation from 290 full UV spectrum (290 to 400 nano- to 400 nanometers. meters). The transmittance values (iv) Input optics. Unless the spectrom- should be measured at 1 nanometer in- eter is equipped with an integrating tervals. Measurements of spectral irra- sphere, an radiation dif- diance transmitted for each wave- fuser should be placed between the length λ through control PMMA plates sample and the input optics of the coated with 15 microliters of glycerin spectrometer. The diffuser will be con- (no sunscreen product) should be ob- structed from any UV radiation trans- tained from at least 5 different loca- parent material (e.g., Teflon® or tions on the PMMA plate [C1(λ), C2(λ), quartz). The diffuser ensures that the C3(λ), C4(λ), and C5(λ)]. In addition, a radiation received by the spectrometer minimum of 5 measurements of spec- is not collimated. The spectrometer tral irradiance transmitted for each input slits should be set to provide a wavelength λ through the PMMA plate bandwidth that is less than or equal to covered with the sunscreen product 1 nanometer. will be similarly obtained after pre-ir- (v) Dynamic range of the spectrometer. radiation of the sunscreen product The dynamic range of the spectrometer [P1(λ), P2(λ), P3(λ), P4(λ), and P5(λ)]. should be sufficient to measure trans- The mean transmittance for each mittance accurately through a highly wavelength, absorbing sunscreen product at all ter- restrial solar UV wavelengths (290 to 400 nm). is the ratio of the mean of the C(λ) val- (2) Sunscreen product application to λ PMMA plate. The accuracy of the test ues to the mean of the P( ) values, as depends upon the application of a pre- follows: cisely controlled amount of sunscreen product with a uniform distribution over the PMMA plate. The product is applied at 0.75 mg per square centi- meter to the roughened side of the PMMA plate. The sunscreen product Where n ≥ 5

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(5) Calculation of mean absorbance val- APPENDIX A TO PART 201—EXAMPLES OF ues. (i) Mean transmittance values, GRAPHIC ENHANCEMENTS USED BY FDA

I. SECTION 201.66 STANDARD LABELING FORMAT

A. Overall are converted into mean absorbance values, 1. The ‘‘Drug Facts’’ labeling is set off in a box or similar enclosure by the use of a barline with all black type printed on a white, color contrasting background.

at each wavelength by taking the nega- B. Typeface and size tive logarithm of the mean transmit- 1. ‘‘Drug Facts’’ is set in 14 point Helvetica tance value as follows: Bold Italic, left justified. 2. ‘‘Drug Facts (continued)’’ is set in 8 point Helvetica Bold Italic for the words (ii) The calculation yields 111 ‘‘Drug Facts’’ and 8 point Helvetica Regular for the word ‘‘(continued)’’ and is left justi- monochromatic absorbance values in 1 fied. nanometer increments from 290 to 400 3. The headings (e.g., ‘‘Directions’’) are set nanometers. in 8 point Helvetica Bold Italic, left justified. (6) Number of plates. For each sun- 4. The subheadings (e.g., ‘‘Ask a doctor or screen product, mean absorbance val- pharmacist before use if you are’’) are set in ues should be determined from at least 6 point Helvetica Bold, left justified. 5. The information is set in 6 point three individual PMMA plates. Because Helvetica Regular with 6.5 point leading, left paragraph (d) of this section requires justified. at least 5 measurements per plate, 6. The heading ‘‘Purpose’’ is right justified. there should be a total of at least 15 7. The bullet is a 5-point solid square. measurements. 8. Two em spacing separates bullets when (7) Calculation of the critical wave- more than one bullet is on the same line. length. The critical wavelength is iden- 9. A table format is used for 3 or more dos- age directions. tified as the wavelength at which the 10. A graphic appears at the bottom of the integral of the spectral absorbance first panel leading the reader to the next curve reaches 90 percent of the integral panel. over the UV spectrum from 290 to 400 nm. The following equation defines the C. Barlines and hairlines critical wavelength: 1. A 2.5-point horizontal barline extends to each end of the ‘‘Drug Facts’’ box (or similar enclosure), providing separation between each of the headings. 2. A 0.5-point horizontal hairline extends within 2 spaces on either side of the ‘‘Drug Facts’’ box (or similar enclosure), imme- diately following the title and immediately Where λc = critical wavelength preceding the subheadings. A(λ) = mean absorbance at each wavelength 3. A 0.5-point horizontal hairline follows dλ = wavelength interval between measure- the title, immediately preceding the head- ments ing, when a heading appears on a subsequent panel immediately after the ‘‘Drug Facts A mean critical wavelength of 370 nm (continued)’’ title. or greater is classified as broad spec- D. Box or Enclosure trum protection. 1. All information is enclosed by a 2.5-point [76 FR 35660, June 17, 2011, as amended at 76 barline. FR 38975, July 5, 2011] II. SECTION 201.66 MODIFIED LABELING EFFECTIVE DATE NOTE: At 76 FR 35660, June FORMAT 17, 2011, § 201.327 was added, effective June 18, 2012. A. Overall 1. The ‘‘Drug Facts’’ labeling is presented in all black type printed on a white color contrasting background.

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