WARNING LETTER
Clinical Resolution Laboratory Inc.
MARCS-CMS 615236 —
March 01, 2022
Delivery Method:
Via Email
Product:
Drugs
Recipient:
Recipient Name
Mr. Justin S. Lee
Recipient Title
President
Clinical Resolution Laboratory Inc.
1400 W. Lambert Rd., Ste. C
Brea
,
CA
92821-2874
United States
justin@clinicalresolution.com
Issuing Office:
Division of Pharmaceutical Quality Operations IV
United States
WARNING LETTER
March 1, 2022
Dear Mr. Lee:
The U.S. Food and Drug Administration inspected your drug manufacturing facility, Clinical Resolution Laboratory Inc., FEI 3005727243 at 1400 W. Lambert Rd., Ste. C, Brea, California, from April 6, 2021 to April 27, 2021.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
In addition, “
(b)(4)
” and "
(b)(4)
"
are unapproved new drugs in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a), and are also misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.
We reviewed your May 18, 2021 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
1. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
You failed to provide data to demonstrate that the manufacturing processes for your OTC drug products have been validated. During the inspection, you were unable to provide documentation to support manufacturing conditions for each of the OTC drug products. There were no qualification protocols, reports, or studies to demonstrate that each drug product met predetermined quality requirements consistently and reliably. Furthermore, you did not have an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
In your response, you acknowledged the validation studies for manufacturing processes had not been documented and that you would perform retrospective validations by evaluating the last
(b)(4)
batches.
Your response is inadequate. You failed to provide a detailed process performance protocol for your validations or actions to be implemented to identify all sources of variability. Furthermore, your response did not provide a timeline for completion of prospective PPQ studies for each of your drug products. The use of a retrospective validation approach is not acceptable. Lastly, you did not address the impact this violation has on your drug products currently in the market.
Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established.
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.
In response, provide the following:
• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process design, process performance qualification, and vigilant ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
• Include your process performance protocols, and written procedures for qualification of equipment and facilities.
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
You did not validate the cleaning processes used for cleaning non-dedicated manufacturing equipment, such as Mixing Tank
(b)(4)
, which is used for your human drug and cosmetic products. Additionally, your practice of evaluating cleaning effectiveness for microbiological contamination via
(b)(4)
testing for
(b)(4)
was not validated.
Inadequate removal of microbiological and product residues from surfaces of non-dedicated manufacturing equipment can lead to contamination of drug products subsequently manufactured on that equipment.
In your response, you stated that you will write and execute a validation protocol to evaluate your cleaning procedures. Additionally, you plan to validate the
(b)(4)
testing.
Your response is inadequate. You did not provide a comprehensive assessment of your cleaning processes for all equipment as well as your cleaning validation protocol and report. Additionally, you did not provide interim measures to assure non-dedicated manufacturing equipment is appropriately cleaned until cleaning validation studies are complete.
In response to this letter, provide
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
o drugs with higher toxicities
o drugs with higher drug potencies
o drugs of lower solubility in their cleaning solvents
o drugs with characteristics that make them difficult to clean
o swabbing locations for areas that are most difficult to clean
o maximum hold times before cleaning
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
• A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
3. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
You released your OTC topical drug products prior to completing and reviewing all quality control testing. Specifically, your
(b)(4)
, Lot No.
(b)(4)
was released by your quality unit on July 2, 2020. However, final contract laboratory testing for active assay and microbiological quality was not reported to your firm until July 20, 2020 and July 22, 2020, respectively.
Testing, prior to batch disposition, is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes that are appropriate for their intended use, including both chemical and microbiological specifications.
In your response, it was stated the root cause of releasing drug product prior to completion of all quality control testing was “due to the belief that such could be proceeded to next step with customer’s approval.” Additionally, you modified your standard operating procedure regarding the process for releasing drug product.
Your response is inadequate. You did not perform a retrospective review of all drug product batches within expiry to identify other instances in which drug product was released by the quality unit prior to completion of quality control testing. Notably, this was a repeat observation from your May 8 to May 15, 2018 FDA inspection.
