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  5. Laboratorio Pharma International SRL - 614766 - 09/15/2021
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WARNING LETTER

Laboratorio Pharma International SRL MARCS-CMS 614766 —

Delivery Method:
VIA UPS
Product:
Drugs
Recipient:
Recipient Name
Aurelio Nembrini
Recipient Title
General Manager
Laboratorio Pharma International SRL

Pharma Internacional Bldg, Main Street, Colonia Los Angeles
Tegucigalpa,
11101
Honduras

anembrini@pdpharmaintusa.com
Issuing Office:
Center for Drug Evaluation and Research | CDER

United States

Warning Letter 320-21-57

September 15, 2021

Dear Mr. Nembrini:

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our November 6, 2020, request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), including in response to follow-up correspondence on March 24, 2021, for your facility, Laboratorio Pharma International S. de R.L., FEI 3012015184, at Pharma Internacional Bldg, Main Street, Colonia Los Angeles, Tegucigalpa, Honduras 11101.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations, 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, GELAZUL Topical Analgesic is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a), and is misbranded under sections 502 (x) and (ee) of the FD&C Act, 21 U.S.C. 352(x) and (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.

1. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your response to our 704(a)(4) request and subsequent correspondence indicates that your firm failed to establish appropriate specifications for the lidocaine hydrochloride and menthol active ingredients in your GELAZUL finished drug product. For example, in your response to our request for records or other information pursuant to section 704(a)(4) you provided finished product testing records for lots identified as distributed to the U.S. Our review of these records indicates that you have failed to establish a specification for your active ingredient, menthol, in the finished drug product. In addition, it does not appear that you tested the incoming component of menthol.

In response to this letter, provide the following:

• A comprehensive, independent assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your finished product testing. Your remediated program should include, but not be limited to:
   o Your commitment to using current USP compendial monograph specifications (as applicable).

• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
   o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
   o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

2. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Your response to our 704(a)(4) request and subsequent correspondence indicates that your firm lacks an adequate stability testing program to show that the chemical properties of your drug products are acceptable throughout the labeled expiry period of three years. For example, we requested details about your stability program, including a list of all stability studies or any records or data (separate from an established stability program) used to support your documented 3-year labeled expiry for GELAZUL. You clarified that “all products have either accelerated or shelf or (real time) stability”. However, your response to our request for records or other information pursuant to section 704(a)(4) indicates for product released and distributed to the United States, you have not established an adequate stability program, in that, lots which have been evaluated are not subjected to a quantitative assay determination to support your label claims over time. In addition, you did not provide adequate stability data to support the shelf life of hand sanitizer batches released and distributed to the United States.

In response to this letter, provide the following:

• A comprehensive, independent assessment and corrective actions and preventive actions (CAPA) plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
   o Stability-indicating methods, including both analytical and microbiological test methods.
   o Stability studies for each drug product based on quantitative analysis to support label claim.
   o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
   o Detailed definition of the specific attributes to be tested at each station (timepoint).

• All procedures that describe these and other elements of your remediated stability program.

• Stability data to support your hand sanitizer’s drug product shelf life.

• Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications, recalls, or market withdrawals.

3. Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)).

In response to our 704(a)(4) request and subsequent correspondence pertaining to testing of incoming component ingredients, your firm failed to demonstrate adequate testing for impurities or identity of incoming components used in the manufacture of your drug products before release and distribution to the United States. For example, your response to our request for records or other information pursuant to section 704(a)(4) indicated that you have failed to ensure appropriate component testing for Pharmaint Gel Hand Sanitizer1. Specifically, you have failed to evaluate the component ethyl alcohol for impurities and to execute an appropriate identification test.

In response to this letter, provide the following:

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component 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 other methods are used in lieu of established compendial methods, we request that you provide justification. If you intend to accept any results from your supplier’s Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always 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 program for qualifying and overseeing contract facilities that test the drug products you manufacture.

• A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.

• Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications, recalls, or market withdrawals.

Unapproved New Drug and Misbranding Violations
GELAZUL Topical Analgesic 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 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 it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as a consumer topical analgesic.

Examples of claims observed on the GELAZUL Topical Analgesic product label and labeling that provide evidence of the intended use (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

    “Topical Analgesic . . . Drug Facts …. Uses: For the temporary relief of minor aches and pains of muscles and joints associated with simple backache, arthritis, strains, bruises, and sprains.”

This topical external analgesic product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are lawfully marketed under section 505G of the FD&C Act (which is not the case for this product, as further described below), or under other exceptions not applicable here. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for this drug product, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your GELAZUL Topical Analgesic drug product is GRASE for use under the conditions suggested, recommended, or prescribed in its labeling. Accordingly, this 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).

Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under section 505G(a)(1) of the FD&C Act, 21 U.S.C. 355h(a)(1), category I drugs that were subject to a tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 are deemed to be GRASE and not “new drugs,” as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM and comply with all other applicable requirements. We note that over-the-counter (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.

Under 505G(b)(8) of the FD&C Act, 21 U.S.C. 355h(b)(8), the 1983 external analgesic TFM, in combination with subsequent determinations, is deemed to be a final administrative order. However, your GELAZUL Topical Analgesic product does not conform to the final administrative order, because it is inconsistent with the applicable TFM or any other applicable TFM or proposed rule, and it accordingly does not meet the conditions under section 505G(a)(1) of the FD&C Act for marketing without an approved application under section 505. Specifically, your product purports to contain 3% menthol and 4% lidocaine. The indication labeled on your product (“For the temporary relief of minor aches and pains of muscles and joints associated with simple backache, arthritis, strains, bruises, and sprains”) would be consistent with that of a “counterirritant” described in the applicable TFM (see 48 FR 5852, at 5868). While menthol at a concentration of 1.25 to 16 percent as a counterirritant active ingredient would be consistent with the applicable TFM, the combination of lidocaine and menthol is not permitted for this indication. In fact, lidocaine as a counterirritant active ingredient, in any combination or as a sole ingredient, is not consistent with the applicable TFM. The TFM does permit combinations of menthol and lidocaine, with a labeled indication as an external analgesic, which is different from that of a counterirritant. However, a combination would be permitted only at a concentration of menthol 0.1-1% and lidocaine 0.5-4%, respectively, and your product exceeds the level of menthol that would be consistent with the TFM.

In addition, GELAZUL Topical Analgesic is misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x), because the product label fails to disclose a complete domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug.

Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because GELAZUL Topical Analgesic is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.

The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Beta-Lactam Containment

The records you provided also indicate that you manufacture potent compounds such as beta-lactams at your facility in addition to other finished drug products. In response to multiple requests that you clarify beta-lactam production controls, the records provided in each of your responses do not assure complete and comprehensive separation was established between beta-lactam and non-beta-lactam production. For example, the following controls for monitoring and personnel flow were not established:

• Environmental monitoring data that establishes containment.
• Limitations on personnel flow in shared areas, such as, breakrooms and gymnasium facilities.

Due to the extremely low threshold dose at which an allergic response could occur, beta-lactam facilities need to be complete and comprehensively separated from non-beta-lactam facilities. For additional information, please refer to the guidance for industry, “Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination,” available at https://www.fda.gov/media/79971/download.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility/in connection with your products. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

FDA placed all drugs and drug products manufactured by your firm on Import Alert 66-40 on June 16, 2021.

All drugs and drug products manufactured by your firm may remain listed on this import alert until there is evidence establishing that the conditions that gave rise to the appearance of a violation have been resolved, and the Agency has confidence that future entries will be in compliance with the FD&C Act. This may include an inspection prior to the Agency considering the appearance of adulteration to be addressed.

In addition, shipments of articles manufactured at Laboratorio Pharma International S. de R.L. Pharma, Internacional Bldg, Main Street, Colonia Los Angeles, Tegucigalpa, Honduras 11101, into the United States that appear to be adulterated or misbranded are subject to being detained or refused admission pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).

FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until violations are completely addressed and we confirm your compliance with CGMP.

Failure to address any violations may also result in FDA continuing to refuse admission of articles manufactured at Laboratorio Pharma International S. de R.L. Pharma, Internacional Bldg, Main Street, Colonia Los Angeles, Tegucigalpa, Honduras 11101, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated or misbranded may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

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 to address any deviations and 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.

If you decide you want to manufacture drugs intended for U.S. distribution in the future, request a Regulatory Meeting to discuss your corrective actions as well as the adequacy of your beta-lactam containment to prevent cross-contamination.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3012015184 and ATTN: Matthew R. Dionne, Pharm.D., Compliance Officer.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

 

CC: Carlos Barahona, U.S. Agent
999 Ponce De Leon Blvd., Suite 650
Coral Gables, FL 33134
cbarahona@pdpharmaintusa.com

__________________________

1 Due to increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, FDA published the Guidance for Industry: Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) on March 19, 2020, and subsequently updated the guidance several times, most recently on August 7, 2020. This guidance communicates the Agency’s temporary policy that we do not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepare alcohol-based hand sanitizers for consumer use (or for use as health care personnel hand rub) during the public health emergency, provided certain circumstances described in the guidance are present. These circumstances include preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. A review of the formulations on the drug product labeling further indicates that your product was not prepared consistent with FDA’s temporary policy set forth in the guidance. Therefore, these products do not fall within the Agency’s temporary policy not to take action against firms manufacturing hand sanitizer products for violations of section 501(a)(2)(B) of the FD&C Act.

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