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WARNING LETTER

Kingston Pharma LLC MARCS-CMS 572904 —


Delivery Method:
VIA UPS
Product:
Drugs

Recipient:
Recipient Name
Mr. Venkat Kakani
Recipient Title
Chief Executive Officer
Kingston Pharma LLC

5 County Route 42
Massena, NY 13662
United States

Issuing Office:
Division of Pharmaceutical Quality Operations I

10 Waterview Blvd, 3rd Floor
Parsippany, NJ 07054
United States


WARNING LETTER
CMS #572904

05/14/2019

VIA UPS OVERNIGHT
Mr. Venkat Kakani
Chief Executive Officer
Kingston Pharma, LLC
5 County Route 42
Massena, NY 13662

Dear Mr. Kakani:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Kingston Pharma LLC (FEI: 3012275336) at 5 County Route 42, Massena, New York, from November 13 to December 10, 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 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 to the CGMP violations, your firm manufactures over-the-counter (OTC) drug products, RESFRIOL-ITO Children’s Cold Cough & Sore Throat and Brosolvan. RESFRIOLITO Children’s Cold Cough & Sore Throat is misbranded under sections 502(f)(2) and 502(x) of the FD&C Act, 21 U.S.C. 352(f)(2) and 352(x). Furthermore, Brosolvan is misbranded under sections 502(c) and 502(x) of the FD&C Act, 21 U.S.C. 352(c) and 352(x). Introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

We reviewed your December 31, 2018, response in detail, and acknowledge receipt of your subsequent correspondence.

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

CGMP Violations

1. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures (21 CFR 211.22(d)).

You manufacture over-the-counter (OTC) drug products marketed for children and other vulnerable patient populations.

Our investigator documented that your quality unit (QU) failed to follow your firm’s written procedures. For example, contrary to your procedure Batch Record Review and Release for Distribution, SOP No. QA-009, Rev. 00, your QU released at least four batches of drug products for distribution prior to reviewing all test results to ensure specifications were met. In another example, your QU did not document the line clearance and filling activities as required by your procedure Filling, Labeling and Packaging Inspection and sample collection, SOP No. PA-003, Rev. 00.

In addition, you have no written documentation describing your audit trail review procedure. During the inspection, your QU personnel could not show the audit trails on your high performance liquid chromatography (HPLC) instruments.

In your response, you acknowledged that before the FDA inspection, you released some batches “on a risk basis while awaiting results.” You stated that you have revised your procedure as of January 2019 and committed to releasing batches for distribution “after obtaining the analytical results.”

You indicated that you have implemented the packaging area clearance procedure and are using a checklist to document completed activities. You also stated that you are developing written procedures to evaluate your chromatographic data to address the lack of your audit trail review.

Your response is inadequate because you did not retrospectively review test results for all released batches to demonstrate that your drug products met specifications for identity and strength of the active ingredients. It is unclear whether you reviewed the results before releasing the batches for distribution.

In response to this letter, provide a retrospective evaluation of all distributed batches of finished drug products within expiry to determine if identity and strength of the active ingredients were within specifications.

2. 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 firm did not validate the processes used to manufacture your drug products, and those procedures were missing key process parameters such as blending speeds, in-process hold times, and bulk product filtration times. Additionally, your firm failed to qualify the equipment used to manufacture your drug products.

In your response, you acknowledged both the lack of a written program for drug process validation and written system for qualification of drug product manufacturing equipment. You provided an overview of your process validation program and intend to complete it for all products by June 2019. You also committed to write and execute an equipment master validation plan and protocol for all equipment by March 2019.

Your response is inadequate because you did not specify any additional controls you would implement while you conduct your process validation and equipment qualification. In addition, you failed to address the potential effects of your failure to validate your manufacturing processes on the quality and safety of all products that you released for distribution in the United States remaining within expiry.

We note that you collect in-process samples from the mixing tank and filling process for assay and microbiological testing. However, these samples do not demonstrate that your manufacturing process is validated to assure final product quality.

In response to this letter, provide:
􀁸 A risk assessment for distributed drug products on the market within expiry that you manufactured using an unvalidated process. This should include, but not be limited to, an evaluation of the potential effects of your lack of validation on all products intended for vulnerable populations, such as children, distributed within the United States, and still within expiry.
􀁸 A validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for each of your drug products. Describe your program for monitoring batch-to-batch variation to ensure an ongoing state of control. Also include your process performance protocols and your written procedures for qualification of equipment and facilities.

See FDA’s guidance document, Process Validation: General Principles and Practices, for approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/media/71021/download.

3. 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 such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

You lack adequate stability data to support the labeled two-year expiration date of RESFRIOLITO Children’s Cold, Cough & Sore Throat. Specifically, you failed to test for assay at the time intervals you specified in your accelerated stability program used to support your expiration date, nor did you have complete long-term stability data. Therefore, you do not have adequate data to support stability of your drug product throughout its labeled shelf life.