In response to this letter, provide:
• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed corrective action and preventive action plan (CAPA) and provisions for evaluating its effectiveness.
• An updated list of chemical and microbiological specifications, including test methods, used to analyze each batch of your drug products prior to a batch disposition decision.
• The actions you will take to determine the overall quality of your U.S. drug product batches within expiry which were previously released prior to adequate QU review. Specifically, determine whether an effective and complete final review of each batch and its related information was conducted before the QU disposition decision. In addition, provide an independent third-party assessment of your current system for batch disposition in a CAPA to remediate all deficiencies.
4. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
Your firm lacked an adequate quality unit (QU). For example, your quality unit failed to establish procedures describing QU roles, responsibilities, and authorities. Furthermore, your QU’s oversight of your drug manufacturing operations was inadequate. For example, your QU failed to perform the following:
• Provide adequate CGMP training to personnel.
• Evaluate and investigate discrepancies and out-of-specification results.
• Maintain and investigate customer complaints.
• Establish and maintain adequate procedures with your contract testing laboratories, for example a quality agreement.
In your response, you stated that you have faced difficulties in recruiting qualified personnel for QU functions during the COVID-19 pandemic.
Your response is inadequate. Many of the failures of the QU were observed during the previous inspection, dated May 8 to May 15, 2018. Many of your commitments from that inspection were not implemented.
In response to this letter, provide a comprehensive independent assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
• A determination of whether procedures used by your firm are robust and appropriate.
• Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
• Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
Also, describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/ quality issues and to assure a continuing state of control.
Use of Contract Manufacturers
Drugs must be manufactured in conformance with CGMP. The FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. The FDA regards contractors as extensions of the manufacturer.
You are responsible for the quality of your drugs, regardless of agreements in place with your CMOs. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See the FDA’s guidance document
Contract Manufacturing Arrangements for Drugs: Quality Agreements
at
https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf
.
Quality Systems
Your firm’s quality systems are inadequate. See the FDA’s guidance document
Quality Systems Approach to Pharmaceutical CGMP Regulations
for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at
https://www.fda.gov/media/71023/download
.
Repeat Observations at Facility
In a previous inspection, dated May 8 to May 15, 2018, the FDA cited similar CGMP observations. You proposed specific remediations for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
Consultant Recommended
Because you failed to correct repeat violations, we strongly recommend engaging a consultant as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
Unapproved New Drug Violations
(b)(4)
are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21, U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, these products are intended for use as skin bleaching products; topical anorectal products; topical external analgesic products; and topical antifungal drug products, respectively.
Examples of claims from the products’ labeling, including websites listed on product labels, that provide evidence of the intended uses (as defined by 21 CFR 201.128) of these products as drugs include, but may not be limited to, the following:
(b)(4)
We note that, as of the date of this letter, some of the claims cited above appear to have been removed. Due to the public health concerns related to the marketing and sale of unapproved drugs for the intended uses described above, it is essential that these violations do not recur.
Skin Bleaching Products
Based on the above labeling claims, “
(b)(4)
” are intended for use as skin bleaching drug products. As described below, these skin bleaching drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
(b)(4)
are skin bleaching drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Specifically, these skin bleaching products fall under section 505G(a)(4) of the FD&C Act, 21 U.S.C. 355h(a)(4), because they are subject to a determination to be not generally recognized as safe and effective (GRASE) in a proposed rule that is the most recently applicable proposal issued under 21 CFR part 330.
1
Thus,
(b)(4)
and
(b)(4)
are deemed to be new drugs under section 201(p)(1) of the FD&C Act and subject to the requirement to have an approved new drug application under section 505 of the FD&C Act, 21 U.S.C. 355, beginning on September 23, 2020.
