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Mr. Garcia:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Laboratorios Quantium LLC (FEI: 3008529478), at 7531 NW 77th Ter, Medley, Florida, from May 16 to August 2, 2018.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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 product is 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).

As formulated and labeled, “Valtrum Soothing Topical Analgesic Ointment” is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction of such product into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d). These violations are described in more detail below.

We reviewed your firm’s August 23, 2018, response in detail.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

CGMP Violations

1. Your firm failed to establish an adequate quality control unit and procedures applicable to the quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a) and (d)).

You lacked an established quality unit (QU) to oversee your drug manufacturing and quality. You lacked written procedures for numerous functions of the QU. For example, there were no procedures to handle complaints, to investigate out-of-specification results, or to clean and maintain equipment. Furthermore, your office manager authorized the release of multiple batches of your drug, Valtrum (applied as a roll-on), that failed to meet your potency specifications.

Your response indicated that corrective actions, including hiring personnel and establishing appropriate procedures, will be implemented to address these deficiencies. Your response is inadequate because you failed to address your insufficient oversight of the quality of drugs you manufacture.

In response to this letter, provide:
• Your test results to demonstrate that retain samples conform to final specifications for all drug product batches within expiry distributed in the United States.
• An action plan to promptly address risks posed by marketed products that may fail to meet specifications.
• A comprehensive assessment with corrective actions and preventive actions (CAPA) to ensure your QU has the needed authority and resources to effectively discharge its function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate;
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices;
o Complete and final review of each batch and its related information prior to the QU disposition decision; and,
o Oversight and approval of investigations and discharging all other QU duties to assure identity, strength, quality, and purity of all products.

See FDA’s guidance document, Quality Systems Approach to Pharmaceutical CGMP Regulations, for help implementing modern quality systems and risk management approaches to meet the requirements of CGMP regulations (21 CFR, parts 210 and 211), at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070337.pdf.

2. Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or examined, as appropriate, and released for use by the quality control unit (21 CFR 211.84(a)).

You failed to test components from your suppliers before releasing them for use in manufacturing your drug, Valtrum Soothing Topical Analgesic Ointment. Instead, you relied solely on certificates of analysis (COA) from your unqualified suppliers. In addition, until the inspection, you used an expired raw material, Devil’s Claw, to manufacture your drug product batches after its August 8, 2013, expiry date. It is unacceptable to manufacture drugs from components that have been held for an extended period without retesting prior to use.

In your response, you stated that you will qualify your supplier after you prepare a supplier qualification standard operating procedure (SOP). Your response is inadequate because you failed to specifically commit to appropriate testing of all component lots prior to use in manufacturing.

In response to this letter, provide:

• A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are qualified and assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent the use of unsuitable containers, closures, and components.
• The chemical and microbiological quality control specifications you use to release or reject each incoming lot of components for use in manufacturing.
• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for purity, strength, and quality, specify how you will establish the reliability and consistency of your supplier’s results through initial validation, followed by periodic re-validation. In addition, include a commitment to conduct at least one specific identity test for each incoming component lot.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
• A summary of your procedures for qualifying and overseeing contract facilities that test the drug products you manufacture.

3. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

Our investigators observed unidentified brown stains on the product contact surfaces of your mixing tank, white residues and brown stagnant water in the holding tank of your filling machine, and brown stains and standing water in transfer hoses. These pieces of equipment were used to manufacture your drug and were staged as clean.

Your response states that you will establish cleaning procedures such that no residues or water are left after cleaning, and hoses will be disconnected from the filling machine after you complete manufacturing operations. Your response is inadequate because it failed to include a retrospective review of Valtrum batches manufactured for the U.S. market on your manufacturing equipment.

In response to this letter, provide:
• A comprehensive plan to evaluate cleaning procedures and practices, and validation studies, for each piece of manufacturing equipment used to manufacture more than one product.
• Scientific rationale for your cleaning validation strategy to ensure your cleaning procedures are effective.
• A summary of updates to your cleaning validation protocol incorporating conditions identified as worst case. This should include, but not be limited to:
o Evaluating drugs of the highest toxicity;
o Assessing drugs of the lowest solubility in your cleaning solvents;
o Evaluating drugs with characteristics that make them difficult to clean; and,
o Swabbing equipment locations that are most difficult to clean.
• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for new products, processes, and equipment.
• The results of a retrospective review including microbiological test results of all drugs within expiry distributed to the United States that you manufactured.

4. Your firm failed to establish 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 acknowledged to our investigators that you have not performed process validation for your Valtrum formulation sold in the U.S. Even though you had not validated your manufacturing process, you released (b)(4) batches since 2013 for distribution.

In your response, you stated that you will validate your manufacturing process as soon as you resume production at your facility. In the interim, you will use a contract manufacturer to produce your drug, Valtrum. Your response is inadequate because you did not specify whether your contract manufacturer would use a validated process to manufacture Valtrum.

In response to this letter, detail your validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing process performance qualification (PPQ) for your drug product and describe your program for vigilantly monitoring batch-to-batch variation to ensure an ongoing state of control.

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 provide a determination whether an initial state of control has been established. Successful process qualification studies are necessary prior to 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.

See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.

5. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

Your drug product bears a four-year expiration date without any supporting stability study. During the inspection, you provided a stability report for a different formulation of Valtrum, manufactured in 2012 in another facility, that did not meet specifications. Without stability data, you cannot assure the quality of your products throughout their labeled shelf lives.

In your response, you stated that you changed the expiration date on your products to two years until a stability study is completed by a contract company.