In your response you acknowledged that due to a delay in method development, you did not test the stability samples. You have committed to stop manufacturing RESFRIOL-ITO Children’s Cold, Cough & Sore Throat, until you complete stability studies for this drug product.

Your response is inadequate because you failed to evaluate whether all drug products currently within expiry have adequate supporting stability data.

In your response to this letter, provide:
􀁸 A retrospective review into all missing or delayed stability testing that is intended to support the shelf life of each of your drug products.
􀁸 An impact assessment for the missed or delayed stability testing, and an updated summary of all stability data (i.e., data obtained for each testing) supporting expiration dates for each of your U.S. products.
􀁸 A comprehensive assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your CAPA plan should include, but not be limited to:
o A remediated SOP describing your stability program.
o Stability indicating methods and attributes to be tested.
o Stability studies for each drug product in its container-closure system before you permit distribution.
􀁸 An ongoing program in which representative batches of each product are added each year to the program to determine if shelf life claims remain valid.

4. Your firm failed to maintain buildings used in the manufacture, processing, packing or holding of drug products in a good state of repair (21 CFR 211.58).

Our investigators observed peeling sealant around ceiling panels and drop-panel ceiling frames directly above the filling machines for your cough syrups and nasal sprays. In addition, the light fixtures over the raw material dispensing area were cracked and missing pieces. It is essential that your facility is in a good state of repair to ensure ongoing suitability for drug manufacturing.

In your response, you acknowledged the deficiencies and stated that you have repaired all issues identified during the inspection.

Your response is inadequate because you did not provide evidence of your repairs such as photographs nor did you provide a plan for performing periodic checks of your facility to ensure it is in a good state of repair.

In response to this letter, provide:
􀁸 A comprehensive review of your preventive maintenance programs for both facilities and equipment.
􀁸 A CAPA plan to ensure the program’s effectiveness. The CAPA plan should formalize routine vigilant oversight of facility conditions to assure that issues are promptly detected, repairs are made, and other appropriate actions are executed.

CGMP consultant recommended

We note that you are using consultants to assist you in meeting FDA requirements. It is your responsibility to ensure that your consultants are qualified as set forth in 21 CFR 211.34. Based upon the nature of the violations we identified at your firm, we strongly recommend that your consultants perform a comprehensive audit of your entire manufacturing operations for CGMP compliance, and evaluate the implementation of the CAPAs.

Your use of consultants 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.

Misbranding Violations

RESFRIOL-ITO Children’s Cold Cough & Sore Throat and Brosolvan 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 the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or as defined 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 as a combination pain reliever/fever reducer, cough suppressant, expectorant, and nasal decongestant.

Examples of claims observed on the product label for RESFRIOL-ITO Children’s Cold Cough & Sore Throat and Brosolvan that establish the intended uses of the products as defined in 21 CFR 201.128 include, but may not be limited to, the following:

RESFRIOL-ITO Children’s Cold Cough & Sore Throat
Uses: commonly relieves these common cold and flu symptoms: stuffy nose, the intensity of coughing….”

Brosolvan
Uses: temporarily relieves cough due to minor throat and bronchial irritation as may occur with the common cold or inhaled irritants….”

The labeling for such drugs, like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in Title 21 of the Code of Federal Regulations (21 CFR). However, these products do not meet these requirements for the reasons described below.

Brosolvan contains labeling information both in English and Spanish. For instance, the outside container label for Brosolvan lists the product’s active ingredients in Spanish. Dual language labeling with English and another language is permissible when labeled in accordance to 21 CFR 201.15 and not otherwise false or misleading. Please note, 21 CFR 201.15 states that “all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language” . . . and “if the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.” The labeling for Brosolvan is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because it is not labeled in accordance to 21 CFR 201.15.

RESFRIOL-ITO Children’s Cold Cough & Sore Throat is misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2) because the product fails to bear the complete Liver Warning on its immediate container as required under 21 CFR 201.326. Instead, the product’s immediate container references the Liver Warning and informs users to refer to the outer carton, which is insufficient because the full Liver Warning must appear on the immediate and outer container.

RESFRIOL-ITO Children’s Cold Cough & Sore Throat and Brosolvan are also misbranded under section 502(x) of the FD&C Act 21 U.S.C. 352(x) because the products’ immediate container label fails to disclose a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. Please note that section 201(k) of the FD&C Act defines the term "label" as "...a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under the authority of this Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such…also appears on the outside container….”

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).

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.

Send your electronic reply to orapharm1_responses@fda.hhs.gov. Your written notification should refer to Warning Letter #572904.

If you have any questions, contact Compliance Officer James Mason at james.mason@fda.hhs.gov or 570-262-0519.

Sincerely,
/S/

Diana Amador-Toro
Program Division Director/District Director
U.S. Food and Drug Administration
OPQO Division I/New Jersey District