2
No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for
(b)(4)
or
(b)(4)
drug products. Accordingly, these skin bleaching drug products are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Topical Anorectal Drug Products
Based on the above labeling claims,
(b)(4)
and
(b)(4)
are topical products intended for use as anorectal drugs, among other uses. As described below, these topical anorectal drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
In general, a drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not GRASE for use under the conditions prescribed, recommended, or suggested in its labeling; and in general, new drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for the three products identified above.
(b)(4)
and
(b)(4)
are topical anorectal drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application —commonly referred to as "OTC monograph drugs"—may be legally marketed if they meet applicable requirements. In particular, topical anorectal drug products are deemed to be GRASE and not a “new drug” if, among other things, they conform to the conditions of use set forth in the Over-the-Counter Monograph MO15: Anorectal Drug Products for Over-the-Counter Human Use (hereinafter “M015”).
3
However, these topical anorectal drug products do not conform to the conditions of use specified in Monograph M015 because the products include indications not covered under M015, such as use as a numbing cream for clinical procedures (
(b)(4)
and
(b)(4)
) and use on anal fissures (
(b)(4)
). Therefore, these products do not meet requirements under section 505G, under which they would be deemed to be GRASE and not a new drug.
In addition, the FDA is not aware of any adequate and well-controlled clinical trials in the published literature that support a determination that “Ebanel NUMB 520 Topical Anesthetic Cream,” “NUMB MASTER Topical Anesthetic Cream,” or “Ebanel HEMORRHOID MASTER HEMORRHOID & FISSURE OINTMENT” are GRASE for use under the conditions prescribed, recommended or suggested in their labeling. Moreover, there is no evident basis under the FD&C Act under which these products would be legally marketed without an approved application. Accordingly, these products are unapproved new drugs marketed in violation of sections 505(a) of the FD&C Act. Introduction or delivery for introduction of such products into interstate commerce is prohibited under section and 301(d) of the FD&C Act, 21 U.S.C. 331(d).
External Analgesic Drug Product
Based on the above labeling claims,
(b)(4)
is a topical product intended for use as an external analgesic, among other uses. As described below, this external analgesic drug product is an unapproved new drug marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
As previously noted, in general, a drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not GRASE for use under the conditions prescribed, recommended, or suggested in its labeling; and in general, new drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for the
(b)(4)
drug product.
(b)(4)
is an external analgesic drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G of the FD&C Act, certain nonprescription drugs without an approved application —commonly referred to as "OTC monograph drugs"—may be legally marketed if they meet applicable requirements. In particular, topical products intended for use as an external analgesic are deemed to be GRASE and not a “new drug” if, among other things, they conform to the tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330. We note that OTC topical external analgesic products were addressed in the TFM for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983) and subsequent rulemakings. The 1983 external analgesic TFM, in combination with subsequent determinations, was deemed to be a final administrative order.
4
However,
(b)(4)
product does not conform to the conditions of use specified in the final administrative order, because the product’s active ingredients,
(b)(4)
and
(b)(4)
, are not active ingredients in any applicable final monograph or TFM. Although the product labeling does not specifically list these ingredients as active ingredients, the claims for these specific ingredients, as noted above, demonstrate that these are each an “active ingredient” as defined in 21 CFR 201.66(b)(2) because each ingredient is intended to furnish pharmacological activity.
5
Thus,
(b)(4)
product does not meet requirements under section 505G of the FD&C Act, under which it would be deemed to be GRASE and not a new drug.
In addition, the FDA is not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that
(b)(4)
drug product is GRASE for use under the conditions prescribed, recommended, or suggested in its labeling. Moreover, there is no evident basis under the FD&C Act under which this product would be legally marketed without an approved application. Accordingly, this product is an unapproved new drug marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under section and 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Topical Antifungal Product
Based on the above labeling claims,
(b)(4)
is topical product intended for use as an antifungal drug, among other uses. As described below, this topical antifungal drug product is an unapproved new drug marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
(b)(4)
is an antifungal drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Specifically, this antifungal drug falls under section 505G(a)(5) of the FD&C Act, 21 U.S.C. 355h(a)(5), because the FDA has determined that a topical antifungal drug product labeled with claims or directions for use on the scalp or on the nails is not GRASE under a final determination issued under 21 CFR part 330.