Your response is inadequate because you have not provided enough information about the tests the outside laboratory will perform to ensure that your products conform to their quality attributes over their labeled shelf lives.

In response to this letter, provide a comprehensive, independent assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but should not be limited to:
• A remediated SOP describing your stability program;
• Stability-indicating methods;
• Stability studies to support your drug product in its container-closure system before you permit distribution; and,
• An ongoing program in which you add representative batches of your product each year to determine if the shelf-life claims remain valid.

CGMP consultant recommended

Based upon the nature of the violations identified at your firm, we strongly recommend engaging a consultant, qualified 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

“Valtrum Soothing Topical Analgesic Ointment” is a drug as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for 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 it is intended to affect the structure or any function of the body. Specifically, this product is intended as an external analgesic.

Examples of claims observed on your product label and on your labeling, which includes your product website, www.valtrum-santoremedio.com, for Valtrum Soothing Topical Analgesic Ointment that establish the intended uses of the product as defined by 21 CFR 201.128 include, but may not be limited to, the following.

Statement that appears on the product label:
“Temporary Relief of Minor Pains associated with Muscle Strain, Neck and Shoulder Stiffness, Sprains and Rheumatism”

Statement that appears on the website, www.valtrum-santoremedio.com:
“It helps in the treatment of minor joint pains. It has a powerful antirheumatic action.”

Drug products intended for external analgesic indications such as the temporary relief of minor aches and pains of muscles and joints are being evaluated under the developing rule for External Analgesic Drug Products for Over-the-Counter (OTC) Human Use (48 Federal Register (FR) 5852, February 8, 1983). Pending the promulgation of a final rule, FDA generally does not intend to object to the marketing of products that meet both the proposed formulation and labeling conditions outlined in the Tentative Final Monograph (TFM) and each general condition in 21 CFR 330.1 unless a product poses a public health concern. Such marketing, however, is subject to the risk that a final rule may require reformulation and/or relabeling, or FDA approval, through the “new drug” procedures of the FD&C Act (section 505).

The formulation for Valtrum is not consistent with the TFM for External Analgesic Drug Products that describes acceptable active ingredients and dosage strengths for external analgesic drug products, see 48 FR 5852 at 5868. According to its label, Valtrum includes the active ingredient camphor at a dosage of 2.5%, which falls below what has been proposed in the TFM.

The TFM covers several types of external analgesic drug products, counterirritants, analgesic/ anesthetics and antipruritics, each having its own proposed allowable active ingredients, dosage strengths, and indications for use (48 FR 5852 at 5867 and 5868, February 8, 1983). Camphor is permitted in both counterirritants and analgesic/anesthetic products, albeit in different dosage strengths. For example, the TFM includes camphor in a dosage range of 3%–11% for indications related to the temporary relief of minor aches and pains of muscles and joints, and a dosage range of 0.1%–3% for indications related to the temporary relief of pain and/or itching associated with minor burns, sunburn, minor cuts, scrapes, insect bites and/or minor skin irritations. Valtrum is labeled for use with counterirritant claims and includes the active ingredient camphor at a dosage of 2.5%, which falls below what has been proposed in the TFM for counterirritants (48 FR 5852 at 5867 and 5868, February 8, 1983).

Furthermore, we are not aware of any adequate and well controlled clinical trials in the published literature that support a determination that Valtrum is generally recognized as safe and effective for its labeled indications. Additionally, we are not aware of a similar OTC product as formulated and labeled that was available in the United States market on or before the inception of the OTC Drug Review.

Valtrum Soothing Topical Analgesic Ointment, as labeled, is therefore a new drug within the meaning of section 201(p) of the FD&C Act because it is not generally recognized among scientific experts as safe and effective for the drug uses described in its labeling. “New drugs” may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FD&C Act is in effect for the drug. Valtrum is not the subject of an approved new drug application; therefore, marketing this product in the United States is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d) and violates section 505 of the FD&C Act.

Further, upon review of some of your labeled inactive ingredients for Valtrum such as “Arnica Plant Extract, Carbopol, Cat’s Claw Plant Extract, Devil’s Claw Plant Extract, Chuchuhuasi Plant Extract, Glucosamine, and Trietanolamina” are not included in FDA’s inactive ingredient database for approved drug products, nor are we aware of these ingredients being used as inactive ingredients in any OTC drug product. We remind you that it is your responsibility to ensure your product contains only suitable inactive ingredients that are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity (21 CFR 330.1(e)).

Lastly, the label for Valtrum includes the term “rheumatism” which is addressed in the External Analgesics TFM (48 FR 5852 at 5861, February 8, 1983). FDA discourages the use of the term “rheumatism” as we believe it is less readily understood by most consumers, does not increase consumers' understanding of the use of counterirritants, and may cause confusion.

Conclusion

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.

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. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Your written notification should refer to the Warning Letter Number above (Case# 569146). Please electronically submit your signed reply on your firm's letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at john.diehl@fda.hhs.gov and orapharm2_responses@fda.hhs.gov and john.diehl@fda.hhs.gov.

If you have questions regarding the contents of this letter, please contact Mr. Mark Rivero, Compliance Officer, at (504) 846-6103 or mark.rivero@fda.hhs.gov.

Sincerely,

/S/

Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II

CC:
Renee Alsobrook, Chief, Compliance and Enforcement
Division of Drugs, Devices and Cosmetics
Department of Business and Professional Regulation
2601 Blair Stone Road
Tallahassee, Florida 32399-1047