6
Therefore
(b)(4)
is deemed to be a “new drug” within the meaning of section 201(p) of the FD&C Act and is subject to the requirement for an approved new drug application for marketing under section 505 of the FD&C Act, 21 U.S.C. 355.
No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for
(b)(4)
topical antifungal drug product. Accordingly, this topical antifungal drug product is an unapproved new drug marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under section and 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Misbranded Drugs
Further,
(b)(4)
are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because these products are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, are not the subjects of applications approved under section 505 of the FD&C Act, 21 U.S.C. 355, and do not comply with the requirements under section 505G of the FD&C Act, 21 U.S.C. 355h. Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act, 21 U.S.C. 331(a) and (d).
Conclusion
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause the FDA to withhold issuance of Export Certificates. The FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Your response should refer to unique identifier CMS 615236 and be sent electronically to ORAPHARM4_Responses@fda.hhs.gov or mailed to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food and Drug Administration
19701 Fairchild Road
Irvine, CA 92612
If you have any questions regarding this letter, please contact Jamie Dion, Compliance Officer, at 303-236-3133 or by email at Jamie.Dion@fda.hhs.gov.
Sincerely,
/S/
Lance M. De Souza
Acting Director, Division of Pharmaceutical Quality Operations IV
___________________
1
Drug products intended for skin bleaching, had been the subject of the developing rule for Skin Bleaching Drug Products for OTC Human Use (47 Federal Register (FR) 39108, September 3, 1982). On August 29, 2006, FDA issued a proposed rule (71 FR 51146) setting forth a determination that OTC skin bleaching drug products, including but not limited to those that contain hydroquinone, are not generally recognized as safe and effective.
2
FDA did not determine that it was in the interest of public health to extend the period during which any drugs subject to section 505G(a)(4) may be marketed without an approved new drug application.
3
Section 505G(a)(1) of the FD&C Act specifies criteria under which certain nonprescription drugs without an approved application are deemed GRASE and not "new drugs", notably conformance with conditions detailed in applicable OTC monograph documents issued by FDA under 21 C.F.R. part 330, prior to enactment of the CARES Act. In the case of OTC topical anorectal drug products, relevant documents were deemed under section 505G to be a final administrative order, Over-the-Counter Monograph M015: Anorectal Drug Products for Over-the-Counter Human Use. (See Order ID OTC000009, available at FDA’s website OTC Monographs@FDA,
https://www.accessdata.fda.gov/scripts/cder/omuf/index.cfmURL
.)
4
Section 505G(a)(1) of the FD&C Act specifies criteria under which certain nonprescription drugs without an approved application are deemed GRASE and not "new drugs", notably conformance with conditions detailed in applicable OTC monograph documents issued by FDA under 21 C.F.R. part 330, prior to enactment of the CARES Act. In the case of OTC topical external analgesic products, relevant documents were deemed under section 505G to be a final administrative order.
5
Under 21 CFR 201.66(b), an active ingredient is a component of a drug intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.
6
On September 2, 1993, FDA issued a final rule establishing that certain labeling claims for OTC topical antifungal drug products, including for use on scalp or on the nails, are not generally recognized as safe and effective. 58 Fed. Reg. 46744. FDA’s final determination was codified in regulations at 21 CFR 310.545(a)(22)(iii). Under section 505G(k)(2)(A) of the FD&C Act, the non-monograph conditions in 21 CFR 310.545 in effect on the day before the date of enactment of the CARES Act (i.e., March 26, 2020) were deemed to be a final administrative order. The final administrative order is entitled “Non-Monograph Conditions NM900: Drug Products Containing Certain Active Ingredients Offered Over-the-Counter for Certain Uses” (See Order ID OTC 000007, available at OTC Monographs@FDA,
https://www.accessdata.fda.gov/scripts/cder/omuf/index.cfmURL
.)
Content current as of:
04/26/2022
Regulated Product(s)
Drugs